Gardasil



Dosage Form: injection, suspension
FULL PRESCRIBING INFORMATION Indications and Usage for Gardasil Girls and Women

Gardasil®1 is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

 Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18 Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS) Cervical intraepithelial neoplasia (CIN) grade 1 Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3  Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 Boys and Men

 Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

 Anal cancer caused by HPV types 16 and 18  Genital warts (condyloma acuminata) caused by HPV types 6 and 11

 And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

 Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 Limitations of Gardasil Use and Effectiveness

  The health care provider should inform the patient, parent, or guardian that vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive Gardasil should continue to undergo cervical cancer screening per standard of care. [See Patient Counseling Information (17).]

 Recipients of Gardasil should not discontinue anal cancer screening if it has been recommended by a health care provider. [See Patient Counseling Information (17).]

  Gardasil has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. [See Clinical Studies (14.4, 14.5).]

  Gardasil is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, and anal cancers; CIN; VIN; VaIN; or AIN.

  Gardasil has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. [See Clinical Studies (14.4, 14.5).]

  Not all vulvar, vaginal, and anal cancers are caused by HPV, and Gardasil protects only against those vulvar, vaginal, and anal cancers caused by HPV 16 and 18.

Gardasil does not protect against genital diseases not caused by HPV.

Vaccination with Gardasil may not result in protection in all vaccine recipients.

Gardasil Dosage and Administration Dosage

Gardasil should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. [See Clinical Studies (14.8).]

Method of Administration

For intramuscular use only.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. Gardasil should not be diluted or mixed with other vaccines. After thorough agitation, Gardasil is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored.

Gardasil should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Syncope has been reported following vaccination with Gardasil and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).]

Single-Dose Vial Use

Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly.

Prefilled Syringe Use With and Without Needle Guard (Safety) Device

Prefilled Syringe With Needle Guard (Safety) Device

Instructions for using the prefilled single-dose syringes preassembled with needle guard (safety) device

NOTE: Please use the enclosed needle for administration. If a different needle is chosen, it should fit securely on the syringe and be no longer than 1 inch to ensure proper functioning of the needle guard device. Two detachable labels are provided which can be removed after the needle is guarded.

At any of the following steps, avoid contact with the Trigger Fingers to keep from activating the safety device prematurely.

Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle by pressing both Anti-Rotation Tabs to secure syringe and by twisting the Luer Needle in a clockwise direction until secured to the syringe. Remove Needle Sheath. Administer injection per standard protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the Plunger while grasping the Finger Flange until the entire dose has been given. The Needle Guard Device will NOT activate to cover and protect the needle unless the ENTIRE dose has been given. While the Plunger is still depressed, remove needle from the vaccine recipient. Slowly release the Plunger and allow syringe to move up until the entire needle is guarded. For documentation of vaccination, remove detachable labels by pulling slowly on them. Dispose in approved sharps container.

Prefilled Syringe Without Needle Guard (Safety) Device

This package does not contain a needle guard (safety device) or a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.

Dosage Forms and Strengths

Gardasil is a suspension for intramuscular administration available in 0.5-mL single dose vials and prefilled syringes. See Description (11) for the complete listing of ingredients.

Contraindications

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of Gardasil. [See Description (11).]

Warnings and Precautions Syncope

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with Gardasil. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position.

Managing Allergic Reactions

Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of Gardasil.

Adverse Reactions

Overall Summary of Adverse Reactions

Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with Gardasil.

Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with Gardasil and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).] 

Anaphylaxis has been reported following vaccination with Gardasil.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Studies in Girls, Women, Boys, and Men 9 Through 26 Years of Age

In 6 clinical trials (4 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 14,273 individuals were administered Gardasil or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of Gardasil or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 8180 individuals 9 through 26 years of age at enrollment who received Gardasil and 6093 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian. The race distribution of the boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian.

Common Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age

The injection site adverse reactions that were observed among recipients of Gardasil at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1.

Table 1: Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age*

Adverse Reaction

(1 to 5 Days Postvaccination)

Gardasil

(N = 5088)

%

AAHS Control†

(N = 3470)

%

Saline

Placebo

(N = 320)

%

* The injection-site adverse reactions that were observed among recipients of Gardasil were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Injection Site

    Pain

    Swelling

    Erythema

    Pruritus

    Bruising


83.9

25.4

24.7

3.2

2.8


75.4

15.8

18.4

2.8

3.2


48.6

7.3

12.1

0.6

1.6

Common Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age

The injection site adverse reactions that were observed among recipients of Gardasil at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 2.

Table 2: Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age*

Adverse Reaction

(1 to 5 Days Postvaccination)

Gardasil

(N = 3093)

%

AAHS Control†

(N = 2029)

%

Saline

Placebo

(N = 274)

%

* The injection-site adverse reactions that were observed among recipients of Gardasil were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Injection Site

    Pain

    Erythema

    Swelling

    Hematoma


61.4

16.7

13.9

1.0


50.8

14.1

9.6

0.3


41.6

14.5

8.2

3.3

Evaluation of Injection-Site Adverse Reactions by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injection-site reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity.

Table 3: Postdose Evaluation of Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination)

Gardasil

(% occurrence)

AAHS Control*

(% occurrence)

Saline Placebo

(% occurrence) * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up ‡ Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ?1; Moderate = >1 to ?2; Severe = >2.

Adverse

Reaction

Post-

dose

1

N† = 5011

Post-

dose

2

N = 4924

Post-

dose

3

N = 4818

Post-

dose

1

N = 3410

Post-

dose

2

N = 3351

Post-

dose

3

N = 3295

Post-

dose

1

N = 315

Post-

dose

2

N = 301

Post-

dose

3

N = 300

Pain

Mild/Moderate

Severe

63.4

62.5

0.9

60.7

59.7

1.0

62.7

61.2

1.5

57.0

56.6

0.4

47.8

47.3

0.5

49.6

48.9

0.6

33.7

33.3

0.3

20.3

20.3

0.0

27.3

27.0

0.3

Swelling‡

Mild/Moderate

Severe

10.2

9.6

0.6

12.8

11.9

0.8

15.1

14.2

0.9

8.2

8.1

0.2

7.5

7.2

0.2

7.6

7.3

0.2

4.4

4.4

0.0

3.0

3.0

0.0

3.3

3.3

0.0

Erythema‡

Mild/Moderate

Severe

9.2

9.0

0.2

12.1

11.7

0.3

14.7

14.3

0.4

9.8

9.5

0.3

8.4

8.4

0.1

8.9

8.8

0.1

7.3

7.3

0.0

5.3

5.3

0.0

5.7

5.7

0.0

Evaluation of Injection-Site Adverse Reactions by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity.

Table 4: Postdose Evaluation of Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination)

Gardasil

(% occurrence)

AAHS Control*

(% occurrence)

Saline Placebo

(% occurrence)

Adverse

Reaction

Post-

dose

1

N† = 3003

Post-

dose

2

N = 2898

Post-

dose

3

N = 2826

Post-

dose

1

N = 1950

Post-

dose

2

N = 1854

Post-

dose

3

N = 1799

Post-

dose

1

N = 269

Post-

dose

2

N = 263

Post-

dose

3

N = 259 * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up ‡ Intensity of swelling and erythema was measured by size (inches): Mild = 0 to ?1; Moderate = >1 to ?2; Severe = >2.

Pain

Mild/Moderate

Severe

44.7

44.5

0.2

36.9

36.4

0.5

34.4

34.1

0.3

38.4

37.9

0.4

28.2

28.2

0.1

25.8

25.5

0.3

27.5

27.5

0.0

20.5

20.2

0.4

16.2

16.2

0.0

Swelling‡

Mild/Moderate

Severe

5.6

5.3

0.2

6.6

6.2

0.3

7.7

7.1

0.5

5.6

5.4

0.2

4.5

4.5

0.0

4.1

4.0

0.1

4.8

4.8

0.0

1.5

1.5

0.0

3.5

3.1

0.4

Erythema‡

Mild/Moderate

Severe

7.2

6.8

0.3

8.0

7.7

0.2

8.7

8.3

0.3

8.3

8.0

0.2

6.3

6.2

0.1

5.7

5.6

0.1

7.1

7.1

0.0

5.7

5.7

0.0

5.0

5.0

0.0

Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 13.0% and AAHS control or saline placebo = 11.2%).

Adverse reactions that were observed among recipients of Gardasil, at a frequency of greater than or equal to 1.0% where the incidence in the Gardasil group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5.

Table 5: Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age (Gardasil ?Control)*

Adverse Reactions

(1 to 15 Days Postvaccination)

Gardasil

(N = 5088)

%

AAHS Control† or Saline Placebo

(N = 3790)

% * The adverse reactions in this table are those that were observed among recipients of Gardasil at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Pyrexia 13.0 11.2 Nausea 6.7 6.5 Dizziness 4.0 3.7 Diarrhea 3.6 3.5 Vomiting 2.4 1.9 Cough 2.0 1.5 Toothache 1.5 1.4 Upper respiratory tract infection 1.5 1.5 Malaise 1.4 1.2 Arthralgia 1.2 0.9 Insomnia 1.2 0.9 Nasal congestion 1.1 0.9

Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age

Headache was the most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (Gardasil = 8.3% and AAHS control or saline placebo = 6.5%).

Adverse reactions that were observed among recipients of Gardasil, at a frequency of greater than or equal to 1.0% where the incidence in the group that received Gardasil was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6.

Table 6: Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age (Gardasil ?Control)*

Adverse Reactions

(1 to 15 Days Postvaccination)

Gardasil

(N = 3093)

%

AAHS Control† or Saline Placebo

(N = 2303)

% * The adverse reactions in this table are those that were observed among recipients of Gardasil at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. † AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Headache 12.3 11.2 Pyrexia 8.3 6.5 Oropharyngeal pain 2.8 2.1 Diarrhea 2.7 2.2 Nasopharyngitis 2.6 2.6 Nausea 2.0 1.0 Upper respiratory tract infection 1.5 1.0 Abdominal pain upper 1.4 1.4 Myalgia 1.3 0.7 Dizziness 1.2 0.9 Vomiting 1.0 0.8

Evaluation of Fever by Dose in Girls and Women 9 Through 26 Years of Age

An analysis of fever in girls and women by dose is shown in Table 7.

Table 7: Postdose Evaluation of Fever in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination)

Gardasil

(% occurrence)

AAHS Control* or Saline Placebo

(% occurrence) * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of subjects with follow-up

Temperature

(°F)

Postdose 1

N† = 4945

Postdose 2

N = 4804

Postdose 3

N = 4671

Postdose 1

N = 3681

Postdose 2

N = 3564

Postdose 3

N = 3467 ?100 to <102 3.7 4.1 4.4 3.1 3.8 3.6 ?102 0.3 0.5 0.5 0.2 0.4 0.5

Evaluation of Fever by Dose in Boys and Men 9 Through 26 Years of Age

An analysis of fever in boys and men by dose is shown in Table 8.

Table 8: Postdose Evaluation of Fever in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination)

Gardasil

(% occurrence)

AAHS Control* or Saline Placebo

(% occurrence)

Temperature

(°F)

Postdose 1

N† = 2972

Postdose 2

N = 2849

Postdose 3

N = 2792

Postdose 1

N = 2194

Postdose 2

N = 2079

Postdose 3

N = 2046 * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † N = Number of individuals with follow-up ?100 to <102 2.4 2.5 2.3 2.1 2.2 1.6 ?102 0.6 0.5 0.5 0.5 0.3 0.3

Serious Adverse Reactions in the Entire Study Population

Across the clinical studies, 258 individuals (Gardasil N = 128 or 0.8%; placebo N = 130 or 1.0%) out of 29,323 (Gardasil N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction.

Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either Gardasil, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were:

Headache [0.02% Gardasil (3 cases) vs. 0.02% AAHS control (2 cases)],
Gastroenteritis [0.02% Gardasil (3 cases) vs. 0.02% AAHS control (2 cases)],
Appendicitis [0.03% Gardasil (5 cases) vs. 0.01% AAHS control (1 case)],
Pelvic inflammatory disease [0.02% Gardasil (3 cases) vs. 0.03% AAHS control (4 cases)],
Urinary tract infection [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)],
Pneumonia [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)],
Pyelonephritis [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (3 cases)],
Pulmonary embolism [0.01% Gardasil (2 cases) vs. 0.02% AAHS control (2 cases)].

One case (0.006% Gardasil; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases (0.01% Gardasil; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit.

In addition, there was 1 individual in the clinical trials, in the group that received Gardasil, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment).

Deaths in the Entire Study Population

Across the clinical studies, 40 deaths (Gardasil N = 21 or 0.1%; placebo N = 19 or 0.1%) were reported in 29,323 (Gardasil N = 15,706; AAHS control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received Gardasil and 4 individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received Gardasil and 6 individuals who received AAHS control), gun shot wound (1 individual who received Gardasil and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis (1 individual who received Gardasil and 1 individual who received AAHS control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received Gardasil; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma in the saline placebo group.

Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age

In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received Gardasil or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least one dose of Gardasil or AAHS control or saline placebo, and had safety data available.

Table 9: Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials of Gardasil, Regardless of Causality Conditions

Gardasil

(N = 10,706)

AAHS Control* or Saline Placebo

(N = 9412) n (%) n (%) N = Number of individuals enrolled
n = Number of individuals with specific new Medical Conditions
NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories. * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate † Arthralgia/Arthritis/Arthropathy includes the following terms: Arthralgia, Arthritis, Arthritis reactive, and Arthropathy ‡ Hyperthyroidism includes the following terms: Basedow's disease, Goiter, Toxic nodular goiter, and Hyperthyroidism § Hypothyroidism includes the following terms: Hypothyroidism and thyroiditis ¶ Inflammatory bowel disease includes the following terms: Colitis ulcerative, Crohn's disease, and Inflammatory bowel disease # Nephritis includes the following terms: Nephritis, Glomerulonephritis minimal lesion, Glomerulonephritis proliferative ? Pigmentation disorder includes the following terms: Pigmentation disorder, Skin depigmentation, and Vitiligo ? Psoriasis includes the following terms: Psoriasis, Pustular psoriasis, and Psoriatic arthropathy ? Rheumatoid arthritis includes juvenile rheumatoid arthritis. One woman counted in the rheumatoid arthritis group reported rheumatoid arthritis as an adverse experience at Day 130. Arthralgia/Arthritis/Arthropathy† 120 (1.1) 98 (1.0) Autoimmune Thyroiditis 4 (0.0) 1 (0.0) Celiac Disease 10 (0.1) 6 (0.1) Diabetes Mellitus Insulin-dependent 2 (0.0) 2 (0.0) Erythema Nodosum 2 (0.0) 4 (0.0) Hyperthyroidism‡
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Anastrozole 1mg film-coated tablets (medac GmbH)


1. Name Of The Medicinal Product

Anastrozole 1 mg film-coated tablets

2. Qualitative And Quantitative Composition

One film-coated tablet contains 1 mg of anastrozole.

Excipients: Lactose monohydrate 92.75 mg

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet.

White, round, biconvex tablets with imprint 'A1' on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

• Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.

4.2 Posology And Method Of Administration

Adults including the elderly:

One film-coated tablet (1 mg) to be taken orally once a day.

Children and adolescents:

Anastrozole is not recommended for use in children due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).

Renal and hepatic impairment:

No dose change is recommended in patients with mild or moderate renal impairment.

No dose change is recommended in patients with mild hepatic disease.

4.3 Contraindications

Anastrozole is contraindicated in:

• premenopausal women

• pregnant or lactating women

• patients with severe renal impairment (creatinine clearance less than 20 ml/min)

• patients with moderate or severe hepatic disease

• patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1

Oestrogen-containing therapies should not be co-administered with Anastrozole as they would negate its pharmacological action.

Concurrent tamoxifen therapy (see section 4.5).

4.4 Special Warnings And Precautions For Use

Anastrozole is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, Anastrozole must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.

The menopause should be defined biochemically in any patient where there is doubt about hormonal status.

There are no data to support the safe use of Anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Phenazone and cimetidine clinical interaction studies indicate that the co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.

A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs.

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

4.6 Pregnancy And Lactation

Anastrozole is contraindicated in pregnant and lactating women (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable Effects

Rates of incidence:

very common

(> 1/10)

common

(

uncommon

(

rare

(

very rare

(

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in postmenopausal women with operable breast cancer treated for five years.

 

very common

common

uncommon

rare

not known

Nervous system disorders

Headache, mainly mild or moderate in nature

Somnolence, mainly mild or moderate in nature, Carpal tunnel syndrome

     

Gastrointestinal disorders

Nausea, mainly mild or moderate in nature

Diarrhoea, mainly mild or moderate in nature, vomiting, mainly mild or moderate in nature

     

Skin and subcutaneous tissue disorders

Rash, mainly mild or moderate in nature

Hair thinning (alopecia), mainly mild or moderate in nature, allergic reactions

Urticaria

Erythema multiforme, anaphylactoid reactions

Stevens-Johnson syndrome**, Angioedema**

Musculo-skeletal, connective tissue and bone disorders

Joint pain/stiffness, mainly mild or moderate in nature, arthritis

Bone pain

Trigger finger

   

Metabolism and nutrition disorders

 

Anorexia, mainly mild or moderate in nature, hypercholesterolaemia, mainly mild or moderate in nature

     

Vascular disorders

Hot flushes, mainly mild or moderate in nature

       

General disorders and administration site conditions

Asthenia, mainly mild or moderate in nature

       

Hepatobiliary disorders

 

Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Increases in gamma-GT and bilirubin, hepatitis

   

Reproductive system and breast disorders

 

Vaginal dryness, mainly mild or moderate in nature, Vaginal bleeding*, mainly mild or moderate in nature

     

*Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

** Cannot be estimated from the available data.

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4).

The table below presents the frequency of pre-specified adverse events in a study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Adverse event

Anastrozole

(N = 3092)

Tamoxifen

(N = 3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

           Fractures of the spine, hip, or wrist/Colles fractures

133 (4.3%)

91 (2.9%)

           Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

           Spine fractures

43 (1.4%)

22 (0.7%)

           Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

           Angina pectoris

71 (2.3%)

51 (1.6%)

           Myocardial infarct

37 (1.2%)

34 (1.1%)

           Coronary artery disorder

25 (0.8%)

23 (0.7%)

           Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

          Deep venous thromboembolic events including pulmonary embolism

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.

The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity.

Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdose and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Enzyme inhibitors

ATC Code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay method.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.

Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

Paediatrics

Anastrozole is not indicated for use in children. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children are available (see also section 5.3).

The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome.

Short stature due to Growth Hormone Deficiency

A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11

After 3 years anastrozole was found to statistically significantly slow down bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS, and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo.

Testotoxicosis

An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2

Gynaecomastia studies

Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11

Trial 0001 was an open-label, multiple-dose pharmacokinetic study of anastrozole 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of patients with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50% between day 1 and after 6 months of study treatment, and patient tolerability and safety.

A pharmacodynamic subpopulation of 25 boys was selected in this study to explore the potential benefits of anastrozole. It was noted a decrease in total breast volume of 50% or greater at 6 months was seen in 55.6% (as measured by ultrasound) and 77.8% (as measured by caliper) of the boys (observational data only, no statistical analysis conducted on these results).

McCune-Albright Syndrome study

Trial 0046 was an international, multi-centre, open-label exploratory trial of anastrozole in 28 girls (aged 2 to

No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p < 0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12). Of the patients with baseline vaginal bleeding, 28% experienced a

The overall assessment of the adverse events in children less than 18 years of age raised no safety or tolerability concerns.

5.2 Pharmacokinetic Properties

Absorption

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of Anastrozole tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters.

Distribution

Anastrozole is only 40% bound to plasma proteins.

Elimination

Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours.

The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.

Metabolism

Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N

Age dependency of pharmacokinetics

Anastrozole pharmacokinetics are independent of age in postmenopausal women.

Pharmacokinetics in children and adolescents

In boys with pubertal gynaecomastia, anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls than in boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days.

5.3 Preclinical Safety Data

In animal studies, toxicity related to the pharmacodynamic action was only seen at high doses.

In a fertility study weanling male rats were dosed orally with 50 or 400 mg/l anastrozole via their drinking water for 10 weeks. Measured mean plasma concentrations were 44.4 (± 14.7) ng/ml and 165 (± 90) ng/ml respectively. Mating indices were adversely affected in both dose groups, whilst a reduction in fertility was evident only at the 400 mg/l dose level. The reduction was transient as all mating and fertility parameters were similar to control group values following a 9

Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.

Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.

The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above was compromised. These effects were related to the pharmacological effects of the compound on parturition.

Genetic toxicology studies with anastrozole show that it is neither a mutagen nor a clastogen.

Carcinogenicity studies have been performed in rats and mice.

In rats, increases in the incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males were observed at a dose which represents 100

In mice induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas) were observed. These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Sodium starch glycolate (Type A)

Povidone K

Magnesium stearate

Film coating:

Hypromellose

Macrogol 6000

Cottonseed oil, hydrogenated

Starch, pregelatinised modified (origin: maize)

Titanium dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

4 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/Aluminium blister

The following pack sizes are available:

20, 28, 30, 84, 98, 100 or 300 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

medac

Gesellschaft f?r klinische

Spezialpr?parate mbH

Fehlandtstr. 3

20354 Hamburg

Germany

8. Marketing Authorisation Number(S)

PL 11587/0064

9. Date Of First Authorisation/Renewal Of The Authorisation

28/05/2009

10. Date Of Revision Of The Text

26/11/2010


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Testosterone Enanthate Ampoules (Cambridge Laboratories)


What you should know about Testosterone Enantate Ampoules

Please read this leaflet carefully. This leaflet contains information about Testosterone Enantate Ampoules, which will be given to you by injection. Although you will not be taking this medicine yourself, this leaflet contains important information to help you understand how Testosterone Enantate is used. Keep it until the course of treatment has been finished, as you may want to read it again.

