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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Nolvadex


tamoxifen citrate
Dosage Form: tablets
BOXED WARNING

For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer: Serious and life-threatening events associated with Nolvadex in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY-Clinical Studies ? Reduction in Breast Cancer Incidence In High Risk Women). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for Nolvadex vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for Nolvadex vs 0.04 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for Nolvadex vs 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for Nolvadex versus 0.25 for placebo**.

Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.

Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering Nolvadex to reduce their risk of developing breast cancer.

The benefits of Nolvadex outweigh its risks in women already diagnosed with breast cancer.

*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.

**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies

Nolvadex Description

Nolvadex® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. Nolvadex Tablets are available as:

10 mg Tablets:

Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.

20 mg Tablets:

Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.

Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, Nolvadex is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:

Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.

Nolvadex - Clinical Pharmacology

Nolvadex is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.

In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.

Absorption and Distribution:

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg Nolvadex tablets given twice a day vs. a 20 mg Nolvadex tablet given once daily, the 20 mg Nolvadex tablet was bioequivalent to the 10 mg Nolvadex tablets.

Metabolism:

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion:

Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Special Populations:

The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Pediatric Patients:

The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of Nolvadex in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data.

In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of Nolvadex for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Nolvadex therapy in girls have not been established. In adults treated with Nolvadex an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING).

Drug-Drug Interactions:

In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.

Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

In the anastrozole adjuvant trial, co-administration of anastrozole and Nolvadex in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions). Nolvadex should not be co-administered with anastrozole.

Clinical Studies Metastatic Breast Cancer: Premenopausal Women (Nolvadex vs. Ablation):

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared Nolvadex to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (Nolvadex/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving Nolvadex, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during Nolvadex therapy responded to subsequent ovarian ablation.

Male Breast Cancer:

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with Nolvadex have shown that Nolvadex is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to Nolvadex which constitutes a 50% objective response rate.

Adjuvant Breast Cancer: Overview:

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant Nolvadex using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing Nolvadex to no adjuvant therapy and 42% were entered into trials comparing Nolvadex in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for Nolvadex vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for Nolvadex vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for Nolvadex vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for Nolvadex versus 64.3% for control (logrank 2p < 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of Nolvadex, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of Nolvadex on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

Anastrozole Adjuvant ATAC Trial Study of Anastrozole compared to Nolvadex for Adjuvant Treatment of Early Breast Cancer:

An anastrozole adjuvant trial was conducted in 9366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, Nolvadex 20 mg daily, or a combination of these two treatments for five years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and Nolvadex did not demonstrate any efficacy benefit when compared with Nolvadex therapy alone, in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY-Special Populations-Drug-Drug Interactions, PRECAUTIONS-Laboratory Tests, PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections for safety information from this trial. Please refer to the full prescribing information for ARIMIDEX® (anastrozole) 1 mg Tablets for additional information on this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anatrozole arm compared to the Nolvadex arm.

Node Positive - Individual Studies:

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when Nolvadex was added to adjuvant cytotoxic chemotherapy. In the Hubay study, Nolvadex was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, Nolvadex was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of Nolvadex without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using Nolvadex adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

Node Negative - Individual Studies:

NSABP B-14, a prospective, double-blind, randomized study, compared Nolvadex to placebo in women with axillary node-negative, estrogen-receptor positive (?10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving Nolvadex. This benefit was apparent both in women under age 50 and in women at or beyond age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for Nolvadex compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of Nolvadex appeared to be independent of estrogen receptor status.

Duration of Therapy:

In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional 5 years of Nolvadex or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of Nolvadex were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of Nolvadex (p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95% CI 0.87-1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant Nolvadex 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.

Contralateral Breast Cancer:

The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving Nolvadex compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with Nolvadex of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving Nolvadex were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of Nolvadex reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant Nolvadex 40 mg/day for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

Ductal Carcinoma in Situ:

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of Nolvadex or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.

In this trial 1,804 women were randomized to receive either Nolvadex or placebo for 5 years: 902 women were randomized to Nolvadex 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.

The Nolvadex and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to Nolvadex (44 cases - Nolvadex, 74 cases - placebo; p=0.004; relative risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

Table 1Major Outcomes of the NSABP B-24 Trial

Type of Event

Lumpectomy, radiotherapy and placebo

Lumpectomy, radiotherapy, and Nolvadex

RR

95% CI Limits

No. of events

Rate per 1000 women per year

No. of events

Rate per 1000 women per year

* Updated follow-up data (median 8.1 years)

Invasive breast cancer (Primary endpoint)

74

16.73

44

9.60

0.57

0.39 to 0.84

-Ipsilateral

47

10.61

27

5.90

0.56

0.33 to 0.91

-Contralateral

25

5.64

17

3.71

0.66

0.33 to 1.27

-Side undetermined

2

--

0

--

--

Secondary Endpoints

DCIS

56

12.66

41

8.95

0.71

0.46 to 1.08

-Ipsilateral

46

10.40

38

8.29

0.88

0.51 to 1.25

-Contralateral

10

2.26

3

0.65

0.29

0.05 to 1.13

All Breast Cancer Events

129

29.16

84

18.34

0.63

0.47 to 0.83

-All ipsilateral events

96

21.70

65

14.19

0.65

0.47 to 0.91

-All contralateral events

37

8.36

20

4.37

0.52

0.29 to 0.92

Deaths

32

28

Uterine Malignancies*

4

9

Endometrial Adenocarcinoma*

4

0.57

8

1.15

Uterine Sarcoma*

0

0.0

1

0.14

Second primary malignancies (other than endometrial and breast)

30

29

Stroke

2

7

Thromboembolic events (DVT, PE)

5

15

Survival was similar in the placebo and Nolvadex groups. At 5 years from study entry, survival was 97% for both groups.

Reduction in Breast Cancer Incidence in High Risk Women:

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (See INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of Nolvadex, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation and surgery (See WARNINGS).

The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of breast cancer of ? 1.67% was required for entry into the trial.

In this trial, 13,388 women of at least 35 years of age were randomized to receive either Nolvadex or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to Nolvadex (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.

Table 2Demographic Characteristics of Women in the NSABP P-1 Trial

Characteristic

Placebo

Tamoxifen

#

%

#

%

Age (yrs)

35-39

184

3

158

2

40-49

2,394

36

2,411

37

50-59

2,011

31

2,019

31

60-69

1,588

24

1,563

24

?70

393

6

393

6

Age at first live birth (yrs.)

Nulliparous

1,202

18

1,205

18

12-19

915

14

946

15

20-24

2,448

37

2,449

37

25-29

1,399

21

1,367

21

?30

606

9

577

9

Race

White

6,333

96

6,323

96

Black

109

2

103

2

Other

128

2

118

2

Age at menarche

?14

1,243

19

1,170

18

12-13

3,610

55

3,610

55

?11

1,717

26

1,764

27

# of first degree relatives with breast cancer

0

1,584

24

1,525

23

1

3,714

57

3,744

57

2+

1,272

19

1,275

20

Prior Hysterectomy

No

4,173

63.5

4,018

62.4

Yes

2,397

36.5

2,464

37.7

# of previous breast biopsies

0

2,935

45

2,923

45

1

1,833

28

1,850

28

?2

1,802

27

1,771

27

History of atypical hyperplasia in the breast

No

5,958

91

5,969

91

Yes

612

9

575

9

History of LCIS at entry

No

6,165

94

6,135

94

Yes

405

6

409

6

5-year predicated breast cancer risk (%)

?2.00

1,646

25

1,626

25

2.01-3.00

2,028

31

2,057

31

3.01-5.00

1,787

27

1,707

26

?5.01

1,109

17

1,162

18

Total

6,570

100.0

6,544

100.0

Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to Nolvadex (86 cases-Nolvadex, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (? 49, 50-59, ? 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23-Nolvadex, 35-placebo; RR=0.66; 95% CI: 0.39-1.11).

