Mesna
Tablets / Injection

What is the most important information I should know about MESNA?

MESNA can cause serious allergic reactions and skin reactions. These side effects can happen the first time you are treated with MESNA, or after several months of treatment with MESNA. Stop treatment with MESNA and call your doctor or go to the nearest hospital emergency room right away if you develop any of the symptoms listed below:

• fever
• swelling of your face, lips, mouth, or tongue
• trouble breathing or wheezing
• itching
• burning
• skin rash or hives
• skin redness or swelling
• skin blisters or peeling
• feel lightheaded or faint
• feel like your heart is racing
• nausea or vomiting
• joint or muscle aches
• mouth sores

See “What are the possible side effects of MESNA?” for more information about side effects.

What is MESNA?

MESNA is a prescription medicine used to reduce the risk of inflammation and bleeding of the bladder (hemorrhagic cystitis) in people who receive ifosfamide (a medicine used to treat cancer).

MESNA is not for use to reduce the risk of blood in the urine (hematuria) due to other medical conditions.

It is not known if MESNA is safe and effective in children.

Who should not receive MESNA?

Do not take MESNA if you are allergic to MESNA or any of the ingredients in MESNA. See the end of this leaflet for a complete list of ingredients in MESNA.

What should I tell my doctor before receiving MESNA?

Before you receive MESNA, tell your doctor if you:

• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if MESNA will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if MESNA passes into your breast milk. You and your doctor should decide if you will receive MESNA or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive MESNA?

• MESNA is given on the same day that you receive ifosfamide.
• MESNA can be given by an intravenous (IV) infusion into a vein or tablets taken by mouth.
• You will receive MESNA in one of two ways:

1. MESNA intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4 and 8 hours after you receive ifosfamide.
2. MESNA intravenous (IV) infusion into a vein at the time you receive ifosfamide and MESNA tablets taken by mouth 2 and 6 hours after you receive ifosfamide.

• Take MESNA tablets at the exact times and the exact dose your doctor tells you to take it.
• You may need to take half of a MESNA tablet for your complete dose. Each tablet has a groove in the middle that will make it easier to break the tablet in half.
• During treatment with MESNA,you should drink 4 to 8 cups of liquid (1 to 2 liters) each day, whether you receive MESNA by intravenous infusion or take MESNA tablets by mouth.
• Tell your doctor if you:
• vomit within 2 hours of taking MESNA tablets by mouth
• miss a dose of MESNA tablets
• have pink or red colored urine

What are the possible side effects of MESNA?

MESNA may cause serious side effects, including:
See “What is the most important information I should know about MESNA?”

• MESNA that is given by intravenous infusion contains the preservative benzyl alcohol. Benzyl alcohol has been shown to cause serious side effects and death in newborn and premature babies. MESNA tablets do not contain benzyl alcohol.

The most common side effects of MESNA when given with ifosfamide include:

• nausea
• vomiting
• constipation
• decreased white blood cell count
• tiredness
• fever
• decreased appetite
• decreased platelet count
• decreased red blood cell count
• diarrhea
• weakness
• stomach (abdomen) pain
• headache
• hair loss
• sleepiness

Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of MESNA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA.

How should I store MESNA tablets?

• Store MESNA tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep MESNA and all medicines out of the reach of children.

General information about the safe and effective use of MESNA
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MESNA for a condition for which it was not prescribed. Do not give MESNA to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about MESNA that is written for health professionals.

What are the ingredients in MESNA?
Active ingredient: mesna

Inactive ingredients:
MESNA injection: edetate disodium, sodium hydroxide, and benzyl alcohol as a preservative.
MESNA tablets: calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Mesna
Tablets / Injection

DESCRIPTION

Mesna 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+

Mesna Injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. Mesna Injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna 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.

Mesna 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.

CLINICAL PHARMACOLOGY

Mesna 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.

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 mesna 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 Mesna , 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 mesna 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 mesna.

Drug-Drug Interaction
No clinical drug interaction studies have been conducted with mesna.

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 mesna 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 mesna was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

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.

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

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

CONTRAINDICATIONS

Mesna 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.

Mesna 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.

Mesna 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 mesna 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, mesna must be administered with each dose of ifosfamide as outlined in the DOSAGE AND ADMINISTRATION section. Mesna 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

Healthcare providers should advise patients taking mesna 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 Mesna , or if they miss a dose of oral Mesna . See Patient Information Leaflet for Mesna Tablets.

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

No clinical drug studies have been conducted.

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

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 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.

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.

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

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

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

Mesna adverse reaction data are available from four phase I studies in which single IV bolus doses of 600-1200 mg mesna Injection without concurrent chemotherapy were administered to a total of 53 subjects and single oral doses of 600-2400 mg of Mesna 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 mesna 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 Mesna Tablets alone or IV mesna followed by repeated doses of Mesna Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by patients who had received repeated doses of IV mesna.

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 mesna 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.

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 mesna. 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.

DOSAGE AND ADMINISTRATION

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

Mesna 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:

Mesna 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. Mesna 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:

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 ifosfamide 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 mesna to ifosfamide should be maintained.

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

For IV administration the drug can be diluted by adding the mesna 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 mesna 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 SUPPLIED

Mesna Injection 100 mg/mL

• 1 g Multidose Vial, Box of 1 vial of 10 mL
• 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 Temperature]

Mesna  (mesna) Tablets

• 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 Temperature]