Always follow your doctor's advice, and if there is anything you do not understand, please ask your doctor or nurse to explain it.

What do Testosterone Enantate Ampoules contain?

Each ampoule contains 250 mg of Testosterone Enantate (the active ingredient) together with the inactive ingredients benzyl benzoate and castor oil for injection.

Testosterone Enantate is supplied in packs of 3 ampoules, each ampoule containing 1 ml.

Testosterone Enantate is an androgen, a male type of hormone.

The holder of the product licence for this medicine is

Cambridge Laboratories Limited Deltic House Kingfisher Way Silverlink Business Park Wallsend Tyne & Wear NE28 9NX

The ampoules are made by

Schering AG Berlin Germany What is Testosterone Enantate used for?

In men Testosterone Enantate is used when natural levels of this hormone are low, which can cause loss of interest in sex, low fertility and other problems. In women Testosterone Enantate is used to treat certain diseases of the breast.

When should Testosterone Enantate not be used?

Since androgens (male hormones) can stimulate the growth of cancer of the prostate gland, men must not be given Testosterone Enantate if they have prostatic cancer. For this reason, men should have regular examinations of the prostate gland during treatment with Testosterone Enantate. Men with breast cancer should not be given Testosterone Enantate.

Testosterone Enantate Ampoules should not be used to treat women who are pregnant or breast-feeding.

You should not be given Testosterone Enantate Ampoules if you have a liver tumour or a history of such tumours, if you have a kidney disease called nephrosis or if you have too much calcium in your blood.

What else should you know before having an injection of Testosterone Enantate?

Male hormones such as Testosterone Enantate are not suitable for increasing muscular development in healthy people or for increasing physical ability.

Special care is needed when Testosterone Enantate is used in the elderly and in patients with the following conditions:

Kidney problems Heart disease Liver disease High blood pressure Migraine Diabetes Cancer that has spread to the bones

If you suffer from any of these and think that the doctor who has prescribed Testosterone Enantate for you is not aware of this, you should tell him or her straight away.

Regular blood tests may be needed if you are also being treated with some medicines that slow down the clotting of the blood. Testosterone Enantate may be less effective in epileptic patients who are taking Phenobarbital, so if this applies to you please make sure that the doctor treating you knows about it.

How Testosterone Enantate is used

Testosterone Enantate is given by injection into a muscle, usually every 2 to 3 weeks. The injections are continued for as long as your doctor considers necessary, but men receiving long-term treatment may later be given injections at 3 to 6 week intervals.

If you would like any other information about the use of Testosterone Enantate, please ask your doctor or nurse.

Side-effects

When hormones such as Testosterone Enantate are used in high doses or over a long period of time, they may result in the retention of too much water, and even swelling of the ankles in some cases. If you have a tendency to this problem, make sure your doctor checks you very carefully while you are receiving treatment with Testosterone Enantate Ampoules.

Women who receive Testosterone Enantate may develop acne, increased growth of hair on the face and body, thinning of scalp hair and deepening of the voice (particular care is necessary in women whose occupations involve singing or speaking).

If men receive long-term and high-dose treatment with Testosterone Enantate, the number of sperms they produce is reduced. Men may experience frequent or persistent erections whilst under Testosterone Enantate treatment. If this happens, make sure to tell your doctor so that he may reduce the dose or stop the treatment in order to avoid injury to the penis.

Occasionally coughing, shortness of breath and changes in the circulation of the blood may develop while Testosterone Enantate is being injected or immediately after the injection.

The doctor may arrange for women receiving Testosterone Enantate to have regular blood tests. If these show an increased level of calcium, he will stop the treatment.

In very rare cases liver tumours have been observed after the use of hormones such as Testosterone Enantate. In a few isolated cases this has been followed by internal bleeding which can be life-threatening. Tell your doctor if you have any new "stomach" discomfort or pain that does not soon clear up.

Other side effects that have sometimes occurred with Testosterone Enantate are headache, depression, feeling sick, jaundice, breast enlargement in men, an increase in the number of red blood cells, anxiety, feeling weak, abnormal sensations, increased bone growth and premature sexual development in boys.

If you are worried about side-effects or if you think that Testosterone Enantate has caused any other side-effect, please tell your doctor, nurse or pharmacist about it.

Storing Testosterone Enanthate

Testosterone Enantate Ampoules should not be used after the expiry date given on the label. They should be stored away from light.

All medicines should be kept out of the reach of children.

Date of preparation of this leaflet: August 2001


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Pregnyl


Generic Name: chorionic gonadotropin (Subcutaneous route, Intramuscular route, Injection route)

kor-ee-ON-ok goe-nad-oh-TROE-pin

Commonly used brand name(s)

In the U.S.

Chorex Novarel Ovidrel Pregnyl Profasi

In Canada

Chorionic Gonadotropin

Available Dosage Forms:

Powder for Solution Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Gonadotropin

Uses For Pregnyl

Chorionic gonadotropin is a drug whose actions are almost the same as those of luteinizing hormone (LH), which is produced by the pituitary gland. It is a hormone also normally produced by the placenta in pregnancy. Chorionic gonadotropin has different uses for females and males.

In females, chorionic gonadotropin is used to help conception occur. It is usually given in combination with other drugs such as menotropins and urofollitropin. Many women being treated with these drugs usually have already tried clomiphene alone (e.g., Serophene) and have not been able to conceive yet. Chorionic gonadotropin is also used in in vitro fertilization (IVF) programs.

In males, LH and chorionic gonadotropin stimulate the testes to produce male hormones such as testosterone. Testosterone causes the enlargement of the penis and testes and the growth of pubic and underarm hair. It also increases the production of sperm.

Although chorionic gonadotropin has been prescribed to help some patients lose weight, it should never be used this way. When used improperly, chorionic gonadotropin can cause serious problems.

Chorionic gonadotropin is to be administered only by or under the immediate supervision of your doctor.

Before Using Pregnyl

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Chorionic gonadotropin, when used for treating cryptorchidism (a birth defect where the testes remain inside the body), has caused the sexual organs of some male children to develop too rapidly.

Pregnancy Pregnancy Category Explanation All Trimesters X Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Asthma or Epilepsy (seizures) or Heart problems or Kidney problems or Migraine headaches—This medication may worsen these conditions. Cancer of the prostate or Precocious puberty (a condition that causes early puberty in boys before 9 years of age)—Increases in the amount of testosterone in the bloodstream may make these conditions worse. Cyst on ovary or Fibroid tumors of the uterus—Chorionic gonadotropin can cause further growth of cysts on the ovary or fibroid tumors of the uterus Unusual vaginal bleeding—Irregular vaginal bleeding is a sign that the endometrium is growing too much, of endometrial cancer, or of other hormone imbalances; the increases in estrogen production caused by ovulation can aggravate these problems of the endometrium. If other hormone imbalances are present, they should be treated before beginning ovulation induction Proper Use of chorionic gonadotropin

This section provides information on the proper use of a number of products that contain chorionic gonadotropin. It may not be specific to Pregnyl. Please read with care.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For injection dosage form: For treating men with problems related to low levels of male hormones: Adults—1000 to 4000 Units injected into the muscle two to three times a week. You may need to receive this medicine for several weeks, months, or longer. If you are being treated for a low sperm count and have been on this medicine for six months, your doctor may give you another hormone medicine (menotropin or urofollitropin injection). You may need to receive both of these medicines together for up to twelve more months. To help pregnancy occur in women: Adults—5000 to 10,000 Units injected into the muscle on a day chosen by your doctor. The dose and day will depend on your hormone levels and the other medicines that you have been using. For the treatment of cryptorchidism (condition where testes do not develop properly): Children—1000 to 5000 Units injected into the muscle two to three times a week for up to ten doses. Precautions While Using Pregnyl

It is very important that your doctor check your progress at regular visits to make sure that the medicine is working and to check for unwanted effects.

For women taking this medicine to become pregnant :

Record your basal body temperature every day if told to do so by your doctor, so that you will know if you have begun to ovulate. It is important that intercourse take place around the time of ovulation to give you the best chance of becoming pregnant. Your doctor will likely want to monitor the development of the ovarian follicle(s) by measuring the amount of estrogen in your bloodstream and by checking the size of the follicle(s) with ultrasound examinations. Pregnyl Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

For females onlyMore common Bloating (mild) stomach or pelvic pain Less common or rare Abdominal or stomach pain (severe) bloating (moderate to severe) decreased amount of urine feeling of indigestion nausea, vomiting, or diarrhea (continuing or severe) pelvic pain (severe) shortness of breath swelling of feet or lower legs weight gain (rapid) For boys onlyLess common Acne enlargement of penis and testes growth of pubic hair increase in height (rapid) Frequency not determined difficult or labored breathing difficulty breathing flushing of skin hives or welts itching of skin large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs pain in chest, groin, or legs, especially the calves redness of skin severe, sudden headache skin rash slurred speech sudden loss of coordination sudden, severe weakness or numbness in arm or leg sudden, unexplained shortness of breath tightness in chest unusually warm skin vision changes wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common Discouragement enlargement of breasts feeling sad or empty headache irritability lack of appetite loss of interest or pleasure pain at place of injection trouble concentrating trouble sleeping tiredness

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

For females onlyLess common or rare Abdominal or stomach pain (severe) bloating (moderate to severe) decreased amount of urine feeling of indigestion nausea, vomiting, or diarrhea (continuing or severe) pelvic pain (severe) shortness of breath weight gain (rapid)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Pregnyl side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Pregnyl resources Pregnyl Side Effects (in more detail) Pregnyl Use in Pregnancy & Breastfeeding Pregnyl Drug Interactions Pregnyl Support Group 1 Review for Pregnyl - Add your own review/rating Pregnyl Prescribing Information (FDA) Pregnyl MedFacts Consumer Leaflet (Wolters Kluwer) Hcg Consumer Overview Novarel Prescribing Information (FDA) Ovidrel Prescribing Information (FDA) Ovidrel Monograph (AHFS DI) Ovidrel MedFacts Consumer Leaflet (Wolters Kluwer) Compare Pregnyl with other medications Female Infertility Hypogonadism, Male Obesity Ovulation Induction Prepubertal Cryptorchidism
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Chorex


Generic Name: chorionic gonadotropin (Subcutaneous route, Intramuscular route, Injection route)

kor-ee-ON-ok goe-nad-oh-TROE-pin

Commonly used brand name(s)

In the U.S.

Chorex Novarel Ovidrel Pregnyl Profasi

In Canada

Chorionic Gonadotropin

Available Dosage Forms:

Powder for Solution Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Gonadotropin

Uses For Chorex

Chorionic gonadotropin is a drug whose actions are almost the same as those of luteinizing hormone (LH), which is produced by the pituitary gland. It is a hormone also normally produced by the placenta in pregnancy. Chorionic gonadotropin has different uses for females and males.

In females, chorionic gonadotropin is used to help conception occur. It is usually given in combination with other drugs such as menotropins and urofollitropin. Many women being treated with these drugs usually have already tried clomiphene alone (e.g., Serophene) and have not been able to conceive yet. Chorionic gonadotropin is also used in in vitro fertilization (IVF) programs.

In males, LH and chorionic gonadotropin stimulate the testes to produce male hormones such as testosterone. Testosterone causes the enlargement of the penis and testes and the growth of pubic and underarm hair. It also increases the production of sperm.

Although chorionic gonadotropin has been prescribed to help some patients lose weight, it should never be used this way. When used improperly, chorionic gonadotropin can cause serious problems.

Chorionic gonadotropin is to be administered only by or under the immediate supervision of your doctor.

Before Using Chorex

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Chorionic gonadotropin, when used for treating cryptorchidism (a birth defect where the testes remain inside the body), has caused the sexual organs of some male children to develop too rapidly.

Pregnancy Pregnancy Category Explanation All Trimesters X Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Asthma or Epilepsy (seizures) or Heart problems or Kidney problems or Migraine headaches—This medication may worsen these conditions. Cancer of the prostate or Precocious puberty (a condition that causes early puberty in boys before 9 years of age)—Increases in the amount of testosterone in the bloodstream may make these conditions worse. Cyst on ovary or Fibroid tumors of the uterus—Chorionic gonadotropin can cause further growth of cysts on the ovary or fibroid tumors of the uterus Unusual vaginal bleeding—Irregular vaginal bleeding is a sign that the endometrium is growing too much, of endometrial cancer, or of other hormone imbalances; the increases in estrogen production caused by ovulation can aggravate these problems of the endometrium. If other hormone imbalances are present, they should be treated before beginning ovulation induction Proper Use of chorionic gonadotropin

This section provides information on the proper use of a number of products that contain chorionic gonadotropin. It may not be specific to Chorex. Please read with care.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For injection dosage form: For treating men with problems related to low levels of male hormones: Adults—1000 to 4000 Units injected into the muscle two to three times a week. You may need to receive this medicine for several weeks, months, or longer. If you are being treated for a low sperm count and have been on this medicine for six months, your doctor may give you another hormone medicine (menotropin or urofollitropin injection). You may need to receive both of these medicines together for up to twelve more months. To help pregnancy occur in women: Adults—5000 to 10,000 Units injected into the muscle on a day chosen by your doctor. The dose and day will depend on your hormone levels and the other medicines that you have been using. For the treatment of cryptorchidism (condition where testes do not develop properly): Children—1000 to 5000 Units injected into the muscle two to three times a week for up to ten doses. Precautions While Using Chorex

It is very important that your doctor check your progress at regular visits to make sure that the medicine is working and to check for unwanted effects.

For women taking this medicine to become pregnant :

Record your basal body temperature every day if told to do so by your doctor, so that you will know if you have begun to ovulate. It is important that intercourse take place around the time of ovulation to give you the best chance of becoming pregnant. Your doctor will likely want to monitor the development of the ovarian follicle(s) by measuring the amount of estrogen in your bloodstream and by checking the size of the follicle(s) with ultrasound examinations. Chorex Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

For females onlyMore common Bloating (mild) stomach or pelvic pain Less common or rare Abdominal or stomach pain (severe) bloating (moderate to severe) decreased amount of urine feeling of indigestion nausea, vomiting, or diarrhea (continuing or severe) pelvic pain (severe) shortness of breath swelling of feet or lower legs weight gain (rapid) For boys onlyLess common Acne enlargement of penis and testes growth of pubic hair increase in height (rapid) Frequency not determined difficult or labored breathing difficulty breathing flushing of skin hives or welts itching of skin large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs pain in chest, groin, or legs, especially the calves redness of skin severe, sudden headache skin rash slurred speech sudden loss of coordination sudden, severe weakness or numbness in arm or leg sudden, unexplained shortness of breath tightness in chest unusually warm skin vision changes wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common Discouragement enlargement of breasts feeling sad or empty headache irritability lack of appetite loss of interest or pleasure pain at place of injection trouble concentrating trouble sleeping tiredness

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

For females onlyLess common or rare Abdominal or stomach pain (severe) bloating (moderate to severe) decreased amount of urine feeling of indigestion nausea, vomiting, or diarrhea (continuing or severe) pelvic pain (severe) shortness of breath weight gain (rapid)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Chorex side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Chorex resources Chorex Side Effects (in more detail) Chorex Use in Pregnancy & Breastfeeding Chorex Drug Interactions Chorex Support Group 0 Reviews for Chorex - Add your own review/rating Hcg Consumer Overview Novarel MedFacts Consumer Leaflet (Wolters Kluwer) Novarel Prescribing Information (FDA) Ovidrel Prescribing Information (FDA) Ovidrel Monograph (AHFS DI) Ovidrel MedFacts Consumer Leaflet (Wolters Kluwer) Pregnyl Prescribing Information (FDA) Compare Chorex with other medications Female Infertility Hypogonadism, Male Ovulation Induction Prepubertal Cryptorchidism
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Anastrozole tablets


1. Name Of The Medicinal Product

Anastrozole 1 mg, film-coated tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 1 mg anastrozole.

Excipient: each tablet contains 93 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White film-coated round biconvex tablets, debossed with “ANA” and “1” on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.

4.2 Posology And Method Of Administration

Adults including the elderly

One tablet (1 mg) to be taken orally once a day.

Children

Anastrozole is not recommended for use in children due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).

Renal impairment

No dose change is recommended in patients with mild or moderate renal impairment.

Hepatic impairment

No dose change is recommended in patients with mild hepatic disease.

4.3 Contraindications

Anastrozole is contraindicated in:

– Premenopausal women.

– Pregnant or lactating women.

– Patients with severe renal impairment (creatinine clearance less than 20 ml/min).

– Patients with moderate or severe hepatic disease.

– Patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Concurrent tamoxifen therapy (see section 4.5).

4.4 Special Warnings And Precautions For Use

Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients (see section 5.1)

Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, it must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.

The menopause should be defined biochemically in any patient where there is doubt about hormonal status.

There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequential increased risk of fracture. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole in postmenopausal women and should be considered.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450

A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see section 5.1)

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

4.6 Pregnancy And Lactation

Anastrozole is contraindicated in pregnant and lactating women.

4.7 Effects On Ability To Drive And Use Machines

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable Effects

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for five years (ATAC study)

System Organ Class

Frequency

Adverse Reaction

Metabolism and nutrition

Common

(

Anorexia, mainly mild in nature

Hypercholesterolaemia, mainly mild or moderate in nature

Nervous system disorders

Very common

(

Headache, mainly mild or moderate in nature

 

Common

(

Somnolence, mainly mild or moderate in nature

Carpal Tunnel Syndrome

Vascular disorders

Very common

(

Hot flushes, mainly mild or moderate in nature

Gastrointestinal disorders

Very common

(

Nausea, mainly mild or moderate in nature

 

Common

(

Diarrhoea, mainly mild or moderate in nature

Vomiting, mainly mild or moderate in nature

Hepatobiliary disorders

Common

(

Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

 

Uncommon

(

Increases in gamma-GT and bilirubin Hepatitis

Skin and subcutaneous disorders

Very common

(

Rash, mainly mild or moderate in nature

 

Common

(

Hair thinning (Alopecia), mainly mild or moderate in nature.

Allergic reactions

 

Uncommon

(

Urticaria

 

Rare

(

Erythema multiforme

Anaphylactoid reaction

 

Not known

Stevens-Johnson syndrome**

Angioedema**

Musculoskeletal and connective tissue disorders

Very common

(

Joint pain/stiffness, mainly mild or moderate in nature

 

Common

(

Bone pain

 

Uncommon

(

Trigger finger

Reproductive system and breast disorders

Common

(

Vaginal dryness, mainly mild or moderate in nature

Vaginal bleeding, mainly mild or moderate in nature*

General disorders and administration site conditions

Very common

(

Asthenia, mainly mild or moderate in nature

*Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

**Cannot be estimated from the available data.

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4)The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Undesirable effect

anastrozole (n=3092)

tamoxifen (n=3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.

The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdosage.

In animal studies, anastrozole demonstrated low acute toxicity.

Clinical trials have been conducted with various doses of anastrozole, up to 60 mg in a single dose given to healthy male volunteers, and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.

There is no specific antidote to overdosage and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken.

Vomiting may be induced if the patient is alert.

Dialysis may be helpful because anastrozole is not highly protein-bound.

General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Enzyme inhibitors

ATC Code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily by the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Lowering circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer.

In postmenopausal women, a daily dose of 1 mg of anastrozole produced oestradiol suppression of greater than 80% using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.

Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

Primary adjuvant treatment of early breast cancer

In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, anastrozole was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of anastrozole versus tamoxifen for the prospectively defined hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in time to recurrence. The difference was of even greater magnitude than in disease-free survival for both the Intention To Treat (ITT) population and hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in terms of time to distant recurrence. The incidence of contralateral breast cancer was statistically reduced for anastrozole compared to tamoxifen. Following 5 years of therapy, anastrozole is at least as effective as tamoxifen in terms of overall survival. However, due to low death rates, additional follow-up is required to determine more precisely the long-term survival for anastrozole relative to tamoxifen. With 68 months median follow-up, patients in the ATAC study have not been followed up for sufficient time after 5 years of treatment, to enable a comparison of long-term post treatment effects of anastrozole relative to tamoxifen.

ATAC endpoint summary: 5-year treatment completion analysis

       

Efficacy endpoints

Number of events (frequency)

     

Intention to treat population

Hormone receptor positive tumour status

     

anastrozole (n=3125)

tamoxifen (n=3116)

anastrozole (n=2618)

tamoxifen (n=2598)

 

Disease-free survivala

575 (18.4)

651 (20.9)

424 (16.2)

497 (19.1)

Hazard ratio

0.87

0.83

   

2-sided 95% CI

0.78 to 0.97

0.73 to 0.94

   

p-value

0.0127

0.0049

   

Distant disease-free survivalb

500 (16.0)

530 (17.0)

370 (14.1)

394 (15.2)

Hazard ratio

0.94

0.93

   

2-sided 95% CI

0.83 to 1.06

0.80 to 1.07

   

p-value

0.2850

0.2838

   

Time to recurrencec

402 (12.9)

498 (16.0)

282 (10.8)

370 (14.2)

Hazard ratio

0.79

0.74

   

2-sided 95% CI

0.70 to 0.90

0.64 to 0.87

   

p-value

0.0005

0.0002

   

Time to distant recurrenced

324 (10.4)

375 (12.0)

226 (8.6)

265 (10.2)

Hazard ratio

0.86

0.84

   

2-sided 95% CI

0.74 to 0.99

0.70 to 1.00

   

p-value

0.0427

0.0559

   

Contralateral breast primary

35 (1.1)

59 (1.9)

26 (1.0)

54 (2.1)

Odds ratio

0.59

0.47

   

2-sided 95% CI

0.39 to 0.89

0.30 to 0.76

   

p-value

0.0131

0.0018

   

Overall survival

411 (13.2)

420 (13.5)

296 (11.3)

301 (11.6)

Hazard ratio

0.97

0.97

   

2-sided 95% CI

0.85 to 1.12

0.83 to 1.14

   

p-value

0.7142

0.7339

   

a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason).

b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).

c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer.

d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.

e Number (%) of patients who had died.

