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Container Label 400 mg Tablets

Container Label 400 mg Tablets

List 3565-9

Rx only

400 mg

Mesnex®
(mesna) Tablets

Baxter Healthcare
Corporation
460-656-00

Lot-number/Expires:

JMXXXA JJJJ - MM

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 the accompanying literature.

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

Barcode
N3 6710835659 1

C
926

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

HA-80-02-274
USA

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

2640B4050

Barcode

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

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 Logo
Baxter Healthcare Corporation
****Deerfield, IL 60015

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

51741274

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

MESNEX may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue MESNEX and provide supportive care.

5.2 Dermatologic Toxicity

Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. MESNEX may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue MESNEX and provide supportive care.

5.3 Benzyl Alcohol Toxicity

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants who received benzyl alcohol dosages of 99 to 234 mg/kg/day (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Symptoms associated with “gasping syndrome” and other potential adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Premature neonates and low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known. MESNEX injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of MESNEX injection in premature neonates and low-birth weight infants. MESNEX tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4)].

5.4 Laboratory Test Interferences

False-Positive Urine Tests for Ketone Bodies

A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).

False-Negative Tests for Enzymatic CPK Activity

MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.

False-Positive Tests for Ascorbic Acid

MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.

5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds

MESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to mesna and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to MESNEX.

Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue MESNEX and provide supportive care. (5.1)

Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If a reaction occurs, discontinue MESNEX and provide supportive care. (5.2)

Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including MESNEX injection. Avoid use in premature neonates and low-birth weight infants. (5.3)

Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

MESNEX injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm including embryo-fetal lethality. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

In embryo-fetal development studies, oral administration of mesna to pregnant rats (500, 1000, 1500, and 2000 mg/kg) and rabbits (500 and 1000 mg/kg) during the period of organogenesis revealed no adverse developmental outcomes at doses approximately 10 times the maximum recommended total daily human equivalent dose based on body surface area.

8.2 Lactation

Risk Summary

MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide is excreted in breast milk. Refer to the ifosfamide prescribing information for more information on use during lactation. There are no data on the presence of mesna in human or animal milk, the effect on the breastfed child, or the effect on milk production.

MESNEX injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for 1 week after the last dose of MESNEX or ifosfamide.

8.3 Females and Males of Reproductive Potential

MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiation of MESNEX in combination with ifosfamide.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for 6 months after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for 3 months after the last dose.

8.4 Pediatric Use

MESNEX injection contains the preservative benzyl alcohol which has been associated with serious adverse reactions and death when administered intravenously to premature neonates and low birth weight infants. Avoid use of MESNEX injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].

8.5 Geriatric Use

Clinical studies of MESNEX 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. The ratio of ifosfamide to MESNEX should remain unchanged.

8.6 Use in Patients with Renal Impairment

No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of MESNEX.

8.7 Use in Patients with Hepatic Impairment

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of MESNEX.

Pregnancy: MESNEX in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to a fetus. (8.1)

Lactation: Do not breastfeed. (8.2)

Females and Males of Reproductive Potential: Advise patients to use effective contraception. Verify pregnancy status prior to initiation of MESNEX in combination with ifosfamide. (8.3)

Pediatric use: In premature neonates and low-birth weight infants, avoid use of benzyl alcohol–containing solutions. (8.4)

Geriatric use: Dose selection should be cautious. (8.5)

Baxter Logo
MESNEX (mesna) injection manufactured by:

MESNEX (mesna) tablets manufactured for:

Baxter Healthcare Corporation
****Deerfield, IL 60015 USA
For Product Inquiry 1800 ANA DRUG (1-800-262-3784)

Made in Germany

Baxter and Mesnex are registered trademarks of Baxter International Inc.

Material No. HA-30-01-811

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mesna 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 non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.

12.3 Pharmacokinetics

Absorption

Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.

Food does not affect the urinary availability of orally administered MESNEX.

Distribution

Mean apparent volume of distribution (Vd) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).

Metabolism

Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration.

Excretion

Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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.

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 (≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.

14 CLINICAL STUDIES

14.1 Intravenous MESNEX

Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 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%.

Table 4. Percent of MESNEX Patients Developing Hematuria (≥50 RBC/hpf or macrohematuria)

Ifosfamide dose 1.2 g/m2 d x 5 † Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to 5
Study	Conventional Uroprophylaxis (number of patients)	Standard MESNEX**(mesna)** Intravenous Regimen (number of patients)
Uncontrolled Studies*
Study 1	16% (7/44)
Study 2	26% (11/43)
Study 3	18% (7/38)	0% (0/21)
Study 4		0% (0/32)
Controlled Studies†
Study 5	31% (14/46)	6% (3/46)
Study 6	100% (7/7)	0% (0/8)

14.2 Oral MESNEX

Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 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 5.

Table 5. Percent of MESNEX Patients Developing Grade 3 or 4 Hematuria

	MESNEX Dosing Regimen
Study	Standard Intravenous Regimen (number of patients)	Intravenous + Oral Regimen (number of patients)
Study 7	0% (0/30)	3.6% (1/28)
Study 8	3.7% (1/27)	4.3% (1/23)