Mesnex^® (mesna) Tablets
Mesna Injection
Rx only

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.

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.

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.

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

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

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 (³50 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 span, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.

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 Mesnex 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.

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 Mesnex Tablets in pediatric patients have not been established.

Because of the benzyl alcohol span 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.

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 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 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 Mesnex Tablets alone or IV Mesna 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 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.

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.

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 Mesnex 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. 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:

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 Mesna to IFEX 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 uled 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.

Mesna Injection 100 mg/mL

• NDC 10019-953-01 - 1 g Multidose Vial, Box of 1 vial of 10 mL
• NDC 10019-953-02 - 1 g Multidose Vial, Box of 10 vials of 10 mL

Mesnex^® (mesna) Tablets

• NDC 67108-3565-9 - 400 mg scored tablets, Boxes containing 10 bulers per card

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

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

Mesnex^® (mesna) Tablets manufactured for:

Mesna Injection manufactured by:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

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

USA 5663 9331 C66 Issued August 2004

Rx only

Read this information carefully before you start taking Mesnex (MES-nex) and each time you get more Mesnex. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Mesnex, ask your doctor. Only your doctor can determine if Mesnex is right for you.

• It is important to drink at least a quart (4 cups) of liquid a day whenever you take Mesnex, whether it is intravenous (through a tube placed in a vein) or oral (by mouth).
• A small number of patients who take Mesnex get blood in their urine (hematuria). Therefore, it is important that your doctor check your urine in the laboratory each day that you get Mesnex. The laboratory test can find low levels of blood in the urine that you cannot see just by looking at it.
• If you notice that your urine has turned a pink or red color, contact your doctor as soon as possible. Certain prescription medicines and foods, such as red beets, may also cause your urine to change color. A laboratory test of your urine will show if the source of the color is due to one of these causes or hematuria.
• You need to take your Mesnex Tablets at the exact times your doctor tells you. If you miss a dose, take it as soon as you remember, and contact your doctor for more instructions. Do not double your dose to make up for the missed dose.
• If you vomit within 2 hours of taking oral Mesnex, contact your doctor right away.

Mesnex reduces the chance of your getting one of the side effects of another medicine, IFEX^® (ifosfamide) for Injection.

IFEX is used to treat certain types of cancers. Mesnex should only be given with IFEX.

Mesnex reduces the chance of your getting hemorrhagic cystitis from IFEX. This condition causes bloody urine from damage to the bladder lining. The damage to the bladder may show up as blood in your urine (hematuria). If a very small amount of blood is in your urine, you may not be able to see it, but your doctor or nurse can test for it in the laboratory. If there is a larger amount of blood in your urine, you will see that the urine has turned a pink or red color. Mesnex does not reduce the chance of getting other side effects of cancer chemotherapy.

When IFEX is given without Mesnex, hematuria occurs in a large number of patients. Therefore, it is very important to always take Mesnex when getting IFEX treatment.

Do not take Mesnex if you have had an allergic reaction to Mesnex or other medicines that contain sulfur.

Before beginning treatment with Mesnex, check with your doctor if you are:

• Pregnant. You and your doctor should discuss if Mesnex is right for you.
• Breast-feeding. Your doctor may advise you to stop breast-feeding or not to use Mesnex.
• Have an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosis (SLE), or nephritis (a type of kidney problem). You may be more likely to get an allergic reaction from Mesnex.

Take Mesnex at the exact times in the exact amounts your doctor tells you to. If your first dose is intravenous and the other doses are oral, you will get the intravenous dose at the same time as the IFEX. You should take the tablets 2 and 6 hours after the IFEX.

• The dose of Mesnex depends on the amount of the IFEX dose. Pay careful attention to the number of tablets your doctor instructs you to take. You may need to take half tablets for your dose. Each tablet has a groove in the middle that makes it easy to break the tablets in half.

For more information about how to take Mesnex, see the section “What is the most important information I should know?”

The most common side effects reported for Mesnex Tablets are headache; digestive symptoms such as nausea (feeling sick to your stomach), vomiting (throwing up), diarrhea (frequent or watery stools or bowel movements), stomach pain and low or no appetite; flu-like symptoms including dizziness, flushing, and fever; sensitive skin; sleepiness; coughing; sore throat; cold-like symptoms; injection site reactions. Some patients may get allergic reactions, rash, constipation, paleness, fluid retention (water stays in your body), and decreased blood pressure. These are not all the possible side effects of Mesnex. For a complete ul, ask your doctor.

If you suspect that someone may have taken more than the prescribed dose of Mesnex, contact your local poison control center or emergency room right away.

Store Mesnex Tablets in a cool, dry place protected from excess moisture and heat. If possible do not store in the kitchen or bathroom. Throw away any unused portion after the expiration date.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Mesnex for a condition for which it was not prescribed. Do not give Mesnex to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Mesnex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Mesnex that is written for health professionals.

IFEX^® is a registered trademark of Bristol-Myers Squibb Company.

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

Mesnex^® (mesna)Tablets manufactured for:

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

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

70037322-2004/66 Issued August 2004