As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment.

When anastrozole and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of estradiol suppression produced by anastrozole.

Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen

In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy, switching to anastrozole after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months.

Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for anastrozole, consistent with the results of disease-free survival. The incidence of contralateral breast cancer was very low in the two treatment arms with a numerical advantage for anastrozole. Overall survival was similar for the two treatment groups.

ABCSG 8 trial endpoint and results summary

   

Efficacy endpoints

Number of events (frequency)

 

anastrozole (n=1297)

tamoxifen (n=1282)

 

Disease-free survival

65 (5.0)

93 (7.3)

Hazard ratio

067

 

2-sided 95% CI

0.49 to 0.92

 

p-value

0.014

 

Time to any recurrence

36 (2.8)

66 (5.1)

Hazard ratio

0.53

 

2-sided 95% CI

0.35 to 0.79

 

p-value

0.002

 

Time to local or distant recurrence

29 (2.2)

51 (4.0)

Hazard ratio

0.55

 

2-sided 95% CI

0.35 to 0.87

 

p-value

0.011

 

Time to distant recurrence

22 (1.7)

41 (3.2)

Hazard ratio

0.52

 

2-sided 95% CI

0.31 to 0.88

 

p-value

0.015

 

New contralateral breast cancer

7 (0.5)

15 (1.2)

Odds ratio

0.46

 

2-sided 95% CI

0.19 to 1.13

 

p-value

0.090

 

Overall survival

43(3.3)

45 (3.5)

Hazard ratio

0.96

 

2-sided 95% CI

0.63 to 1.46

 

p-value

0.840

 

Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.

The anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer.

Study of anastrozole with the bisphosphonate risedronate (SABRE)

Bone Mineral Density (BMD)

In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with anastrozole 1mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone (N=42), those in the moderate group were randomised to anastrozole plus risedronate 35mg once a week (N=77) or anastrozole plus placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35mg once a week (N=38). The primary endpoint was changed from baseline in lumbar spine bone mass density at 12 months.

The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using anastrozole 1mg/day in combination with risedronate 35mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with anastrozole 1mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline total hip BMD at 12 months.

This study provides evidence that the use of bisphosphonates should be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with anastrozole.

Lipids

In the SABRE study there was a neutral effect on plasma lipids in those patients treated with anastrozole plus risedronate.

Paediatrics

Anastrozole is not indicated for use in children. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children are available (see also section 5.3)

The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome.

Short stature due to Growth Hormone Deficiency

A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11-16 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months. After 3 years anastrozole was found to statistically significantly slow bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo.

Testotoxicosis

An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2-9) with familial male-limited precocious puberty, also known as testotoxicosis, treated with a combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study.

Gynaecomastia studies

Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with anastrozole 1mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed b


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Decapeptyl SR 11.25mg


1. Name Of The Medicinal Product

Decapeptyl SR 11.25mg, powder for suspension for injection.

2. Qualitative And Quantitative Composition

Triptorelin (I.N.N.) 15mg, as triptorelin acetate.

The vial contains an overage to ensure that a dose of 11.25mg is administered to the patient.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for suspension for injection, sustained release formulation.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of patients with locally advanced, non-metastatic prostate cancer, as an alternative to surgical castration (see section 5.1).

Treatment of metastatic prostate cancer.

As adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

Treatment of endometriosis.

Treatment of precocious puberty (onset before 8 years in girls and 10 years in boys).

4.2 Posology And Method Of Administration

Prostate cancer

One intramuscular injection should be administered every 3 months.

No dosage adjustment is necessary in the elderly.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3mg) and as a 6-month treatment (Decapeptyl SR 22.5mg) for prostate cancer.

Endometriosis

One intramuscular injection should be administered every 3 months. The treatment must be initiated in the first five days of the menstrual cycle. Treatment duration depends on the initial severity of the endometriosis and the changes observed in the clinical features (functional and anatomical) during treatment. The maximum duration of treatment should be 6 months (two injections).

A further course of treatment with Decapeptyl SR 11.25mg, or with other GnRH agonists, beyond 6 months should not be undertaken due to concerns about bone density losses.

Decapeptyl is also available as a 1-month treatment (Decapeptyl SR 3mg) for endometriosis.

Precocious puberty (before 8 years in girls and 10 years in boys)

One intramuscular injection should be administered every 3 months.

The treatment of children with Decapeptyl SR 11.25mg should be under the overall supervision of a paediatric endocrinologist or of a paediatrician or endocrinologist with expertise in the treatment of central precocious puberty.

Treatment should be stopped around the physiological age of puberty in boys and girls and should not be continued in girls with a bone maturation of more than 12 years. There are limited data available in boys relating to the optimum time to stop treatment based on bone age, however it is advised that treatment is stopped in boys with a bone maturation age of 13-14 years.

4.3 Contraindications

Hypersensitivity to GnRH, its analogues or any other component of the medicinal product (see section 4.8).

Pregnancy and lactation

4.4 Special Warnings And Precautions For Use

The use of GnRH agonists may cause a reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Particular caution is therefore necessary since reduction in bone mineral density is likely to be more detrimental in these patients. Treatment with Decapeptyl SR 11.25mg should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

It should be confirmed that the patient is not pregnant before prescription of triptorelin.

Rarely, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy characterised by sudden headache, vomiting, visual impairment and ophthalmoplegia.

Mood changes, including depression have been reported. Patients with known depression should be monitored closely during therapy.

Prostate cancer

Initially, Decapeptyl SR 11.25mg, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, isolated cases of transient worsening of signs and symptoms of prostate cancer may occasionally develop during the first weeks of treatment. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.

A small number of patients may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare) and temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchidectomy (surgical castration) should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastasis, at the risk of spinal cord compression, and in patients with urinary tract obstruction.

After surgical castration, Decapeptyl SR 11.25mg does not induce any further decrease in serum testosterone levels.

Long-term androgen deprivation either by bilateral orchidectomy or administration of GnRH agonists is associated with increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH agonists and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and their glucose, cholesterol and blood pressure adequately monitored during androgen deprivation therapy.

Metabolic changes may be more severe in these high risk patients. Patients at high risk of metabolic or cardiovascular disease and receiving androgen deprivation therapy should be monitored at appropriate intervals not exceeding 3 months.

Administration of triptorelin in therapeutic doses result in suppression of the pituitary gonadal system. Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during treatment and after discontinuation of therapy with GnRH agonists may therefore be misleading.

Endometriosis

The use of GnRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during a six month treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk.

In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

Used at the recommended dose, Decapeptyl SR 11.25mg causes constant hypogonadotropic amenorrhoea. If vaginal haemorrhage occurs after the first month, plasma oestradiol levels should be measured and if levels are below 50 pg/mL, possible organic lesions should be investigated.

After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 5 months after the last injection. A non-hormonal method of contraception should be used throughout treatment including for 3 months after the duration of the last injection.

Since menses should stop during Decapeptyl SR 11.25mg treatment, the patient should be instructed to notify her physician if regular menstruation persists.

Precocious puberty

Treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen withdrawal, may lead, in the first month, to vaginal bleeding of mild or moderate intensity.

After discontinuation of treatment the development of puberty characteristics will occur.

Information with regards to future fertility is still limited. In most girls, regular menses will start on average one year after ending the therapy.

Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.

Bone mineral density may decrease during GnRH agonist therapy for central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved, and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped capital femoral epiphysis can be seen after withdrawal of GnRH agonist treatment. The suggested theory is that the low concentrations of oestrogen during treatment with GnRH agonists weaken the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce the level of GnRH receptors in the pituitary.

When Decapeptyl SR 11.25mg is co-administered with drugs affecting pituitary secretion of gonadotropins, caution should be exercised and it is recommended that the patient's hormonal status be supervised.

4.6 Pregnancy And Lactation

Triptorelin should not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or foetal abnormality. Prior to treatment, potentially fertile women should be examined to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume.

Animal studies have not revealed any teratogenic effects. During post-marketing surveillance and in a limited number of pregnant women who were exposed inadvertently to triptorelin, there were no reports of malformation or foetotoxicity attributable to the product. However, as the number of patients is too small to draw conclusions regarding the risk of foetal malformations or foetotoxicity, if a patient becomes pregnant while receiving triptorelin, therapy should be discontinued.

Triptorelin is not recommended for use during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, the ability to drive and use machines may be impaired should the patient experience dizziness, somnolence and visual disturbances (being possible undesirable effects of treatment), or resulting from the underlying disease.

4.8 Undesirable Effects

Clinical trials experience

General tolerance in men

As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expected pharmacological effects: Initial increase in testosterone levels, followed by almost complete suppression of testosterone. These effects included hot flushes (50%), erectile dysfunction (4%) and decreased libido (3%).

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration. The frequency of the adverse reactions is classified as follows: very common (

System Organ Class

Very Common AEs

Common AEs

Uncommon AEs

Rare AEs

Additional post-marketing AEs

 

 

Blood and lymphatic system disorders

     

Purpura

 

Ear and labyrinth disorders

   

Tinnitus

Vertigo

 

Endocrine disorders

     

Diabetes mellitus

Gynaecomastia

Eye disorders

     

Abnormal sensation in eye

Visual disturbance

Vision blurred

Gastrointestinal disorders

 

Nausea

Abdominal pain

Constipation

Diarrhoea

Vomiting

Abdominal distension

Dry mouth

Dysgeusia

Flatulence

 

General disorders and administration site conditions

Asthenia

Hyperhidrosis

Fatigue

Injection site erythema

Injection site inflammation

Injection site pain

Injection site reaction

Oedema

Lethargy

Pain

Rigors

Somnolence

Chest pain

Dysstasia

Influenza like illness

Pyrexia

Malaise

Immune system disorders

     

Anaphylactic reaction

Hypersensitivity

Hypersensitivity reaction

Infections and infestations

     

Nasopharyngitis

 

Investigations

   

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood creatinine increased

Blood urea increased

Weight increased

Blood alkaline phosphatase increased

Body temperature increased

Weight decreased

Blood pressure increased

Metabolism and nutrition disorders

   

Anorexia

Gout

Increased appetite

   

Musculoskeletal and connective tissue disorders

Back pain

Musculoskeletal pain

Pain in extremity

Arthralgia

Muscle cramp

Muscular weakness

Myalgia

Joint stiffness

Joint swelling

Musculoskeletal stiffness

Osteoarthritis

Bone pain

Nervous system disorders

Paraesthesia in lower limbs

Dizziness

Headache

Paraesthesia

Memory impairment

 

Psychiatric disorders

 

 

Depression

Insomnia

Irritability

Mood swings

Confusional state

Decreased activity

Euphoric mood

Anxiety and Confusional state

Reproductive system and breast disorders

 

Erectile dysfunction

Loss of libido

Gynaecomastia

Breast pain

Testicular atrophy

Testicular pain

Ejaculation failure

 

Respiratory, thoracic and mediastinal disorders

 

 

Dyspnoea

Orthopnoea

 

Skin and subcutaneous tissue disorders

Hyperhidrosis

 

Acne

Alopecia

Pruritus

Rash

Blister

Angioneurotic oedema

Urticaria

Vascular disorders

Hot flush

 

Hypertension

Epistaxis

Hypotension

 

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (

Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see special warnings and special precautions for use).

The use of GnRH agonists to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases in the risk of bone fracture.

General tolerance in women (see section 4.4)

As a consequence of decreased oestrogen levels, the most commonly reported adverse events (expected in 10% of women or more) were headache, decreased libido, sleep disorder, mood alterations, dyspareunia, dysmenorrhoea, genital haemorrhage, ovarian hyperstimulation syndrome, ovarian hypertrophy pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes and asthenia.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: very common (

System Organ Class

Very Common AEs

Common AEs

Additional post-marketing AEs

   

Gastrointestinal disorders

 

Nausea

Abdominal pain

Abdominal discomfort

Diarrhoea

Vomiting

General disorders and administration site conditions

 

Injection site erythema

Injection site inflammation

Injection site pain

Pyrexia

Malaise

Investigations

 

Weight increased

Blood pressure increased

Musculoskeletal and connective tissue disorders

 

Arthralgia

Muscle spasms

Myalgia

Muscular weakness

Nervous system disorders

Headache

Libido decreased

 

Dizziness

Psychiatric disorders

Sleep disorder

Mood altered

 

Depression

Anxiety and Confusional state

Reproductive system and breast disorders

Dyspareunia

Dysmenorrhoea

Genital haemorrhage (including menorrhagia, metrorrhagia)

Libido decreased

Ovarian hyperstimulation syndrome

Ovarian hypertrophy

Pelvic pain

Vulvovaginal dryness

Breast pain

Amenorrhoea

Skin and subcutaneous tissue disorders

Hyperhidrosis

 

Angioneurotic oedema

Pruritus

Rash

Urticaria

Vascular disorders

Hot flush

   

Respiratory, thoracic and mediastinal disorders

 

 

Dyspnoea

Eye disorders

   

Vision blurred

Visual disturbance

Ear and labyrinth disorders

   

Vertigo

Immune system disorders

   

Hypersensitivity reaction

At the beginning of treatment, the symptoms of endometriosis including pelvic pain and dysmenorrhoea are commonly exacerbated during the initial transient increase in plasma oestradiol levels. These symptoms are transient and usually disappear in one to two weeks.

Genital haemorrhage including menorrhagia and metrorrhagia may occur in the month following the first injection.

General tolerance in children (see section 4.4)

The frequency of the adverse reactions is classified as follows: very common (

System Organ Class

Very Common AEs

Common AEs

Additional post-marketing AEs

 

 

Gastrointestinal disorders

   

Vomiting

Abdominal pain

Abdominal discomfort

General disorders and administration site conditions

 

Pain

Erythema

Injection site erythema

Injection site inflammation

Injection site pain

Malaise

Investigations

   

Blood pressure increased

Weight increased

Musculoskeletal and connective tissue disorders

   

Myalgia

Nervous system disorders

 

Headache

 

Psychiatric disorders

   

Affect lability

Nervousness

Reproductive system and breast disorders

 

Genital haemorrhage

Vaginal bleeding

 

Vascular disorders

 

Hot flush

 

Respiratory, thoracic and mediastinal disorders

   

Epistaxis

Eye disorders

   

Vision blurred

Visual disturbance

Skin and subcutaneous tissue disorders

   

Angioneurotic oedema

Rash

Urticaria

Immune system disorders

 

Hypersensitivity reaction

Hypersensitivity reaction

4.9 Overdose

No case of overdose has been reported. Animal data do not predict any effects other than those on sex hormone concentration and consequent effect on the reproductive tract. If overdose occurs, symptomatic management is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group:

Gonadotropin-Releasing Hormone analogue

L 02 A E 04: Antineoplastic and immunomodulator

Triptorelin is a synthetic decapeptide analogue of natural GnRH.

Prostate cancer

The first administration of Decapeptyl SR 11.25mg stimulates the release of pituitary gonadotropins with a transient increase in testosterone levels (“flare-up”) in men. Prolonged administration leads to a suppression of gonadotropins and a fall in plasma testosterone or oestradiol to castrate levels after approximately 20 days, which is maintained for as long as the product is administered.

The efficacy and safety of triptorelin has been determined in clinical studies involving 645 patients with locally advanced or metastatic prostate cancer.

Of these, three long term controlled studies compared the efficacy and safety of triptorelin to bilateral orchidectomy as an initial therapy in patients with locally advanced or metastatic prostate cancer (stage C or D). In one of these three long term studies, 7 patients in the triptorelin group and 7 patients in the orchidectomy group had also undergone prostatectomy. Triptorelin induced biochemical castration at least as rapidly as surgical pulpectomy and was as effective as surgical castration in the long term palliative treatment of locally advanced or metastatic prostate cancer. Both the triptorelin and orchidectomy groups showed improvements in dysuria and pain, and reduction in volume of prostate. Analysis after six and eight years in two of the studies showed that there was no significant difference in the median survival rates in the triptorelin group versus the orchidectomy group.

A study assessing the pharmacodynamic equivalence between triptorelin 3-month and 28-day prolonged release formulations in patients with locally advanced or metastatic prostate cancer, found that equivalent testosterone suppression was achieved, whether 3 doses of Decapeptyl SR 3mg (n=68) or a single dose of Decapeptyl SR 11.25mg (n=63) was given. The percentage of patients who achieved a testosterone castrate level

In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis compared the short-term to long-term concomitant and adjuvant hormonal treatment with triptorelin (62.2%) or goserelin (30.1%). The 5-year overall mortality was 19.0% and 15.2%, in the short-term and long-term groups, respectively. The observed Hazard Ratio of 1.42 with an upper one-sided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p = 0.65 for non inferiority), demonstrate that the combination of radiotherapy plus 6 months of androgen deprivation therapy provides inferior survival as compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years of long-term treatment and short-term treatment shows 84.8% survival and 81.0%, respectively.

Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P= 0.37).

Endometriosis

The first administration of Decapeptyl SR 11.25mg stimulates the release of pituitary gonadotropins with a transient increase in oestradiol levels in women. Prolonged administration leads to a suppression of gonadotropins and a fall in plasma testosterone or oestradiol to castrate levels after approximately 20 days, which is maintained for as long as the product is administered.

Continued administration of Decapeptyl SR 11.25mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue.

Precocious puberty

Inhibition of the increased hypophyseal gonadotropic activity in children with precocious puberty leads to suppression of oestradiol and testosterone secretion in girls and boys, respectively, and to lowering of the LH peak due to the GnRH stimulation test. The consequence is a regression or stabilisation of secondary sex characteristics and an improvement in median predicted adult height of 2.3cm after one year's treatment.

5.2 Pharmacokinetic Properties

Following intramuscular injection of Decapeptyl SR 11.25mg in patients (men and women), a peak of plasma triptorelin is observed in the first 3 hours after injection. After a phase of decrease, the circulating triptorelin levels remain stable at around 0.04-0.05ng/mL in endometriosis patients and around 0.1ng/mL in prostate cancer patients until day 90.

5.3 Preclinical Safety Data

The compound did not demonstrate any specific toxicity in animal toxicological studies. The effects observed are related to the pharmacological properties of triptorelin on the endocrine system.

6. Pharmaceutical Particulars 6.1 List Of Excipients

D,L lactide-glycolide copolymer

Mannitol

Carmellose sodium

Polysorbate 80.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except the one mentioned in 6.6.

6.3 Shelf Life

2 years.

The product should be used immediately after reconstitution.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep container in the outer carton.

6.5 Nature And Contents Of Container

A type I, 4mL capacity glass vial with an elastomer stopper and an aluminium cap containing the powder.

A type I, 3mL capacity glass ampoule containing 2mL of the suspension vehicle.

Box containing 1 vial and 1 ampoule with 1 syringe and 2 needles.

6.6 Special Precautions For Disposal And Other Handling

The suspension for injection must be reconstituted using an aseptic technique and only using the ampoule of mannitol solution 0.8% for injection that is provided as the suspension vehicle for Decapeptyl SR 11.25mg.

The suspension vehicle should be drawn into the syringe provided using one of the injection needles and transferred to the vial containing the powder for injection. The vial should be shaken from side to side until a homogenous suspension is formed, and the mixture then drawn back into the syringe without inverting the vial. The injection needle should then be changed and the second needle used to administer the injection. As the product is a suspension, the injection should be administered immediately after reconstitution to prevent sedimentation. The suspension should be discarded if it is not administered immediately after reconstitution.

To ensure patients receive the correct dose, each vial of Decapeptyl contains a small overage to allow for predictable losses on reconstitution and injection.

The vial is intended for single use only and any remaining product should be discarded. Used injection needles should be disposed of in a designated sharps container.

7. Marketing Authorisation Holder

Ipsen Limited,

190 Bath Road,

Slough,

SL1 3XE,

United Kingdom.

8. Marketing Authorisation Number(S)


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Deca-Durabolin 50mg / ml


1. Name Of The Medicinal Product

Deca Durabolin 50mg/ml

2. Qualitative And Quantitative Composition

Each ml of Deca Durabolin contains 50mg nandrolone decanoate.

3. Pharmaceutical Form

Solution for injection.

4. Clinical Particulars 4.1 Therapeutic Indications

For use in osteoporosis in post-menopausal women.

Established osteoporosis should have been diagnosed by the following

parameters:

i) crush or wedge fractures of the vertebrae

ii) other osteoporotic fractures

iii) established reduction in bone mineral content as measured by accepted BMC measurements.

4.2 Posology And Method Of Administration

Dosage

Post-menopausal women

50 mg every three weeks.

The duration of treatment depends on the clinical response and the possible occurrence of side-effects.

We would recommend that the effectiveness of therapy be monitored with the appropriate methods for osteoporosis on a 6-12 monthly basis.

Children

There are no recommendations for use in children.