There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61-Nolvadex, 59-placebo; RR=1.04, 95% CI: 0.73-1.49).

No overall difference in mortality (53 deaths in Nolvadex group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in Nolvadex group vs. 5 deaths in placebo group).

Although there was a non-significant reduction in the number of hip fractures (9 on Nolvadex, 20 on placebo) in the Nolvadex group, the number of wrist fractures was similar in the two treatment groups (69 on Nolvadex, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving Nolvadex. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, Nolvadex was associated with significant bone loss of the lumbar spine and hip in premenopausal women.

The risks of Nolvadex therapy include endometrial cancer, DVT, PE, stroke, cataract formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the Nolvadex group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27-4.92). Deep vein thrombosis was observed in 30 women receiving Nolvadex vs. 19 in women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the Nolvadex group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the Nolvadex arm and 24 on the placebo arm (RR=1.42; 95% CI: 0.82-2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking Nolvadex vs. 483 women receiving placebo (RR=1.13, 95% CI: 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking Nolvadex vs. 129 women receiving placebo (RR=1.51, 95% CI: 1.21-1.89) (See WARNINGS).

Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit (See INDICATIONS AND USAGE).

Table 3Major Outcomes of the NSABP P-1 Trial

# of Events

Rate/1000 Women/Year

95% CI

Type of Event

Placebo

Nolvadex

Placebo

Nolvadex


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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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Saizen 3.33mg


1. Name Of The Medicinal Product

Saizen 3.33 mg powder and solvent for solution for injection

2. Qualitative And Quantitative Composition

Each vial of Saizen 3.33 mg contains somatropin* (recombinant human growth hormone).

*produced by recombinant DNA technology in mammalian cells

After reconstitution with the enclosed solvent, each vial shall contain

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection

Appearance of the powder: white lyophilised powder.

Appearance of the solvent: clear colourless solution.

The pH of the reconstituted solution is 7.4 - 8.5.

4. Clinical Particulars 4.1 Therapeutic Indications

Saizen is indicated in the treatment of:

Children:

 

- Growth failure in children caused by decreased or absent secretion of endogenous growth hormone.

 

- Growth failure in girls with gonadal dysgenesis (Turner Syndrome), confirmed by chromosomal analysis.

 

- Growth failure in prepubertal children due to chronic renal failure (CRF).

 

- Growth disturbance (current height SDS <-2.5 and parental adjusted height SDS <-1) in short children born small for gestational age (SGA) with a birth weight and/or length below -2 SD, who failed to show catch-up growth (HV SDS <0 during the last year) by 4 years of age or later.

Adults:

- Replacement therapy in adults with pronounced growth hormone deficiency as diagnosed by a single dynamic test for growth hormone deficiency. Patients must also fulfil the following criteria:

 

- Childhood Onset:

Patients who were diagnosed as growth hormone deficient during childhood, must be retested and their growth hormone deficiency confirmed before replacement therapy with Saizen is started.

 

- Adult Onset:

Patients must have growth hormone deficiency as a result of hypothalamic or pituitary disease and at least one other hormone deficiency diagnosed (except for prolactin) and adequate replacement therapy instituted, before replacement therapy using growth hormone may begin.

4.2 Posology And Method Of Administration

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Saizen 3.33 mg is intended for multiple dose use.

Saizen dosage should be individualised for each patient based on body surface area (BSA) or on body weight (BW).

It is recommended that Saizen be administered at bedtime according to the following dosage:

Children and adolescents:

 

- Growth failure due to inadequate endogenous growth hormone secretion:

0.7-1.0 mg/m2 body surface area (BSA) per day or 0.025-0.035 mg/kg body weight (BW) per day by subcutaneous or intramuscular administration.

 

- Growth failure in girls due to gonadal dysgenesis (Turner Syndrome)

1.4 mg/m2 body surface area (BSA) per day or 0.045-0.050 mg/kg body weight (BW) per day by subcutaneous administration.

 

- Concomitant therapy with non-androgenic anabolic steroids in patients with Turner Syndrome can enhance the growth response.

 

- Growth failure in prepubertal children due to chronic renal failure (CRF):

1.4 mg/m2 body surface area (BSA), approximately equal to 0.045-0.050 mg/kg body weight (BW), per day by subcutaneous administration.

 

- Growth failure in short children born small for gestational age (SGA):

The recommended daily dose is 0.035 mg/kg body weight (or 1 mg/m2/day, equal to 0.1 U/kg/day or 3 IU/m2/day) per day, by subcutaneous administration.

 

Treatment should be discontinued when the patient has reached a satisfactory adult height, or the epiphyses are fused.

 

For growth disturbance in short children born SGA, treatment is usually recommended until final height is reached. Treatment should be discontinued after the first year if height velocity SDS is below +1. Treatment should be discontinued when final height is reached (defined as height velocity <2 cm/year), and if confirmation is required if bone age is>14 years (girls) or>16 years (boys), corresponding to closure of the epiphyseal growth plates.

Adults:

 

- Growth Hormone Deficiency in adults:

At the start of somatropin therapy, low doses of 0.15-0.3 mg are recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by Insulin-like Growth Factor 1 (IGF-1) values. The recommended final GH dose seldom exceeds 1.0mg/day. In general the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.

The powder for solution for injection should be used with the enclosed solvent for parenteral use. The reconstituted solution for injection should be clear with no particles. For instructions for preparation, please see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Somatropin should not be used for growth promotion in children with closed epiphyses.

Any evidence of active malignant tumours. Intracranial neoplasm must be inactive and antitumor therapy should be completed prior to institution of therapy.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin.

In children with chronic renal disease, treatment with somatropin should be discontinued at renal transplantation.

4.4 Special Warnings And Precautions For Use

Treatment should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of patients with growth hormone deficiency.

Patients with an intra or extracranial neoplasia in remission who are receiving treatment with growth hormone should be examined carefully and at regular intervals by the physician.

Patients with growth hormone deficiency secondary to an intracranial tumour should be examined frequently for progression or recurrence of the underlying disease process.

Prader-Willi Syndrome

Saizen is not indicated for the long-term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi Syndrome, unless they also have a diagnosis of growth hormone deficiency. There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in paediatric patients with Prader-Willi Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.

Insulin sensitivity

Because somatropin may reduce insulin sensitivity , patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin containing product therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.

Stable background retinopathy should not lead to discontinuation of somatropin replacement therapy. In case of development of preproliferative changes and the presence of proliferative retinopathy somatropin replacement therapy should be discontinued.

Thyroid function

Growth hormone increases the extra thyroid conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.

Benign intracranial hypertension

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, fundoscopy for papille oedema is recommended. If papille oedema is confirmed a diagnosis of benign intracranial hypertension (or pseudotumor cerebri) should be considered and if appropriate, Saizen treatment should be discontinued. At present there is insufficient evidence to guide clinical decision-making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary

Antibodies

As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Slipped capital femoral epiphysis is often associated with endocrine disorders such as growth hormone deficiency and hypothyroidism, and with growth spurts. In children treated with growth hormone, slipped capital femoral epiphysis may either be due to underlying endocrine disorders or to the increased growth velocity caused by the treatment. Growth spurts may increase the risk of joint-related problems, the hip joint being under particular strain during the prepubertal growth spurt. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in children treated with Saizen.

