Flexbumin


albumin human
Dosage Form: injection
Flexbumin 25% Albumin (Human), USP, 25% Solution in GALAXY single-dose container Flexbumin Description

Flexbumin 25%, Albumin (Human), 25% Solution is a sterile, nonpyrogenic preparation of albumin in a single dosage form for intravenous administration.  Each 100 ml contains 25 g of albumin and was prepared from human venous plasma using the Cohn cold ethanol fractionation process.  Source material for fractionation may be obtained from another U.S. licensed manufacturer.  It has been adjusted to physiological pH with sodium bicarbonate and/or sodium hydroxide and stabilized with  N-acetyltryptophan and sodium caprylate.  The sodium content is 145 ± 15 mEq/L.  This solution contains no preservative and none of the coagulation factors found in fresh whole blood or plasma. 

Flexbumin 25%, Albumin (Human), 25% Solution is a transparent or slightly opalescent solution which may have a greenish tint or may vary from a pale straw to an amber color.

The likelihood of the presence of viable hepatitis viruses has been minimized by heating the product for 10 hours at 60°C.  This procedure has been shown to be an effective method of inactivating hepatitis virus in albumin solutions even when those solutions were prepared from plasma known to be infective.1-3

The GALAXY plastic container is fabricated from a specially designed multilayered plastic (PL 2501).  Solutions are in contact with the polyethylene layer of the container and can leach out certain chemical components of the plastic in very small amounts within the expiration period.  The suitability and safety of the plastic have been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

Flexbumin - Clinical Pharmacology

Albumin is responsible for 70-80% of the colloid osmotic pressure of normal plasma, thus making it useful in regulating the volume of circulating blood.4-6  Albumin is also a transport protein and binds naturally occurring, therapeutic and toxic materials in the circulation.5,6

Flexbumin 25%, Albumin (Human), 25% Solution is osmotically equivalent to approximately five times its volume of human plasma.  When injected intravenously, 25% albumin will draw about 3.5 times its volume of additional fluid into the circulation within 15 minutes, except when the patient is markedly dehydrated.  This extra fluid reduces hemoconcentration and blood viscosity.  The degree and duration of volume expansion depends upon the initial blood volume.  With patients treated for diminished blood volume, the effect of infused albumin may persist for many hours; however, in patients with normal volume, the duration will be shorter.7,8

Total body albumin is estimated to be 350 g for a 70 kg man and is distributed throughout the extracellular compartments; more than 60% is located in the extravascular fluid compartment.  The half-life of albumin is 15 to 20 days with a turnover of approximately 15 g per day.5

The minimum plasma albumin level necessary to prevent or reverse peripheral edema is unknown.  Some investigators recommend that plasma albumin levels be maintained at approximately 2.5 g/dL.  This concentration provides a plasma oncotic value of 20 mm Hg.4

Flexbumin 25%, Albumin (Human) 25% Solution is manufactured from human plasma by the modified Cohn-Oncley cold ethanol fractionation process, which includes a series of cold-ethanol precipitation, centrifugation and/or filtration steps followed by pasteurization of the final product at 60 ± 0.5°C for 10 - 11 hours.  This process accomplishes both purification of albumin and reduction of viruses.

In vitro studies, demonstrate that the manufacturing process for Flexbumin 25%, Albumin (Human), 25% Solution provides for significant viral reduction.  These viral reduction studies, summarized in Table 1, demonstrate viral clearance during the manufacturing process for Flexbumin 25%, Albumin (Human), 25% Solution using human immunodeficiency virus, type 1 (HIV-1) both as a target virus and as model virus for HIV-2 and other enveloped RNA viruses; bovine viral diarrheal virus (BVDV), a model for lipid enveloped RNA viruses, such as hepatitis C virus (HCV); West Nile Virus (WNV), a target virus and model for other similar enveloped RNA viruses; pseudorabies virus (PRV), a model for other enveloped DNA viruses such as hepatitis B virus (HBV);  mice minute virus (MMV), models for non-lipid enveloped DNA viruses such as human parvovirus B 1912; and hepatitis A virus (HAV), a target virus and a model for other non-lipid enveloped RNA viruses.

These studies indicate that specific steps in the manufacture of Flexbumin 25%, Albumin (Human), 25% Solution are capable of eliminating/inactivating a wide range of relevant and model viruses.  Since the mechanism of virus elimination/inactivation at specific process steps is different, the overall manufacturing process of Flexbumin 25%, Albumin (Human), 25% Solution is robust in reducing viral load.

TABLE 1
Summary of Viral Reduction Factor for Each Virus and Processing Step * Other Abumin fractionation process steps (processing of cryo-poor plasma to Fraction I+II+III/II+III supernatant and processing of Fraction V suspension to Cuno 90LP filtrate) showed significant virus reduction capacity in in vitro viral clearance studies. These process steps also contribute to the overall viral clearance robustness of the manufacturing process. However, since the mechanism of virus removal is similar to that of this particular process step, the viral inactivation data from other steps were not used in the calculation of the Mean Cumulative Reduction Factor. † n.d. = not determined ‡ Recent scientific data suggest that the actual human parvovirus B19 (B19V), is far more effectively inactivated by pasteurization than indicated by model virus data12. Process Step Viral Reduction Factor (log10) Lipid Enveloped Non-Lipid Enveloped HIV-1 Flaviviridae PRV HAV Parvoviridae BVDV WNV MMV         Processing of Fraction I+II+III/II + III supernatant to Fraction IV4 Cuno 70C filtrate* > 4.9 > 4.8 > 5.7 >5.5 >4.5 3.0 Pasteurization > 7.8 > 6.5 n.d.† > 7.4 3.2 1.6‡ Mean Cumulative Reduction Factor > 12.7 > 11.3 > 5.7 > 12.9 > 7.7 4.6 Indications and Usage for Flexbumin
1. Hypovolemia

Hypovolemia is a possible indication for Flexbumin 25%, Albumin (Human), 25% Solution. Its effectiveness in reversing hypovolemia depends largely upon its ability to draw interstitial fluid into the circulation.  It is most effective with patients who are well hydrated.
When hypovolemia is long standing and hypoalbuminemia exists accompanied by adequate hydration or edema, 25% albumin is preferable to 5% protein solutions.4,6   However, in the absence of adequate or excessive hydration, 5% protein solutions should be used or 25% albumin should be diluted with crystalloid.
Although crystalloid solutions and colloid-containing plasma substitutes can be used in emergency treatment of shock, Albumin (Human) has a prolonged intravascular half-life.9  When blood volume deficit is the result of hemorrhage, compatible red blood cells or whole blood should be administered as quickly as possible.

2. Hypoalbuminemia

A.  General

Hypoalbuminemia is another possible indication for use of Flexbumin 25%, Albumin (Human), 25% Solution.  Hypoalbuminemia can result from one or more of the following:5

(1)    Inadequate production (malnutrition, burns, major injury, infections, etc.)

(2)    Excessive catabolism (burns, major injury, pancreatitis, etc.)

(3)    Loss from the body (hemorrhage, excessive renal excretion, burn exudates, etc.)

(4)    Redistribution within the body (major surgery, various inflammatory conditions, etc.)

When albumin deficit is the result of excessive protein loss, the effect of administration of albumin will be temporary unless the underlying disorder is reversed.  In most cases, increased nutritional replacement of amino acids and/or protein with concurrent treatment of the underlying disorder will restore normal plasma albumin levels more effectively than albumin solutions.  Occasionally hypoalbuminemia accompanying severe injuries, infections or pancreatitis cannot be quickly reversed and nutritional supplements may fail to restore serum albumin levels.  In these cases, Flexbumin 25%, Albumin (Human), 25% Solution might be a useful therapeutic adjunct.

B.   Burns

An optimum regimen for the use of albumin, electrolytes and fluid in the early treatment of burns has not been established, however, in conjunction with appropriate crystalloid therapy, Flexbumin 25%, Albumin (Human), 25% Solution may be indicated for treatment of oncotic deficits after the initial 24 hour period following extensive burns and to replace the protein loss which accompanies any severe burn.4,6

C.   Adult Respiratory Distress Syndrome (ARDS)

A characteristic of ARDS is a hypoproteinemic state, which may be causally related to the interstitial pulmonary edema.  Although uncertainty exists concerning the precise indication of albumin infusion in these patients, if there is a pulmonary overload accompanied by hypoalbuminemia, 25% albumin solution may have a therapeutic effect when used with a diuretic.4

D.   Nephrosis

Flexbumin 25%, Albumin (Human), 25% Solution may be a useful aid in treating edema in patients with severe nephrosis who are receiving steroids and/or diuretics.

3. Cardiopulmonary Bypass Surgery

Flexbumin 25%, Albumin (Human), 25% Solution has been recommended prior to or during cardiopulmonary bypass surgery, although no clear data exist indicating its advantage over crystalloid solutions. 4,6,10

4. Hemolytic Disease of the Newborn (HDN)

Flexbumin 25%, Albumin (Human), 25% Solution may be administered in an attempt to bind and detoxify unconjugated bilirubin in infants with severe HDN.

There is no valid reason for use of albumin as an intravenous nutrient.

CONTRAINDICATONS

A history of allergic reactions to albumin is a specific contraindication to the use of this product.  Flexbumin 25%, Albumin (Human), 25% Solution is also contraindicated in severely anemic patients and in patients with cardiac failure.

Warnings

Do not use if turbid.  Do not begin administration more than 4 hours after the container has been entered.  Discard unused portion.

There exists a risk of potentially fatal hemolysis and acute renal failure from the inappropriate use of Sterile Water for Injection as a diluent for Flexbumin 25%, Albumin (Human), 25% Solution.  Acceptable diluents include 0.9% Sodium Chloride or 5% Dextrose in Water.

Flexbumin 25%, Albumin (Human), 25% Solution is made from human plasma.  Products made from human plasma may contain infectious agents, such as viruses, that can cause disease.  The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses (See Description).  Despite these measures, such products can still potentially transmit disease.  Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk for transmission of viral diseases.  A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.  ALL infections thought by a physician possibly to have been transmitted by this product, should be reported by the physician, or other healthcare provider to Baxter Healthcare Corporation at 1-800-423-2862.  The physician should discuss the risks and benefits of this product with the patient.

Precautions

Flexbumin 25%, Albumin (Human), 25% Solution must be administered intravenously at a rate not to exceed 1ml/min to patients with normal blood volume.  More rapid administration might cause circulatory overload and pulmonary edema.

A rise in blood pressure after 25% albumin infusion necessitates careful observation of the injured or post-operative patient in order to detect and treat severed blood vessels that may not have bled at a lower blood pressure.

Pregnancy-Category C

Animal reproduction studies have not been conducted with Flexbumin 25%, Albumin (Human), 25% Solution.  It is not known whether Flexbumin 25%, Albumin (Human), 25% Solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.  Flexbumin 25%, Albumin (Human), 25% Solution should be given to a pregnant woman only if clearly needed.