Administration

Deep intramuscular injection

4.3 Contraindications

Pregnancy

Breast-feeding

Porphyria

Allergies to any of the components

Known or suspected carcinoma of prostate or mammary carcinoma in the male

4.4 Special Warnings And Precautions For Use

If signs of virilisation develop, discontinuation of the treatment should be considered.

Patients, especially the elderly, with the following conditions should be monitored:

• latent or overt cardiac failure, renal dysfunction, hypertension, epilepsy or migraine (or a history of these conditions), since anabolic steroids may occasionally induce sodium and water retention;

• incomplete statural growth, since anabolic steroids in high dosages may accelerate epiphyseal closure;

• skeletal metastases, since anabolic steroids may induce hypercalcaemia and hypercalciuria in these patients;

• liver dysfunction - caution should be used in patients with severe hepatic impairment and Deca Durabolin 50mg/ml should only be used if the benefits outweigh the risks.

• diabetes mellitus

Deca Durabolin 50mg/ml contains Arachis oil (peanut oil) and should not be taken / applied by patients known to be allergic to peanut. As there is a possible relationship between allergy to peanut and allergy to Soya, patients with Soya allergy should also avoid Deca Durabolin 50mg/ml.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anabolic steroids may improve glucose tolerance and decrease the need for insulin or other antidiabetic drugs in diabetics.

4.6 Pregnancy And Lactation

Deca-Durabolin is contra-indicated during pregnancy because of possible masculinisation of the foetus. There are insufficient data on the use of this medicine during breast-feeding to assess potential harm to the infant or a possible influence on milk production.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Deca-Durabolin at the recommended dosages is unlikely to produce virilising effects. High dosages, prolonged treatment and/or too frequent administration may cause:

• Virilisation which appears in sensitive women as hoarseness, acne, hirsutism and increase of libido; in prepubertal boys as an increased frequency of erections and phallic enlargement, and in girls as an increase of pubic hair and clitoral hypertrophy. Hoarseness may be the first symptom of vocal change which may end in long-lasting, sometimes irreversible deepening of the voice;

• Amenorrhoea and inhibition of spermatogenesis;

• Premature epiphyseal closure;

• Sodium and water retention.

Abnormal liver function tests have been reported in patients treated with (high doses) of Deca-Durabolin.

Liver tumours have been reported occasionally on prolonged treatment with orally active C17-alpha alkylated anabolic steroids. A relationship between liver tumours and non-C17-alkylated injectable steroids, such as nandrolone esters, appears to be highly unlikely, but cannot be absolutely excluded.

4.9 Overdose

The acute toxicity of nandrolone decanoate in animals is very low. There are no reports of acute overdosage with Deca-Durabolin in the human.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Nandrolone is chemically related to testosterone and shows enhanced anabolic and a reduced androgenic activity.

In humans Deca-Durabolin has been shown to positively influence calcium metabolism and to increase bone mass in osteoporosis.

Androgenic effects (e.g. virilisation) are relatively uncommon at the recommended dosages. Nandrolone lacks the C17 alpha-alkyl group which is associated with the occurrence of liver dysfunction and cholestasis.

5.2 Pharmacokinetic Properties

Nandrolone decanoate is slowly released from the injection site into the blood with a half-life of 6 days. The ester is rapidly hydrolysed to nandrolone in the blood with a half-life of one hour or less. The half-life for the combined process of hydrolysis of nandrolone decanoate and of distribution and elimination of nandrolone is 4.3 hours.

Nandrolone is metabolised by the liver. 19-norandrosterone, 19-noretiocholanolone and 19-norepiandrosterone have been identified as metabolites in the urine. It is not known whether these metabolites display a pharmacological action.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzyl alcohol

Arachis oil

6.2 Incompatibilities

None known

6.3 Shelf Life

1 ml ampoule 60 months.

6.4 Special Precautions For Storage

Do not store above 30°C

Do not refrigerate or freeze.

Keep in the container in the outer carton.

6.5 Nature And Contents Of Container

1 x 1ml ampoules

3 x 1ml ampoules

6 x 1ml ampoules

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Organon Laboratories Limited,

Cambridge Science Park,

Milton Road,

Cambridge, CB4 0FL

8. Marketing Authorisation Number(S)

PL0065/5063R

9. Date Of First Authorisation/Renewal Of The Authorisation

28/2/73 / 27/04/05

10. Date Of Revision Of The Text

20 April 2010

11 Legal Category

Prescription Only Medicine

Ref:USDD50v4.2

RA 1220 GB S1 (ref 1.0)

DecaDurabolin/UK/04-10/1


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Gonapeptyl Depot 3.75 mg


1. Name Of The Medicinal Product

GONAPEPTYL DEPOT

3.75 mg

Powder and solvent for suspension for injection.

2. Qualitative And Quantitative Composition

One pre-filled syringe contains 3.75 mg triptorelin (as acetate) to be suspended in one ml suspension agent.

For excipients, see 6.1.

3. Pharmaceutical Form

Powder and solvent for suspension for injection

prolonged release in pre-filled syringes.

4. Clinical Particulars 4.1 Therapeutic Indications

Men:

Treatment of advanced, hormone-dependent prostate carcinoma.

Women:

Preoperative reduction of myoma size to reduce the symptoms of bleeding and pain in women with symptomatic uterine myomas.

Symptomatic endometriosis confirmed by laparoscopy when suppression of the ovarian hormonogenesis is indicated to the extent that surgical therapy is not primarily indicated.

Children:

Treatment of confirmed central precocious puberty (girls under 9 years, boys under 10 years).

4.2 Posology And Method Of Administration

The product should only be used under the supervision of an appropriate specialist having requisite facilities for regular monitoring of response.

It is important that the injection of the sustained release form be performed strictly in accordance with the instructions given in section 6.6.

Following reconstitution, the suspension has to be injected immediately.

Dosage and method of administration

The dosage of one syringe, equivalent to 3.75 mg triptorelin, is injected every 28 days either subcutaneously (e.g. into the skin of the abdomen, the buttock or thigh) or deep intramuscularly. The injection site should be changed each time.

Men:

Once every four weeks an injection with one syringe, equivalent to 3.75 mg triptorelin. In order to continually suppress testosterone levels, it is important to comply with a 4-weekly administration.

Women:

? Uterine myomas and endometriosis:

Once every four weeks an injection with one syringe, equivalent to 3.75 mg triptorelin. The treatment must be initiated in the first 5 days of the cycle.

Children:

At the beginning of treatment one injection with one syringe, equivalent to 3.75 mg triptorelin, on days 0, 14, and 28. Thereafter one injection every 4 weeks. Should the effect be insufficient, the injections may be given every 3 weeks. Dosing should be based on body weight. Children weighing less than 20 kg are injected with 1.875 mg (half dose), children between 20 and 30 kg receive 2.5 mg (2/3 dose), and children with more than 30 kg body weight are injected with 3.75 mg triptorelin (full dose).

Note for specific patient groups:

? There is no need to adjust the dose for the elderly.

? According to current data, dose reduction or prolongation of the dosage interval in patients with impaired renal function is not necessary.

Duration of administration

? Prostate carcinoma:

Treatment with Gonapeptyl Depot is usually a long-term therapy.

- Uterine myomas and endometriosis:

The duration of treatment depends on the initial degree of severity of endometriosis and on the evolution of its clinical manifestations (functional and anatomical) and on the evolution of the volume of the uterine myomas, determined by ultrasonography during treatment. Normally, the maximum attainable result is achieved after 3 to 4 injections.

In view of the possible effect on bone density, therapy should not exceed a duration of 6 months (see 4.4).

- Central precocious puberty (CPP):

Treatment should be stopped if a bone maturation of older than 12 years in girls and older than 13 years in boys has been achieved.

4.3 Contraindications

General:

Known hypersensitivity to triptorelin, poly-(d,l lactide coglycolide), dextran, or to any of the excipients.

In men:

? Hormone independent prostate carcinoma

? As sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases (see also section 4.4)

? After orchiectomy (in case of surgical castration Gonapeptyl Depot does not cause further decrease of serum testosterone)

In women:

? Pregnancy

? Clinically manifest osteoporosis

? Lactation period

In children:

? Progressive brain tumours

4.4 Special Warnings And Precautions For Use

Men:

The initial transient increase of serum testosterone has, in few patients, been associated with a temporary aggravation of symptoms of the disease (see 4.8). The patient should be advised to consult the physician, if any of these symptoms aggravates. For that reason, the use of Gonapeptyl Depot has to be carefully evaluated in patients with premonitory signs of medullary compression and the medical surveillance has to be closer in the first weeks of treatment, particularly in patients with urinary tract obstructions due to metastases and/or in patients with spinal metastases.

In order to prevent accentuation of the clinical symptoms, supplementary administration of an appropriate antiandrogen agent should be considered in the initial phase of the treatment.

In order to control the therapeutic effect, the prostate-specific antigen (PSA) and the testosterone plasma levels should be regularly monitored during treatment. Testosterone levels should not exceed 1 ng/ml.

Women:

Gonapeptyl Depot should only be prescribed after careful diagnosis (e.g. laparoscopy). Pregnancy should be precluded prior to treatment.

- Uterine myomas and endometriosis:

Menstruation does not occur during treatment. A supervening metrorrhagia in the course of treatment is abnormal (apart from the first month), and should lead to verification of plasma oestrogen level. Should this level be less than 50 pg/ml, possible associated organic lesions should be sought. After withdrawal of treatment, ovarian function resumes, e.g. menstrual bleeding will resume after 7-12 weeks after the final injection.

Non-hormonal contraception should be used during the initial month of treatment as ovulation may be triggered by the initial release of gonadotrophins. It should also be used from 4 weeks after the last injection until resumption of menstruation or until another contraceptive method has been established.

During treatment of uterine myomas the size of uterus and myoma should be determined regularly, e.g. by means of ultrasonography. Disproportionally fast reduction of uterus size in comparison with the reduction of myoma tissue has in isolated cases led to bleeding and sepsis.

Treatment with Gonapeptyl Depot over several months can lead to a decrease of bone density (see 4.8). For this reason, therapy should not exceed a duration of 6 months. After withdrawal of treatment, the bone loss is generally reversible within 6 - 9 months.

Particular caution is therefore advised in patients with additional risk factors in view of osteoporosis.

Children:

The chronological age at the beginning of therapy should be under 9 years in girls and under 10 years in boys.

After finalising the therapy, development of puberty characteristics will occur. Information with regards to future fertility is still limited. In most girls menses will start on average one year after ending the therapy, which in most cases is regular.

Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.

Allergic and anaphylactic reactions have been reported in adults and children. These include both local site reactions and systemic symptoms. The pathogenesis could not be elucidated. A higher reporting rate was seen in children.

General:

When triptorelin is co-administered with drugs affecting pituitary secretion of gonadotrophins caution should be given and the patient's hormonal status should be supervised.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Oestrogen containing medicinal products should not be used during treatment with Gonapeptyl Depot.

4.6 Pregnancy And Lactation

Very limited data on the use of triptorelin during pregnancy do not indicate an increased risk of congenital malformations. However, long-term follow-up studies on development are far too limited. Animal data do not indicate direct or indirect harmful effects with respect to pregnancies or postnatal developments, but there are indications for foetotoxicity and delayed parturition. Based on the pharmacological effects disadvantageous influence on the pregnancy and the offspring cannot be excluded and Gonapeptyl Depot should not be used during pregnancy. Women of childbearing potential should use effective non-hormonal contraception. It is not known whether triptorelin is excreted in human milk. Because of the potential for adverse reactions from triptorelin in nursing infants, breastfeeding should be discontinued prior to and throughout administration.

4.7 Effects On Ability To Drive And Use Machines

Gonapeptyl Depot has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse experiences reported among patients treated with triptorelin during clinical trials and from post-marketing surveillance are shown below. As a consequence of decreased testosterone or oestrogen levels, most patients are expected to experience adverse reactions, with hot flushes being the most frequently reported (30% in men and 75-100% in women). Additionally, impotence and decreased libido should be expected in 30-40% of male patients, while bleeding/spotting, sweating, vaginal dryness and/or dyspareunia, decrease in libido and mood changes are expected in more than 10% of women.

Due to the fact that the testosterone levels normally increase during the first week of treatment, worsening of symptoms and complaints may occur (e.g. urinary obstruction, skeletal pain due to metastases, compression of the spinal cord, muscular fatigue and lymphatic oedema of the legs). In some cases urinary tract obstruction decreases the kidney function. Neurological compression with asthenia and paraesthesia in the legs has been observed.

Organ class

Common Adverse Reactions ( > 1/100, < 1/10)

Uncommon Adverse Reactions ( > 1/1000, < 1/100)

 

Men and women

 

   

Endocrine

 

Depressive mood; irritation

 

Metabolic and nutritional

 

Elevated enzyme levels (LDH, ?GT, SGOT, SGPT)

Gastrointestinal

 

Nausea

 

Musculo-skeletal system

 

Myalgia; arthralgia

 

Body as a whole – general:

Tiredness; sleep disturbances; hypersensitivity reactions (itching; skin rash; fever)

Anaphylaxis

Application site disorders

Temporary pain at injection site

Foreign body reaction at injection site

 

Men

 

   

Platelet, bleeding and clotting disorders

 

 

Thrombo-embolic disorder

Endocrine

Gynecomastia; headache; perspiration

Testicular atrophy; reduced growth of beard; hair loss on chest, arms and legs

Cardiovascular

 

Hypertension

Gastro-intestinal

 

Loss of appetite; gastralgia; dry mouth

Respiratory system disorders

 

Recurrence of asthma

General

 

 

Weight changes

 

Women

   

Metabolic and nutritional

 

Slight rise in serum cholesterol

Central and peripheral nervous system

 

Visual disturbances; paraesthesia

General

 

 

Aching of back

Children

 

   

Endocrine

 

Vaginal bleeding and discharge

Gastrointestinal

 

 

Vomiting; nausea

Body as a whole – general

 

Anaphylaxis

Slight trabecular bone loss may occur. This is generally reversible within 6-9 months after treatment discontinuation (see section 4.4).

 

Two cases of epiphysiolysis capitis femoris have been reported during use with triptorelin. Whether or not a causal relationship exists is unknown.

4.9 Overdose

There is insufficient experience of overdosing with triptorelin to draw conclusions on possible adverse effects. Considering the package form and the pharmaceutical form, overdosing is not expected.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Gonadorelinanaloga

ATC code: L02AE04

Triptorelin is a synthetic decapeptide analogue of the natural gonadotrophin-releasing hormone (GnRH). GnRH is a decapeptide, which is synthesised in the hypothalamus and regulates the biosynthesis and release of the gonadotrophins LH (luteinising hormone) and FSH (follicle stimulating hormone) by the pituitary. Triptorelin stimulates the pituitary more strongly to secretion of LH and FSH than a comparable dose of gonadorelin, whereas the duration of action is longer. The increase of LH and FSH levels will initially lead to an increase of serum testosterone concentrations in men or serum oestrogen concentrations in women. Chronic administration of a GnRH agonist results in an inhibition of pituitary LH- and FSH-secretion. This inhibition leads to a reduction in steroidogenesis, by which the serum estradiol concentration in women and the serum testosterone concentration in men fall to within the postmenopausal or castrate range, respectively, i.e. a hypogonadotrophic hypogonadal state. In children with precocious puberty, the concentration of estradiol or testosterone will decrease to within the prepubertal range. Plasma DHEAS (dihydroepiandrostenedion sulphate) levels are not influenced. Therapeutically, this leads to a decrease in growth of testosterone-sensitive prostate tumours in men, and to reduction of endometriosis foci and oestrogen-dependent uterus myomas in women. Regarding uterine myoma, maximal benefit of treatment is observed in women with anaemia (haemoglobin inferior or equal to 8 g/dl). In children suffering from CPP triptorelin treatment leads to a suppression of the secretion of gonadotropins, estradiol, and testosterone to prepubertal levels. This results in arrest or even regression of pubertal signs and an increase in adult height prediction in CPP patients.

5.2 Pharmacokinetic Properties

After intramuscular administration of Gonapeptyl Depot, the plasma concentrations of triptorelin are determined by the (slow) degradation of the poly-(d,l lactide coglycolide) polymer. The mechanism inherent to this administration form enables this slow release of triptorelin from the polymer.

After I.M. or S.C. application of a triptorelin depot-formulation (sustained-release microcapsules), a rapid increase in the concentration of triptorelin in plasma is recorded, with a maximum in the first hours. Then the triptorelin concentration declines notably within 24 hours. On day 4 the value reaches a second maximum, falling below the detection limit in a biexponential course after 44 days. After S.C. injections the triptorelin increase is more gradual and in a somewhat lower concentration than after I.M. injections. After S.C. injection, the decline in the triptorelin concentration takes longer, with values falling below the detection limit after 65 days.

During treatment over a period of 6 months and an administration every 28 days, there was no evidence of triptorelin accumulation in both modes of administration. Plasma triptorelin values decreased to approx. 100 pg/ml before the next application after I.M. or S.C. application (median values). It is to be assumed that the non-systemically available proportion of triptorelin is metabolized at the injection site, e.g. by macrophages.

In the pituitary, the systemically available triptorelin is inactivated by N-terminal cleavage via pyroglutamyl-peptidase and a neutral endopeptidase. In the liver and the kidneys, triptorelin is degraded to biologically inactive peptides and amino acids.

40 minutes after the end of an infusion of 100 ?g triptorelin (over 1 hour) 3-14% of the administered dose has already been eliminated by the kidney.

For patients with an impaired renal function, adaptation and individualization of therapy with the triptorelin depot-formulation seems to be unnecessary, on account of the subordinate significance of the renal elimination route and the broad therapeutic range of triptorelin as an active component.

Bioavailability:

Men:

The systemic bioavailability of the active component triptorelin from the intramuscular depot is 38.3% in the first 13 days. Further release is linear at 0.92% of the dose per day on average. Bioavailability after S.C. application is 69% of I.M. availability.

Women:

After 27 test days, 35.7% of the applied dose can be detected on average, with 25.5% being released in the first 13 days and further release being linear at 0.73% of the dose per day on average.

General:

Calculation of the model-depending kinetic parameters (t?, Kel, etc.) is inapplicable in presentations with a strongly protracted release of the active component.

5.3 Preclinical Safety Data

In rats, but not in mice treated over a long period of time with triptorelin, an increase in pituitary tumors has been detected. The influence of triptorelin on pituitary abnormalities in humans is unknown. The observation is considered not to be relevant to humans. Pituitary tumors in rodents in connection with other LHRH analogues have also been known to occur. Triptorelin has been shown to be embryo-/foetotoxic and to cause a delay in embryo-/foetal development as well as delay in parturition in rats. Preclinical data reveal no special hazard to humans based on repeat dose toxicity and genotoxicity studies. Single I.M. or S.C. injection of Gonapeptyl Depot or its suspension agent produced delayed foreign body reactions at the injection site. Within 8 weeks, these late reactions were nearly reversed after I.M. injection but only slightly reversed after S.C. injection. Local tolerance of Gonapeptyl Depot after I.V. injection was limited

6. Pharmaceutical Particulars 6.1 List Of Excipients

One pre-filledsyringe with powder contains:

Poly-(d,l lactide coglycolide)

Propyleneglycol octanoate decanoate

One pre-filledsyringe with one ml suspension agent contains:

Dextran 70

Polysorbate 80

Sodium chloride

Sodium hydrogen phosphate dihydrate

Sodium hydroxide

Water for injection

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product should not be mixed with other medicinal products.

6.3 Shelf Life

3 years

Reconstituted suspension: 3 minutes

6.4 Special Precautions For Storage

Store at 2°C - 8°C (in a refrigerator). Keep the container in the outer carton.

6.5 Nature And Contents Of Container

Powder: Pre-filled syringe

Solvent: Pre-filled syringe

Pre-filled syringes (borosilicate glass type I, clear) with a connector (polypropylene), black chlorobutyl rubber stopper (plunger stopper, type I) and injection needle.

Pack sizes:

1 pre-filled syringe (powder) plus

1 pre-filled syringe (solvent)

3 pre-filled syringes (powder) plus

3 pre-filled syringes (solvent)

6.6 Special Precautions For Disposal And Other Handling

GonapeptylDepot is for single use only and any unused suspension should be discarded.

1. Preparation

Instructions for the physician how to prepare the suspension.

Since successful treatment depends upon correct preparation of the suspension, the following instructions must be strictly followed.

- Take the package of Gonapeptyl Depot from the refrigerator.

- Remove the cap from the disposable syringe containing the powder. Keep upright to prevent spilling.

- Open the package with the connector without removing the connector.

- Screw the syringe containing the sustained release microparticles on the connector in the package, then remove it.

Screw the syringe containing the suspension agent tightly on the free end of the connector and ensure that it fits tightly.

2. Reconstitution of a suspension

Empty the liquid into the syringe with the powder, then shoot it back and forth into the first syringe – the first two or three times without pushing the injection rod all the way in. Repeat this about 10 times or until you have a homogeneous milky-like suspension. While preparing the suspension, you might possibly create some foam. It is important that the foam be dissolved or removed from the syringe before giving the injection.

Mixing

Mix approximately 10 times

3. Injection

- Remove the connector together with the empty syringe.

- Mount the injection needle on the syringe with the ready-to-use suspension.

- Inject subcutaneously or deep into the muscle immediately.

7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd.

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ

United Kingdom

8. Marketing Authorisation Number(S)

PL 03194/0085

9. Date Of First Authorisation/Renewal Of The Authorisation

14th May 2003

10. Date Of Revision Of The Text
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Simvador 80mg


1. Name Of The Medicinal Product

Simvastatin 80mg Tablets

Simvador 80mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 80 mg of simvastatin.