Patients with growth failure due to chronic renal failure should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy and it is uncertain whether these problems are affected by growth hormone therapy. X-rays of the hip should be obtained prior to initiating therapy.

In children with chronic renal failure, renal function should have decreased to below 50% of normal before therapy is instituted. To verify the growth disturbance, growth should have been followed for a year before institution of therapy. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment should be discontinued at the time of renal transplantation.

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

For SGA patients it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, increased body mass index, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

For SGA patients it is recommended to measure IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment.

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience with SGA patients with Silver-Russel syndrome is limited.

Some of the height gain obtained with treating short children born SGA with somatropin may be lost if treatment is stopped before final height is reached.

Fluid retention is expected during growth hormone replacement therapy in adults.

In case of persistent oedema or severe paraesthesia the dosage should be decreased in order to avoid the development of carpal tunnel syndrome.

The injection site should be varied to prevent lipoatrophy.

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Growth Hormone Deficiency in the Adult is a lifelong condition and should be treated accordingly, however experience with patients over sixty years and experience with prolonged treatment is limited

In all patients developing acute critical illness, the possible benefit of treatment with somatropin must be weighed against the potential risk involved.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin containing products. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth hormone.

Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P 450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Pregnancy And Lactation

Pregnancy:

Animal studies are insufficient and/or animal data is not available with regard to effects on pregnancy, embryofoetal development, parturition or postnatal development (See section Preclinical safety data 5.3) No clinical data on exposed pregnancies are available. Therefore, somatropin containing products are not recommended during pregnancy and in woman of childbearing potential not using contraception

Lactation:

There have been no clinical studies conducted with somatropin in breast-feeding women. It is not known whether somatropin is excreted in human milk. Therefore caution should be exercised when somatropin is administered to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

Somatropin-containing products have no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Up to 10 % of patients may experience redness and itching at the site of injection, particularly when the subcutaneous route is used.

Fluid retention is expected during growth hormone replacement therapy in adults. Oedema, joint swelling, arthralgias, myalgias and paresthesias may be clinical manifestations of fluid retention. However, these symptoms / signs are usually transient and dose dependent.

Adult patients with growth hormone deficiency, following diagnosis of growth hormone deficiency in childhood, reported side-effects less frequently than those with adult onset growth hormone deficiency.

Antibodies to somatropin can form in some patients; the clinical significance of these antibodies is unknown, though to date the antibodies have been of low binding capacity and have not been associated with growth attenuation except in patients with gene deletions. In very rare instances, where short stature is due to deletion of the growth hormone gene complex, treatment with growth hormone may induce growth attenuating antibodies.

Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Common

(

Uncommon

(

Very rare

(<1/10,000)

Frequency unknown

Nervous system disorders

 

 

Idiopathic intracranial hypertension (benign intracranial hypertension)

Carpal tunnel syndrome

 

 

(Isolated) headache

Musculoskeletal and connective tissue disorders

 

 

 

 

Slipped capital femoral epiphysis (Epiphysiolysis capitis femoris), or avascular necrosis of the femoral head

 

 

Endocrine disorders

 

 

 

 

Hypothyroidism

 

 

Metabolism and nutrition disorders

In adults: Fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paresthesia.

In children: Fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paresthesia.

 

 

Insulin resistance can result in hyperinsulinism and in rare cases in hyperglycemia.

General disorders and administration site conditions

Injection site reactions: Localized lipoatrophy, which can be avoided by varying the site of injection

 

 

 

 

 

 

 

4.9 Overdose

No cases of acute overdose has been reported. However, exceeding the recommended doses can cause side effects. Overdosage can lead to hypoglycaemia and subsequently to hyperglycaemia. Moreover, somatropin overdose is likely to cause manifestations of fluid retention.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: H01AC01.

Saizen contains recombinant human growth hormone produced by genetically engineered mammalian cells.

It is a peptide of 191 amino acids identical to human pituitary growth hormone with respect to aminoacid sequence and composition as well as peptide map, isoelectric point, molecular weight, isomeric structure and bioactivity.

Growth hormone is synthesised in a transformed murine cell line that has been modified by the addition of the gene for pituitary growth hormone.

Saizen is an anabolic and anticatabolic agent, which exerts effects not only on growth but also on body composition and metabolism. It interacts with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes and hematopoietic cells. Some, but not all of its effects are mediated through another class of hormones known as somatomedins (IGF-1 and IGF-2).

Depending on the dose, the administration of Saizen elicits a rise in IGF-1, IGFBP-3, non-esterified fatty acids and glycerol, a decrease in blood urea, and decreases in urinary nitrogen, sodium and potassium excretion. The duration of the increase in GH levels may play a role in determining the magnitude of the effects. A relative saturation of the effects of Saizen at high doses is probable. This is not the case for glycemia and urinary C-peptide excretion, which are significantly elevated only after high doses (20 mg).

In a randomized clinical trial, three years treatment of pre-pubertal short children born SGA with a dose of 0.067 mg/kg/day resulted in a mean gain of +1.8 height-SDS. In those children who did not receive treatment beyond 3 years, part of the treatment benefit was lost, but the patients retained a significant gain of +0.7 height-SDS at final height (p<0.01 compared to baseline). Patients who received a second treatment course after a variable period of observation experienced a total gain of +1.3 height-SDS (p=0.001 compared to baseline) at final height. (The mean cumulative treatment duration in the latter group was 6.1 years). The gain in height-SDS (+1.3±1.1) at final height in this group was significantly (p<0.05) different from the gain in height-SDS obtained in the first group (+0.7±0.8) that received only 3.0 years of treatment on average.

A second clinical trial investigated two different dose regimens over four years. One group was treated with 0.067 mg/kg/day for 2 years and then observed without treatment for 2 years. The second group received 0.067 mg/kg/day in the first and third year and no treatment in the second and fourth year. Either treatment regimen resulted in a cumulative administered dose of 0.033 mg/kg/day over the four-year study period. Both groups showed a comparable acceleration of growth and a significant improvement of +1.55 (p<0.0001) and + 1.43 (p<0.0001) height-SDS respectively at the end of the four year study period. Long-term safety data are still limited.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Saizen are linear at least up to doses of 8 IU (2.67 mg). At higher doses (60 IU/20 mg) some degree of non-linearity cannot be ruled out, however with no clinical relevance.

Following IV administration in healthy volunteers the volume of distribution at steady-state is around 7 L, total metabolic clearance is around 15 L/h while the renal clearance is negligible, and the drug exhibits an elimination half-life of 20 to 35 min.

Following single-dose SC and IM administration of Saizen, the apparent terminal half-life is much longer, around 2 to 4 hours. This is due to a rate limiting absorption process.

Maximum serum growth hormone (GH) concentrations are reached after approximately 4 hours and serum GH levels return to baseline within 24 hours, indicating that no accumulation of GH will occur during repeated administrations.

The absolute bioavailability of both routes is 70-90 %.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Formal carcinogenicity bioassays were not performed. This is justified, given the proteinous nature of the drug substance and the negative outcome of the genotoxicity testing. The potential effects of r-hGH on the growth of pre-existing tumours have been evaluated through in vitro and in vivo experiments which have shown that r-hGH is not expected to cause or stimulate tumours in patients.

Reproductive toxicology studies do not indicate any adverse effect on fertility and reproduction, despite administration of doses sufficiently high to produce some pharmacological effects on growth.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder:

- Mannitol, Disodium phosphate dihydrate, Sodium dihydrogen phosphate monohydrate

Solvent:

- sodium chloride (0.9 % w/v) and benzyl alcohol (0.9 % w/v, as preservative) solution for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

2 years.