Pediatric Use

The safety of albumin solutions has been demonstrated in children provided the dose is appropriate for body weight, however, the safety of Flexbumin 25%, Albumin (Human), 25% Solution has not been evaluated in pediatric patients.

Adverse Reactions

Untoward reactions to Flexbumin 25%, Albumin (Human), 25% Solution are extremely rare, although nausea, fever, chills or urticaria may occasionally occur.  Such symptoms usually disappear when the infusion is slowed or stopped for a short period of time.

Flexbumin Dosage and Administration

Flexbumin 25%, Albumin (Human), 25% Solution must be administered intravenously.  This solution may be administered in conjunction with or combined with other parenterals such as whole blood, plasma, saline, glucose or sodium lactate.  The addition of four volumes of normal saline or 5% glucose to 1 volume of Flexbumin 25%, Albumin (Human), 25% Solution gives a solution, which is approximately isotonic and isosmotic with citrated plasma.

Albumin solutions should not be mixed with protein hydrolysates or solutions containing alcohol.


Recommended Dosages

1.   Hypovolemic Shock
The dosage of Flexbumin 25%, Albumin (Human), 25% Solution must be individualized.  As a guideline, the initial treatment should be in the range of 100 to 200 ml for adults and 2.5 to 5 ml per kilogram body weight for children.  This may be repeated after 15 to 30 minutes, if the response is not adequate.  For patients with significant plasma volume deficits, albumin replacement is best administered in the form of 5% Albumin (Human).

Upon administration of additional albumin or if hemorrhage has occurred, hemodilution and a relative anemia will follow.  This condition should be controlled by the supplemental administration of compatible red blood cells or compatible whole blood.

2.   Burns
The optimal therapeutic regimen for administration of crystalloid and colloid solutions after extensive burns has not been established.  When Flexbumin 25%, Albumin (Human), 25% Solution is administered after the first 24 hours following burns, the dose should be determined according to the patient’s condition and response to treatment.

3.    Hypoalbuminemia
Hypoalbuminemia is usually accompanied by a hidden extravascular albumin deficiency of equal magnitude.  This total body albumin deficit must be considered when determining the amount of albumin necessary to reverse the hypoalbuminemia.  When using patient’s serum albumin concentration to estimate the deficit, the body albumin compartment should be calculated to be 80 to100 ml per kg of body weight.5,6  Daily dose should not exceed 2 g of albumin per kilogram of body weight.

4.   Hemolytic Disease of the Newborn
Flexbumin 25%, Albumin (Human), 25% Solution may be administered prior to or during exchange transfusion in a dose of 1 g per kilogram body weight.11 Preparation of Administration

Check the GALAXY container for minute leaks prior to use by squeezing the bag firmly.  If leaks are found, discard solution as sterility may be impaired.  Do not add supplementary medication.  Do not use unless solution is clear and seal is intact.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete.

Preparation for administration:

1.    Suspend container from eyelet support.

2.    Remove plastic protector from outlet port at bottom of container.

3.    Attach administration set.  Refer to complete directions accompanying set.  Make certain that the administration set contains an adequate filter.

How is Flexbumin Supplied

Flexbumin 25%, Albumin (Human), 25% Solution is supplied in 50 ml (NDC 0944-0493-01) and 100 ml (NDC 0944-0493-02) in single dose GALAXY plastic container (PL 2501).

STORAGE

Store Flexbumin 25%, Albumin (Human), 25% Solution at room temperature, not to exceed 30°C (86°F).  Protect from freezing.

REFERENCES

1.  Gellis SS, Neefe JR, Stokes J Jr, et al: Chemical, clinical and immunological studies on the products of human plasma fractionation.  XXXVI.  Inactivation of the virus of homologous serum hepatitis in solutions of normal human serum albumin by means of heat.  J Clin Invest 27:239-244, 1948

2.  Gerety RJ, Aronson DL: Plasma derivatives and viral hepatitis.  Transfusion 22:347?351, 1982

3.  Murray R, Diefenbach WCL, Geller H, et al: Problem of reducing danger of serum hepatitis from blood and blood products.  NY State J Med 55:1145-1150, 1955

4.  Tullis JL: Albumin 1.  Background and use, and 2.  Guidelines for clinical use. JAMA 237:355-360, 460-463, 1977

5.  Peters T Jr: Serum albumi, in The Plasma Proteins, 2nd ed, Vol 1.  Putnam FW (ed).  New York, Academic Press, 1975, pp 133-181

6.  Finlayson JS: Albumin products.  Semin Thromb Hemostas. 6:85-120, 1980

7.  Janeway CA, Berenberg W, Hutchins G: Indications and uses of blood, blood derivatives and blood substitutes.  Med Clin N Amer 29:1069-1094, 1945

8.  Janeway CA, Gibson ST, Woodruff LM, et al: Chemical, clinical and immunological studies on the products of human plasma fractionation.  VII.  Concentrated human serum albumin.  J Clin Invest 23:465-490, 1944

9.  Shoemaker WC, Schluchter M, Hopkins JA, el at: Comparison of the relative effectiveness of colloids and crystalloids in emergency resuscitation.  Am J Surg 142:73-83, 1981.

10. Lowenstein E, Hallowell P, Bland JHL: Use of colloid and crystalloid solutions in open heart surgery: Physiological basis and clinical results in, Proceedings of the Workshop on Albumin.  Sgouris JT, Rene A (eds).  DHEW Publication No. (NIH) 76-925, Washington, DC, US Government Printing Office, 1976, pp 195-210

11. Tsao YC, Yu VYH: Albumin in management of neonatal hyperbilirubinaemia.  Arch Dis Childhood 47:250-256, 1972

12. J. Blumel et al., Inactivation of Parvovirus B19 During Pasteurization of Human Serum Albumin.  Transfusion 42: 1011-1018, 2002

To enroll in the confidential industry-wide Patient Notification System, call 1-888-UPDATE U (1-888-873-2838).

Baxter, Flexbumin and GALAXY are trademarks of Baxter International Inc.

Baxter Healthcare Corporation
Westlake Village, CA 91362  USA
U.S. License No. 140


Flexbumin   25%
albumin human  solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0944-0493 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Albumin human (Albumin human) Albumin human 0.25 g  in 1 mL Inactive Ingredients Ingredient Name Strength acetyltryptophan   Sodium caprylate   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0944-0493-01 50 mL In 1 BAG None 2 0944-0493-02 100 mL In 1 BAG None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA bla101452 01/06/2006
Labeler - Baxter Healthcare Corporation (123412376) Establishment Name Address ID/FEI Operations Baxter Healthcare Corporation 194684502 manufacture Revised: 06/2007Baxter Healthcare Corporation More Flexbumin resources Flexbumin Side Effects (in more detail) Flexbumin Use in Pregnancy & Breastfeeding Flexbumin Support Group 0 Reviews for Flexbumin - Add your own review/rating Flexbumin Consumer Overview Albumin Human Monograph (AHFS DI) Albuminar-25 Albuminar-5 Albutein MedFacts Consumer Leaflet (Wolters Kluwer) Compare Flexbumin with other medications Burns, External Hypoproteinemia Pancreatitis Peritonitis Postoperative Albumin Loss Shock
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Mesnex


mesna
Dosage Form: tablet, injection
Mesnex (mesna) Injection
Mesnex (mesna) Tablets
Rx only Mesnex Description

Mesnex is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide (IFEX ). The active ingredient mesna is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:

HS—CH2—CH2SO3—Na+

Mesnex Injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. Mesnex Injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesnex Injection multidose vials also contain 10.4 mg of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.

Mesnex Tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg mesna. Excipients include lactose, microcrystalline cellulose, calcium phosphate, cornstarch, povidone, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, and simethicone.

Mesnex - Clinical Pharmacology Mechanism of Action

Mesnex was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced by ifosfamide.

Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly eliminated by the kidneys.

In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites.

In multiple human xenograft or rodent tumor model studies of limited scope, using IV or IP routes of administration, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate interference with antitumor efficacy.

Pharmacokinetics

At doses of 2-4 g/m2, the terminal elimination half-life of ifosfamide is about 4-8 hours. As a result, in order to maintain adequate levels of mesna in the urinary bladder during the course of elimination of the urotoxic ifosfamide metabolites, repeated doses of Mesnex are required.

IV-IV-IV Regimen

After intravenous administration of an 800-mg dose, the half-lives of mesna and dimesna in the blood are 0.36 hours and 1.17 hours, respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours. Mesna has a plasma clearance of 1.23 L/h/kg.

IV-Oral-Oral Regimen

The half-life of mesna ranged from 1.2-8.3 hours after administration of intravenous plus oral doses of Mesnex, as recommended in the DOSAGE AND ADMINISTRATION section. The urinary bioavailability of oral mesna ranged from 45-79% of intravenously administered mesna. Food does not affect the urinary availability of orally administered mesna. Approximately 18-26% of the combined intravenous and oral mesna dose appears as free mesna in the urine. When compared to intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures (150%) and provides more sustained excretion of mesna in the urine over a 24-hour period. Approximately 5% of the mesna dose is excreted during the 12-24 hour interval, as compared to negligible amounts in patients given the IV regimen. The fraction of the administered dose of mesna excreted in the urine is independent of dose. Protein binding of mesna is in a moderate range (69-75%).

Special Populations Gender Effect

An analysis was conducted in four male and four female volunteers; no differences in plasma pharmacokinetics were detected.

Pediatrics and Geriatrics

Pharmacokinetic data of Mesnex in pediatric and geriatric patients are not available.

Hepatic and Renal Insufficiency

No clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of Mesnex.

Drug-Drug Interaction

No clinical drug interaction studies have been conducted with Mesnex.

Clinical Studies IV Mesna

Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 1). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16-26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC/hpf or macrohematuria) (Morgan, Einhorna, Costanzi). In contrast, none of the patients who received Mesnex Injection together with this dose of ifosfamide developed hematuria (Einhorna,b ). In two randomized studies, (Fukuoka, Scheef), higher doses of ifosfamide, from 2 to 4 g/m2 administered for 3-5 days, produced hematuria in 31-100% of the patients. When Mesnex was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

* Ifosfamide dose 1.2 g/m2 d x 5 † Ifosfamide dose 2 to 4 g/m2 d x 3-5 Table 1 Percent of Mesnex Patients Developing Hematuria (?50 RBC/hpf or macrohematuria) Study Conventional Uroprophylaxis (number of patients) Standard Mesnex IV Regimen (number of patients) Uncontrolled Studies     MORGAN* 16% (7/44) - COSTANZI* 26% (11/43) - EINHORNa* 18% (7/38) 0% (0/21) EINHORNb* - 0% (0/32) Controlled Studies     FUKUOKA† 31% (14/46) 6% (3/46) SCHEEF† 100% (7/7) 0% (0/8) Oral Mesna

Clinical studies comparing recommended intravenous and oral mesna dosing regimens demonstrated incidences of grade 3-4 hematuria of <5%. Study D07093-0018 was an open label, randomized, two-way crossover study comparing three IV doses with an initial IV dose followed by two oral doses of mesna in patients with cancer treated with ifosfamide at a dose of 1.2-2.0 g/m2 for 3-5 days. Study MED504 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 2.