Excipients: Lactose monohydrate

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-Coated Tablet

Simvastatin 80 mg tablets, are brick red coloured, capsule shaped, biconvex, film-coated tablets, debossed with '80' on one side and '123' on the other side, containing Simvastatin 80 mg.

4. Clinical Particulars 4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening.

Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is Simvastatin 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either> 2 hours before or> 4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone orverapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. In patients taking diltiazem or amtopidine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40mg/day (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of simvastatin in pre-pubertal children is limited.

4.3 Contraindications

Hypersensitivity to simvastatin or to any of the excipients

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6)

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Simvastatin 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age

- Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), as well as gemfibrozil, ciclosporin and danazol (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlopidine with simvastatin 80 mg (see sections 4.2 and 4.5).

The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid

Physicians contemplating combined therapy with simvastatin and lipid

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastain treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to> 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods> 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone. The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

 

Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors:

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

 

Contraindicated with simvastatin

Gemfibrozil

Avoid but if necessary, do not exceed 10 mg simvastatin daily

Ciclosporin

Danazol

Other fibrates (except fenofibrate)

Do not exceed 10 mg simvastatin daily

Amiodarone

Verapamil

Do not exceed 20 mg simvastatin daily

Diltiazem

Amlopidine

Do not exceed 40 mg simvastatin daily

Fusidic acid

Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.

Grapefruit juice

Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.4).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin increases the AUC of simvastatin acid presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3

Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7

Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlopidine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin comax of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Effects of simvastatin on the pharmacokinetics of other medicinal products.

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy: Simvastatin is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.

Treatment with Simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.)

Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin should not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Simvastatin has no or negligible influence on the ability to drive and use machines.

However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Simvastatin 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simvastatin 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (

Investigations:   Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, ?-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4). Blood and lymphatic system disorders:   Rare: anaemia Nervous system disorders:   Rare: headache, paresthesia, dizziness, peripheral neuropathy Very rare: memory impairment Gastrointestinal disorders:   Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis Hepato-biliary disorders:   Rare: hepatitis/jaundice Very rare: hepatic failure Skin and subcutaneous tissue disorders:   Rare: rash, pruritus, alopecia Musculoskeletal, connective tissue and bone disorders:   Rare: myopathy*, rhabdomyolysis (see section 4.4), myalgia, muscle cramps *In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).   General disorders and administration site conditions:   Rare: asthenia An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.  

Psychiatric disorders:

Very rare: insomnia

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitor

ATC-Code: C10A A01

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of VLDL cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Simvastatin. In addition, Simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with Simvastatin were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with Simvastatin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Simvastatin 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups Simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level> 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the betahydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin.

Concomitant food intake does not affect the absorption. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is> 95 %.

Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 %


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Simvador 40mg


1. Name Of The Medicinal Product

Simvastatin 40mg Tablets

Simvador 40mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 40 mg of simvastatin.

Excipients: Lactose monohydrate

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-Coated Tablet

Simvastatin 40 mg tablets, are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed with '40' on one side and plain on the other side, containing Simvastatin 40 mg.

4. Clinical Particulars 4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening.

Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is Simvastatin 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either> 2 hours before or> 4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone orverapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. In patients taking diltiazem or amtopidine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40mg/day (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of simvastatin in pre-pubertal children is limited.

4.3 Contraindications

Hypersensitivity to simvastatin or to any of the excipients

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6)

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Simvastatin 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age

- Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), as well as gemfibrozil, ciclosporin and danazol (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlopidine with simvastatin 80 mg (see sections 4.2 and 4.5).

The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid

Physicians contemplating combined therapy with simvastatin and lipid

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastain treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to> 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods> 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone. The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

 

Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors:

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

 

Contraindicated with simvastatin

Gemfibrozil

Avoid but if necessary, do not exceed 10 mg simvastatin daily

Ciclosporin

Danazol

Other fibrates (except fenofibrate)

Do not exceed 10 mg simvastatin daily

Amiodarone

Verapamil

Do not exceed 20 mg simvastatin daily

Diltiazem

Amlopidine

Do not exceed 40 mg simvastatin daily

Fusidic acid

Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.

Grapefruit juice

Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.4).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin increases the AUC of simvastatin acid presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3

Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7

Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlopidine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin comax of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Effects of simvastatin on the pharmacokinetics of other medicinal products.

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy: Simvastatin is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.

Treatment with Simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.)

Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin should not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Simvastatin has no or negligible influence on the ability to drive and use machines.

However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Simvastatin 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simvastatin 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (

Investigations:   Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, ?-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4). Blood and lymphatic system disorders:   Rare: anaemia Nervous system disorders:   Rare: headache, paresthesia, dizziness, peripheral neuropathy Very rare: memory impairment Gastrointestinal disorders:   Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis Hepato-biliary disorders:   Rare: hepatitis/jaundice Very rare: hepatic failure Skin and subcutaneous tissue disorders:   Rare: rash, pruritus, alopecia Musculoskeletal, connective tissue and bone disorders:   Rare: myopathy*, rhabdomyolysis (see section 4.4), myalgia, muscle cramps *In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).   General disorders and administration site conditions:   Rare: asthenia An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.  

Psychiatric disorders:

Very rare: insomnia

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitor

ATC-Code: C10A A01

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of VLDL cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Simvastatin. In addition, Simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with Simvastatin were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with Simvastatin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Simvastatin 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups Simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level> 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the betahydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin.

Concomitant food intake does not affect the absorption. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is> 95 %.

Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of


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Zocor 10mg, 20mg, 40mg and 80mg film-coated tablets


1. Name Of The Medicinal Product

Zocor®

Zocor®* 20 mg, film-coated tablets.

Zocor ®*40 mg, film-coated tablets.

Zocor ®*80 mg, film-coated tablets.

* Intensive monitoring is requested only when used in children and adolescents (10-17 years of age), in line with the recently licensed paediatric dosing recommendation.

2. Qualitative And Quantitative Composition

Each tablet contains 10 mg of simvastatin.

Each tablet contains 20 mg of simvastatin.

Each tablet contains 40 mg of simvastatin.

Each tablet contains 80 mg of simvastatin.

Excipients (s):

For a full list of excipients, see section 6.1.

Each 10 mg tablet contains 70.7 mg of lactose monohydrate.

Each 20 mg tablet contains 141.5 mg of lactose monohydrate.

Each 40 mg tablet contains 283.0 mg of lactose monohydrate.

Each 80 mg tablet contains 565.8 mg of lactose monohydrate.

3. Pharmaceutical Form

Film-coated tablet.

The peach-coloured, oval-shaped tablets marked 'MSD 735' contain 10 mg simvastatin. The tan-coloured, oval-shaped tablets marked 'MSD 740' contain 20 mg simvastatin. The brick-red coloured, oval-shaped tablets marked 'MSD 749' contain 40 mg simvastatin. The brick-red coloured, capsule-shaped tablets marked '543' on one side and '80' on the other contain 80 mg simvastatin.

4. Clinical Particulars 4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with 'Zocor'. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is 'Zocor' 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. 'Zocor' should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of 'Zocor' is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

'Zocor' is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant.

In patients taking ciclosporin, danazol, gemfibrozil, or other fibrates (except fenofibrate) concomitantly with 'Zocor', the dose of 'Zocor' should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly with 'Zocor', the dose of 'Zocor' should not exceed 20 mg/day. In patients taking diltiazem or amlopidine concomitantly with Zocor, the dose of Zocor should not exceed 40 mg/day (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency.

In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of Zocor in pre-pubertal children is limited.

4.3 Contraindications

• Hypersensitivity to simvastatin or to any of the excipients

• Active liver disease or unexplained persistent elevations of serum transaminases

• Pregnancy and lactation (see section 4.6)

• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Zocor 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Zocor 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age

• Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), nefazodone), as well as gemfibrozil, ciclosporin and danazol (see section 4.2)

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlopidine with simvastatin 80 mg (see sections 4.2 and 4.5).. The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol, or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher then 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (

Physicians contemplating combined therapy with simvastatin and lipid-modifying doses (

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses (

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastain treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins ,including simvastatin especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased

Risk of Myopathy/Rhabdomyolysis

 

Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors:

Itraconazole

Ketoconazole

Posaconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors (e.g.nelfinavir)

Nefazodone

 

Contraindicated with simvastatin

Gemfibrozil

Avoid but if necessary, do not exceed 10 mg simvastatin daily

Ciclosporin

Danazol

Other fibrates (except fenofibrate)

Do not exceed 10 mg simvastatin daily

Amiodarone

Verapamil

Do not exceed 20 mg simvastatin daily

Diltiazem

Amlopidine

Do not exceed 40 mg simvastatin daily

Fusidic acid

Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.

Grapefruit juice

Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving inhibitors of CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g.nelfinavir), and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.4).

Fluconazole

Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4.).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlopidine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (max of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Colchicine

There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin, in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin

Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.

Effects of simvastatin on the pharmacokinetics of other medicinal products

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy

'Zocor' is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to 'Zocor' or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking 'Zocor' or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with 'Zocor' may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, 'Zocor' must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with 'Zocor' must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3. and 5.3)

Lactation

It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking 'Zocor' should not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

'Zocor' has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of 'Zocor' (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with 'Zocor' 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with 'Zocor' 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with 'Zocor' 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with 'Zocor' 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (

Blood and lymphatic system disorders:

Rare: anaemia

Psychiatric disorders:

Very rare: insomnia

Not known: depression

Nervous system disorders:

Rare: headache, paresthesia, dizziness, peripheral neuropathy

Very rare: memory impairment

Respiratory,thoracic and mediastinal disorders:

Not known: interstitial lung disease (see section 4.4)

Gastrointestinal disorders:

Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis

Hepatobiliary disorders:

Rare: hepatitis/jaundice

Very rare: hepatic failure

Skin and subcutaneous tissue disorders:

Rare: rash, pruritus, alopecia

Musculoskeletal and connective tissue disorders:

Rare: myopathy* (including myositis), rhabdomyolysis with ot without acute renal failure (see section 4.4), myalgia, muscle cramps

*In a clinical trial, myopathy occurred commonly in patients treated with Zocor 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).

Reproductive system and breast disorders:

Not known: erectile dysfunction

General disorders and administration site conditions:

Rare: asthenia

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Investigations:

Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, ?-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).

The following additional adverse events have been reported with some statins:

• sleep disturbances, including nightmares

• memory loss

• sexual dysfunction.

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with 'Zocor' was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitor

ATC-Code: C10A A01

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

'Zocor' has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of 'Zocor' may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with 'Zocor'. In addition, 'Zocor' moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with 'Zocor' were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with 'Zocor' 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with 'Zocor' 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. 'Zocor' also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). 'Zocor' reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. 'Zocor' reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, 'Zocor' reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with 'Zocor' on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either 'Zocor' 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. 'Zocor' reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). 'Zocor' also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, 'Zocor' significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Zocor 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; 'Zocor' 20 mg (n = 1553; 25.7 %) vs. 'Zoco'r 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on 'Zocor' 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level > 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

'Zoco'r significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Zocor 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8-week intervals), 'Zocor' decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of Zocor on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption.

The pharmacokinetic


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Simvastatin 20mg


1. Name Of The Medicinal Product

Simvastatin 20 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 20 mg simvastatin.

Excipient: Lactose monohydrate

One film-coated tablet contains 140 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Light pink, round and biconvex film-coated tablets with the inscription “A” debossed on one side and “02” on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (such as exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL-apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80 mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see sections 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue with this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDC-C (more than 45%) may be started at 20-40-mg/ day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended simvastatin dose is 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL-apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant treatment

Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant.

In patients taking cyclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. (See sections 4.4 and 4.5). In patients taking diltiazem or amlodipine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40 mg/day (see sections 4.4 & 4.5).

Dosage in renal insufficiency

No modification of dosages should be necessary in patients with moderate renal insufficiency.

In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), doses above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of simvastatin in pre-pubertal children is limited.

4.3 Contraindications

• Hypersensitivity to the simvastatin or to any of the excipients

• Active liver disease or unexplained persistent elevations of serum transaminases

• Pregnancy and lactation (see section 4.6)

• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, fluconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.31% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0 % compared with 0.02 % for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 % (see sections 4.8 and 5.1).

Creatine kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age > 65 years)

• Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, fluconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV-protease inhibitors [e.g. nelfinavir], nefazodone), as well as gemfibrozil, cyclosporin and danazol (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlodipine with simvastatin 80 mg (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, fluconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, fluconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: cyclosporin, verapamil, diltiazem (see sections 4.2 and 4.5).

Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporin, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), cyclosporin or danazol should be carefully weighed against the potential risks of these combinations. (see sections 4.2 and 4.5)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to overweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (

Physicians contemplating combined therapy with simvastatin and lipid-modifying doses (

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses (

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastatin treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The medicinal product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited 3 controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged <18 years, efficacy and safety have not been studied for treatment periods >48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

 

Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors:

Itraconazole

Ketoconazole

Posaconazole, fluconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors (e.g. nelfinavir)

Nefazodone

 

 

Contraindicated with simvastatin

Gemfibrozil

Avoid but if necessary, do not exceed 10 mg simvastatin daily

Cyclosporin

Danazol

Other fibrates (except fenofibrate)

Do not exceed 10 mg simvastatin daily

Amiodarone

Verapamil

Do not exceed 20 mg simvastatin daily

Diltiazem

Amlodipine

Do not exceed 40mg simvastatin daily

Fusidic acid

Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.

Grapefruit juice

Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving inhibitors of CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV-protease inhibitors and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, HIV-protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: cyclosporin, verapamil and diltiazem (see sections 4.2 and 4.4).

Cyclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporin. Although the mechanism is not fully understood, cyclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase inAUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (max of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P4503A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Colchicine

There have been reports of myopathy with the concomitant administration of colchicine and simvastatin, however the data are limited.

Rifampicin

Because rifampicin is an inducer of P450 3A4, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) concomitantly with simvastatin should have their plasma cholesterol levels monitored. Appropriate adjustment of simvastatin dosage may be warranted to ensure a satisfactory reduction in lipid levels. In a pharmacokinetic study of normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.

Effects of simvastatin on the pharmacokinetics of other medicinal products

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy

Simvastatin is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (see sections 4.3 and 5.3).

Lactation

It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin must not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Simvastatin has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including Heart Protection Study (HPS) and Scandinavian Simvastatin Survival Study (4S) with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with simvastatin 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with simvastatin 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequency of the adverse events are ranked according to the following:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000),

Not known (cannot be estimated from the available data)

Investigations:

Rare: increases in serum transaminases (alanine-aminotransferase, aspartate aminotransferase, ?Hepatic effects), elevated alkaline phosphatase, increase in serum CK levels (see section 4.4).

Blood and lymphatic system disorders:

Rare: anaemia

Nervous system disorders:

Rare: headache, paraesthesia, dizziness, peripheral neuropathy

Uncommon: sleep disorders including insomnia, nightmares, depression, memory loss

Very rare: memory impairment

Respiratory, Thoracic and Mediastinal disorder:

Very rare: interstitial lung disease.

Gastrointestinal disorders:

Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis

Skin and subcutaneous tissue disorders:

Rare: rash, pruritus, alopecia

Musculoskeletal, connective tissue and bone disorders:

Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps

* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0 % vs 0.02 %, respectively).

Reproductive System disorders:

Uncommon: sexual dysfunction

General disorders and administration site conditions:

Rare: asthenia

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, (ESR) increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Hepato-biliary disorders:

Rare: hepatitis/jaundice

Very rare: hepatic failure

Psychiatric disorders:

Very rare: insomnia

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n=175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1).

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA-reductase inhibitor

ATC code: C10A A01

After oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl-CoA-reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High risk of coronary heart disease (CHD) or existing coronary heart disease

In the Heart Protection Study (HPS), the effects of therapy with simvastatin were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with simvastatin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either simvastatin 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; simvastatin 20 mg (n = 1553; 25.7 %) vs. simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary hypercholesterolaemia and combined hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8-week intervals), simvastatin decreased the mean LDL-C by 36.8% (placebo: 1.1% increase from baseline), Apo B by 32.4% (placebo: 0.5%), and median TG levels by 7.9% (placebo: 3.2%) and increased mean HDL-C levels by 8.3% (placebo: 3.6%). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA-reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is > 95%.

Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal


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Chorionic Gonadotropin


Pronunciation: KORE-ee-ON-ik goe-NAD-oh-troe-pin
Generic Name: Chorionic Gonadotropin
Brand Name: Examples include Novarel and Pregnyl
Chorionic Gonadotropin is used for:

Treating fertility problems in certain women who have not gone through menopause. Treating certain testicular development problems and stimulating the development of secondary sexual characteristics in certain patients. It is also used to treat boys 4 to 9 years old who have testicles that have not moved into the scrotum.

Chorionic Gonadotropin is a hormone. Human chorionic gonadotropin (HCG) stimulates cells in the testicles to produce androgens and in the ovaries to produce progesterone. Androgens cause the development of male secondary sexual characteristics (eg, hair growth, deepening voice) and may cause the testicles to drop. HCG acts like luteinizing hormone (LH) by stimulating ovulation (release of an egg) in women.

Do NOT use Chorionic Gonadotropin if: you are allergic to any ingredient in Chorionic Gonadotropin you have androgen (male sex hormone)-dependent tumors, prostate cancer, an active blood clot, brain lesions, unexplained uterine or genital bleeding, an enlarged ovary or ovarian cysts, or an enlargement or tumor of the pituitary gland you are experiencing abnormally early puberty you are pregnant

Contact your doctor or health care provider right away if any of these apply to you.

Before using Chorionic Gonadotropin:

Some medical conditions may interact with Chorionic Gonadotropin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have asthma, uterine fibroids, heart or kidney problems, migraine headaches, polycystic ovarian syndrome, or epilepsy

Some MEDICINES MAY INTERACT with Chorionic Gonadotropin. However, no specific interactions with Chorionic Gonadotropin are known at this time.

Ask your health care provider if Chorionic Gonadotropin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Chorionic Gonadotropin:

Use Chorionic Gonadotropin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Chorionic Gonadotropin is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Chorionic Gonadotropin at home, carefully follow the injection procedures taught to you by your health care provider. If Chorionic Gonadotropin contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it. Using the technique described to you by your doctor, add the diluent to the vial that contains the medicine. Mix the solution by gently rotating the vial. DO NOT SHAKE. The solution should be clear and free of particles. Wipe the rubber stopper of the vial with an alcohol swab. Insert the needle straight through the center circle of the rubber stopper. Draw up the solution for injection. After drawing up the solution, switch needles. Be sure all air bubbles are tapped out of the syringe. Wipe the appropriate injection site (usually the upper thigh or buttocks) with an alcohol swab, then insert the syringe. To be sure that the needle is not in a vein, pull back on the plunger of the syringe while holding the syringe in place. If the syringe begins to fill with blood, the needle is in a vein. If this happens, remove the needle from the skin, throw the syringe away, and start the procedure again using new materials (drugs, syringes, etc.). After giving the injection, cover the injection site with a small bandage if necessary. Keep this product, as well as syringes and needles, out of the reach of children. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal. If you miss a dose of Chorionic Gonadotropin, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Chorionic Gonadotropin.

Important safety information: Women need to have a thorough gynecological exam before beginning treatment with Chorionic Gonadotropin. Men need to have a complete medical and hormone evaluation before starting therapy with Chorionic Gonadotropin. Chorionic Gonadotropin may increase your chance of multiple births (eg, twins). Talk with your doctor to discuss your chances of multiple births. Use of Chorionic Gonadotropin can increase your risk of serious blood clots and ruptured ovarian cysts. Discuss the risk of these effects with your doctor. Ovarian hyperstimulation syndrome (OHSS) is a severe side effect that may occur in some women who use Chorionic Gonadotropin. Contact your doctor right away if you develop severe stomach pain or bloating; nausea, vomiting, or diarrhea; sudden unexplained weight gain; shortness of breath; or decreased urination. Chorionic Gonadotropin may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Chorionic Gonadotropin. Lab tests, including hormone levels, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments. Chorionic Gonadotropin is not recommended for use in CHILDREN younger than 4 years; safety and effectiveness in these children have not been confirmed. Chorionic Gonadotropin may have benzyl alcohol in it. Do not use it in NEWBORNS or INFANTS. It may cause serious and sometimes fatal nervous system problems and other side effects. PREGNANCY and BREAST-FEEDING: Do not use Chorionic Gonadotropin if you are pregnant. It may cause harm to the fetus. If you think you may be pregnant, contact your doctor right away. It is not known if Chorionic Gonadotropin is found in breast milk. If you are or will be breast-feeding while you are using Chorionic Gonadotropin, check with your doctor. Discuss any possible risks to your baby. Possible side effects of Chorionic Gonadotropin:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Fatigue; headache; irritability; nausea; pain, swelling, bruising, or redness at the injection site; restlessness; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal breast development; bloating or swelling in the stomach or pelvic area; breast tenderness; depression; infrequent urination; persistent or severe nausea, vomiting, or diarrhea; stomach or pelvic pain; sudden shortness of breath; swelling of the hands, feet, or legs; symptoms of a serious blood clot (eg, calf or leg pain, swelling, redness, or tenderness; chest, jaw, or left arm pain; confusion; fainting; numbness of an arm or leg; one-sided weakness; slurred speech; sudden, severe headache; vision changes); unusual early onset of puberty; weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Chorionic Gonadotropin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Chorionic Gonadotropin:

Before mixing, store Chorionic Gonadotropin at room temperature between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Different products have different storage instructions after mixing. Check with your doctor or pharmacist about how to store Chorionic Gonadotropin and how long it is good for after mixing. Keep Chorionic Gonadotropin out of the reach of children and away from pets.