After reconstitution, the product may be stored for a maximum of 7 days in a refrigerator (2°C

6.4 Special Precautions For Storage

Store in a refrigerator (2°C

For storage conditions of the reconstituted medicinal product, see section 6.3

Store the reconstituted product in a refrigerator (2°C

Do not freeze.

6.5 Nature And Contents Of Container

The 10 ml vials containing 3.33 mg of powder and the 5 ml vials containing 5 ml of solvent are of neutral glass (Type I). The vials are closed by rubber stoppers.

Saizen 3.33 mg is available in the following pack sizes:

1 vial of Saizen 3.33 mg product and 1 vial of bacteriostatic solvent.

5 vials of Saizen 3.33 mg product and 5 vials of bacteriostatic solvent.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

To reconstitute Saizen, inject 1 ml of the bacteriostatic solvent into the vial of Saizen 3.33 mg aiming the liquid against the glass wall. Swirl the vial with a gentle rotary motion until the content is dissolved completely. Avoid vigorous shaking. Discard any unused solvent.

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Serono Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

8. Marketing Authorisation Number(S)

PL 03400/0034

9. Date Of First Authorisation/Renewal Of The Authorisation

23 April 2009

10. Date Of Revision Of The Text

04/2009


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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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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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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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thiopental


Generic Name: thiopental (THYE oh PEN tal)
Brand Names: Pentothal

What is thiopental?

Thiopental is in a group of drugs called barbiturates (bar-BIT-chur-ates). Thiopental slows the activity of your brain and nervous system.

Thiopental is used to help you relax before you receive general anesthesia with an inhaled medication.

Thiopental may be used for other purposes not listed in this medication guide.

What is the most important information I should know about thiopental? You should not receive this medication if you are allergic to thiopental or other barbiturates such as amobarbital (Amytal), butabarbital (Butisol), mephobarbital (Mebaral), secobarbital (Seconal), or phenobarbital (Solfoton).

You also should not receive thiopental if you have liver disease, Addison's disease, a severe thyroid disorder (myxedema), severe heart disease, severe low blood pressure, a severe breathing disorder, or a history of porphyria (an enzyme disorder that often causes blue discoloration of the skin).

Avoid drinking alcohol for at least 24 hours after you leave the hospital or surgery center. Thiopental can cause severe drowsiness or dizziness, which may last for several hours. You will need someone to drive you home after your surgery or procedure. Do not drive yourself or do anything that requires you to be awake and alert for at least 24 hours. What should I discuss with my health care provider before I receive thiopental? You should not receive this medication if you are allergic to thiopental or other barbiturates such as amobarbital (Amytal), butabarbital (Butisol), mephobarbital (Mebaral), secobarbital (Seconal), or phenobarbital (Solfoton), or if you have:

liver disease;

Addison's disease;

severe thyroid disorder (myxedema);

severe heart disease;

severe low blood pressure;

a severe breathing disorder; or

a history of porphyria (an enzyme disorder that often causes blue discoloration of the skin).

Tell your doctor if you have any of the conditions listed above.

FDA pregnancy category C. Thiopental may be harmful to an unborn baby. Tell your doctor if you are pregnant before you receive this medication. Thiopental can pass into breast milk and may harm a nursing baby. Before you receive this medication, tell your doctor if you are breast-feeding a baby. How is thiopental given?

Thiopental is given as an injection through a needle placed into a vein. You will receive this injection in a hospital or surgical setting.

You will be given this medication while you are lying down. You will fall asleep very quickly after thiopental is injected.

Your caregivers will monitor your heart function, blood pressure, and breathing while you are under the effects of thiopental.

What happens if I miss a dose?

Since thiopental is usually given just for anesthesia, you are not likely to be on a dosing schedule.

What happens if I overdose?

An overdose of thiopental is unlikely to occur since the medication is given by a doctor. Your vital signs will be closely watched while you are under anesthesia to make sure the medication is not causing any harmful effects.

What should I avoid after receiving thiopental? Avoid drinking alcohol for at least 24 hours after you leave the hospital or surgery center. Thiopental can cause severe drowsiness or dizziness, which may last for several hours. You will need someone to drive you home after your surgery or procedure. Do not drive yourself or do anything that requires you to be awake and alert for at least 24 hours. Thiopental side effects You will remain under constant supervision during treatment with thiopental. Your caregivers will watch for any serious side effects. Tell your caregivers at once if you feel severe pain while receiving this medication.

Less serious side effects may include:

coughing;

sneezing; or

hiccups.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Thiopental Dosing Information

Usual Adult Dose for Anesthesia:

When used for induction in balanced anesthesia with a skeletal muscle relaxant and an inhalation agent:
The total dose can be estimated and then injected in two to four fractional doses. With this technique, brief periods of apnea may occur which may require assisted or controlled pulmonary ventilation. As an initial dose, 210 to 280 mg (3 to 4 mg/kg) is usually required for rapid induction in the average adult (70 kg).
When used as the sole anesthetic agent:
Moderately slow induction can usually be accomplished in the "average" adult by injection of 50 to 75 mg (2 to 3 mL of a 2.5% solution) at intervals of 20 to 40 seconds, depending on the reaction of the patient. Once anesthesia is established, additional injections of 25 to 50 mg can be given whenever the patient moves. The desired level of anesthesia can be maintained by injection of small repeated doses as needed or by using a continuous intravenous drip in a 0.2% or 0.4% concentration. With continuous drip, the depth of anesthesia is controlled by adjusting the rate of infusion.

Usual Adult Dose for Seizures:

For the control of convulsive states following anesthesia (inhalation or local) or other causes, 75 to 125 mg (3 to 5 mL of a 2.5% solution) should be given as soon as possible after the convulsion begins. Convulsions following the use of a local anesthetic may require 125 to 250 mg given over a ten minute period.

Usual Adult Dose for Coma Induction:

In neurosurgical patients, intermittent bolus injections of 1.5 to 3.5 mg/kg of body weight may be given to reduce intraoperative elevations of intracranial pressure, if adequate ventilation is provided.

Usual Adult Dose for Psychosis:

For narcoanalysis and narcosynthesis in psychiatric disorders, premedication with an anticholinergic agent may precede administration of thiopental. After a test dose, thiopental is injected at a slow rate of 100 mg/min (4 mL/min of a 2.5% solution) with the patient counting backwards from 100. Shortly after counting becomes confused but before actual sleep is produced, the injection is discontinued. Allow the patient to return to a semidrowsy state where conversation is coherent. Alternatively, thiopental may be administered by rapid IV drip using a 0.2% concentration in 5% dextrose and water. At this concentration, the rate of administration should not exceed 50 mL/min.

Usual Pediatric Dose for Anesthesia:

Induction anesthesia:
less than 1 month: 3 to 4 mg/kg intravenously
less than 1 year: 5 to 8 mg/kg intravenously
1 year to 12 years: 5 to 6 mg/kg intravenously
over 12 years: 3 to 5 mg/kg intravenously
Maintenance anesthesia:
1 year and older: 1 mg/kg intravenously as needed

Usual Pediatric Dose for Seizures:

1 year or older: 2 to 3 mg/kg/dose intravenously, repeat as needed.

Usual Pediatric Dose for Head Injury:

1 year or older: 1.5 to 5 mg/kg/dose intravenously; repeat as needed to control intracranial pressure - larger doses (30 mg/kg) to induce coma after hypoxic-ischemic injury do not appear to improve neurologic outcome.

What other drugs will affect thiopental?

Tell your doctor about all other medications you use, especially:

blood pressure medication; or

a diuretic (water pill).