Table 2 Percent of Mesnex Patients Developing Grade 3 or 4 Hematuria   Mesnex Dosing Regimen Study Standard IV Regimen (number of patients) IV + Oral Regimen (number of patients) D07093-0018 0% (0/30) 3.6% (1/28) MED504 3.7% (1/27) 4.3% (1/23)

A crossover pharmacokinetic study supports the low incidence of grade 3 or 4 hematuria with the recommended intravenous and oral mesna dosing regimens used in the two controlled studies.

Indications and Usage for Mesnex

Mesnex is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

Contraindications

Mesnex is contraindicated in patients known to be hypersensitive to mesna or other thiol compounds.

Warnings

Allergic reactions to mesna ranging from mild hypersensitivity to systemic anaphylactic reactions have been reported. Patients with autoimmune disorders who were treated with cyclophosphamide and mesna appeared to have a higher incidence of allergic reactions. The majority of these patients received mesna orally.

Mesnex has been developed as an agent to reduce the risk of ifosfamide-induced hemorrhagic cystitis. It will not prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide therapy.

Mesnex does not prevent hemorrhagic cystitis in all patients. Up to 6% of patients treated with mesna have developed hematuria (>50 RBC/hpf or WHO grade 2 and above). As a result, a morning specimen of urine should be examined for the presence of hematuria (microscopic evidence of red blood cells) each day prior to ifosfamide therapy. If hematuria develops when Mesnex is given with ifosfamide according to the recommended dosage schedule, depending on the severity of the hematuria, dosage reductions or discontinuation of ifosfamide therapy may be initiated.

In order to reduce the risk of hematuria, Mesnex must be administered with each dose of ifosfamide as outlined in the DOSAGE AND ADMINISTRATION section. Mesnex is not effective in reducing the risk of hematuria due to other pathological conditions such as thrombocytopenia.

Because of the benzyl alcohol content, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.

Precautions Information for Patients

Healthcare providers should advise patients taking Mesnex to drink at least a quart of liquid a day. Patients should be informed to report if their urine has turned a pink or red color, if they vomit within 2 hours of taking oral Mesnex, or if they miss a dose of oral Mesnex. See Patient Information Leaflet for Mesnex Tablets.

Laboratory Tests

A false positive test for urinary ketones may arise in patients treated with Mesnex. In this test, a red-violet color develops which, with the addition of glacial acetic acid, will return to violet.

Drug Interactions

No clinical drug studies have been conducted.

Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Mesnex.

Mutagenesis

Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.

Impairment of Fertility

No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (at doses up to 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day; both studies approximately 10-fold higher than the maximum recommended human dose on a body surface area basis).

Pregnancy Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at oral doses of 1000 mg/kg in rabbits and 2000 mg/kg in rats (approximately 10 times the maximum recommended total daily IV-oral-oral human dose on a body surface area basis) and have revealed no evidence of harm to the fetus due to mesna. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether mesna or dimesna is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mesna, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Mesnex Tablets in pediatric patients have not been established.

Because of the benzyl alcohol content in Mesnex Injection, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.

Geriatric Use

Clinical studies of mesna did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. However, the ratio of ifosfamide to mesna should remain unchanged.

Adverse Reactions

Mesnex adverse reaction data are available from four phase I studies in which single IV bolus doses of 600-1200 mg Mesnex Injection without concurrent chemotherapy were administered to a total of 53 subjects and single oral doses of 600-2400 mg of Mesnex Tablets were administered to a total of 82 subjects.

The most frequently reported side effects (observed in two or more patients) for patients receiving single doses of Mesnex IV were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperaesthesia, influenza-like symptoms, and coughing. Among patients who received a single 1200-mg dose as an oral solution, rigors, back pain, rash, conjunctivitis, and arthralgia were also reported. In two phase I multiple-dose studies where patients received Mesnex Tablets alone or IV Mesnex followed by repeated doses of Mesnex Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by patients who had received repeated doses of IV Mesnex.

Because mesna is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to Mesnex from those caused by the concomitantly administered cytotoxic agents.

Adverse reactions reasonably associated with mesna administered IV and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.

* All grades Table 3 Incidence of Adverse Events and Incidence of Most Frequently Reported Adverse Events in Controlled Studies Mesna Regimen IV-IV-IV IV-Oral-Oral N exposed 119 (100.0%) 119 (100.0%) Incidence of AEs 101 (84.9%) 106 (89.1%) Most Frequently Reported Adverse Events (Preferred Terms)   N (%) N (%) Nausea 65 (54.6) 64 (53.8) Vomiting 35 (29.4) 45 (37.8) Constipation 28 (23.5) 21 (17.6) Leukopenia 25 (21.0) 21 (17.6) Fatigue 24 (20.2) 24 (20.2) Fever 24 (20.2) 18 (15.1) Anorexia 21 (17.6) 19 (16.0) Thrombocytopenia 21 (17.6) 16 (13.4) Anemia 20 (16.8) 21 (17.6) Granulocytopenia 16 (13.4) 15 (12.6) Asthenia 15 (12.6) 21 (17.6) Abdominal Pain 14 (11.8) 18 (15.1) Alopecia 12 (10.1) 13 (10.9) Dyspnea 11 (9.2) 11 (9.2) Chest Pain 10 (8.4) 9 (7.6) Hypokalemia 10 (8.4) 11 (9.2) Diarrhea 9 (7.6) 17 (14.3) Dizziness 9 (7.6) 5 (4.2) Headache 9 (7.6) 13 (10.9) Pain 9 (7.6) 10 (8.4) Sweating Increased 9 (7.6) 2 (1.7) Back Pain 8 (6.7) 6 (5.0) Hematuria* 8 (6.7) 7 (5.9) Injection Site Reaction 8 (6.7) 10 (8.4) Edema 8 (6.7) 9 (7.6) Edema Peripheral 8 (6.7) 8 (6.7) Somnolence 8 (6.7) 12 (10.1) Anxiety 7 (5.9) 4 (3.4) Confusion 7 (5.9) 6 (5.0) Face Edema 6 (5.0) 5 (4.2) Insomnia 6 (5.0) 11 (9.2) Coughing 5 (4.2) 10 (8.4) Dyspepsia 4 (3.4) 6 (5.0) Hypotension 4 (3.4) 6 (5.0) Pallor 4 (3.4) 6 (5.0) Dehydration 3 (2.5) 7 (5.9) Pneumonia 2 (1.7) 8 (6.7) Tachycardia 1 (0.8) 7 (5.9) Flushing 1 (0.8) 6 (5.0) Postmarketing Surveillance

Allergic reactions, decreased platelet counts associated with allergic reactions, hypertension, hypotension, increased heart rate, increased liver enzymes, injection site reactions (including pain and erythema), limb pain, malaise, myalgia, ST-segment elevation, tachycardia, and tachypnea have been reported as part of postmarketing surveillance.

Overdosage

There is no known antidote for Mesnex. Oral doses of 6.1 and 4.3 g/kg were lethal to mice and rats, respectively. These doses are approximately 15 and 22 times the maximum recommended human dose on a body surface area basis. Death was preceded by diarrhea, tremor, convulsions, dyspnea, and cyanosis.

Mesnex Dosage and Administration

For the prophylaxis of ifosfamide induced hemorrhagic cystitis, Mesnex may be given on a fractionated dosing schedule of three bolus intravenous injections or a single bolus injection followed by two oral administrations of Mesnex Tablets as outlined below.

Intravenous Schedule

Mesnex is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose.

The recommended dosing schedule is outlined below:

  0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m2 – – Mesnex 240 mg/m2 240 mg/m2 240 mg/m2 Intravenous and Oral Dosing

Mesnex Injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesnex Tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose.

The recommended dosing schedule is outlined below:

  0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m2 – – Mesnex Injection 240 mg/m2 – – Mesnex Tablets – 480 mg/m2 480 mg/m2

Patients who vomit within two hours of taking oral mesna should repeat the dose or receive intravenous mesna. The efficacy and safety of this ratio of IV and PO mesna has not been established as being effective for daily doses of IFEX  higher than 2.0 g/m2.

The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted (either increased or decreased), the ratio of Mesnex to IFEX should be maintained.

Preparation of Intravenous Solutions/Stability

The Mesnexmultidose vials may be stored and used for up to 8 days.

For IV administration the drug can be diluted by adding the Mesnex Injection solution to any of the following fluids obtaining final concentrations of 20 mg mesna/mL:

5% Dextrose Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP 5% Dextrose and 0.33% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 0.92% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP

For example:

One mL of Mesnex Injection multidose vial 100 mg/mL may be added to 4 mL of any of the solutions listed above to create a final concentration of 20 mg mesna/mL.

Diluted solutions are chemically and physically stable for 24 hours at 25°C (77°F).

Mesna is not compatible with cisplatin or carboplatin.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

How is Mesnex Supplied

Mesnex (mesna) Injection 100 mg/mL

NDC 0338-1305-01 1 g Multidose Vial, Box of 1 vial of 10 mL NDC 0338-1305-03 1 g Multidose Vial, Box of 10 vials of 10 mL

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]

Mesnex (mesna) Tablets

NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]

Mesnex  (mesna) Injection manufactured by:

Mesnex (mesna) Tablets manufactured for:

Baxter, Mesnex and Ifex are trademarks of Baxter International Inc.

U.S. Patent Nos.:5,262,169, 5,252,341 and 5,696,172

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

Made in Germany

Rev Feb 2009

USA C 18

HA-30-01-119

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL Container Label - Vial

Container Label 1g Multidose Vial

1 Multidose Vial

NDC 0338-1305-01

Mesnex (mesna) Injection

FOR INTRAVENOUS USE

1g

Rx only

Carton Label - Vial

Carton Label 1g Multidose Vial

1 Multidose Vial

NDC 0338-1305-01

Mesnex (mesna) Injection

1g

FOR INTRAVENOUS USE

Rx only

Baxter

Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA

Container Label - Tablets

Container Label 400 mg Tablets

List 3565-9

Rx only

400 mg

Mesnex
(mesna) Tablets

Baxter Healthcare Corporation
460-656-00
USA 5363 9222

(01)00067108356590
Lot-number:/Expires:

JMXXX

MM.JJJJ

Carton Label - Tablets

Carton Label 400 mg Tablets

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Mesnex
(mesna) Tablets

Rx only

Each tablet contains 400 mg mesna.
Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F)
[see USP Controlled Room Temperature].

For ORAL ADMINISTRATION

Dosage: See package insert for directions for use. Should not be prescribed without thorough
knowledge of dose, indications, and toxicology as contained in accompanying literature.