General information: If you have any questions about Chorionic Gonadotropin, please talk with your doctor, pharmacist, or other health care provider. Chorionic Gonadotropin is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Chorionic Gonadotropin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Chorionic Gonadotropin resources Chorionic Gonadotropin Side Effects (in more detail) Chorionic Gonadotropin Use in Pregnancy & Breastfeeding Chorionic Gonadotropin Drug Interactions Chorionic Gonadotropin Support Group 0 Reviews for Chorionic Gonadotropin - Add your own review/rating Chorex Advanced Consumer (Micromedex) - Includes Dosage Information Hcg Consumer Overview Novarel Prescribing Information (FDA) Ovidrel Prescribing Information (FDA) Ovidrel Monograph (AHFS DI) Pregnyl Prescribing Information (FDA) Compare Chorionic Gonadotropin with other medications Female Infertility Hypogonadism, Male Ovulation Induction Prepubertal Cryptorchidism
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Welchol



Dosage Form: tablet, film coated, oral suspension
FULL PRESCRIBING INFORMATION Indications and Usage for Welchol Primary Hyperlipidemia

Welchol is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

 Welchol is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
a. LDL-C remains ? 190 mg/dL or
b. LDL-C remains ? 160 mg/dL and

 there is a positive family history of premature cardiovascular disease or  two or more other CVD risk factors are present in the pediatric patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate [See Clinical Studies (14.1)].

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are < 100 mg/dL. An LDL-C goal of < 70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is > 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C.

Type 2 Diabetes Mellitus

Welchol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [See Clinical Studies (14.2)].

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted [See Indications and Usage (1.1) and Warnings and Precautions (5.2)].

Important Limitations of Use Welchol should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Welchol has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones. Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.  Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls. Welchol Dosage and Administration Primary Hyperlipidemia

The recommended dose of Welchol Tablets in adults, whether used as monotherapy or in combination with a statin, is 6 tablets once daily or 3 tablets twice daily. Welchol Tablets should be taken with a meal and liquid.

 The recommended dose of Welchol for Oral Suspension, in adults and children 10 to 17 years of age, is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ? to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Due to tablet size, it is recommended that any patient who has difficulty swallowing tablets use Welchol for Oral Suspension.

Welchol can be dosed at the same time as a statin or the two drugs can be dosed apart [See Clinical Studies (14.1)].

After initiation of Welchol, lipid levels should be analyzed within 4 to 6 weeks.

Type 2 Diabetes Mellitus

The recommended dose of Welchol Tablets is 6 tablets once daily or 3 tablets twice daily. Welchol should be taken with a meal and liquid.

 The recommended dose of Welchol for Oral Suspension is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ? to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form.

Dosage Forms and Strengths Tablets: 625 mg tablets are off-white, oval, film-coated and imprinted with "Sankyo" and "C01" on one side. Oral Suspension: a white to pale yellow powder containing yellow granules packaged in single-dose packets: 3.75 gram single-dose packet, 1.875 gram single-dose packet. Contraindications

Welchol is contraindicated in patients with

A history of bowel obstruction [See Warnings and Precautions (5.4)] Serum TG concentrations >500 mg/dL [See Warnings and Precautions (5.2)] A history of hypertriglyceridemia-induced pancreatitis [See Warnings and Precautions (5.2)] Warnings and Precautions General

The effect of Welchol on cardiovascular morbidity and mortality has not been determined.

Serum Triglycerides (TG)

Welchol, like other bile acid sequestrants, can increase serum TG concentrations.

Welchol had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [See Adverse Reactions (6.1) and Clinical Studies (14.1)].

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Welchol was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when Welchol was used in combination with insulin (median increase 22% compared to placebo in combination with insulin) [See Adverse Reactions (6.1) and Clinical Studies (14.2)]. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of Welchol on LDL-C levels may be attenuated by Welchol’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the Welchol clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. In addition, the use of Welchol is contraindicated in patients with TG levels >500 mg/dL [See Contraindications (4)]. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Welchol and periodically thereafter. Welchol should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis [See Adverse Reactions (6.1)].

Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions

Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of Welchol on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.

Gastrointestinal Disorders

 Because of its constipating effects, Welchol is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

Drug Interactions

Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug [See Drug Interactions (7) and Clinical Pharmacology (12.3)].

Phenylketonurics

 Welchol for Oral Suspension contains 24 mg phenylalanine per 1.875 gram packet and 48 mg phenylalanine per 3.75 gram packet [See Description (11)].

Adverse Reactions Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice.

In the lipid-lowering trials, 807 adult patients received at least one dose of Welchol (total exposure 199 patient-years). In the type 2 diabetes trials, 566 patients received at least one dose of Welchol (total exposure 209 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving Welchol vs. 64% of patients receiving placebo reported an adverse reaction. In clinical trials of type 2 diabetes, 60% of patients receiving Welchol vs. 56% of patients receiving placebo reported an adverse reaction.

Primary Hyperlipidemia: In 7 double-blind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with Welchol 1.5 g/day to 4.5 g/day from 4 to 24 weeks.

Table 1 Placebo-Controlled Clinical Studies of Welchol for Primary Hyperlipidemia: Adverse Reactions Reported in ? 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Welchol
N = 807 Placebo
N = 258 Constipation 89 (11.0) 18 (7.0) Dyspepsia 67 (8.3) 9 (3.5) Nausea 34 (4.2) 10 (3.9) Accidental injury 30 (3.7) 7 (2.7) Asthenia 29 (3.6) 5 (1.9) Pharyngitis 26 (3.2) 5 (1.9) Flu syndrome 26 (3.2) 8 (3.1) Rhinitis 26 (3.2) 8 (3.1) Myalgia 17 (2.1) 1 (0.4)

 Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with Welchol tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies (14.1)].

 Table 2 Placebo-Controlled Clinical Study of Welchol for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ?2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality    Number of Patients (%)      Welchol  Placebo    N = 129  N = 65  Nasopharyngitis  8 (6.2)  3 (4.6)  Headache  5 (3.9)  2 (3.1)  Fatigue  5 (3.9)  1 (1.5)  Creatine Phosphokinase Increase  3 (2.3)  0 (0.0)  Rhinitis  3 (2.3)  0 (0.0)  Vomiting  3 (2.3)  1 (1.5)

 The reported adverse reactions during the additional 18-week open-label treatment period with Welchol 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%) [See Clinical Studies (14.1)].

Type 2 Diabetes Mellitus: The safety of Welchol in patients with type 2 diabetes mellitus was evaluated in 4 double-blind, 12-26 week, placebo-controlled clinical trials. These trials involved 1128 patients (566 patients on Welchol; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the pivotal trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received Welchol 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents.

A total of 6.7% of Welchol-treated patients and 3.2% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of Welchol, which may represent a hypersensitivity reaction to Welchol.

Table 3 Placebo-Controlled Clinical Studies of Welchol Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ? 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Welchol
N = 566 Placebo
N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea 17 (3.0) 8 (1.4) Hypertension 16 (2.8) 9 (1.6)

Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2)]. In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [See Clinical Studies (14.1)].

Treatment-emergent fasting TG concentrations ?500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ?1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with Welchol and 2.3% in patients treated with placebo. No Welchol treated patients developed severe hypoglycemia.

Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of Welchol. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions with concomitant Welchol administration include:

Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to Welchol. Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during Welchol initiation then periodically thereafter. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to Welchol [See Drug Interactions (7)].

Gastrointestinal Adverse Reactions
Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia (tablet and oral suspension formulations) or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases.

Laboratory Abnormalities
Hypertriglyceridemia

Drug Interactions

Table 4 lists the drugs that have been tested in in vitro binding or in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug.

Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports a Should be administered at least 4 hours prior to Welchol b No significant alteration of warfarin drug levels with warfarin and Welchol coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)] c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Welchol. Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with Welchol phenytoina, warfarinb Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

In an in vivo drug interaction study, Welchol and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of Welchol and warfarin coadministration on INR. In postmarketing reports, concomitant use of Welchol and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating Welchol and frequently enough during early Welchol therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin. [See Post-marketing Experience (6.2)]

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed.

In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Nursing Mothers

Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

Pediatric Use

 The safety and effectiveness of Welchol as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH [See Clinical Studies (14.1)]. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [See Adverse Reactions (6.1)].

 Due to tablet size, Welchol for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Welchol is administered to children 10 to 17 years of age.

 Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls.

Geriatric Use

Primary Hyperlipidemia:  Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ?65 years old, and 58 (4%) were ?75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 249 (22%) were ?65 years old, and 12 (1%) were ?75 years old. In these trials, Welchol 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

No special considerations or dosage adjustments are recommended when Welchol is administered to patients with hepatic impairment.

Renal Impairment

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl?50 mL/min (n=1075).

Overdosage

Doses of Welchol in excess of 4.5 g/day have not been tested. Because Welchol is not absorbed, the risk of systemic toxicity is low. However, excessive doses of Welchol may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

Welchol Description

Welchol (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule.

Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:

wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ? 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.

Welchol Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink.

Welchol for Oral Suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in single-dose packets containing either 1.875 gram or 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate.

PHENYLKETONURICS: Welchol for Oral Suspension contains 24 mg phenylalanine per 1.875 gram dose and 48 mg phenylalanine per 3.75 gram dose.

Welchol - Clinical Pharmacology Mechanism of Action

Primary Hyperlipidemia:  Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-?-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

Type 2 Diabetes Mellitus:  The mechanism by which Welchol improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of Welchol was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to Welchol, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

Pharmacokinetics

Absorption:  Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution:  Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism:  Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion:  In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.

Drug Interactions:  Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of Welchol with these drugs is unlikely. Welchol was found to have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, pioglitazone, and warfarin. The results of additional in vivo drug interactions of Welchol are presented in Table 5.

Drug interactions between Welchol and other commonly co-administered drugs in patients with type 2 diabetes (including rosiglitazone maleate, glimepiride, glipizide, sitagliptin phosphate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sustained-release formulations of anti-diabetic and anti-hypertensive drugs, and aspirin) have not been evaluated.

Table 5 Mean Change in Drug Exposure (AUC0-? and Cmax) when Administered with Welchol (3.75 g)a a With verapamil, the dose of Welchol was 4.5 g b Should be administered at least 4 hours prior to Welchol. [See Drug Interactions (7)] * Oral contraceptive containing norethindrone and ethinyl estradiol. N/A — Not Available
Drug
Dose
Co-administered
1 hr prior to
Welchol
4 hr prior to
Welchol AUC0-? Cmax AUC0-? Cmax AUC0-? Cmax Verapamil sustained-release 240 mg -31% -11% N/A N/A N/A N/A Glyburideb 3 mg -32% -47% -20% -15% -7% 4% Levothyroxineb 600 µg -22% -33% 6% -2% 1% 8% Norethindrone*b 1 mg -1% -20% 5% -3% 6% 7% Ethinyl Estradiol*b 0.035 mg -24% -24% -18% -1% -12% 0% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:  A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).

Mutagenesis:  Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.

Impairment of Fertility:  Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies
      Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

Clinical Studies Primary Hyperlipidemia

Welchol reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia.

Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to Welchol was achieved within 2 weeks and was maintained during long-term therapy.

Monotherapy:  In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), Welchol was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Welchol at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both Welchol doses but the changes were not statistically different from placebo.

Table 6 Response to Welchol Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline * p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline. a Median % change from baseline. Grams/Day N TC LDL-C Apo B HDL-Ca Non-HDL-C TGa Placebo 88 +1 0 0 -1 +1 +5 3.8 g (6 tablets) 95 -7* -15* -12* +3* -10* +10 4.5 g (7 tablets) 94 -10* -18* -12* +3 -13* +9

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), Welchol 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.

Combination Therapy: Co-administration of Welchol and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin stu


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Tegretol


Generic Name: carbamazepine
Dosage Form: chewable tablets, tablets, extended release tablets and oral suspension
Tegretol

Tegretol®

carbamazepine USP

Chewable Tablets of 100 mg - red-speckled, pink

Tablets of 200 mg – pink

Suspension of 100 mg/5 mL

Tegretol®-XR

(carbamazepine extended-release tablets)

100 mg, 200 mg, 400 mg

Rx only

Prescribing Information

WARNINGS

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH Tegretol. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH Tegretol. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH Tegretol UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS).

APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF Tegretol. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.

ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF Tegretol, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.

BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON Tegretol ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.

Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

DESCRIPTION

Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).

CLINICAL PHARMACOLOGY

In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established.

Pharmacokinetics

In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.

The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

INDICATIONS AND USAGE Epilepsy

Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
Generalized tonic-clonic seizures (grand mal).
Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia

Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.

Beneficial results have also been reported in glossopharyngeal neuralgia.

This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

CONTRAINDICATIONS

Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

WARNINGS Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients
Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

General

Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome.

To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

PRECAUTIONS General

Before initiating therapy, a detailed history and physical examination should be made.

Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol.

AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.

Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).

Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.

Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine.

In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).

Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).

Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

Information for Patients

Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers

Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS).

Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products.

Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with Tegretol administered alone.

Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Drug Interactions

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Tegretol Plasma Levels

CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:
      cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
      fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
      omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
      azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
      ticlopidine, grapefruit juice, protease inhibitors, valproate*.

CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:
      cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
      methsuximide, theophylline, aminophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

*increased levels of the active 10,11-epoxide

†decreased levels of carbamazepine and increased levels of the 10,11-epoxide

Effect of Tegretol on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of co-medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following:

      acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
      citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
      dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
      levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
      contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors,
      risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,
      imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.

Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.

Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).

Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy

Pregnancy Category D (see WARNINGS).

Labor and Delivery

The effect of Tegretol on human labor and delivery is unknown.

Nursing Mothers

Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

Geriatric Use

No systematic studies in geriatric patients have been conducted.

ADVERSE REACTIONS

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported.

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients).

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

DRUG ABUSE AND DEPENDENCE

No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans.

OVERDOSAGE

Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.

Elimination of the Drug: Induction of vomiting.

Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.

Measures to Reduce Absorption: Activated charcoal, laxatives.

Measures to Accelerate Elimination: Forced diuresis.

Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Convulsions: Diazepam or barbiturates.

Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.

Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.


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Epitol


carbamazepine
Dosage Form: tablet
Epitol®
CARBAMAZEPINE TABLETS USP, 200 mg
0090
Rx only

Prescribing Information

WARNINGS

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, Laboratory Tests).

APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.

ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.

BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.

Before prescribing Epitol®, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

Epitol Description

Epitol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as tablets of 200 mg. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

C15H12N2O M.W. 236.27

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone.

Epitol 200 mg tablets contain the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, ethylcellulose, glycerin, lactose monohydrate, magnesium stearate, and sodium starch glycolate.

Epitol 200 mg tablets meet USP Dissolution Test 3.

Epitol - Clinical Pharmacology

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Epitol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Epitol has not been established.

Pharmacokinetics

In clinical studies, carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the extended-release tablet slightly slower, than the conventional tablet. The bioavailability of the extended-release tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, carbamazepine suspension affords steady-state plasma levels comparable to carbamazepine tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, carbamazepine extended-release tablets afford steady-state plasma levels comparable to conventional carbamazepine tablets given q.i.d., when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of carbamazepine are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional carbamazepine tablets, and 3 to 12 hours after administration of carbamazepine extended-release tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from carbamazepine. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine.

The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and carbamazepine dose in children. Epitol is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

Indications and Usage for Epitol Epilepsy

Epitol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. Generalized tonic-clonic seizures (grand mal). Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by carbamazepine (see PRECAUTIONS, General). Trigeminal Neuralgia

Epitol is indicated in the treatment of the pain associated with true trigeminal neuralgia.

Beneficial results have also been reported in glossopharyngeal neuralgia.

This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

Contraindications

Epitol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Epitol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

Warnings Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in < 1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating carbamazepine therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Carbamazepine should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with carbamazepine will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Epitol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Epitol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

General

Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

The use of carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, Epitol should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Epitol use. These symptoms may represent a neonatal withdrawal syndrome.

To provide information regarding the effects of in utero exposure to Epitol, physicians are advised to recommend that pregnant patients taking Epitol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Precautions General

Before initiating therapy, a detailed history and physical examination should be made.

Epitol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients carbamazepine has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with carbamazepine.

AV heart block, including second and third degree block, have been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.

Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Otherand PRECAUTIONS, Information for Patients).

Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.

Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine.

In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine.

Information for Patients

Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Epitol.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients, their caregivers, and families should be counseled that AEDs, including Epitol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that serious skin reactions have been reported in association with Epitol. In the event a skin reaction should occur while taking Epitol, patients should consult with their physician immediately (see WARNINGS).

Carbamazepine may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products.

Caution should be exercised if alcohol is taken in combination with carbamazepine therapy, due to a possible additive sedative effect.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution 'HLA-B*1502 typing' is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.

Hyponatremia has been reported in association with carbamazepine use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Drug Interactions

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Carbamazepine Plasma Levels

CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:

cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate*.

CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:

cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

* increased levels of the active 10,11-epoxide 

† decreased levels of carbamazepine and increased levels of the 10,11-epoxide

Effect of Carbamazepine on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Carbamazepine is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of comedications mainly metabolized by 3A4 through induction of their metabolism. Carbamazepine causes, or would be expected to cause, decreased levels of the following:

acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine), citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.

Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia. Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium). Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of carbamazepine with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy Teratogenic Effects Pregnancy category D

(See WARNINGS.)

Labor and Delivery

The effect of carbamazepine on human labor and delivery is unknown.

Nursing Mothers

Carbamazepine and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for carbamazepine and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2 to 5 mg daily for carbamazepine and 1 to 2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Substantial evidence of carbamazepine’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4 to 12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

Geriatric Use

No systematic studies in geriatric patients have been conducted.

Adverse Reactions

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXEDWARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXEDWARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving carbamazepine orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with carbamazepine use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported.

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients).

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

Drug Abuse and Dependence

No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Overdosage Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (> 60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigatin


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Luvinsta XL Prolonged-Release Tablets


1. Name Of The Medicinal Product

Luvinsta XL 80 mg Prolonged-Release Tablets

Fluvastatin

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains 80 mg fluvastatin (as fluvastatin sodium).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablet

Yellow, round, biconvex tablet.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of primary hypercholesterolaemia and mixed hyperlipidaemia (Fredrickson Types IIa and IIb) as an adjunct to diet when response to diet and other non-pharmacological treatments is inadequate.

Luvinsta is also indicated in patients with coronary heart disease for the secondary prevention of coronary events (cardiac death, non-fatal myocardial infarction and coronary revascularisation) after percutaneous coronary intervention, see Section 5.1.

4.2 Posology And Method Of Administration

Prior to initiating Luvinsta, secondary causes of hypercholesterolaemia should be excluded, and the patient placed on a standard cholesterol-lowering diet. Dietary therapy should be continued during treatment.

Treatment of primary hypercholesterolaemia and mixed hyperlipidaemia (Fredrickson Types IIa and IIb)

Luvinsta XL 80 mg Prolonged-Release Tablets are not suitable for treatment initiation, for this purpose alternative pharmaceutical forms and tablet strengths (20 mg and 40 mg) are appropriate.

The recommended starting dose is 20 mg to 40 mg once daily as immediate release capsule. A dose of 20 mg once daily may be adequate in mild cases. Most patients will require a dose of 20 mg to 40 mg once daily but the dose may be increased to 80 mg daily (1 prolonged-release tablet fluvastatin 80 mg daily or 1 immediate-release capsule fluvastatin 40 mg twice daily), individualised according to the baseline LDL-cholesterol (LDL-C) levels and the recommended goal of therapy to be accomplished. The maximum recommended daily dose is 80 mg.

Dose recommendations for the secondary prevention of coronary events after percutaneous coronary intervention

In patients with coronary heart disease after percutaneous coronary intervention, the dose is 80 mg daily.

Luvinsta can be administered as a single dose at any time of the day with or without food and must be swallowed whole with a glass of water.

The maximum lipid-lowering effect with a given dose of the drug is achieved within 4 weeks. Doses should be adjusted according to the patient's response and dose adjustment made at intervals of 4 weeks or more. The therapeutic effect of Luvinsta is maintained with prolonged administration.

When fluvastatin is used in combination with cholestyramine or other resins, it should be administered at least 4 hours after the resin to avoid a significant interaction due to binding of the drug to the resin.

Children and adolescents with heterozygous familial hypercholesterolemia

Prior to initiating treatment with fluvastatin in children and adolescents aged 9 years and older with heterozygous familial hypercholesterolaemia, the patient should be placed on a standard cholesterol-lowering diet. Dietary therapy should be continued during treatment.

The recommended starting dose is 40 mg (1 immediate-release capsule fluvastatin 40 mg) or 80 mg fluvastatin (1 prolonged-release tablet fluvastatin 80 mg daily or 1 immediate-release capsule fluvastatin 40 mg twice daily). The dose of 20 mg fluvastatin may be adequate in mild cases.

Starting doses should be individualized according to baseline LDL-C levels and the recommended goal of therapy to be accomplished.

The use of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrates in children and adolescents has not been investigated.

Elderly

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients thus, no dose adjustment is required in such patients.

Impaired kidney function

Fluvastatin is cleared by the liver, with less than 6% of the administered dose excreted into the urine. The pharmacokinetics of fluvastatin remain unchanged in patients with mild to severe renal insufficiency. No dose adjustments are therefore necessary in these patients.

