WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
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.
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.
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].
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.
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.
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION).
Hypersensitivity
- Advise the patient to
discontinue MESNEX and seek immediate medical attention if any signs or
symptoms of a hypersensitivity reaction, including systemic anaphylactic
reactions occur [see WARNINGS AND PRECAUTIONS].
Dosing Instructions
- Advise the patient to take MESNEX at the exact time and
in the exact amount as prescribed. Advise the patient to contact their
healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if
they miss a dose of oral MESNEX [see DOSAGE AND ADMINISTRATION].
Hemorrhagic Cystitis
- MESNEX does not prevent hemorrhagic cystitis in all
patients nor does it prevent or alleviate any of the other adverse reactions or
toxicities associated with ifosfamide. Advise the patient to report to their
healthcare provider if his/her urine has turned a pink or red color [see DOSAGE
AND ADMINISTRATION].
- Advise the patient to drink 1 to 2 liters of fluid each
day during MESNEX therapy [see DOSAGE AND ADMINISTRATION].
Dermatologic Toxicity
- Advise the patient that
Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with
eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal
reactions have occurred with MESNEX. Advise the patient to report to their healthcare
provider if signs and symptoms of these syndromes occur [see WARNINGS
AND PRECAUTIONS].
Benzyl Alcohol Toxicity
- Advise patients that serious
adverse reactions are associated with the benzyl alcohol found in MESNEX and
other medications in premature neonates and low-birth weight infants [see WARNINGS
AND PRECAUTIONS and Use In Specific
Populations].
Embryo-Fetal Toxicity
- MESNEX is used in combination
with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when
administered to a pregnant woman. Inform female patients of the risk to a fetus
and potential loss of the pregnancy. Advise females to inform their healthcare
provider if they are pregnant or become pregnant [see Use In Specific
Populations].
Contraception
- Advise females of reproductive potential to use effective
contraception during treatment with MESNEX in combination with ifosamide and
for 6 months after the last dose [see Use In Specific Populations].
- Advise male patients with female partners of reproductive
potential to use effective contraception during treatment with MESNEX in
combination with ifosamide and for 3 months after the last dose [see Use In Specific
Populations].
Lactation
- Advise lactating women not to
breastfeed during treatment with MESNEX or ifosfamide and for 1 week after the
last dose [see Use In Specific Populations].
Nonclinical Toxicology
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.
Use In Specific Populations
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 and Use In Specific
Populations].
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.
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 and Use In Specific Populations].
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.
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.
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].
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.
Use In Patients With Renal Impairment
No clinical studies were conducted to evaluate the effect
of renal impairment on the pharmacokinetics of MESNEX.
Use In Patients With Hepatic Impairment
No clinical studies were conducted to evaluate the effect
of hepatic impairment on the pharmacokinetics of MESNEX.