Rx Drugs Info

mesnex (mesnatablet 
mesna (Mesnainjection, solution 
[Baxter Healthcare Corporation]

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.

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.

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

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 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.

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 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%.

Table 1
Percent of Mesna Patients Developing Hematuria (≥50 RBC/hpf or macrohematuria)
Study Conventional Uroprophylaxis (number of patients) Standard Mesna 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)
*Ifosfamide dose 1.2 g/m2 d x 5
**Ifosfamide dose 2 to 4 g/m2 d x 3-5

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 Mesna Patients Developing Grade 3 or 4 Hematuria
  Mesna 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

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 (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 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 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.

Laboratory Tests

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.

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 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

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 Mesna 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

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.

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)
* All grades

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 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 Mesnex Tablets as outlined below.

Intravenous Schedule

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:

  0 Hours 4 Hours 8 Hours
Ifosfamide 1.2 g/m2
Mesna 240 mg/m2 240 mg/m2 240 mg/m2

Intravenous and Oral Dosing

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:

  0 Hours 2 Hours 6 Hours
Ifosfamide 1.2 g/m2
Mesna 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 Mesna to IFEX should be maintained.

Preparation of Intravenous Solutions/Stability

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:

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

Mesnex® (mesna) Tablets

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

PATIENT INFORMATION

Mesnex® (mesna) Tablets

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.

What is the most important information I should know?

What is Mesnex?

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.

Who should not take Mesnex?

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:

How should I take 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.

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

What are the most common side effects of Mesnex?

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 list, 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.

Storage

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.

General advice about prescription medicines

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


Mesnex (mesna)
PRODUCT INFO
Product Code 67108-3565 Dosage Form TABLET
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Mesna (mesna) Active 400 MILLIGRAM  In 1 TABLET
Lactose Inactive 59.3 MILLIGRAM  In 1 TABLET
Microcrystalline Cellulose Inactive 38.7 MILLIGRAM  In 1 TABLET
Dibasic Calcium Phosphate Inactive 32.1 MILLIGRAM  In 1 TABLET
Corn Starch Inactive 23.3 MILLIGRAM  In 1 TABLET
Povidone Inactive 16 MILLIGRAM  In 1 TABLET
Magnesium Stearate Inactive 5.6 MILLIGRAM  In 1 TABLET
Hydroxypropyl Methylcellulose Inactive 8.6 MILLIGRAM  In 1 TABLET
Polyethylene Glycol 6000 Inactive 3.6 MILLIGRAM  In 1 TABLET
Titanium Dioxide Inactive 2.8 MILLIGRAM  In 1 TABLET
Simethicone Inactive .07 MILLIGRAM  In 1 TABLET
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE Score 2
Shape OVAL Symbol false
Imprint Code M4 Coating true
Size 16mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 67108-3565-9 1 BLISTER PACK In 1 BOX contains a BLISTER PACK
1 10 TABLET In 1 BLISTER PACK This package is contained within the BOX (67108-3565-9)

Mesna (Mesna)
PRODUCT INFO
Product Code 10019-953 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Mesna (Mesna) Active 100 MILLIGRAM  In 1 MILLILITER
edetate disodium Inactive .25 MILLIGRAM  In 1 MILLILITER
sodium hydroxide Inactive  
benzyl alcohol Inactive 10.4 MILLIGRAM  In 10 MILLILITER
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 10019-953-01 1 VIAL In 1 BOX contains a VIAL, MULTI-DOSE
1 10 MILLILITER In 1 VIAL, MULTI-DOSE This package is contained within the BOX (10019-953-01)
2 10019-953-02 10 VIAL In 1 BOX contains a VIAL, MULTI-DOSE
2 10 MILLILITER In 1 VIAL, MULTI-DOSE This package is contained within the BOX (10019-953-02)

Revised: 05/2006Baxter Healthcare Corporation

Data are from FDA and U.S. National Library of Medicine.