Manufactured for:
Baxter
Baxter Healthcare Corporation
Deerfield, IL 60015 USA


Mesnex 
mesna  injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0338-1305 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MESNA (MESNA) MESNA 100 mg  in 1 mL Inactive Ingredients Ingredient Name Strength EDETATE DISODIUM 0.25 mg  in 1 mL SODIUM HYDROXIDE   BENZYL ALCOHOL 10.4 mg  in 10 mL Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0338-1305-01 1 VIAL In 1 BOX contains a VIAL, MULTI-DOSE 1 10 mL In 1 VIAL, MULTI-DOSE This package is contained within the BOX (0338-1305-01) 2 0338-1305-03 10 VIAL In 1 BOX contains a VIAL, MULTI-DOSE 2 10 mL In 1 VIAL, MULTI-DOSE This package is contained within the BOX (0338-1305-03)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019884 12/30/1988
Labeler - Baxter Healthcare Corporation (005083209) Registrant - Baxter Healthcare Corporation (005083209) Establishment Name Address ID/FEI Operations BAXTER ONCOLOGY GMBH 344276063 MANUFACTURE Revised: 07/2009Baxter Healthcare Corporation More Mesnex resources Mesnex Side Effects (in more detail) Mesnex Dosage Mesnex Use in Pregnancy & Breastfeeding Mesnex Drug Interactions Mesnex Support Group 0 Reviews for Mesnex - Add your own review/rating Mesnex Concise Consumer Information (Cerner Multum) Mesnex Monograph (AHFS DI) Mesnex Advanced Consumer (Micromedex) - Includes Dosage Information Mesnex MedFacts Consumer Leaflet (Wolters Kluwer) Mesna Professional Patient Advice (Wolters Kluwer) Mesna MedFacts Consumer Leaflet (Wolters Kluwer) Compare Mesnex with other medications Hemorrhagic Cystitis Prophylaxis
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Sterile Water Irrigation



Directions for Use of Flexible Plastic Irrigation Containers

If desired, warm in overwrap to near body temperature in a water bath or oven heated to not more than 45°C.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

DIRECTIONS FOR USE

Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing bag firmly. If leaks are found, discard solution as sterility may be impaired.

Use Aseptic Technique.

Suspend container using hanger hole. Remove plastic protector from outlet port at bottom of container. Attach irrigation set. Refer to complete directions accompanying set.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not adversely affect the product.

Baxter Healthcare Corporation

Deerfield, Il 60015 USA

Printed in USA

©Copyright 1980, 1984, 1989, Baxter Healthcare Corporation. All rights reserved.

7-19-4-268

Rev. July 1997

PACKAGE LABEL.PRINCIPLE DISPLAY PANEL

Sterile Water for Irrigation USP Container Label

NOT FOR INJECTION

5000 mL

2B7119

NDC 0338-0003-49

STERILE WATER

For Irrigation USP

FOR IRRIGATION ONLY PREPARED BY DISTILLATION

NO ANTIMICROBIAL AGENT OR OTHER SUBSTANCE HAS

BEEN ADDED pH 5.5 (5.0 to 7.0) OSMOLARITY

0 mOsmol/L (CALC) STERILE NONPYROGENIC

SINGLE DOSE CONTAINER

DO NOT USE UNLESS SOLUTION IS CLEAR

DISCARD UNUSED PORTION

CAUTIONS THIS SOLUTION IS NOT ISOTONIC AND IS

HEMOLYTIC SQUEEZE AND INSPECT INNER BAG

WHICH MAINTAINS PRODUCT STERILITY DISCARD IF

LEAKS ARE FOUND RX ONLY STORE UNIT IN

MOISTURE BARRIER OVERWRAP AT ROOM

TEMPERATURE (25°C) UNTIL READY TO USE AVOID

EXCESSIVE HEAT SEE INSERT

Sterile Water

H2O

For Irrigation USP

UROMATIC CONTAINER PL 146 PLASTIC

BAXTER HEALTHCARE CORPORATION

DEERFIELD IL 60015 USA

MADE IN USA

BAXTER UROMATIC AND

PL 146 ARE TRADEMARKS OF

BAXTER INTERNATIONAL INC

FOR PRODUCT INFORMATION

1-800-933-0303

Sterile Water for Irrigation USP Carton Label

STERILE WATER FOR IRRIGATION, USP

UROMATIC CONT

2-5000ML

SECONDARY BAR CODE

(17) YYMM00 (10) XXXXX

PRIMARY BAR CODE

(01) 50303380003490

LOT XXXXX

EXP XXXXX

2B7119


STERILE WATER 
water  irrigant Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0338-0003 Route of Administration IRRIGATION DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength WATER (WATER) WATER 1 mL  in 1 mL Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0338-0003-44 1000 mL In 1 BAG None 2 0338-0003-46 2000 mL In 1 BAG None 3 0338-0003-47 3000 mL In 1 BAG None 4 0338-0003-49 5000 mL In 1 BAG None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA017866 05/30/1980
Labeler - BAXTER HEALTHCARE CORPORATION (005083209) Establishment Name Address ID/FEI Operations BAXTER HEALTHCARE CORPORATION 059140764 MANUFACTURE Revised: 12/2009BAXTER HEALTHCARE CORPORATION
More Sterile Water Irrigation resources Sterile Water Irrigation Support Group 0 Reviews · Be the first to review/rate this drug
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Timodine


TIMODINE

PLEASE READ THIS LEAFLET CAREFULLY BEFORE YOU USE THIS MEDICINE. IF YOU ARE NOT SURE ABOUT ANYTHING ASK YOUR PHARMACIST OR DOCTOR.

What Is Timodine?

Timodine is a pale yellow cream which is applied thinly to the inflamed skin. It contains an antifungal agent, a corticosteroid, an antiseptic and a water-repellent.

Each tube of Timodine contains 30 g.

The active ingredients are nystatin BP 100,000 IU/g, hydrocortisone Ph Eur 0.5% w/w, dimeticone 350 BP 10% w/w and benzalkonium chloride solution BP 0.2% w/w.

The other ingredients are butylated hydroxyanisole, cetostearyl alcohol, cellulose nitrate, dibutyl phthalate, glyceryl monostearate, methyl hydroxybenzoate, propyl hydroxybenzoate, sorbic acid, stearic acid, sodium metabisulphite and water.

Marketing Authorisation Holder:

Alliance Pharmaceuticals Ltd Avonbridge House Bath Road Chippenham Wiltshire SN15 2BB UK

Manufacturer:

Reckitt Benckiser Healthcare (UK) Limited Dansom Lane Hull HU8 7DS What Is Timodine Used For?

Timodine is a medicine to treat inflamed skin conditions, particularly where infection by a germ called Candida albicans can occur.

Where two folds of skin rub together, chafing can occur, leading to a sore inflamed area of skin. This particularly happens in places such as the groin or under the breasts where frequent sweating occurs. This combination of irritated skin and wetness is called intertrigo. The same condition happens under babies’ nappies when it is known as nappy rash. In both intertrigo and nappy rash the inflamed skin is easily infected by germs, in particular a fungus called Candida albicans.

Timodine is specially formulated to ease the soreness and treat the infections in intertrigo and inflamed nappy rash.

Nystatin kills Candida albicans. Hydrocortisone reduces the pain and soreness. Dimeticone stops wetting and chafing. Benzalkonium chloride kills bacteria.

Timodine can also be used to treat the following conditions when there is infection with Candida albicans:

Eczema. “Housewives’ hands”, a skin irritation caused by chemicals such as washing powders. Seborrhoeic dermatitis: inflammation of the scalp with excessive amounts of dandruff scales and oily secretions. Pruritis ani and vulvae: irritation of the external area around the anus and the vagina. Before Using Timodine

As with all medicines, Timodine may not be suitable for everybody:

Do not use this medicine if you are allergic to the product or any of its ingredients. You should ask your doctor before using Timodine if you are pregnant. Avoid prolonged exposure on the face and keep away from eyes. How To Use Timodine

For intertrigo, seborrhoeic dermatitis and “housewives’ hands”

Apply a thin layer of Timodine to the sore area and rub into the skin gently until the cream disappears. The treatment should be repeated three times a day until the skin is healed.

For severe nappy rash

Remove the soiled nappy, then clean and dry your baby’s skin. Rub a thin layer of Timodine into the sore areas until the cream disappears. The treatment should be repeated after every napkin change.

Do not use Timodine for more than seven days unless your doctor tells you to. Once the infection has cleared up, use a barrier cream instead of Timodine.

In the case of a missed dose, simply apply when the next dose is due. In the case of accidental ingestion, seek medical advice.

How Much To Use

A finger-tip length of cream should be enough for each inflamed area.

What Side-Effects May Occur?

Tell your doctor or pharmacist if any side-effects occur after use of this product.

Storage

Keep all medicines away from children. Do not use after the expiry date shown on the pack.

Keep Timodine below 15°C.

Further Information

You may find a yellow stain on terry cotton nappies after using Timodine. This will disappear after soaking in bleach or nappy bucket solution followed by rinsing and normal washing.

Timodine is a registered trademark of Alliance Pharmaceuticals Limited.

Alliance and associated devices are registered trademarks of Alliance Pharmaceuticals Limited.

Leaflet last revised March 2010.

xxxxxx

UK 002


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Endometrin



Dosage Form: vaginal tablet
FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE

Endometrin is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.

DOSAGE AND ADMINISTRATION General Dosing Information

The dose of Endometrin is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of Endometrin in this age group has not been determined.

Dosage Forms and Strengths

100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side.

Contraindications

Endometrin should not be used in individuals with any of the following conditions:

Previous allergic reactions to progesterone or any of the ingredients of Endometrin [see Description (11)] Known missed abortion or ectopic pregnancy Liver disease Known or suspected breast cancer Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events Warnings and Precautions Cardiovascular or Cerebrovascular Disorders

The physician should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. Endometrin should be discontinued if any of these are suspected.

Depression

Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.

Use of Other Vaginal Products

Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [see Drug Interactions (7)].

Adverse Reactions Clinical Studies Experience

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

The safety data reflect exposure to Endometrin in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Endometrin was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either Endometrin group are summarized in Table 1.

Table 1: Number and Frequency of Reported Adverse Reactions in Women Treated with Endometrin in an Assisted Reproductive Technology Study Body System Endometrin
100 mg twice
daily
(N=404) Endometrin
100 mg three
times daily
(N=404)   Preferred Term     Gastrointestinal Disorders   Abdominal pain 50 (12%) 50 (12%)   Nausea 32 (8%) 29 (7%)   Abdominal distension 18 (4%) 17 (4%)   Constipation 9 (2%) 14 (3%)   Vomiting 13 (3%) 9 (2%) General Disorders & Administration Site Conditions   Fatigue 7 (2%) 12 (3%) Infections and Infestations   Urinary tract infection 9 (2%) 4 (1%) Injury, Poisoning and Procedural Complications   Post-oocyte retrieval pain 115 (28%) 102 (25%) Nervous System Disorders   Headache 15 (4%) 13 (3%) Reproductive System and Breast Disorders   Ovarian hyperstimulation syndrome 30 (7%) 27 (7%)   Uterine spasm 15 (4%) 11 (3%)   Vaginal bleeding 13 (3%) 14 (3%)

Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.