This list is not complete and there may be other drugs that can interact with thiopental. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More thiopental resources Thiopental Side Effects (in more detail) Thiopental Dosage Thiopental Use in Pregnancy & Breastfeeding Thiopental Drug Interactions Thiopental Support Group 1 Review for Thiopental - Add your own review/rating Thiopental MedFacts Consumer Leaflet (Wolters Kluwer) Pentothal Prescribing Information (FDA) Pentothal Monograph (AHFS DI) Compare thiopental with other medications Anesthesia Anesthetic Adjunct Coma Induction Head Injury Psychosis Seizures Where can I get more information? Your doctor or pharmacist can provide more information about thiopental.

See also: thiopental side effects (in more detail)


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Rifamycin derivatives


A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Rifamycin derivatives are antibiotics that work by binding to and inhibiting the mycobacterial DNA dependent RNA polymerase. These antibiotics are bacteriocidal and therefore extremely effective antituberculosis agents, but resistance can develop rapidly if used as a single agent. They easily penetrate into cells, body fluids and cerebrospinal fluid so can be used against organisms in the extracellular component and those that may be present in cells such as macrophages. Rifamycin antibiotics should be used throughout the course of tuberculosis treatment, which can be between nine months to a year.

See also

Medical conditions associated with rifamycin derivatives:

Bartonellosis Endocarditis Haemophilus influenzae Prophylaxis Legionella Pneumonia Leprosy Leprosy, Borderline Leprosy, Tuberculoid Meningitis Meningococcal Meningitis Prophylaxis Mycobacterium avium-intracellulare, Prophylaxis Mycobacterium avium-intracellulare, Treatment Nasal Carriage of Staphylococcus aureus Tuberculosis, Active Tuberculosis, HIV Positive Tuberculosis, Latent Tuberculosis, Prophylaxis Drug List: Rifadin Mycobutin Priftin Rifadin-Iv Rimactane
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troleandomycin


Generic Name: troleandomycin (troe lee an doe MYE sin)
Brand Names: Tao

What is troleandomycin?

Troleandomycin is in a class of drugs called macrolide antibiotics. It fights bacteria in the body.

Troleandomycin is used to treat many different types of bacterial infections, such as tonsillitis, bronchitis, sinusitis, and pneumonia.

Troleandomycin may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about troleandomycin? Take all of the troleandomycin that has been prescribed for you even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated. What should I discuss with my healthcare provider before taking troleandomycin?

Before taking troleandomycin, tell your doctor if you have liver disease. You may not be able to take troleandomycin, or you may require special monitoring during therapy.

It is not known whether troleandomycin will be harmful to an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is also not known whether troleandomycin passes into breast milk. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. How should I take troleandomycin?

Take troleandomycin exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass (8 ounces) of water. Take all of the troleandomycin that has been prescribed for you even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated. Store this medication at room temperature away from moisture and heat.

See also: Troleandomycin dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and take the next one as directed. Do not take a double dose of this medication unless otherwise directed by your doctor.

What happens if I overdose? Seek emergency medical attention.

Symptoms of a troleandomycin overdose might include nausea, vomiting, diarrhea, and abdominal discomfort.

What should I avoid while taking troleandomycin? Avoid prolonged exposure to sunlight. Troleandomycin may increase the sensitivity of your skin to sunlight. Use a sunscreen and wear protective clothing when exposure to the sun is unavoidable. Troleandomycin side effects If you experience any of the following serious side effects, stop taking troleandomycin and seek emergency medical attention:

an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); or

liver problems (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, unusual bleeding or bruising, severe fatigue).

Other, less serious side effects may be more likely to occur. Continue to take troleandomycin and talk to your doctor if you experience

nausea, vomiting, diarrhea, or abdominal pain;

dizziness, fatigue, or headache; or

vaginal yeast infection.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

Troleandomycin Dosing Information

Usual Adult Dose for Pneumonia:

250 to 500 mg orally 4 times a day.

Usual Adult Dose for Streptococcal Infection:

250 to 500 mg orally 4 times a day.

Usual Pediatric Dose for Pneumonia:

The safety and efficacy of troleandomycin in children
>= 1 year: 125 to 250 mg every 6 hours.
When used in streptococcal infections, therapy should be continued for 10 days.

Usual Pediatric Dose for Streptococcal Infection:

The safety and efficacy of troleandomycin in children
>= 1 year: 125 to 250 mg every 6 hours.
When used in streptococcal infections, therapy should be continued for 10 days.

What other drugs will affect troleandomycin?

Before taking troleandomycin, tell your doctor if you are taking any of the following drugs:

a seizure medication such as carbamazepine (Tegretol), phenytoin (Dilantin), or valproic acid (Depakote, Depakene);

the asthma medication theophylline (Theo-Dur, Theolair, Theochron, others);

the anticoagulant (blood thinner) warfarin (Coumadin); or

another antibiotic.

Drugs other than those listed here may also interact with troleandomycin. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

More troleandomycin resources Troleandomycin Dosage Troleandomycin Drug Interactions Troleandomycin Support Group 0 Reviews for Troleandomycin - Add your own review/rating Compare troleandomycin with other medications Pneumonia Streptococcal Infection Where can I get more information? Your pharmacist has additional information about troleandomycin written for health professionals that you may read. What does my medication look like?

Troleandomycin is available with a prescription under the brand name Tao. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

Tao 250 mg--white capsules


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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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Vitamin E Suspension 100mg / ml (Cambridge Laboratories)


1. Name Of The Medicinal Product

Vitamin E Suspension 100mg/ml

2. Qualitative And Quantitative Composition

Each 5ml of suspension contains 500mg of DL-alpha-tocopheryl acetate.

3. Pharmaceutical Form

Oral Suspension

4. Clinical Particulars 4.1 Therapeutic Indications

For the correction of Vitamin E deficiency occurring in malabsorption disorders ie. cystic fibrosis, chronic cholestasis and abetalipoproteinaemia.

4.2 Posology And Method Of Administration

Route of administration: For oral use.

Adults (including the elderly)

For the treatment of malabsorption disorders the following doses should be administered:

Cystic fibrosis 100-200mg/day

Abetalipoproteinaemia 50-100mg/kg/day

Children

For the treatment of cystic fibrosis a dose of 50mg/day should be given to children less than 1 year and 100mg/day to children 1 year and over.

The adult dosage should be used for the treatment of abetalipoproteinaemia (50-100mg/kg/day).

Infants with vitamin E deficiency which is secondary to chronic cholestasis may be treated with doses of 150-200mg/kg/day.

4.3 Contraindications

Use in patients with a known hypersensitivity to Vitamin E.

4.4 Special Warnings And Precautions For Use

Vitamin E has been reported to increase the risk of thrombosis in patients predisposed to this condition, including patients taking oestrogens. This finding has not been confirmed but should be borne in mind when selecting patients for treatment, in particular women taking oral contraceptives containing oestrogens.

A higher incidence of necrotising enterocolitis has been noted in lower weight premature infants (less than 1.5kg) treated with vitamin E.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Vitamin E may increase the risk of thrombosis in patients taking oestrogens (see 4.4 above).

4.6 Pregnancy And Lactation

There is no evidence of the safety of high doses of vitamin E in pregnancy nor is there evidence from animal work that it is free from hazard, therefore do not use in pregnancy especially in the first trimester. No information is available on excretion in breast milk, therefore it is advisable not to use during lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Diarrhoea and abdominal pain may occur with doses greater than 1g daily.