Impaired liver function

Fluvastatin is contraindicated in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see sections 4.3 , 4.4 and 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see section 4.2 and 4.8).

Pregnancy and lactation (see section 4.6)

4.4 Special Warnings And Precautions For Use

Liver function

As with other lipid-lowering drugs, it is recommended that liver function tests be performed before the initiation of treatment and at 12 weeks following initiation of treatment or elevation in dose and periodically thereafter in all patients. Patients whose levels increase in response to the drug should be monitored particularly closely, with immediate repetition of the measurement followed by more frequent measurements. Should an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) exceed 3 times the upper limit of normal and persist, therapy should be discontinued. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.

Caution should be exercised when fluvastatin is administered to patients with a history of liver disease or heavy alcohol consumption.

Skeletal muscle

With fluvastatin, myopathy has rarely been reported, whereas myositis and rhabdomyolysis have been reported very rarely. In patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness, and/or marked elevation of creatine kinase (CK) values, myopathy, myositis or rhabdomyolysis have to be considered. Patients should therefore be advised to promptly report unexplained muscle pain, muscle tenderness or muscle weakness, particularly if accompanied by malaise or fever.

Creatine kinase measurement

There is no current evidence to require routine monitoring of plasma total creatine kinase or other muscle enzyme levels in asymptomatic patients on statins. If creatine kinase has to be measured it should not be done following strenuous exercise or in the presence of any plausible alternative cause of CK-increase as this makes the value interpretation difficult.

Before the treatment

As with all other statins physicians should prescribe fluvastatin with caution in patients with pre-disposing factors for rhabdomyolysis and its complications. A creatine kinase level should be measured before starting fluvastatin treatment in the following situations:

• Renal impairment

• Hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse

• In elderly (age>70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.

In such situations, the risk of treatment should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK-levels are significantly elevated at baseline >5x upper limit of normal, levels should be re-measured within 5 to 7 days later to confirm the results. If CK-levels are still significantly elevated >5x upper limit of normal at baseline, treatment should not be started.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Whilst on treatment

If muscular symptoms like pain, weakness or cramps occur in patients receiving fluvastatin, their CK-levels should be measured. Treatment should be stopped, if these levels are found to be significantly elevated (>5xULN).

If muscular symptoms are severe and cause daily discomfort, even if CK-levels are elevated to less than 5 x ULN, treatment discontinuation should be considered.

Should the symptoms resolve and CK-levels return to normal, then re-introduction of fluvastatin or another statin may be considered at the lowest dose and under close monitoring.

The risk of myopathy has been reported to be increased in patients receiving immunosuppressive drugs (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. However, in clinical trials in patients receiving fluvastatin in combination with nicotinic acid, fibrates, or ciclosporin, myopathy has not been observed. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicine. The benefits of the combined use of fluvastatin with fibrates, niacin or colchicin should be carefully weighed against the potential risks of these combinations and fluvastatin should be used with caution in patients receiving such concomitant medication (see section 4.5).

Hyperlipoproteinemia

No data are available for the use of fluvastatin in patients with hyperlipoproteinemia with a major increase in triglycerides.

Homozygous familial hypercholesterolemia

No data are available for the use of fluvastatin in patients with a rare condition known as homozygous familial hypercholesterolemia. The effect is expected to be low due to LDL – receptor deficiency in these patients. Therefore use of fluvastatin is not recommended in these patients.

Children and adolescents with heterozygous familial hypercholesterolemia

In patients aged <18 years, efficacy and safety have not been studied for treatment periods longer than two years. No data are available about the physical, intellectual and sexual maturation for prolonged treatment period. The long-term efficacy of fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established (see section 5.1).

Fluvastatin has only been investigated in children of 9 years and older with heterozygous familial hypercholesterolaemia (for details see section 5.1). In the case of pre-pubertal children, as experience is very limited in this group, the potential risks and benefits should be carefully evaluated before the initiation of treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drug interactions

Fibric acid derivatives (fibrates) and niacin (nicotinic acid)

Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or niacin (nicotinic acid) has no clinically relevant effect on the bioavailability of fluvastatin or the other lipid-lowering agent. An increased risk of myopathy and/ or rhabdomyolysis has been observed in patients receiving other HMG-CoA reductase inhibitors together with any of these molecules, probably because they can produce myopathy when given alone. Therefore, the benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4).

Colchicines

Myotoxicity, including muscle pain and weakness and rhabdomyolysis, have been reported in isolated cases with concomitant administration of colchicine. The benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4)

Ciclosporin

Studies in renal transplant patients indicate that the bioavailability of fluvastatin (up to 40 mg/day) is not elevated to a clinically significant extent in patients on stable regimens of ciclosporin. The results from another study wherein 80 mg fluvastatin was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (Cmax) were increased by 2 fold compared to historical data in healthy subjects. Although these increases in fluvastatin levels were not clinically significant, this combination should be used with caution. Starting and maintaining fluvastatin therapy should be in a dose as low as possible when combined with ciclosporin.

Fluvastatin (40 mg and 80 mg) had no effect on ciclosporin bioavailability when co-administered.

Warfarin and other coumarin derivatives

In healthy volunteers, the use of fluvastatin and warfarin (single dose) did not adversely influence warfarin plasma levels and prothrombin times compared to warfarin alone. However, isolated incidences of bleeding episodes and/or increased prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dosage changed in patients receiving warfarin or other coumarin derivatives.

Rifampicin (rifampin)

Administration of fluvastatin to healthy volunteers pre-treated with rifampicin (rifampin) resulted in a reduction of the bioavailability of fluvastatin by about 50%. Although at present there is no clinical evidence that fluvastatin efficacy in lowering lipid levels is altered, for patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis), appropriate adjustment of fluvastatin dosage may be warranted to ensure a satisfactory reduction in lipid levels.

Oral antidiabetic agents

For patients receiving oral sulfonylureas (glibenclamide [glyburide], tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellutis (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycemic control.

In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide approximately 50%, 69% and 121%, respectively. Glibenclamide (5 to 20 mg daily) increased the mean Cmax and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Bile acid sequestrants

Fluvastatin should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a significant interaction due to drug binding of the resin.

Fluconazole

Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP 2C9 inhibitor) resulted in an increase in the exposure and peak concentration of fluvastatin by about 84% and 44%.

Although there was no clinical evidence that the safety profile of fluvastatin was altered in patents pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

Itraconazole and erythromycin

Concomitant administration of fluvastatin with the potent cytochrome P450 (CYP) 3A4 inhibitors itraconazole and erythromycin has minimal effects on the bioavailability of fluvastatin. Given the minimal involvement of this enzyme in the metabolism of fluvastatin, it is expected that other CYP3A4 inhibitors (e.g. ketoconazole, ciclosporin) are unlikely to affect the bioavailability of fluvastatin.

Histamine H2-receptor antagonists and proton pump inhibitors

Concomitant administration of fluvastatin with cimetidine, ranitidine, or omeprazole results in an increase in the bioavailability of fluvastatin, which, however, is of no clinical relevance.

Phenytoin

In an interaction study concomitant administration of fluvastatin and phenytoin resulted in an increase of fluvastatin mean AUC and Cmax values by 40% and 27% respectively. This combination should be used with caution due to the increased risk of developing myopathy and/or rhabdomyolysis. Co-administration of fluvastatin (40 mg b.i.d. for 5 days) increased the mean Cmax of phenytoin by 5% whereas the mean AUC was increased by 22%. Patients on phenytoin should be carefully monitored when fluvastatin therapy is initiated or when the dose is increased.

Cardiovascular agents

No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with propranolol, digoxin, losartan, amlodipine or ACE- inhibitors. Based on the pharmacokinetic data, no monitoring or dosage adjustments are required when fluvastatin is concomitantly administered with these agents.

Food interactions

Mean AUC and Cmax were increased by 49% and 45% respectively and tmax prolonged when fluvastatin was taken with food, compared to fasting state. However, no clinically obvious differences in the lipid

4.6 Pregnancy And Lactation

Pregnancy

Fluvastatin is contraindicated during pregnancy (see section 4.3)

For fluvastatin no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal/foetal development (see section 5.3). Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. For these reasons, fluvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with fluvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).

Women of childbearing potential / Contraception in males and females

Women of childbearing potential have to use effective contraception. If a patient becomes pregnant while taking fluvastatin, therapy must be discontinued.

Lactation

Fluvastatin is excreted in rat milk with a milk: plasma ratio of 2. It is not known whether fluvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking fluvastatin must not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

The following adverse events have been reported with some statins:

• Memory loss

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Blood and lymphatic system disorders

 

Very rare:

Thrombocytopenia

 

 

Nervous system disorders

 

Common:

Headache, fatigue, dizziness.

Very rare:

Paraesthesia, dysaesthesia, hypoaesthesia and peripheral neuropathy also known to be associated with the underlying hyperlipidemic disorders.

Gastrointestinal disorders

 

Common:

Very rare

Dyspepsia, abdominal pain, nausea, constipation, flatulence, diarrhoea.

Acute pancreatitis

Skin and subcutaneous tissue disorders

 

Rare:

Hypersensitivity reactions such as rash, urticaria.

Very rare:

Other skin reactions (e.g. eczema, dermatitis, bullous exanthema), face oedema, angioedema

Musculoskeletal and connective tissue disorders

 

Common:

Rare:

Joint pain

Myalgia, muscle weakness, myopathy.

Very rare:

Rhabdomyolysis, myositis, lupus erythematosus-like reactions.

Vascular disorders

 

Very rare: Vasculitis

 

Hepatobiliary disorders

 

Very rare: Hepatitis.

 

Psychiatric disorders

 

Common: Sleep disturbances including insomnia and nightmares.

 

Laboratory Findings

Confirmed elevations of transaminase levels to more than 3 times the upper limit of normal (ULN) developed in a small number of patients (less than or equal to 2%). Marked elevations of CK levels to more than 5 x ULN developed 0.3 - 1.0% of patients receiving licensed doses of fluvastatin in clinical trials.

Children and adolescents with heterozygous familial hypercholesterolemia

The safety profile of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia assessed in 114 patients aged 9-17 years treated in two open non-comparative clinical trials was similar to the one observed in adults. In both clinical trials no effect was observed on growth and sexual maturation. The ability of the trials to detect any effect of treatment in this area was however low.

4.9 Overdose

The experience with overdoses of fluvastatin is very limited. Should an accidental overdosage occur, administration of activated charcoal is recommended. In the case of a very recent oral intake gastric lavage may be considered. Treatment should be symptomatic.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors ATC code: C 10 AA 04

Fluvastatin is a racemate of the two erythro enantiomers of which one exerts the pharmacological activity.

Fluvastatin, a synthetic cholesterol-lowering agent, is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Fluvastatin exerts its main effect in the liver. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The ultimate result of these mechanisms is a reduction of the plasma cholesterol concentration.

. The overall cholesterol profile is improved with the principal effects being the reduction of total-C and LDL-C. Fluvastatin also produces a moderate reduction in triglycerides and a moderate increase in HDL-C.Therapeutic response is well established within 2 weeks, and maximum response is achieved within 4 weeks from treatment initiation and maintained during chronic therapy.

In the Lescol Intervention Prevention Study (LIPS), the effect of fluvastatin on major adverse cardiac events (MACE) was assessed in patients with coronary heart disease who had first successful transcathether therapy (TCT). The study included male and female patients (18-80 years old) and with baseline total cholesterol levels ranging from 3.5-7.0 mmol/L.

In this randomised, double-blind, placebo-controlled trial, a total of 1677 patients were recruited (844 in fluvastatin group and 833 in placebo group). The MACE was defined as cardiac death, non fatal MI and re-intervention (including CABG, repeat TCT, or TCT of a new lesion). The dose of fluvastatin used in this study was 80 mg daily over 4 years. Although the overall composite endpoint showed significant reduction in MACE (22%) compared to placebo (p=0.013), the individual components (cardiac death, non fatal MI and re-intervention) failed to reach statistical significance. There was however a trend in favour of fluvastatin. Therapy with fluvastatin reduced the risk of cardiac death and/or myocardial infarction by 31% (p=0.065).

Children and adolescents with heterozygous familial hypercholesterolemia

The safety and efficacy of fluvastatin in children and adolescent patients aged 9 - 16 years of age with heterozygous familial hypercholesterolemia has been evaluated in 2 open label, uncontrolled clinical trials of 2 years' duration. 114 patients (66 boys and 48 girls) were treated with fluvastatin administered as either fluvastatin capsules 20 mg - 40 mg twice daily or fluvastatin 80 mg extended release tablets using a dose-titration regimen based upon LDL-C response.

The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level> 90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL equivalent to 5.8 mmol/L (range: 137 - 354 mg/dL equivalent to 3.6 – 9.2 mmol/L). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg twice daily) to achieve an LDL-C goal of 96.7 to 123.7 mg/dL (2.5 mmol/L to 3.2 mmol/L).

The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C> 190 mg/dL (equivalent to 4.9 mmol/L) or LDL-C> 160 mg/dL (equivalent to 4.1 mmol/L) and one or more risk factors for coronary heart disease, or LDL-C> 160 mg/dL (equivalent to 4.1 mmol/L) and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL equivalent to 5.8 mmol/L (range: 148 - 343 mg/dL equivalent to 3.8 – 8.9 mmol/L). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily to achieve an LDL-C goal of < 130 mg/dL (3.4 mmol/L).

In the first study, fluvastatin 20 to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL equivalent to 4.2 mmol/L (range: 74 - 336 mg/dL equivalent 1.9 – 8.7 mmol/L). In the second study, fluvastatin 20 to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL equivalent to 4.1 mmol/L (range: 90 - 295 mg/dL equivalent to 2.3 – 7.6 mmol/L).

The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26 to 30% of patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL (3.4 mmol/L).

5.2 Pharmacokinetic Properties

Absorption

Fluvastatin is absorbed rapidly and completely (98%) following oral administration to fasted volunteers. In a fed state, the drug is absorbed at a reduced rate. Fluvastatin exerts its main effect in the liver, which is also the main organ for its metabolism. The absolute bioavailability assessed from systemic blood concentrations is 24%.

Distribution

The apparent volume of distribution (Vzf) for the drug is 330 L. More than 98% of the circulating drug is bound to plasma proteins, and this binding is unaffected by drug concentration.

The major circulating blood components are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically.

Biotransformation

The hepatic metabolic pathways of fluvastatin in humans have been characterised. There are multiple, alternative cytochrome P450 (CYP450) pathways involved. However, the major pathway is mediated by CYP2C9 and this pathway is subject to potential interactions with other CYP2C9 substrates or inhibitors. In addition there are several minor pathways (e.g. CYP3A4).

Elimination

Several detailed in vitro studies have addressed the inhibitory potential of fluvastatin on common CYP isoenzymes. Fluvastatin inhibited only the metabolism of compounds that are metabolised by CYP2C9.

Following administration of 3H-fluvastatin to healthy volunteers, excretion of radioactivity is about 6% in the urine and 93% in the faeces, and fluvastatin accounts for less than 2% of the total radioactivity excreted. The plasma clearance (CL/f) for fluvastatin in man is calculated to be 1.8 ± 0.8 L/min. Steady-state plasma concentrations show no evidence of fluvastatin accumulation following administration of 80 mg daily. Following oral administration of 40 mg of fluvastatin, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Food

Mean AUC and Cmax were increased by 49% and 45% respectively and tmax prolonged when fluvastatin was taken with food, compared to fasting state. However, no clinically obvious differences in the lipid

Children and adolescents with heterozygous familial hypercholesterolemia

No pharmacokinetic data in children are available.

5.3 Preclinical Safety Data

Acute toxicity

The estimated oral LD50 is> 2 g/kg in mice and> 0.7g/kg in rats.

Repeated dose toxicity

Repeated dose toxicity studies with fluvastatin identified a variety of changes that are common to HMG-CoA reductase inhibitors, viz. hyperplasia and hyperkeratosis of the rodent non-glandular stomach, cataracts in dogs, myopathy in rodents, mild liver changes in most laboratory animals, with gall bladder changes in the dog, monkey and hamster, thyroid weight increases in the rat and testicular degeneration in the hamster. Fluvastatin is devoid of the CNS vascular and degenerative changes recorded in dogs with other members of this class of compounds.

Carcinogenicity

Carcinogenicity studies in rats and mice revealed a low incidence of forestomach squamous papillomas in mice and rats and one carcinoma in rats at the highest dose (18 mg/kg per day escalated to 24 mg/kg per day after 1 year). The forestomach neoplasms reflect chronic hyperplasia caused by direct contact exposure to fluvastatin rather than a genotoxic effect of the drug. In addition, an increase incidence of thyroid follicular cell neoplasms in male rats given the highest dose of fluvastatin was recorded. This is consistent with species-specific findings with other HMGCoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no treatment-related increases in the incidence of hepatic adenomas or carcinomas were observed.

Mutagenicity

In vitro and in vivo mutagenicity studies revealed no evidence of mutagenicity.

Toxicity to reproduction

Reproductive toxicity studies indicated that fluvastatin had no adverse effects on fertility or reproductive performance in males or females, nor was it embryotoxic or teratogenic. Late gestational effects at high doses resulted in maternal mortality and fetal and neonatal lethality attributable to exaggerated pharmacological effects of fluvastatin during pregnancy.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Povidone

Microcrystalline cellulose

Hydroxyethyl cellulose

Mannitol

Magnesium stearate

Film-coating:

Hypromellose 50

Macrogol 6000

Iron oxide yellow (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 30°C.

Blisters: Keep the blisters in the outer carton in order to protect from light.

Glass bottle and HDPE bottle: Keep the container tightly closed in order to protect from moisture and light.

6.5 Nature And Contents Of Container

Blister (OPA/Alu/PVC-Alu). Pack sizes of 10, 20, 28, 30, 50, 60, 98 and 100 prolonged release tablets.

HDPE bottle with desiccant and snap-on cap (LDPE) with a tamper evident ring. Desiccants are HDPE plastic canisters filled with activated silica gel. Pack sizes of 250 prolonged release tablets.

Round, brown glass container closed with rubbed plastic cap (HDPE) with thread including seal. Desiccants are HDPE plastic canisters filled with activated silica gel. Pack sizes of 250 prolonged release tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavikurvegur 76-78,

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

25.11.08

10. Date Of Revision Of The Text

05/03/2010

11 DOSIMETRY (IF APPLICABLE)

Not applicable.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not applicable.


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Cholestagel 625 mg film-coated tablets


1. Name Of The Medicinal Product

Cholestagel 625 mg film

2. Qualitative And Quantitative Composition

Each tablet contains 625 mg colesevelam (as hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film

Off

4. Clinical Particulars 4.1 Therapeutic Indications

Cholestagel co

Cholestagel as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated total

Cholestagel can also be used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia (see section 5.1).

4.2 Posology And Method Of Administration

Posology

Combination therapy

The recommended dose of Cholestagel for combination with a statin with or without ezetimibe is 4 to 6 tablets per day. The maximum recommended dose is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets taken once per day with a meal. Clinical trials have shown that Cholestagel and statins can be co

Monotherapy

The recommended starting dose of Cholestagel is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets once per day with a meal. The maximum recommended dose is 7 tablets per day.

During therapy, the cholesterol

When a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, or where no clinical data are available on co-administration, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication in order to minimize the risk of reduced absorption of the concomitant medication (see section 4.5).

Elderly population

There is no need for dose adjustment when Cholestagel is administered to elderly patients.

Paediatric population

Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

Cholestagel tablets should be taken orally with a meal and liquid.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients

• Bowel or biliary obstruction

4.4 Special Warnings And Precautions For Use

Prior to initiating therapy with Cholestagel, if secondary causes of hypercholesterolaemia (i.e., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease) are considered, these should be diagnosed and properly treated.

For patients on ciclosporin starting or stopping Cholestagel or patients on Cholestagel with a need to start ciclosporin: Cholestagel reduces the bioavailability of ciclosporin (see also section 4.5). Patients starting on ciclosporin already taking Cholestagel should have their ciclosporin blood concentrations monitored as normal and their dose adjusted as normal. Patients starting on Cholestagel already taking ciclosporin should have their blood concentrations monitored prior to combination therapy and frequently monitored immediately starting co

Caution should be exercised when treating patients with triglyceride levels greater than 3.4 mmol/L due to the triglyceride increasing effect with Cholestagel. Safety and efficacy are not established for patients with triglyceride levels greater than 3.4 mmol/L, since such patients were excluded from the clinical studies.

The safety and efficacy of Cholestagel in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, inflammatory bowel disease, liver failure or major gastrointestinal tract surgery have not been established. Consequently, caution should be exercised when Cholestagel is used in patients with these disorders.

Cholestagel can induce or worsen present constipation. The risk of constipation should especially be considered in patients with coronary heart disease and angina pectoris.

Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin's anticoagulant effect (see also section 4.5).

Cholestagel can affect the bioavailability of the oral contraceptive pill when administered simultaneously. It is important to ensure that Cholestagel is administered at least 4 hours after the oral contraceptive pill to minimise the risk of any interaction (see also section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In general

Cholestagel may affect the bioavailability of other medicinal products. Therefore when a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication to minimize the risk of reduced absorption of the concomitant medication. For concomitant medications which require administration via divided doses, it should be noted that the required dose of Cholestagel can be taken once a day.

When administering medicinal products for which alterations in blood levels could have a clinically significant effect on safety or efficacy, physicians should consider monitoring serum levels or effects.