Expected Adverse Reaction Profile Seen with Progesterone

Endometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.

Drug Interactions

No formal drug-drug interaction studies have been conducted for Endometrin. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from Endometrin has not been assessed. Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [see Warnings and Precautions(5.3)].

USE IN SPECIFIC POPULATIONS Pregnancy

Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows:

Among the 404 subjects treated with Endometrin twice daily, 143 subjects had livebirths consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths). Among the 404 subjects treated with Endometrin three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths).

Birth defects reported in the Endometrin twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly.

Birth defects reported in the Endometrin three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down’s and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge’s syndrome, one fetus with a hand deformity, and one fetus with cleft palate.

For additional information on the pharmacology of Endometrin and pregnancy outcome information [see Clinical Pharmacology (12) and Clinical Studies Sections (14)].

Nursing Mothers

Detectable amounts of progesterone have been identified in the milk of nursing mothers. The effect of this on the nursing infant has not been determined.

Pediatric Use

This drug is not intended for pediatric use and no clinical data have been collected in children. Therefore, the safety and effectiveness of Endometrin in pediatric patients have not been established.

Geriatric Use

No clinical data have been collected in patients over age 65.

Overdosage

Treatment of overdosage consists of discontinuation of Endometrin together with institution of appropriate symptomatic and supportive care.

Endometrin Description

Endometrin (progesterone) Vaginal Insert contains micronized progesterone. Endometrin is supplied with polyethylene vaginal applicators.

The active ingredient, progesterone, is present in 100 mg amount along with other excipients. The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21H30O2 and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in Endometrin, the alpha-form, has a melting point of 127-131°C.

The structural formula is:

C21H30O2

Each Endometrin Vaginal Insert delivers 100 mg of progesterone in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

Endometrin - Clinical Pharmacology Mechanism of Action

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain a pregnancy.

Pharmacokinetics

Absorption

Progesterone serum concentrations increased following the administration of the Endometrin Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax was 17.0 ng/mL in the Endometrin twice daily group and 19.8 ng/mL in the Endometrin three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with Endometrin. Both Endometrin regimens provided average serum concentrations of progesterone exceeding 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2.

Table 2: Mean (±Standard Deviation) Serum Progesterone Pharmacokinetic Parameters Cmax Maximum progesterone serum concentration.
Tmax Time to maximum progesterone serum concentration.
Cavg Average progesterone serum concentration.
AUC0-24 Area under the drug concentration versus time curve from 0-24 hours post dose.
Cmin Minimum progesterone serum concentration. Pharmacokinetic
Parameter (unit) Endometrin
100 mg twice
daily (N=6) Endometrin
100 mg three times
daily (N=6)   Single Dosing Cmax (ng/mL) 17.0 ± 6.5 19.8 ± 7.2 Tmax (hr) 24.0 ± 0.0 17.3 ± 7.4 AUC0-24
(ng•hr/mL) 217 ± 113 284 ± 143 Day 5 of Multiple Dosing Cmax (ng/mL) 18.5 ± 5.5 24.1 ± 5.6 Tmax (hr) 18.0 ± 9.4 18.0 ± 9.4 Cmin (ng/mL) 8.9 ± 4.5 10.9 ± 6.7 Cavg (ng/ml) 14.0 ± 4.8 15.9 ± 4.3 AUC0-24
(ng•hr/mL) 327 ± 127 436 ± 106

Distribution

Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.

Metabolism

Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

Excretion

Progesterone undergoes renal and biliary elimination. Following injection of labeled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and feces. Overall recovery of the labeled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility

Nonclinical toxicity studies to determine the potential of Endometrin to cause carcinogenicity or mutagenicity have not been performed. The effect of Endometrin on fertility has not been evaluated in animals.

Clinical Studies Luteal Supplementation During Assisted Reproductive Treatment Study

A randomized, open-label, active-controlled study evaluated the efficacy of 10 weeks of treatment with two different daily dosing regimens of Endometrin (100 mg twice daily and 100 mg three times daily) for support of implantation and early pregnancy in infertile women participating in an Assisted Reproductive Technology treatment program. Efficacy was assessed on the endpoint of ongoing pregnancies, defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer. The study randomized to Endometrin 808 infertile women (74.9% White; 10.3% Hispanic, 5.4% Black, 5 % Asian, and 4.6% Other) between 19 and 42 years of age (mean age 33) who had a body mass index < 34 kg/m2 at screening.

The ongoing pregnancy rates for subjects treated with both dosing regimens of Endometrin were non-inferior (lower bounds of the 95% confidence interval of the difference between Endometrin and the active comparator excluded a difference greater than 10%) to the ongoing pregnancy rate for subjects treated with the active comparator. The results of this study are shown in Table 3.

Table 3: Ongoing Pregnancy Rates* in Patients Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program *Ongoing pregnancy defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer.   Endometrin
100 mg twice
daily Endometrin
100 mg three
times daily Number of subjects 404 404 Ongoing pregnancy: n (%) 156 (39%) 171 (42%) 95% Confidence Interval of
pregnancy rate [33.8,43.6] [37.5,47.3] Pregnancy rate percentage
difference between
Endometrin and comparator -3.6% 0.1% 95% Confidence Interval for
difference vs. comparator [-10.3, 3.2] [-6.7, 6.9]

Subjects participating in the study were stratified at randomization by age and ovarian reserve (as measured by serum FSH levels). The ongoing pregnancy rates for these subgroups are shown in Table 4.

Table 4: Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program   Endometrin
100 mg twice
daily Endometrin
100 mg three
times daily Subjects age < 35 years (N) 247 247 Ongoing pregnancy: n (%) 111 (45%) 117 (47%) Pregnancy rate percentage difference between Endometrin and comparator 0.5% 2.9% 95% Confidence Interval for difference vs. comparator [-8.3, 9.3] [-5.9, 11.7] Subjects 35-42 years of age (N) 157 157 Ongoing pregnancy: n (%) 45 (28%) 54 (34%) Pregnancy rate percentage difference between Endometrin and comparator -10.1% -4.4% 95% Confidence Interval for difference vs. comparator [-20.3, 0.3] [-14.9, 6.3] Subjects with FSH < 10 IU/L (N) 350 347 Ongoing pregnancy: n (%) 140 (40%) 150 (43%) Pregnancy rate percentage difference between Endometrin and comparator -2.0% 1.2% 95% Confidence Interval for difference vs. comparator [-9.3, 5.3] [-6.1, 8.5] Subjects with FSH between 10 and 15 IU/L (N) 46 51 Ongoing pregnancy: n (%) 16 (35 %) 20 (39%) Pregnancy rate percentage difference between Endometrin and comparator -12.2% -7.7% 95% Confidence Interval for difference vs. comparator [-31.0, 7.7] [-26.6, 11.6]

In subjects under the age of 35 or with serum FSH levels less than 10 IU/L, results from both dosing regimens were non-inferior to the results from the comparator with respect to ongoing pregnancy rates. In women age 35 and older and in women with serum FSH levels between 10 and 15 IU/L, the results with respect to ongoing pregnancy rate for both dosing regimens of Endometrin did not reach the criteria for non-inferiority.

Subjects who became pregnant received study medication for a total of 10 weeks. Patients over 34 kg/m2 were not studied. The efficacy of Endometrin in this patient group is unknown.

How Supplied/Storage and Handling

Each Endometrin Vaginal Insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each Endometrin® (progesterone) Vaginal Insert, 100 mg, is packed individually in a sealed foil pouch. These pouches are available in cartons packed:

21 vaginal inserts with 21 disposable vaginal applicators (NDC 55566-6500-3)

Store at 25°C (77°F); excursions permitted between 15-30°C (59-86°F).

Patient Counseling Information

See FDA-Approved Patient Labeling (17.4)

Vaginal Bleeding

Inform patients of the importance of reporting irregular vaginal bleeding to their doctor as soon as possible.

Common Adverse Reactions with Progesterone

Inform patients of the possible side effects of progesterone therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness.

Coadministration of Vaginal Products

Inform patients that Endometrin is not recommended for use with other vaginal products.

FDA-Approved Patient Labeling

IMPORTANT:For Vaginal Use Only.

Read the patient information that comes with Endometrin before you start to use it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Your doctor may do a physical exam before prescribing Endometrin.

What is Endometrin?

Endometrin is a vaginal insert that contains the hormone progesterone. Endometrin is for women who need extra progesterone while undergoing treatment in an Assisted Reproductive Technology (ART) program.

Progesterone is one of the hormones essential for helping you to become and to stay pregnant. If you are undergoing ART treatment, your doctor may prescribe Endometrin to provide the progesterone your body needs.

Who should not use Endometrin?

Do not use Endometrin if you:

Are allergic to anything in Endometrin. See the end of this leaflet for a complete list of ingredients. Have unusual vaginal bleeding that has not been evaluated by a doctor. Currently have or have had liver problems. Have or have had blood clots in the legs, lungs, eyes, or elsewhere in your body.

Endometrin may not be right for you. Before starting Endometrin, tell your doctor about all your health problems.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vaginal products, vitamins, herbal supplements. Some medicines may affect Endometrin.

Know what medicines you take. Keep a list of your medicines to show to the doctor and pharmacist.

How should I use Endometrin? Use Endometrin exactly as prescribed. The usual dose of Endometrin is one insert placed in your vagina 2 to 3 times a day for up to a total of 10 weeks, unless your healthcare provider advises otherwise. Place an Endometrin insert in your vagina with the disposable applicator provided.

Follow the steps below:

Unwrap the applicator. Put one insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out. Place applicator with the insert into the vagina while you are standing, sitting, or when lying on your back with your knees bent. Gently place the thin end of the applicator well into the vagina. Push the plunger to release the insert. Remove the applicator and throw it away in the trash.

Other information for using Endometrin

If you forget a dose of Endometrin, take the dose as soon as you remember, but do not use more than your daily dose. Call your doctor if you use too much Endometrin. Do not use any other vaginal products when you are using Endometrin. What are the possible side effects of Endometrin?

Common side effects seen with ART and Endometrin included pelvic pain after surgery, abdominal pain, nausea, and swollen ovaries (ovarian hyperstimulation syndrome).

Other reported side effects included abdominal bloating, headache, urinary infections, uterine cramping, constipation, vomiting, tiredness, and vaginal bleeding.

Vaginal products with progesterone may also cause vaginal irritation, burning, and discharge.

Serious Risks of Progesterone

Progesterone can increase your chance of getting blood clots. Blood clots can be serious and lead to death.