4.9 Overdose

Transient gastro-intestinal disturbances have been reported with doses greater than 1g daily and where necessary, general supportive measures should be employed.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The exact role of vitamin E in the animal organism has not yet been established. Vitamin E is known to exert an important physiological function as an antioxidant for fats, with a sparing action on vitamin A, carotenoids and on unsaturated fatty acids. Other work has demonstrated that vitamin E is connected with the maintenance of certain factors essential for the normal metabolic cycle.

5.2 Pharmacokinetic Properties

Vitamin E is absorbed from the gastrointestinal tract. Most of the vitamin appears in the lymph and is then widely distributed to all tissues. Most of the dose is slowly excreted in the bile and the remainder is eliminated in the urine as glucuronides of tocopheronic acid or other metabolites.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Castor oil polyethylene glycol ether

Benzoic acid

Sorbic acid

Glycerol

Syrup

Flavour raspberry

Purified Water

6.2 Incompatibilities

None.

6.3 Shelf Life

Unopened: Two years.

After first opening: One month (The product will be stable after opening for the normal duration of treatment providing the cap is replaced after use and the recommended storage conditions on the label are observed).

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Amber glass bottles with aluminium screw caps or Vistop tamper-evident caps.

6.6 Special Precautions For Disposal And Other Handling

Vitamin E Suspension may be diluted with Syrup BP but should be used immediately and not stored.

7. Marketing Authorisation Holder

Cambridge Laboratories Limited

Deltic House

Kingfisher Way

Silverlink Business Park

Wallsend

Tyne & Wear

NE28 9NX

8. Marketing Authorisation Number(S)

PL 12070/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

8 March 1993

10. Date Of Revision Of The Text

March 2000


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Tamiflu Suspension


Pronunciation: OH-sel-TAM-i-vir
Generic Name: Oseltamivir
Brand Name: Tamiflu
Tamiflu Suspension is used for:

Treating influenza, including H1N1 influenza (swine flu), in patients 1 year of age and older who have had symptoms for no more than 2 days. It may also be used to prevent influenza in patients 1 year of age and older.

Tamiflu Suspension is an antiviral. It works by stopping the flu virus from reproducing within the body.

Do NOT use Tamiflu Suspension if: you are allergic to any ingredient in Tamiflu Suspension you are going to have an intranasal live attenuated influenza vaccine (LAIV) within the next 2 days or you have had such a vaccine within the past 2 weeks

Contact your doctor or health care provider right away if any of these apply to you.

Before using Tamiflu Suspension:

Some medical conditions may interact with Tamiflu Suspension. 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 kidney problems, liver problems, heart problems, breathing problems, or mood or mental problems

Some MEDICINES MAY INTERACT with Tamiflu Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

Intranasal live attenuated influenza vaccine (LAIV) because its effectiveness may be decreased by Tamiflu Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tamiflu Suspension 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 Tamiflu Suspension:

Use Tamiflu Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Tamiflu Suspension by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation. Shake well before each use. Use the measuring device that is provided with Tamiflu Suspension to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose. If you are taking Tamiflu Suspension to treat the flu, start taking it as soon as possible from when you begin noticing flu symptoms. If you are using Tamiflu Suspension to prevent the flu, start taking it as soon as possible, as directed by your doctor. Take Tamiflu Suspension on a regular schedule to get the most benefit from it. To clear up your infection completely, take Tamiflu Suspension for the full course of treatment. Keep taking it even if you feel better in a few days. Continue to take Tamiflu Suspension even if you feel well. Do not miss any doses. If you miss a dose of Tamiflu Suspension, take it as soon as possible. If it is within 2 hours of your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tamiflu Suspension.

Important safety information: Tamiflu Suspension is effective against influenza types A (including H1N1 influenza [swine flu]) and B. Tamiflu Suspension may cause dizziness or lightheadedness. These effects may be worse if you take it with alcohol or certain medicines. Use Tamiflu Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it. Tamiflu Suspension may cause dizziness or lightheadedness; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects. Tamiflu Suspension will not prevent you from spreading influenza to others. Tamiflu Suspension works only against influenza types A and B; it does not treat bacterial or other viral infections. Patients with flu who take Tamiflu Suspension may have an increased risk of confusion and unusual behavioral changes. The risk may be greater in children. Contact your doctor if you notice symptoms of confusion or any other unusual behavioral changes. Tell your doctor or dentist that you take Tamiflu Suspension before you receive any medical or dental care, emergency care, or surgery. Tell your doctor that you take Tamiflu Suspension before you receive any vaccines, including the intranasal live attenuated influenza vaccine (LAIV). Tamiflu Suspension is not a substitute for a flu vaccine. Continue to get an annual flu shot if your doctor has recommended it. If your symptoms do not get better within a few days or if they get worse, check with your doctor. Tamiflu Suspension has sorbitol in it. If you have hereditary fructose intolerance, check with your doctor or pharmacist before you use Tamiflu Suspension. Tamiflu Suspension should be used with extreme caution in CHILDREN younger than 1 year old; safety and effectiveness in these children have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tamiflu Suspension while you are pregnant. It is not known if Tamiflu Suspension is found in breast milk. If you are or will be breast-feeding while you use Tamiflu Suspension, check with your doctor. Discuss any possible risks to your baby. Possible side effects of Tamiflu Suspension:

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:

Diarrhea; nausea; stomach pain; vomiting.

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); abnormal behavior; confusion; hallucinations; mood or mental changes; reddened, blistered, peeling, or swollen skin; seizures; severe or persistent nausea, vomiting, or diarrhea; symptoms of infection (eg, fever, chills, persistent sore throat).

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: Tamiflu 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. Symptoms may include nausea or vomiting.

Proper storage of Tamiflu Suspension:

Store Tamiflu Suspension in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Tamiflu Suspension should be used within 10 days of preparation. Keep Tamiflu Suspension out of the reach of children and away from pets.

General information: If you have any questions about Tamiflu Suspension, please talk with your doctor, pharmacist, or other health care provider. Tamiflu Suspension 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 summary only. It does not contain all information about Tamiflu Suspension. 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 Tamiflu resources Tamiflu Side Effects (in more detail) Tamiflu Use in Pregnancy & Breastfeeding Drug Images Tamiflu Drug Interactions Tamiflu Support Group 20 Reviews for Tamiflu - Add your own review/rating Compare Tamiflu with other medications Avian Influenza Influenza Influenza Prophylaxis Swine Flu
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Folic Acid 5mg Tablets (Wockhardt UK Ltd)


FOLIC ACID 5MG TABLETS

Please read this leaflet carefully before you start to take this medicine. It gives an outline of the more important things you should know. If you want to know more about this medicine, or you are not sure about anything, ask your doctor or pharmacist. You should keep this leaflet throughout your course of treatment.

The Name Of Your Medicine Is Folic Acid 5Mg Tablets

Folic Acid 5mg Tablets contain the active ingredient folic acid. The tablet comes in one strength, 5mg.

Other ingredients in your tablet are lactose, maize starch, acacia spray-dried, magnesium stearate and stearic acid.

Folic Acid 5mg Tablets are plain yellow, biconvex tablets with breakline on one face and CP on the reverse.

Folic Acid 5mg Tablets are available in polypropylene or polyethylene tablet containers containing 100, 500 or 1000 tablets, glass bottles containing 100, 500 or 1000 tablets and blister packs containing 28 tablets.

Marketing Authorisation Holder: Wockhardt UK Limited Ash Road North Wrexham LL13 9UF UK Manufacturer: CP Pharmaceuticals Limited Ash Road North Wrexham LL13 9UF UK How Does Your Medicine Work?

Folic acid is a vitamin used to prevent or treat a deficiency (lack) of folic acid in the body.

What Are Folic Acid 5Mg Tablets For?

