| Application
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| Supplement Number
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020855
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| Complete Label
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| Formatted in PDF
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MESNEX
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| Description
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| Mechanism of Action
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MESNEX (mesna) Injection 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 C 2 H 5 NaO 3 S 2 and a molecular weight of 164.18.
MESNEX Injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass single dose ampules or 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 6.5-8.5.
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| Generic Drug Name
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mesna
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| Manufacturer
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| Manufacturer
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Manufactured by:
ASTA MEDICA
A Degussa Company
Frankfurt am Mein
Germany
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| Distributor
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| Distributor
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Mead Johnson
ONCOLOGY PRODUCTS
A Bristol-Myers Squibb Company
Princeton, NJ 08543
U.S.A.
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| Actions
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| Summary
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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 i.v. or i.p. 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.
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| Clinical Pharmacology
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| Summary
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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.
After 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 volume of distribution of 0.652 L/kg and a plasma clearance of 1.23 L/kg/hour.
IV-oral-oral regimen
The half-life of mesna ranged from 1.2 to 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 i.v. 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.
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| Clinical Studies
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| Summary
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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 three to five days, produced hematuria in 31 to 100% of the patients. When Mesnex was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
(See Table)
Clinical studies comparing recommended intravenous and oral mesna dosing regimens demonstrated incidences of grade 3-4 hematuria of <5% in both arms when used in conjunction with ifosfamide 1.2-2.0 gm/m2 for 3-5 days. Study D07093-0018 was an open label, randomized, two-way crossover study comparing three i.v. doses with an initial i.v. 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.
(See Table)
A cross over 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.
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| Indications and Usage
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| Summary
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MESNEX has been shown to be effective as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.
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| Contraindications
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| Summary
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MESNEX is contraindicated in patients known to be hypersensitive to mesna or other thiol compounds.
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| Warnings
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| Summary
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Allergic reactions to mesna were reported in patients with autoimmune disorders. The majority of the patients received high doses of mesna orally. The symptoms ranged from mild hypersensitivity to systemic anaphylactic reactions.
MESNEX has been developed as an agent to prevent 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 (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 obtain adequate protection, MESNEX must be administered with each dose of ifosfamide as outlined in the "DOSAGE AND ADMINISTRATION" section. MESNEX is not effective in preventing 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.
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| Precautions
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| Summary
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Laboratory Tests: A false positive test for urinary ketones may arise in patients treated with MESNEX (mesna) Injection. In this test, a red-violet color develops which, with the addition of glacial acetic acid, will return to violet.
Pediatrics: 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.
Drug Interactions: In vitro and in vivo animal tumor models have shown that mesna does not have any effect on the antitumor efficacy of concomitantly administered cytotoxic agents.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No long term animal studies have been performed to evaluate the carcinogenic potential of mesna. The Ames Salmonella typhimurium test, mouse micronucleus assay and frequency of sister chromatid exchange and chromosomal aberrations in PHA-stimulated lymphocytes in vitro assays revealed no mutagenic activity.
Pregnancy: Pregnancy "Category B". Reproduction studies in rats and rabbits with oral doses up to 1000 mg/kg have revealed no harm to the fetus due to mesna. It is not known whether MESNEX can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MESNEX should be given to a pregnant woman only if the benefits clearly outweigh any possible risks.
Teratology studies in rats and rabbits have shown no effects.
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.
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| Drug Interactions
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| Summary
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In vitro and in vivo animal tumor models have shown that mesna does not have any effect on the antitumor efficacy of concomitantly administered cytotoxic agents.
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| Adverse Reactions
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| Summary
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Mesnex adverse reaction data are available from four phase I studies in which single i.v. 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 multipledose
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 i.v. and orally in four controlled studies in which patients received ifosfamide or ifosfamide containing regimens are presented in Table 3.
(See table)
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.
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| Overdosage
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| Summary
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Laboratory Tests: A false positive test for urinary ketones may arise in patients treated with MESNEX (mesna) Injection. In this test, a red-violet color develops which, with the addition of glacial acetic acid, will return to violet.
Pediatrics: 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.
Drug Interactions: In vitro and in vivo animal tumor models have shown that mesna does not have any effect on the antitumor efficacy of concomitantly administered cytotoxic agents.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No long term animal studies have been performed to evaluate the carcinogenic potential of mesna. The Ames Salmonella typhimurium test, mouse micronucleus assay and frequency of sister chromatid exchange and chromosomal aberrations in PHA-stimulated lymphocytes in vitro assays revealed no mutagenic activity.
Pregnancy: Pregnancy "Category B". Reproduction studies in rats and rabbits with oral doses up to 1000 mg/kg have revealed no harm to the fetus due to mesna. It is not known whether MESNEX can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MESNEX should be given to a pregnant woman only if the benefits clearly outweigh any possible risks.
Teratology studies in rats and rabbits have shown no effects.
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.
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| Dosage and Administration
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| Summary
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For the prophylaxis of ifosfamide-induced hemorrhagic cystitis, MESNEX may be given on a fractionated dosing schedule of bolus intravenous injections as outlined below.
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:
(See Table)
In order to maintain adequate protection, this dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted (either increased or decreased), the dose of MESNEX should be modified accordingly. When exposed to oxygen, mesna is oxidized to the disulfide, dimesna. As a result, if the ampules are used, any unused mesna remaining in the ampules after dosing should be discarded and new ampules used for each administration.
The MESNEX multidose vials may be stored and used for up to 8 days.
PREPARATION OF INTRAVENOUS SOLUTIONS/STABILITY
For I.V. 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 fluid:
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 (mesna) Injection multidose vial 100 mg/mL may be added to 4 mL, or one ampule of MESNEX Injection 200 mg/2 mL may be added to 8 mL of any of the solutions listed above to create a final concentration of 20 mg mesna/mL fluid.
Diluted solutions are chemically and physically stable for 24 hours at 25°C (77°F).
Mesna is not compatible with cisplatin.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
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| How Supplied
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| Summary
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MESNEX (mesna) Injection 100 mg/mL
NDC 0015-3560-41
200 mg Single Dose Ampule, Box of 15 Ampules of
2-mL (color-ring coding: turquoise/yellow)
NDC 0015-3563-02
1 g Multidose Vial,
Box of 1 vial of 10 mL
NDC 0015-3563-03
1 g Multidose Vial,
Box of 10 vials of 10 mL
Store at controlled room temperature 15-30°C (59°-86°F).
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| NDC
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| NDC
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0015-3560-41
0015-3563-02
0015-3563-03
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| Date
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| Date
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March 2, 2002
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