Serious blood clots include those in the:

legs (thrombophlebitis) lungs (pulmonary embolus) eyes (blindness) heart (heart attack) brain (stroke)

Call your doctor or get medical help right away if you have:

persistent pain in the lower leg (calf) sudden shortness of breath coughing up blood sudden blindness, partial or complete severe chest pain sudden, severe headache, vomiting, dizziness, or fainting weakness in an arm or leg, or trouble speaking yellowing of the skin and/or white of the eyes indicating possible liver problem

Other risks of progesterone use include:

headache breast tenderness bloating or fluid retention mood swings and depression irritability drowsiness

Call your doctor immediately if you have abnormal vaginal bleeding

These are not all the side effects with Endometrin. Ask your doctor or pharmacist for more information.

How should I store Endometrin? Store Endometrin at room temperature, 25°C (77°F); excursions permitted between 15 to 30°C (59 to 86°F). Do not use Endometrin after the expiration date that is printed on the carton. Keep Endometrin and all medicines out of the reach of children. General information about Endometrin

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Endometrin for a condition for which it was not prescribed. Do not give Endometrin to other women, even if they have the same condition as you do. It may harm them.

This leaflet summarizes the most important information about Endometrin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Endometrin that was written for healthcare professionals. For more information call Ferring Pharmaceuticals at 1-800-822-8214.

What are the ingredients in Endometrin?

Active Ingredient: progesterone

Inactive Ingredients: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide

Manufactured by:
Pharmaceutics International Inc., Hunt Valley, MD 21031

Manufactured for:
Ferring Pharmaceuticals Inc., Parsippany, NJ 07054

6323-02

PACKAGE LABEL - FOIL PACK LABEL

Endometrin®

(progesterone) Vaginal Insert 100 mg

Manufactured for:

Ferring Pharmaceuticals Inc.

Parsippany, NJ 07054

By: Pharmaceutics International Inc.

Hunt Valley, MD 21031

Store at 20°-25°C (68°-77°F);

exercurstions permitted between

15°-30°C (59°-86°F).

FOR VAGINAL USE ONLY

NDC 55566-6500-1

Rx only 6320-04

LOT XXXX.XXX

EXP XX/XX

PACKAGE LABEL - INNER CARTON

NDC 55566-6500-2

Endometrin®

(progesterone) Vaginal Insert 100 mg

Contents: 21 foil blisters, each containing

1 individually sealed 100 mg vaginal insert.

Endometrin®

(progresterone) Vaginal Insert 100 mg

Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, NJ 07054

By: Pharmaceutics International Inc. Hunt Valley MD 21031

Patent Pending

6321-04

PACKAGE LABEL - OUTER CARTON

NDC 55566-6500-3

Endometrin®

(progesterone) Vaginal Insert 100 mg

Contents:

21 vaginal inserts with 21 disposable vaginal applicators

Each insert contains 100 mg progesterone, USP

FOR VAGINAL USE ONLY

Rx only

Endometrin®

6322-04


Endometrin 
progesterone  insert Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 55566-6500 Route of Administration VAGINAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength progesterone (progesterone) progesterone 100 mg Inactive Ingredients Ingredient Name Strength lactose monohydrate   povidone K29/32   adipic acid   sodium bicarbonate   sodium lauryl sulfate   magnesium stearate   starch, pregelatinized corn   colloidal silicon dioxide   Product Characteristics Color WHITE Score      Shape OVAL Size Flavor Imprint Code 100 Contains          Packaging # NDC Package Description Multilevel Packaging 1 55566-6500-3 1 CARTON In 1 CARTON contains a CARTON (55566-6500-2) 1 55566-6500-2 21 BLISTER PACK In 1 CARTON This package is contained within the CARTON (55566-6500-3) and contains a BLISTER PACK (55566-6500-1) 1 55566-6500-1 1 INSERT In 1 BLISTER PACK This package is contained within a CARTON (55566-6500-2) and a CARTON (55566-6500-3)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022057 06/21/2007
Labeler - Ferring Pharmaceuticals Inc. (103722955) Establishment Name Address ID/FEI Operations Pharmaceutics International Inc. 878265586 manufacture Revised: 02/2008Ferring Pharmaceuticals Inc.
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Minitran 5, Minitran 10, Minitran 15


Minitran

Glyceril trinitrate

What You Need To Know About Minitran Patches

Please read this carefully before you start to use your medication. This leaflet only provides a summary of the information available on your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.

Your medication is called a Minitran patch

It consists of a clear patch containing glyceryl trinitrate which is applied to the skin. The clear film consists of low density polyethylene and silicone-coated polyester. The patch also contains the following ingredients: isooctyl acrylate/acrylamide copolymer, ethyl oleate, glyceryl monolaurate. There are three strengths available ; your doctor will have chosen the strength which best suits your condition.

A Minitran 5 patch contains 18mg of glyceryl trinitrate. The average amount delivered in 24 hours is 5mg.

A Minitran 10 patch contains 36mg of glyceryl trinitrate. The average amount delivered in 24 hours is 10mg.

A Minitran 15 patch contains 54mg of glyceryl trinitrate. The average amount delivered in 24 hours is 15mg.

Each pack (all strengths) contains 30 patches.

Who produces your medication

Name and address of manufacturer:

3M Sant? Zone industrielle Avenue du 11 Novembre F-45312 Pithiviers Cedex France 3M Health Care, Derby Road Loughborough Leicestershire LE11 5SF United Kingdom

Batch numbers Fxxxxxx are batch released at 3M Sant?, Batch numbers Uxxxxxx are batch released at 3M Health Care.

Name and address of product licence holder:

Meda Pharmaceuticals Ltd. Skyway House Parsonage Road Takeley Bishop's Stortford CM22 6PU UK What your medication is prescribed for

Glyceryl trinitrate is one of a group of medicines called vasodilators which widen blood vessels and improve blood flow to the tissues and muscle (including heart muscle). When you apply a patch to your skin the glyceryl trinitrate passes slowly through your skin and into your blood stream.

Minitran patches may be used to help prevent attacks of angina (chest pain). They reduce the need for under-the-tongue glyceryl trinitrate tablets or spray.

Minitran 5 patches may also be used to improve blood flow to the site of an intravenous cannula. In patients receiving injections or infusions via their arm or leg veins, they help to keep the veins open.

Important points to note before using Minitran patches

If medication for erectile dysfunction, such as sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra), is being used by patients taking nitrate preparations such as Minitran a severe and possibly dangerous fall in blood pressure may occur. This would result in collapse, unconsciousness, and could be fatal. You should not take Viagra, Cialis or Levitra whilst using Minitran.

If you are pregnant, think you might be pregnant or are trying to become pregnant, or are taking other medications, please tell your doctor before using Minitran patch.

You should not use these patches if you are known to be allergic to glyceryl trinitrate, or other medicines containing nitrates.

These patches should not be used by patients with glaucoma, low blood pressure, severe anaemia, aortic or mitral stenosis (heart valve disease), pericarditis (inflammation of the lining of the heart) or raised intracranial pressure (high pressure within the skull).

Please tell your doctor if you suffer from any heart or lung conditions.

Minitran patches may be used to help prevent angina attacks. If you do have an attack of chest pain you should use under-the-tongue glyceryl trinitrate tablets or a similar medication as instructed by your doctor.

Glyceryl trinitrate may lower your blood pressure and make you feel dizzy or light-headed, particularly when changing position suddenly. You should be especially careful if you are driving, operating machinery or drinking alcohol.

Minitran patches are not recommended for use in children.

If you see any other doctor or dentist, please tell them that you are using Minitran patch.

What to do if you are taking other medicines

Please tell your doctor if you are receiving any of the following medicines:

vasodilators (medicines used, for example, for angina (e.g. nitrates) or to reduce blood pressure (e.g. hydralazine, minoxidil). calcium antagonists or beta-blockers (medicines used, for example, for angina, heart arrhythmia's (irregular heart beat) or to reduce blood pressure). ACE inhibitors (medicines used, for example, for heart failure or to reduce blood pressure). neuroleptics (medicines for psychiatric illness). diuretics (water tablets). anti-hypertensives (medicines for reducing blood pressure). tricyclic anti-depressants. dihydroergotamine. aspirin or other non-steroidal anti-inflammatory drugs.

Your doctor or pharmacist will advise you about these medicines.

Use of Minitran patches during pregnancy and breast feeding

Glyceryl trinitrate should not normally be used if you are pregnant or if you are breast feeding, unless your doctor tells you to.

When to apply Minitran patches

For angina patients.

The usual starting dose is one Minitran 5 patch each day. Your doctor will have chosen the strength which best suits your condition and will advise you on how long to wear the patch each day. Your patch may be worn for either 24 hours or for only part of each day. A new patch must be applied at approximately the same time each day. Please follow your doctor's instructions.

If you forget to use a new patch, apply it as soon as you remember.

If you are not sure when to use your patch please ask your doctor or pharmacist.

For patients with an intravenous cannula.

Usually your doctor or nurse will apply one Minitran 5 patch next to your intravenous cannula. The patch will be left on for 24 hours and then changed. It will be removed once your intravenous treatment is stopped.

Minitran patches should not be used by children.

Where to apply Minitran patches

For angina patients.

You can apply the patch to the chest, shoulders or upper arm. You should apply the patch to a hairless area of the skin to ensure that good contact is made.

Do not apply the patch to broken skin such as cuts or grazes.

Use a different area of skin every time you apply a patch. It is best to let a few days pass before putting another patch on the same area of skin.

The skin should be clean and dry before applying a patch. This is to make sure that the patch sticks properly.

Do not use dusting powder or any greasy substance e.g. ointments or creams on the skin before applying a patch.

A Minitran patch sticks well to the skin during showering, bathing and swimming.

For patients with an intravenous cannula.

Your doctor or nurse will apply the patch next to your intravenous cannula.

How to apply a Minitran patch 1. Start at notched corner. Tear pouch along dotted line. Remove patch from pouch. 2. Bend patch so that the oval patterned liner notch pops up ; remove tab and discard liner. 3. Apply sticky side of patch to upper arm or chest. Remove and discard oval patterned liner. 4. Press patch firmly in place.

In the unlikely event of a patch not sticking or falling off, simply apply a new patch on a different area of the skin.

Do not re-apply a patch once it has been removed from the skin.

What to do in case of accidental swallowing or application of too many patches

Please contact your nearest hospital casualty department, or tell your doctor, immediately.

What might happen when you are using Minitran patches

Like most medicines, glyceryl trinitrate may cause some side-effects.

When you first use Minitran patches you may notice some side-effects. These include headache, hypotension (low blood pressure), tachycardia (fast heart rate), fainting, palpitations (fast heart beat), hot flushes and dizziness.

Sometimes your skin may become red and/or itchy where you have used the patch. This will usually disappear after you have removed the patch. Please make sure that you use a different area of skin every time you apply a patch.