Folic Acid 5mg Tablets are used in adults and children for the treatment and prevention of folic acid deficiency which causes anaemia. This tends to occur in pregnancy, in patients on kidney dialysis and during treatment with some medicines.

Folic acid is also given to some women before and during pregnancy to prevent spina bifida (an abnormality of the spine) in babies, which can be caused by deficiency of this vitamin.

Before Taking This Medicine

You should not take Folic Acid 5mg Tablets if you have ever had a reaction to or been told that you are allergic to folic acid or any of the other ingredients in the tablet. Check by reading the list of ingredients above.

Before taking this medicine, you should let your doctor know if you are pregnant or breast-feeding or wish to become pregnant or start breast-feeding.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Taking another medicine while you are taking folic acid can affect how it or the other medicine works. Make sure that your doctor knows what other medicines you are taking. Do not take any other medicines while you are taking Folic Acid 5mg Tablets unless you have told your doctor or pharmacist and asked their advice. This includes medicines you may have bought yourself.

Examples of medicines that can affect Folic Acid 5mg Tablets are; Certain antibiotics (trimethoprim and sulphonamides, sometimes combined as co-trimoxazole). Some drugs used in the treatment of epilepsy (phenytoin, phenobarbital and primidone). Fluorouracil, a drug used to treat certain tumours. Some indigestion remedies (edible clay and antacids containing aluminium or magnesium). Allow at least a two hour gap between taking your Folic Acid Tablets and indigestion remedies. Preparations containing zinc such as vitamins or food supplements (this may be important in pregnancy).

If you have any doubts about whether you should take this medicine then talk to your doctor.

Advice When Taking Folic Acid 5Mg Tablets Patients with pernicious anaemia (or the possibility of pernicious anaemia) should be given Vitamin B12 as well as folic acid. Care needs to be taken in patients with certain tumours. Taking This Medicine

In adults and children over one year, the usual dose of Folic Acid 5mg Tablets is one tablet a day for the treatment of anaemia or one tablet every one to seven days for the prevention of anaemia.

Children under one year should be given 500 micrograms per kilogram of body weight daily.

The usual dose for the prevention of spina bifida is one tablet a day, starting before conception and continuing for the first three months of pregnancy.

To obtain a tablet, press on the tablet from the blister (or bubble) side, pushing it through the foil. Do not remove the tablet from the blister until you are ready to take it.

Your doctor will decide the dose that is best for you. Always follow your doctor's instructions completely. Also, follow any instructions or warnings that appear on the label that the pharmacist may put on the pack. If you do not understand, or are in any doubt, ask your doctor or pharmacist.

Unless told otherwise, take your tablet with water.

You should take your medicine for as long as your doctor tells you to. If you forget to take a dose, take another as soon as you remember. If it is almost time for your next dose, then do not take the missed dose at all. Never double the next dose to make up for the one missed. Do not stop taking the medicine without talking to your doctor first.

If you accidentally take too many tablets you should contact your doctor, pharmacist or nearest hospital casualty department immediately. Take this leaflet and any tablets you have left to show the doctor or pharmacist.

Are There Any Side-Effects?

Like many medicines Folic Acid 5mg Tablets may cause side-effects in some patients, particularly when you first start taking them. The side-effects that some other patients have had with Folic Acid 5mg Tablets include loss of appetite, feeling sick, bloating of the stomach and wind. Allergic reactions are rare.

If you experience any other side-effects or feel that the medicine is affecting you badly, tell your doctor or pharmacist.

Safe Keeping For This Medicine

Do not take this medicine if the expiry date on the label has passed or if the tablets show signs of “going off” such as discoloration.

These tablets should not be stored above 25°C. Store in the original package in order to protect from light. Do not transfer Folic Acid 5mg Tablets to another container.

Keep Folic Acid 5mg Tablets out of the reach and sight of children.

Remember this medicine is for you only. Never give it to anyone else. It may harm them, even if their symptoms are the same as yours.

Unless your doctor tells you to, do not keep medicines that you no longer need. Give them back to your pharmacist.

Other formats:

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK Only)

Please be ready to give the following information:

Product Name
Folic Acid 5mg Tablets

Reference Number
29831/0097

This is a service provided by the Royal National Institute of the Blind.

DATE OF REVISION September 2007

CP1

103583/1


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Zymaxid


Generic Name: gatifloxacin (Ophthalmic route)

gat-i-FLOX-a-sin

Commonly used brand name(s)

In the U.S.

Zymar Zymaxid

Available Dosage Forms:

Solution

Therapeutic Class: Antibiotic

Chemical Class: Fluoroquinolone

Uses For Zymaxid

Gatifloxacin ophthalmic (eye) preparation is used to treat infections of the eye, such as bacterial conjunctivitis. Gatifloxacin belongs to a group of medicines called fluoroquinolone antibiotics. It works by killing bacteria that cause conjunctivitis.

This medicine is available only with your doctor's prescription.

Before Using Zymaxid

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

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Zymaxid™ in children. However, safety and efficacy have not been established in children younger than 1 year of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Zymaxid™ in the elderly.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. 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.

Proper Use of gatifloxacin

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

Your doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your doctor tells you to. This medicine is not for long-term use.

To use the eye drops:

First, wash your hands. Then tilt the head back and pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close the eyes. Do not blink. Keep the eyes closed for 1 or 2 minutes to allow the medicine to come into contact with the infection. If you think you did not get the drop of medicine into your eye properly, repeat the directions with another drop. To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

To help clear up your eye infection completely, keep using this medicine for the full time of treatment, even if your symptoms have disappeared and even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon. Do not miss any doses.

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 ophthalmic dosage form (eye drops): For bacterial conjunctivitis: Adults and children 1 year of age and older— Day 1: Put one drop in the affected eye every two hours while awake, up to 8 times. Days 2 through 7: Put one drop in the affected eye two to four times a day while awake. Infants younger than 1 year of age—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Zymaxid

If your eye infection does not improve within a few days, or if it becomes worse, check with your doctor.

Stop using this medicine and check with your doctor right away if you have a rash, itching, or red or swollen skin around the eye or eyelid. These may be symptoms of an allergic reaction.

Do not wear contact lenses while you are using this medicine to avoid further eye irritation.

Zymaxid 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 immediately if any of the following side effects occur:

More common Eye irritation eye pain eye redness Less common Bloody eye decrease in vision swelling of the membrane covering the white part of the eye

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:

More common Blurred vision discharge from the eyes itching eyes stringy mucus secretions swelling of the eye, eyelid, or inner lining of the eyelid watering eyes Less common Bad, unusual, or unpleasant (after) taste change in taste dry eye headache

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: Zymaxid 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 Zymaxid resources Zymaxid Side Effects (in more detail) Zymaxid Use in Pregnancy & Breastfeeding Zymaxid Support Group 0 Reviews for Zymaxid - Add your own review/rating Zymaxid Consumer Overview Zymaxid Prescribing Information (FDA) Zymar Prescribing Information (FDA) Zymar eent Monograph (AHFS DI) Zymar Drops MedFacts Consumer Leaflet (Wolters Kluwer) Compare Zymaxid with other medications Conjunctivitis Conjunctivitis, Bacterial
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Zymar


Generic Name: gatifloxacin (Ophthalmic route)

gat-i-FLOX-a-sin

Commonly used brand name(s)

In the U.S.

Zymar Zymaxid

Available Dosage Forms:

Solution

Therapeutic Class: Antibiotic

Chemical Class: Fluoroquinolone

Uses For Zymar

Gatifloxacin ophthalmic (eye) preparation is used to treat infections of the eye, such as bacterial conjunctivitis. Gatifloxacin belongs to a group of medicines called fluoroquinolone antibiotics. It works by killing bacteria that cause conjunctivitis.