Interaction studies have only been performed in adults.

In interaction studies in healthy volunteers, Cholestagel had no effect on the bioavailability of digoxin, metoprolol, quinidine, valproic acid, and warfarin. Cholestagel decreased the Cmax and AUC of sustained

There have been very rare reports of reduced phenytoin levels in patients who have received Cholestagel administered with phenytoin.

Anticoagulant therapy

Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin's anticoagulant effect. Specific clinical interaction studies with colesevelam and vitamin K have not been performed.

Levothyroxine

In an interaction study in healthy volunteers, Cholestagel reduced the AUC and Cmax of levothyroxine when administered either concomitantly or after 1 hour. No interaction was observed when Cholestagel was administered at least four hours after levothyroxine.

Oral contraceptive pill

In an interaction study in healthy volunteers, Cholestagel reduced the Cmax of norethindrone as well as the AUC and Cmax of ethinylestradiol when administered simultaneously with the oral contraceptive pill. This interaction was also observed when Cholestagel was administered one hour after the oral contraceptive pill. However no interaction was observed when Cholestagel was administered four hours after the oral contraceptive pill.

Ciclosporin

In an interaction study in healthy volunteers, co0 and Cmax of ciclosporin by 34% by 44%, respectively. Therefore advice is given to closely monitor ciclosporin blood concentrations (see also section 4.4). In addition, based on theoretical grounds Cholestagel should be administered at least 4 hours after ciclosporin in order to further minimise the risks related to the concomitant administration of ciclosporin and Cholestagel. Furthermore, Cholestagel should always be administered at the same times consistently since the timing of intake of Cholestagel and ciclosporin could theoretically influence the degree of reduced bioavailability of ciclosporin.

Statins

When Cholestagel was co

Antidiabetic agents

Co0 and Cmax of glyburide by 32% and 47%, respectively. No interaction was observed when Cholestagel was administered four hours after glyburide.

Comax of repaglinide, the clinical significance of which is unknown. No interaction was observed when Cholestagel was administered one hour after repaglinide.

No interaction was observed when Cholestagel and pioglitazone were administered simultaneously in healthy volunteers

Ursodeoxycholic acid

Cholestagel predominantly binds hydrophobic bile acids. In a clinical study Cholestagel did not affect the faecal excretion of endogenous (hydrophilic) ursodeoxycholic acid. However, formal interaction studies with ursodeoxycholic acid have not been performed. As noted in general, when a drug interaction cannot be excluded with a concomitant medicinal product, Cholestagel should be administered at least fours hour before or at least four hours after the concomitant medication to minimise the risk of reduced absorption of the concomitant medication. Monitoring of the clinical effects of treatment with ursodeoxycholic acid should be considered.

Other forms of interaction

Cholestagel did not induce any clinically significant reduction in the absorption of vitamins A, D, E or K during clinical studies of up to one year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies, such as patients with malabsorption. In these patients, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of coagulation parameters is recommended and the vitamins should be supplemented if necessary.

4.6 Pregnancy And Lactation

Pregnancy

No clinical data are available on the use of Cholestagel in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Lactation

The safety of Cholestagel has not been established in breast-feeding women. Caution should be exercised when prescribing to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

Cholestagel has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

In controlled clinical studies involving approximately 1400 patients, the following adverse reactions were reported in patients given Cholestagel. The reporting rate is classified as very common (

Investigations

Common: Serum triglycerides increased

Uncommon :Serum transaminase increased

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Very common : Flatulence, constipation

Common : Vomiting, diarrhoea, dyspepsia, , abdominal pain, abnormal stools, nausea

Musculoskeletal and connective tissue disorders

Uncommon : Myalgia

The background incidence of flatulence and diarrhoea were higher in patients receiving placebo in the same controlled clinical studies. Only constipation and dyspepsia were reported by a higher percentage among those receiving Cholestagel, compared with placebo.

Adverse reactions were generally mild or moderate in intensity.

Cholestagel in combination with statins and in combination with ezetimibe was well tolerated and the adverse reactions observed were consistent with the known safety profile of statins or ezetimibe alone.

4.9 Overdose

Since Cholestagel is not absorbed, the risk of systemic toxicity is low. Gastrointestinal symptoms could occur. Doses in excess of the maximum recommended dose (4.5 g per day (7 tablets)) have not been tested.

Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: bile acid sequestrants, ATC code: C10A C 04

The mechanism of action for the activity of colesevelam, the active substance in Cholestagel, has been evaluated in several in vitro and in vivo studies. These studies have demonstrated that colesevelam binds bile acids, including glycocholic acid, the major bile acid in humans. Cholesterol is the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids is then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation.

Colesevelam is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. The LDL

In a 6-month dose-response study in patients with primary hypercholesterolaemia receiving 3.8 or 4.5 g Cholestagel daily, a 15 to 18% decrease in LDL

In a 6 week study 129 patients with mixed hyperlipidaemia were randomised to fenofibrate 160 mg plus 3.8 g Cholestagel or fenofibrate alone. The fenofibrate plus Cholestagel group (64 patients) demonstrated a 10% reduction on LDL

Multi

The effect of 3.8 g Cholestagel plus 10 mg ezetimibe versus 10 mg ezetimibe alone on LDL-C levels was assessed in a multicentre, randomised, double-blind, placebo-controlled, parallel-group study in 86 patients with primary hypercholesterolaemia over a 6-week treatment period. The combination of ezetimibe 10 mg and Cholestagel 3.8 g daily therapy in the absence of a statin resulted in a significant combined effect for LDL-C lowering by 32% demonstrating an additional effect of 11% LDL-C lowering with Cholestagel and ezetimibe compared to ezetimibe alone.

The addition of Cholestagel 3.8 g daily to maximally-tolerated statin and ezetimibe therapy was assessed in a multi-centre, randomised, double-blind, placebo-controlled study in 86 patients with familial hypercholesterolaemia. A total of 85% of the patients were on either atorvastatin (50% of whom received 80 mg dose) or rosuvastatin (72% of whom received 40 mg dose). Cholestagel resulted in a statistically significant LDL-C reduction of 11% and 11% at 6 and 12 weeks vs an increase of 7% and 1% in the placebo group; mean baseline levels were 3.75mmol/L and 3.86 mmol/L, respectively. Triglycerides in the Cholestagel group increased by 19% and 13% at 6 and 12 weeks vs an increase of 6% and 13% in the placebo group, but the increases were not significantly different. HDL-C and hsCRP levels were also not significantly different compared to placebo at 12 weeks.

In the paediatric population, the safety and efficacy of 1.9 or 3.8 g/day Cholestagel was assessed in an 8 week multi-centre, randomised, double-blind, placebo-controlled study in 194 boys and postmenarchal girls, aged 10-17 years, with heterozygous FH on a stable dose of statins (47 patients, 24%) or treatment-na?ve to lipid-lowering therapy (147 patients, 76%). For all patients, Cholestagel resulted in a statistically significant LDL-C reduction of 11% at 3.8 g/day and 4% at 1.9 g/day, versus a 3% increase in the placebo group. For statin-na?ve patients on monotherapy, Cholestagel resulted in a statistically significant LDL-C reduction of 12% at 3.8 g/day and 7% at 1.9 g/day, versus a 1% reduction in the placebo group (see section 4.2). There were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors, and the adverse reaction profile for Cholestagel was comparable to that seen with placebo.

Cholestagel has not been compared directly to other bile acid sequestrants in clinical trials.

So far, no studies have been conducted that directly demonstrate whether treatment with Cholestagel as monotherapy or combination therapy has any effect on cardiovascular morbidity or mortality.

5.2 Pharmacokinetic Properties

Cholestagel is not absorbed from the gastrointestinal tract.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Cellulose (E460), microcrystalline

Silica, colloidal anhydrous

Magnesium stearate

Water, purified

Film-coating:

Hypromellose (E464)

Diacetylated monoglycerides

Printing ink:

Iron oxide black (E172)

Hypromellose (E464)

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

High density polyethylene bottles with a polypropylene cap.

Package sizes are:

24 tablets (1 X 24)

100 tablets (2 X 50)

180 tablets (1 X 180)

High density polyethylene bottles with a polypropylene cap without outer carton.

Package sizes are: 180 tablets (1 X 180)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.

8. Marketing Authorisation Number(S)

EU/1/03/268/001-004

9. Date Of First Authorisation/Renewal Of The Authorisation

10 March 2004/12 March 2009

10. Date Of Revision Of The Text

03/2010

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/


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Estrogens, Conjugated


Class: Estrogens
VA Class: GU500
Brands: Cenestin, Enjuvia, Premarin, Premphase, Prempro

Estrogens increase the risk of endometrial cancer in postmenopausal women.101 104 105 106 107 121 (See Endometrial Cancer under Cautions.)

Do not use estrogens with or without progestins for prevention of cardiovascular disease101 104 105 106 107 121 (see Cardiovascular Risk Reduction under Uses and Cardiovascular Disorders under Cautions) or dementia (see Alzheimer’s Disease under Uses).101 104 105 107

The Women’s Health Initiative (WHI) study of estrogen alone reported increased risks of stroke and DVT in postmenopausal women receiving approximately 7 years of therapy with conjugated estrogens 0.625 mg daily.101 104 105 107

The WHI study of estrogen plus progestin reported increased risks of MI, stroke, invasive breast cancer, pulmonary embolism, and DVT in postmenopausal women receiving ?5 years of therapy with conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily.101 104 105 106 107

The WHI Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women ?65 years of age receiving long-term therapy (4–5 years) with conjugated estrogens in conjunction with medroxyprogesterone acetate or conjugated estrogens alone.101 104 105 107 Not known whether this finding also applies to younger postmenopausal women.101 104 105 107

Other dosages of conjugated estrogens with medroxyprogesterone and other combinations or dosage forms of estrogens with progestin not studied in WHI trials; in the absence of comparable data, assume risks are similar.101 104 105 107

Prescribe estrogens (with or without progestins) at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.101 104 105 106 107

Introduction

Mixture of estrogens available either as preparations that meet current official USP standards (i.e., conjugated estrogens USP)101 105 107 108 109 or as nonofficial preparations (i.e., synthetic conjugated estrogens A and synthetic conjugated estrogens B, which are prepared synthetically from plant sources).106 108 109 121 122

Uses for Estrogens, Conjugated

Use of estrogens alone in postmenopausal women generally is referred to as estrogen replacement therapy (ERT); use of estrogens in combination with progestins usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy.b

ERT

Management of moderate to severe vasomotor symptoms associated with menopause.101 106 107 121

Management of vulvar and vaginal atrophy associated with menopause.101 105 106 107 If used solely for this indication, consider use of topical vaginal preparations.101 105 106 107

Osteoporosis

Prevention of postmenopausal osteoporosis.100 101 107 Used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and progression of osteoporosis in postmenopausal women.100 101 107

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.100 101 107 If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).101 107 112

Has been effective in the treatment of osteoporosis in postmenopausal women. Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings. (See Boxed Warning.) Evaluate risks and benefits of long-term HRT use in the management of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.101 107

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss† and, thereby, reduce risk of osteoporosis.

Corticosteroid-induced Osteoporosis

Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy†.

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.101 Used for induction of puberty in adolescents with pubertal delay due to hypogonadism.101

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.101 One of several second-line agents.a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.101

Abnormal Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.104

Cardiovascular Risk Reduction†

ERT or HRT does not decrease the incidence of cardiovascular disease.101 105 106 107 AHA, American College of Obstetricians and Gynecologists, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).

Alzheimer’s Disease

Prior use of HRT, but not current HRT unless such use exceeds 10 years, associated with reduced risk of Alzheimer’s disease†. Estrogens have not been shown to prevent progression of Alzheimer’s disease; American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer’s disease.

Initiation of ERT or HRT in women ?65 years of age not associated with an improvement in cognitive function. Some women receiving ERT or HRT experience detrimental effects. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. (See Boxed Warning.) Use of ERT or HRT to prevent dementia or cognitive decline in women ?65 years of age is not recommended.

Postpartum Breast Engorgement

Used in the past for prevention of postpartum breast engorgement†; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.110 (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.101 104 105 106 107 121 (See Pregnancy under Cautions.)

Estrogens, Conjugated Dosage and Administration General

A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.101 104 105 107 121 Addition of a progestin for ?10 days per cycle of estrogen or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.101 104 105 107 121

ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins).101 104 105 107 121

Administration

Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection.101 104 105 107

Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.106 121

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.101 105 107 When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug or once daily for 25 days followed by 5 days off; regimen is repeated as necessary.101 105

When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection.104

Oral Administration

Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package to aid user in complying with the prescribed dosage schedule.107

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV injection.104

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Rate of Administration

Administer slowly (to avoid flushing reaction).104

IM Administration

Administer by deep IM injection.104

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Vaginal Administration

Administer intravaginally as a vaginal cream.105

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.101 104 105 106 107 121

To minimize risk of adverse effects, use the lowest possible effective dosage.101 104 105 106 107 121 Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen and estrogen/progestin therapy to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.101 104 105 107 121

Periodically reevaluate estrogen and estrogen/progestin therapy (i.e., at 3- to 6-month intervals).101 104 105 107 121

Pediatric Patients Hypoestrogenism Oral

Conjugated estrogens USP: 0.15 mg daily may induce breast development.101 Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure.101

Conjugated estrogens USP: 0.625 mg daily (with progestins) sufficient to induce artificial cyclic menses and to maintain bone mineral density (BMD) after skeletal maturity.101

Adults Estrogen Replacement Therapy Vasomotor Symptoms Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: Initially, 0.45 mg daily.106 May increase dosage up to 1.25 mg daily.106

Synthetic conjugated estrogens B: Initially, 0.3 mg daily.121 Adjust dosage based on patient response.121

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Vulvar and Vaginal Atrophy Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: 0.3 mg daily.106

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Vaginal

Conjugated estrogens USP: 0.5–2 g daily in cyclic regimen (3 weeks on, 1 week off).105

Osteoporosis Prevention in Postmenopausal Women Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on clinical and BMD response.101

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107 Adjust dosage based on clinical and BMD response.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Hypoestrogenism Female Hypogonadism Oral

Conjugated estrogens USP: 0.3–0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off).101 Adjust dosage based on symptom severity and endometrial responsiveness.101

Female Castration or Primary Ovarian Failure Oral

Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen.101 Adjust dosage based on symptom severity and clinical response.101

Metastatic Breast Carcinoma Oral

Conjugated estrogens USP: 10 mg 3 times daily for ?3 months.101

Prostate Carcinoma Oral

Conjugated estrogens USP: 1.25–2.5 mg 3 times daily.101

Abnormal Uterine Bleeding IV or IM

Conjugated estrogens USP: 25 mg; can repeat dose in 6–12 hours.104

Cautions for Estrogens, Conjugated Contraindications

Undiagnosed abnormal genital bleeding.101 104 105 106 107 121

Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).101 104 105 106 107 121

Known or suspected estrogen-dependent neoplasia.101 104 105 106 107 121

Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.101 104 105 106 107 121

Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).101 104 105 106 107 121

Liver disease or impairment.101 104 105 107 121

Known or suspected pregnancy.101 104 105 106 107 121

Known hypersensitivity to estrogen or any ingredient in the formulation.101 104 105 106 107 121

Warnings/Precautions Warnings Cardiovascular Disorders

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.101 104 105 106 107 112 113 114 121 Estrogen therapy associated with increased risk of stroke and DVT.101 104 105 107 (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.101 104 105 106 107 121 Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks. (See Contraindications under Cautions.)

Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus).101 104 105 106 107 121 (See Contraindications under Cautions.)

Discontinue estrogens, whenever feasible, at least 4–6 weeks prior to surgery that is associated with an increased risk of thromboembolism or during prolonged immobilization.101 104 105 106 107 121

Endometrial Cancer

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.101 104 105 106 107 121 Clinical surveillance and evaluation are essential.101 104 105 106 107 121 Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.101 104 105 106 107 121

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.101 104 105 106 107 121

Breast Cancer

HRTassociated with increased risk of breast cancer.101 104 105 106 107 112 113 114 121

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.101 104 105 106 107 121 Schedule periodic mammography based on patient age and risk factors.101 104 105 106 107 121

Dementia

ERT or HRT in women ?65 years of age has been associated with increased risk of developing probable dementia.101 104 105 107 121 Whether these findings apply to younger women is unknown.101 104 105 107 121 (See Alzheimer’s Disease under Uses.)

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.101 104 105 106 107 121

Hypercalcemia

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.101 104 105 106 107 121 Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs.101 104 105 106 107 121

Ocular Effects

Retinal thrombosis reported.101 104 105 106 107 121 Discontinue pending examination if sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine occurs.101 104 105 107 121 Discontinue estrogens if papilledema or retinal vascular lesions noted on examination.101 104 105 106 107 104 105 121

General Precautions Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.101 104 105 106 107 121 ERT generally is not associated with elevated BP.101 104 105 107 121 Monitor BP at regular intervals.101 104 105 106 107 121

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.101 104 105 106 107 121

Fluid Retention

Estrogens may cause some degree of fluid retention; use with caution and careful monitoring in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal impairment).101 104 105 106 107 121

Hypocalcemia

Use with caution in patients with severe hypocalcemia.101 104 105 106 107 121

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.101 104 105 106 107 121 Other studies did not show a clinically important association.101 104 105 106 107 121

Endometriosis

Estrogens may exacerbate endometriosis.101 104 105 106 107 121

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.101 104 105 107 Consider the addition of progestin in women with residual endometriosis following hysterectomy.101 104 105 107 121

Other Conditions

Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in patients with these conditions.101 104 105 107 121

Precautions Specific to Vaginal Administration

Exposure to conjugated estrogens USP vaginal cream may weaken latex condoms.105 Consider the potential for the cream to weaken and contribute to protective failure of latex or rubber condoms, diaphragms, or cervical caps.105

Estrogen-Progestin Combinations

When a progestin is used in conjunction with estrogen therapy, consider the cautions, precautions, and contraindications associated with progestin therapy.107 a

Specific Populations Pregnancy

Category X.101 104 105 106 107 121 (See Contraindications under Cautions.)

In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in US]) is associated with increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear-cell vaginal cancer in later life.b

In utero exposure of males to DES is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life.b

Women who receive DES during pregnancy may be at increased risk of breast cancer; causal relationship unproven.b

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.101 104 105 106 107 121 Detectable amounts of estrogens have been identified in milk of women receiving these drugs.101 104 105 106 107 121 Caution advised.101 104 105 106 107 121

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.101 Safety and efficacy of estrogens in children not otherwise established.101 104 105 107 121

Use estrogen therapy with caution and careful monitoring if bone growth is not yet complete, since estrogens may cause premature epiphyseal closure.101

Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding.101 Estrogen therapy in boys may modify the normal pubertal process.101

Geriatric Use

No substantial differences in safety in women ?65 years of age compared with younger women; increased incidence of stroke and invasive breast cancer reported in women?75 years of age compared with younger women.101 104 105 107

Possible increased risk of developing probable dementia in women ?65 years of age. (See Dementia under Cautions.)101 104 105 107

Clinical studies of estrogens alone or in combination with a progestin did not include sufficient numbers of patients ?65 years of age to determine whether geriatric patients respond differently than younger patients.101 104 105 107

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment.101 104 105 106 107 121 (See Contraindications under Cautions.)

Caution advised in patients with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy; discontinue if jaundice recurs.101 104 105 106 107 121

Renal Impairment

Use with caution.101 104 105 107 121 (See Fluid Retention under Cautions.)

Common Adverse Effects

Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal hemorrhage, vaginitis, vaginal moniliasis.101 107

Interactions for Estrogens, Conjugated

Appears to be metabolized partially by CYP3A4.101 104 105 106 107 121

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).101 104 105 106 107 121

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).101 104 105 106 107 121

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticoagulants, oral

Possible decreased anticoagulant actionb

Monitor; increase warfarin dosage if requiredb

Antifungals, azoles (itraconazole, ketoconazole)

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Carbamazepine

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Corticosteroids (hydrocortisone)

Enhanced anti-inflammatory effects in patients with chronic inflammatory skin diseaseb

Observe for signs of excessive corticosteroid effects; adjust corticosteroid dosage when initiating or discontinuing estrogenb

Grapefruit juice

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Macrolide antibiotics (clarithromycin, erythromycin)

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

Medroxyprogesterone

Interaction unlikely101 106 107

Phenobarbital

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Rifampin

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Ritonavir

Possible increased plasma estrogen concentrations; increased potential for adverse effects101 104 105 106 107 121

St. John’s wort (Hypericum perforatum)

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding101 104 105 106 107 121

Thyroid agents

Increased thyroid-binding globulin concentrations101 104 105 106 107 121

Increased dosages of thyroid replacement agents may be needed; monitor thyroid function101 104 105 106 107 121

Estrogens, Conjugated Pharmacokinetics Absorption Bioavailability

Conjugated estrogens are well absorbed through mucous membranes and from the GI tract.101 104 105 106 107 121

Food

Conjugated estrogens USP: High-fat meal does not affect extent of oral absorption.107

Synthetic conjugated estrogens A: Effect of food unknown.106

Synthetic conjugated estrogens B: Effects of food unknown.121

Distribution Extent

Widely distributed; highest concentrations found in sex hormone target organs.101 104 105 106 107 121

Plasma Protein Binding

50–80%.b

Elimination Metabolism

Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent.b Estrogens metabolized partially by CYP3A4.101 104 105 106 107 121

Extensive metabolic conversion takes place in the liver (e.g., estradiol converted to estrone, both converted to estriol).101 104 105 106 107 121

Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.101


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