Other side-effects which may occur include feeling or being sick.

As with other skin preparations, use of Minitran patches over a long period of time may result in your skin becoming sensitive to this product. If this happens to you, please consult your doctor.

If you notice any other side-effects, please tell your doctor or pharmacist.

If any side-effects continue for more than a few days, please tell your doctor.

Storing your medication

Keep Minitran patches in a safe place where children cannot reach them.

Store the patches below 25?C in a dry place and out of direct sunlight.

Do not use this product after the expiry date printed on the original container.

If your doctor decides to stop treatment, return any unused patches to your pharmacist.

Date of update of leaflet : December 2009

REMEMBER: This medication is only for YOU. Never give it to others. It may harm them even if their symptoms seem to be the same as yours.

The information provides a summary of the information available on Minitran patches.

Further information is available from your doctor or pharmacist.

Minitran is a trademark of MEDA AB.

The Triangle Logo on the packaging is a trademark of 3M and is used under license.

562l97M2110UK00


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Dulcolax Suppositories 10mg Dulcolax Suppositories for Children 5mg


Dulcolax Suppositories 10 mg

Dulcolax Suppositories for Children 5 mg

bisacodyl

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription. You need to use DULCOLAX Suppositories as instructed in this leaflet to get the best results from it.

Keep this leaflet. You may need to read it again Ask your pharmacist if you need more information or advice You must contact your pharmacist or doctor if your symptoms worsen or do not improve after 5 days of treatment If a side effect occurs and gets troublesome, or seems serious to you, or if you experience any side effect not listed in this leaflet, please tell your pharmacist or doctor In this leaflet: 1. What DULCOLAX Suppositories are and what they are used for 2. Before you use DULCOLAX Suppositories 3. How to use DULCOLAX Suppositories 4. Possible side effects 5. How to store DULCOLAX Suppositories 6. Further information What Dulcolax Suppositories Are And What They Are Used For

DULCOLAX Suppositories contain a medicine called bisacodyl. This belongs to a group of medicines called laxatives.

DULCOLAX Suppositories are used for relief of constipation DULCOLAX Suppositories are also used in hospitals to clear the bowel before surgery, X-rays or other tests DULCOLAX Suppositories stimulate the muscles of the bowel (large intestine), helping to return the body to its natural rhythm. They have a laxative effect usually within 30 minutes What is constipation?

Normal and regular bowel movement is important for most people. However, what is “normal and regular” varies from person to person. Some may have a bowel movement every day, others less often. Whatever it is like for you, it is best that your bowel movement has a regular pattern.

Constipation is an occasional problem for some people; for others, it may happen more often It happens when the normal muscle actions in the bowel (large intestine) slow down. This can mean that the material is not easily eliminated from the body

The cause of constipation is often not known. It can be associated with:

Sudden change of diet A diet with not enough fibre Loss of ‘tone’ of the bowel muscles in older people Pregnancy Medicines such as morphine or codeine Having to stay in bed for a long time Lack of exercise

Whatever the cause, constipation is uncomfortable. It may make you feel bloated and heavy, or generally “off colour”. Sometimes it causes headaches.

These healthy tips are recommended to try and prevent constipation happening:

Eat a balanced diet including fresh fruit and vegetables Drink enough water so that you do not become dehydrated Keep up your exercise and stay fit Make time to empty your bowels when your body tells you Before You Use Dulcolax Suppositories Do not use DULCOLAX Suppositories if: You are allergic (hypersensitive) to bisacodyl or hard fat You have severe dehydration You have a bowel condition called “ileus” (in the small intestine) You have a serious abdominal condition such as appendicitis You have severe abdominal pain with nausea and vomiting You have a blocked bowel (intestinal obstruction) You have inflammation of the bowel (small or large intestine) You have cracking of the skin around your back passage (anal fissures) You have inflammation or ulcers around your back passage (ulcerative proctitis)

Do not use DULCOLAX Suppositories if any of the above applies to you. If you are not sure, talk to your pharmacist or doctor before using this medicine.

Taking other medicines

Please tell your pharmacist or doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because DULCOLAX Suppositories can affect the way some other medicines work. Also, some other medicines can affect the way DULCOLAX Suppositories work.

In particular, tell your pharmacist or doctor if you are taking any of the following medicines:

Water tablets (diuretics) such as bendrofluazide or furosemide (frusemide) Steroid medicines such as prednisolone

Before using DULCOLAX Suppositories, tell your pharmacist or doctor if you are not sure if any of the above applies to you.

Pregnancy and breast-feeding

Talk to your pharmacist or doctor before using DULCOLAX Suppositories if you are pregnant, planning to become pregnant or are breast-feeding.

How To Use Dulcolax Suppositories

If this medicine is from your doctor or pharmacist, do exactly as they have told you. Otherwise, follow the instructions below. If you do not understand the instructions, or if you are not sure, ask your pharmacist or doctor.

As with all laxatives, DULCOLAX Suppositories should not be used every day for more than 5 days. If you need laxatives every day, or if you have abdominal pain which does not go away, you should see your doctor.

How to use the suppositories

The suppositories should only be used in your back passage.

1. Take off the foil wrapping 2. Lie on one side and pull your knees up towards your chest. Keep one leg drawn up more than the other 3. Use your first finger (index finger) or middle finger to push in the suppository 4. Gently push the suppository as far as possible into your back passage, pointed end first 5. Once it is as far as it will go, push it side-ways to make sure it touches the wall of the bowel 6. Lower your legs to a comfortable position whilst the suppository is retained in place 7. Keep the suppository inside you for at least 30 minutes If you feel the suppository might come out straight away: You may not have put it in high enough. Push it in as far as possible Try to keep it in for 30 minutes, even if you feel like you urgently need to go to the toilet. This is how long it takes to work How much to use

For constipation

Adults and children over 10 years

Put one 10 mg suppository into the back passage for immediate effect. Only use one suppository per day

Children under 10 years

DULCOLAX Suppositories for Children 5 mg should only be used if recommended by a doctor. The usual dose is:

Put one 5 mg suppository into the back passage for immediate effect. Only use one suppository per day

For bowel clearance before surgery, X-rays or other tests

In hospitals, when patients are being prepared for surgery, X-rays or other tests, DULCOLAX Suppositories and DULCOLAX Tablets are both used. This helps to get complete bowel clearance.

Adults and children over 10 years

Take two tablets in the morning and two tablets in the evening and use one 10 mg suppository on the following morning

Children 4 -10 years

Give one tablet in the evening and one 5 mg suppository (DULCOLAX Suppositories for Children) on the following morning If you use more DULCOLAX Suppositories than you should

If you use more of this medicine than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. This is so the doctor knows what you have used.

If you have any questions on the use of this product, ask your pharmacist or doctor.

Possible Side Effects

Like all medicines, DULCOLAX Suppositories can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Common side effects (affect less than 1 in 10 people) Abdominal cramps or pain Nausea Diarrhoea Uncommon side effects (affect less than 1 in 100 people) Vomiting Abdominal discomfort Blood in the stools (usually mild and self-limiting) Discomfort inside and around the back passage Rare side effects (affect less than 1 in 1000 people) Allergic reactions which may cause a skin rash or itching Unknown – incidence of side effect cannot be estimated from the available data Colitis (inflammation of the large intestine which causes abdominal pain or diarrhoea) Dehydration which can make you feel thirsty and produce less urine. If you are dehydrated drink plenty of liquid. Serious allergic reactions which may cause swelling of the face or throat and difficulty in breathing or dizziness. If you have a severe allergic reaction, stop taking this medicine and see a doctor straight away.

If a side effect occurs and gets troublesome or seems serious to you, or if you experience any side effect not listed in this leaflet, please tell your pharmacist or doctor.

How To Store Dulcolax Suppositories Keep this medicine out of the sight and reach of children Do not use DULCOLAX Suppositories after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 25°C The suppositories should be protected from light. Keep them in the outer carton Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment Further Information What DULCOLAX Suppositories contain DULCOLAX Suppositories 10 mg contain 10 mg of the active ingredient bisacodyl DULCOLAX Suppositories for Children 5 mg contain 5 mg of the active ingredient bisacodyl Both the suppositories are made from hard fat, which is an ingredient needed to mould the suppository into the correct shape What DULCOLAX Suppositories look like and contents of the pack The suppositories are white and torpedo shaped DULCOLAX Suppositories 10 mg are available in packs of 12 DULCOLAX Suppositories for Children 5 mg are available in packs of 5 Marketing Authorisations are held by: Boehringer Ingelheim Limited Consumer Healthcare Ellesfield Avenue Bracknell Berkshire RG12 8YS United Kingdom DULCOLAX Suppositories are manufactured by: Instituto De Angeli. S.r.I. Localit? Prulli di Sotto n. 103/c Regello (Fl) Italy

This leaflet was revised in May 2010.

Registered trade mark

© Boehringer Ingelheim Limited 2010

XXXXXX/GB/7

20080918


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Xgeva


Generic Name: denosumab
Dosage Form: injection
FULL PRESCRIBING INFORMATION Indications and Usage for Xgeva Bone Metastasis from Solid Tumors

Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use

Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma [see Clinical Trials (14)].

Xgeva Dosage and Administration Recommended Dosage

The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.

Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia [see Warnings and Precautions (5.1)].

Preparation and Administration

Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way [see How Supplied/Storage and Handling (16)].

Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

Dosage Forms and Strengths

120 mg/1.7 mL (70 mg/mL) single-use vial.

Contraindications

None.

Warnings and Precautions Hypocalcemia

Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia [see Adverse Reactions (6.1) and Patient Counseling Information (17)].

Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, 2.2% of patients receiving Xgeva developed ONJ; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance [see Adverse Reactions (6.1)].

Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva.

Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Adverse Reactions

The following adverse reactions are discussed below and also elsewhere in the labeling:

Hypocalcemia [see Warnings and Precautions (5.1)] Osteonecrosis of the Jaw [see Warnings and Precautions (5.2)]

The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1).

The most common serious adverse reaction in patients receiving Xgeva was dyspnea.

The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience

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

The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials [see Clinical Trials (14)] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selected* Adverse Reactions of Any Severity (Trials 1, 2, and 3) * Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria:
- At least 1% greater incidence in Xgeva-treated patients, or
- Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (U.S. Prescribing Information for zoledronic acid) † Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus]

Body System

Xgeva
n = 2841
%

Zoledronic Acid
n = 2836

% GASTROINTESTINAL Nausea 31 32 Diarrhea 20 19 GENERAL Fatigue/Asthenia 45 46 INVESTIGATIONS Hypocalcemia† 18 9 Hypophosphatemia† 32 20 NEUROLOGICAL Headache 13 14 RESPIRATORY Dyspnea 21 18 Cough 15 15

Severe Mineral/Electrolyte Abnormalities

Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the Jaw

In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group [see Warnings and Precautions (5.2)]. When events occurring during an extended treatment phase of approximately 4 months in each trial are included, the incidence of confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ was 14 months (range: 4 – 25).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

Drug Interactions

No formal drug-drug interaction trials have been conducted with Xgeva.