This medicine is available only with your doctor's prescription.

Before Using Zymar

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

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Zymaxid™ in children. However, safety and efficacy have not been established in children younger than 1 year of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Zymaxid™ in the elderly.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. 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.

Proper Use of gatifloxacin

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

Your doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your doctor tells you to. This medicine is not for long-term use.

To use the eye drops:

First, wash your hands. Then tilt the head back and pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close the eyes. Do not blink. Keep the eyes closed for 1 or 2 minutes to allow the medicine to come into contact with the infection. If you think you did not get the drop of medicine into your eye properly, repeat the directions with another drop. To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

To help clear up your eye infection completely, keep using this medicine for the full time of treatment, even if your symptoms have disappeared and even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon. Do not miss any doses.

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 ophthalmic dosage form (eye drops): For bacterial conjunctivitis: Adults and children 1 year of age and older— Day 1: Put one drop in the affected eye every two hours while awake, up to 8 times. Days 2 through 7: Put one drop in the affected eye two to four times a day while awake. Infants younger than 1 year of age—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Zymar

If your eye infection does not improve within a few days, or if it becomes worse, check with your doctor.

Stop using this medicine and check with your doctor right away if you have a rash, itching, or red or swollen skin around the eye or eyelid. These may be symptoms of an allergic reaction.

Do not wear contact lenses while you are using this medicine to avoid further eye irritation.

Zymar 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 immediately if any of the following side effects occur:

More common Eye irritation eye pain eye redness Less common Bloody eye decrease in vision swelling of the membrane covering the white part of the eye

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:

More common Blurred vision discharge from the eyes itching eyes stringy mucus secretions swelling of the eye, eyelid, or inner lining of the eyelid watering eyes Less common Bad, unusual, or unpleasant (after) taste change in taste dry eye headache

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: Zymar 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 Zymar resources Zymar Side Effects (in more detail) Zymar Use in Pregnancy & Breastfeeding Zymar Support Group 6 Reviews for Zymar - Add your own review/rating Zymar Prescribing Information (FDA) Zymar eent Monograph (AHFS DI) Zymar Drops MedFacts Consumer Leaflet (Wolters Kluwer) Zymaxid Prescribing Information (FDA) Zymaxid Consumer Overview Compare Zymar with other medications Conjunctivitis Conjunctivitis, Bacterial Ophthalmic Surgery
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Lamisil AT 1% Spray


1. Name Of The Medicinal Product

Lamisil® AT 1% Spray

2. Qualitative And Quantitative Composition

10mg terbinafine hydrochloride per 1g spray solution

For excipients, see Section 6.1.

3. Pharmaceutical Form

Cutaneous spray, solution

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of tinea pedis (athlete's foot) and tinea cruris, (dhobie (jock) itch) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum) and Epidermophyton floccosum.

4.2 Posology And Method Of Administration

Adults

Lamisil AT 1% Spray is applied once daily, for one week. Cleanse and dry the affected areas thoroughly before applying Lamisil AT 1% Spray from a distance of 5 to 10 cm. A sufficient amount of spray solution should be applied to wet the treatment area(s) thoroughly, and to cover the affected skin and surrounding area.

Duration and frequency of treatment:

Interdigital type tinea pedis, and tinea cruris: Once a day for one week.

Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, a physician should be consulted.

Use of Lamisil AT 1% Spray in the elderly

There is no evidence to suggest that elderly patients require different dosages or experience side effects different from those in younger patients.

Use of Lamisil AT 1% Spray in children

Not to be used in children under 16 years of age. Experience with Lamisil AT 1% Spray in children is limited and its use cannot, therefore, be recommended.

4.3 Contraindications

Known hypersensitivity to terbinafine or any of the excipients contained in the spray solution (see 6.1 List of excipients).

4.4 Special Warnings And Precautions For Use

Lamisil AT 1% Spray should be used with caution in patients with lesions where alcohol could be irritating.

Lamisil AT 1% Spray is for external use only. It may be irritating to the eyes. Lamisil AT 1% Spray should not be used on the face.

In case of accidental contact with the eyes, rinse eyes thoroughly with running water.

Avoid inhalation. In case of accidental inhalation, consult a physician if any symptoms develop or persist.

Lamisil AT 1% Spray should be kept out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No drug interactions are known with Lamisil AT 1% Spray, however as a precaution it is recommended that other medicinal products are not applied on the treated areas.

4.6 Pregnancy And Lactation

Animal studies did not reveal any teratogenic or embryofoetotoxic potential of terbinafine. No cases of malformations in humans have been reported with Lamisil to date. However, since clinical experience in pregnant women is very limited, Lamisil AT 1% Spray should be used only if clearly indicated during pregnancy. Terbinafine is excreted in breast milk and therefore, mothers should not receive Lamisil AT 1% Spray whilst breast-feeding. Infants should also not be allowed to come into contact with any treated skin, including the breast.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Redness, itching or stinging may occur at the site of application; however, treatment rarely has to be discontinued for this reason. These harmless symptoms must be distinguished from allergic reactions such as pruritus, rash, bullous eruptions and hives, which are rare but require discontinuation.

4.9 Overdose

No case of overdosage has been reported with Lamisil AT 1% Spray. Should, however, Lamisil AT 1% Spray be inadvertently ingested, adverse effects similar to those observed with an overdosage of Lamisil Tablets (e.g. headache, nausea, epigastric pain and dizziness) are to be expected. The alcohol content (23.5%) of the spray solution has to be taken into account.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antifungal for topical use (ATC code D01 A)

Terbinafine is an allylamine which has a broad spectrum of antifungal activity in fungal infections of the skin caused by dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum. At low concentrations terbinafine is fungicidal against dermatophytes and moulds. The activity against yeasts is fungicidal (e.g. Pityrosporum orbiculare or Malassezia furfur) or fungistatic, depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme squalene epoxidase is not linked to the cytochrome P450 system. Terbinafine does not influence the metabolism of hormones or other drugs.

5.2 Pharmacokinetic Properties

Less than 5% of the dose is absorbed after topical application to humans; systemic exposure is thus very slight.

5.3 Preclinical Safety Data

In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.

In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats at the highest dose level, 69mg/kg a day, an increased incidence of liver tumours was observed in males. The changes, which may be associated with peroxisome proliferation, have been shown to be species-specific since they were not seen in the carcinogenicity study in mice or in other studies in mice, dogs or monkeys.

During the studies of high dose oral terbinafine in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level was 50mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.

A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of a mutagenic or clastogenic potential for the drug.

No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Purified water

Ethanol (23.5% w/w)

Propylene glycol

Cetomacrogol 1000

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C. Do not refrigerate.

6.5 Nature And Contents Of Container

Lamisil AT 1% Spray is available as a white round HDPE bottle with a crimped mouth and spray pump in pack sizes of 15ml and 30ml.

6.6 Special Precautions For Disposal And Other Handling

See 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use.

For manipulation of the spray pump the bottle can be held in the upright or inverted position.

When using Lamisil AT 1% Spray for the first time, the patient will need to depress the actuator a few times (usually up to 3 actuations) before the solution is dispensed.

7. Marketing Authorisation Holder

Novartis Consumer Health UK Ltd.

Wimblehurst Road

Horsham

RH12 5AB

UK

Trading as Novartis Consumer Health

8. Marketing Authorisation Number(S)

PL 00030/0147

9. Date Of First Authorisation/Renewal Of The Authorisation

7th December 2001

10. Date Of Revision Of The Text

27th April 2009

Legal Category: GSL


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