In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy.

There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy [see Clinical Pharmacology (12.2)].

USE IN SPECIFIC POPULATIONS Pregnancy: Category C

There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

In an embryofetal developmental study, cynomolgus monkeys received subcutaneous denosumab weekly during organogenesis at doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity or fetal harm was observed. However, this study only assessed fetal toxicity during the first trimester, and fetal lymph nodes were not examined. Potential adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals [see Nonclinical Toxicology (13.2)].

In genetically engineered mice in which the gene for RANK ligand (RANKL) has been deleted (a “knockout mouse”), the absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to impaired lactation postpartum [see Use in Specific Populations (8.3)].

Nursing Mothers

It is not known whether Xgeva is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum [see Nonclinical Toxicology (13.2)].

Pediatric Use

The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg subcutaneously every 4 weeks (based on body weight mg/kg) had abnormal growth plates [see Nonclinical Toxicology (13.2)].

Geriatric Use

Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment

In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

Overdosage

There is no experience with overdosage of Xgeva.

Xgeva Description

Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Xgeva is a sterile, preservative-free, clear, colorless to pale yellow solution.

Each single-use vial of Xgeva contains 120 mg denosumab, 4.6% sorbitol, 18 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

Xgeva - Clinical Pharmacology Mechanism of Action

Xgeva binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases.

Pharmacodynamics

In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of Xgeva 120 mg administered subcutaneously. In Trials 1, 2, and 3, the median reduction in uNTx/Cr from baseline to month 3 was approximately 80% in 2075 Xgeva-treated patients.

Pharmacokinetics

Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60 mg, but approximately dose-proportional increases in exposure at higher doses. With multiple subcutaneous doses of 120 mg every 4 weeks in patients with cancer metastatic to the bone, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6 months. At steady state, the mean ± SD serum trough concentration was 20.5 ± 13.5 mcg/mL at the recommended Xgeva dose, and the mean elimination half-life was 28 days.

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. Denosumab clearance and volume of distribution were proportional to body weight. The steady-state exposure following repeat subcutaneous administration of 120 mg every 4 weeks to 45 kg and 120 kg subjects were, respectively, 48% higher and 46% lower than exposure of the typical 66 kg subject.

Specific Populations

The pharmacokinetics of denosumab were not affected by age, gender, and race. The pharmacokinetics of denosumab in pediatric patients have not been assessed.

Hepatic Impairment: No clinical trials have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.

Renal Impairment: In a trial of 55 subjects with varying degrees of renal function, including subjects on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab [see Use in Specific Populations (8.6)].

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

Mutagenicity

The genotoxic potential of denosumab has not been evaluated.

Impairment of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at exposures that were 6.5- to 25-fold higher than the observed human dose of 120 mg subcutaneously administered once every 4 weeks (based on body weight mg/kg).

Animal Toxicology and/or Pharmacology

Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL. Adolescent nonhuman primates treated with monthly doses of denosumab greater than 5 times the recommended human dose of 120 mg had abnormal growth plates. Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, OPG-Fc and RANK-Fc, provided additional safety information on the inhibition of the RANK/RANKL pathway in rodent models. A study in 2-week-old rats given the RANKL inhibitor OPG-Fc showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued. Neonatal RANK/RANKL knockout mice also exhibited reduced bone growth and lack of tooth eruption. RANK/RANKL knockout mice also exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) [see Use in Specific Populations (8.3, 8.4)].

Clinical Trials

The safety and efficacy of Xgeva for the prevention of skeletal-related events in patients with bone metastases from solid tumors was demonstrated in three international, randomized (1:1), double-blind, active-controlled, noninferiority trials comparing Xgeva with zoledronic acid. In all three trials, patients were randomized to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In each trial, the main outcome measure was demonstration of noninferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. Supportive outcome measures were superiority of time to first SRE and superiority of time to first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Trial 1 enrolled 2046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE (yes or no), receipt of chemotherapy within 6 weeks prior to randomization (yes or no), prior oral bisphosphonate use (yes or no), and region (Japan or other countries). Forty percent of patients had a previous SRE, 40% received chemotherapy within 6 weeks prior to randomization, 5% received prior oral bisphosphonates, and 7% were enrolled from Japan. Median age was 57 years, 80% of patients were White, and 99% of patients were women. The median number of doses administered was 18 for denosumab and 17 for zoledronic acid.

Trial 2 enrolled 1776 adults with solid tumors other than breast and castrate-resistant prostate cancer with bone metastasis and multiple myeloma. Randomization was stratified by previous SRE (yes or no), systemic anticancer therapy at time of randomization (yes or no), and tumor type (non-small cell lung cancer, myeloma, or other). Eighty-seven percent were receiving systemic anticancer therapy at the time of randomization, 52% had a previous SRE, 64% of patients were men, 87% were White, and the median age was 60 years. A total of 40% of patients had non-small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types each comprised less than 5% of the enrolled population. The median number of doses administered was 7 for both denosumab and zoledronic acid.

Trial 3 enrolled 1901 men with castrate-resistant prostate cancer and bone metastasis. Randomization was stratified by previous SRE, PSA level (less than 10 ng/mL or 10 ng/mL or greater) and receipt of chemotherapy within 6 weeks prior to randomization (yes or no). Twenty-six percent of patients had a previous SRE, 15% of patients had PSA less than 10 ng/mL, and 14% received chemotherapy within 6 weeks prior to randomization. Median age was 71 years and 86% of patients were White. The median number of doses administered was 13 for denosumab and 11 for zoledronic acid.

Xgeva delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or castrate-resistant prostate cancer (CRPC) with osseous metastases (Table 2). In patients with bone metastasis due to other solid tumors or lytic lesions due to multiple myeloma, Xgeva was noninferior to zoledronic acid in delaying the time to first SRE following randomization.

Overall survival and progression-free survival were similar between arms in all three trials. Mortality was higher with Xgeva in a subgroup analysis of patients with multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180).

Table 2. Efficacy Results for Xgeva Compared to Zoledronic Acid * CRPC = castrate-resistant prostate cancer. † NR = not reached. ‡ Superiority testing performed only after denosumab demonstrated to be noninferior to zoledronic acid within trial. § All skeletal events postrandomization; new events defined by occurrence ? 21 days after preceding event. ¶ Adjusted p-values are presented.

Trial 1

Metastatic Breast Cancer

Trial 2

Metastatic Solid Tumors or Multiple Myeloma

Trial 3

Metastatic CRPC*

Xgeva Zoledronic Acid Xgeva Zoledronic Acid Xgeva Zoledronic Acid N 1026 1020 886 890 950 951 First On-study SRE Number of Patients who had SREs (%) 315 (30.7) 372 (36.5) 278 (31.4) 323 (36.3) 341 (35.9) 386 (40.6) Components of First SRE Radiation to Bone 82 (8.0) 119 (11.7) 119 (13.4) 144 (16.2) 177 (18.6) 203 (21.3) Pathological Fracture 212 (20.7) 238 (23.3) 122 (13.8) 139 (15.6) 137 (14.4) 143 (15.0) Surgery to Bone 12 (1.2) 8 (0.8) 13 (1.5) 19 (2.1) 1 (0.1) 4 (0.4) Spinal Cord Compression 9 (0.9) 7 (0.7) 24 (2.7) 21 (2.4) 26 (2.7) 36 (3.8) Median Time to SRE (months) NR † 26.4 20.5 16.3 20.7 17.1 Hazard Ratio (95% CI) 0.82 (0.71, 0.95) 0.84 (0.71, 0.98) 0.82 (0.71, 0.95) Noninferiority p-value < 0.001 < 0.001 < 0.001 Superiority p-value‡ 0.010 0.060 0.008 First and Subsequent SRE § Mean Number/Patient 0.46 0.60 0.44 0.49 0.52 0.61 Rate Ratio (95% CI) 0.77 (0.66, 0.89) 0.90 (0.77, 1.04) 0.82 (0.71, 0.94) Superiority  p-value¶ 0.001 0.145 0.009 How Supplied/Storage and Handling

Xgeva is supplied in a single-use vial.

120 mg/1.7 mL 1 vial per carton NDC 55513-730-01

Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label.

Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

Patient Counseling Information

Advise patients to contact a healthcare professional for any of the following:

Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] Persistent pain or slow healing of the mouth or jaw after dental surgery [see Warnings and Precautions (5.2)] Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]


Advise patients of the need for:

Proper oral hygiene and routine dental care Informing their dentist that they are receiving Xgeva Avoiding invasive dental procedures during treatment with Xgeva


Advise patients that denosumab is also marketed as Prolia™. Patients should inform their healthcare provider if they are taking Prolia.

[Amgen Logo]


Xgeva™ (denosumab)

Manufactured by:
Amgen Manufacturing Limited, a subsidiary of Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799

This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,740,522; 7,411,050; 7,097,834; and 7,364,736, as well as other patents or patents pending.

© 2010 Amgen Inc. All rights reserved.

1xxxxx - v1

PACKAGE LABEL - PRINICPAL DISPLAY PANEL - VIAL, 120 MG

1 ? 120 mg Single Use Vial

NDC 55513-730-01

AMGEN®

XgevaTM

(denosumab)

120 mg/1.7 mL

(70 mg/mL)

Injection

For Subcutaneous Use Only

120 mg/1.7 mL

Single Use Vial. Discard Unused Portion.

Sterile Solution – No Preservative

Refrigerate at 2° to 8°C (36° to 46°F).

Do not freeze. Avoid excessive shaking.

Protect from direct light.

Manufactured by: Amgen Manufacturing Ltd.,

a subsidiary of Amgen Inc.

Thousand Oaks, CA 91320-1799


Xgeva 
denosumab  injection Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 55513-730 Route of Administration SUBCUTANEOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DENOSUMAB (DENOSUMAB) DENOSUMAB 120 mg  in 1.7 mL Inactive Ingredients Ingredient Name Strength SORBITOL 78 mg  in 1.7 mL SODIUM ACETATE 1.8 mg  in 1.7 mL WATER   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 55513-730-01 1 VIAL In 1 CARTON contains a VIAL, SINGLE-USE 1 1.7 mL In 1 VIAL, SINGLE-USE This package is contained within the CARTON (55513-730-01)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125320 11/18/2010
Labeler - AMGEN (039976196) Registrant - Amgen, Inc (039976196) Establishment Name Address ID/FEI Operations Amgen, Inc 039976196 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Boehringer Ingelheim Pharma GmbH and Co. KG 340700520 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Amgen, Inc 048053201 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Amgen, Inc 071629633 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Amgen Manufacturing Ltd 785800020 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Amgen Fremont Inc 960193530 ANALYSIS Establishment Name Address ID/FEI Operations WUXI APPTEC INC 136584468 ANALY
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