Patients with pre-existing hepatic insufficiency may suffer adverse effects from the small amounts of ammonia and formaldehyde that are produced. The classical syndrome of acute hepatic failure may be evoked in these patients.
General: Prescribing UREX (methenamine hippurate) in the absence of a proven or strongly suspected
bacterial infection or a prophylactic indication is unlikely to provide benefit
to the patient and increases the risk of the development of drug-resistant bacteria.
Large doses of methenamine (8 g daily for 3 to 4 weeks) have caused bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria.
Care should be taken to maintain an acid pH of the urine especially when treating
infections due to urea-splitting organisms such as Proteus spp. and strains
of Pseudomonas spp.
Laboratory Tests. In a few instances in one study, the serum transaminase
levels showed a mild elevation during treatment which returned to normal while
the patients were still receiving UREX (methenamine hippurate) . Because of this one report, it is recommended
that liver function studies be performed periodically on patients receiving
the drug, especially those with liver dysfunction.
Carcinogenesis, Mutagenesis, and Impairment of Fertility. UREX (methenamine hippurate) has not
been evaluated for carcinogenicity or mutagenicity.
Methenamine was evaluated for mutagenicity in the Ames Salmonella/mammalian
microsome test. Five strains of Salmonella typhimurium (TA98, TA100,
TA1535, TA1537 and TA1538) and a strain of Escherichia coli (WP2uvrA)
were used. At a dose of 10,000 ug/plate methenamine showed mutagenic activity
in Salmonella typhimurium TA98 and TA100 by metabolic activation and
also showed mutagenic activity in TA98 without microsomal activation.
In one large study, no evidence of carcinogenicity was found following long-term
oral administration of methenamine 1.25 g/kg/day to rats (104 weeks)
and mice (60 weeks). The same investigators also reported no suggestion
of carcinogenicity resulting from five subcutaneous injections of 5 g/kg (given
on alternate days for a total dose of 25 g/kg). An earlier, much smaller study
showed a 50% incidence of local sarcomas following subcutaneous injection of
methenamine, totaling 25 g/kg, administered over periods of up to 15 months
to rats concurrently receiving formic acid.
UREX (methenamine hippurate) , administered at a dose level of 800 mg/kg/day, did not adversely affect the fertility of female rats. Effects on male fertility have not been adequately studied.
Teratogenic effects. Pregnancy category C. Oral administration of methenamine
to pregnant dogs, at doses equivalent to the human dose, has been reported to
cause a slight increase in the stillborn rate and slight impairment of weight
gain and survival of live-born offspring. A teratogenicity study, in which Urex (methenamine hippurate)
was administered to pregnant rabbits at doses approximately 3 times the human
dose, revealed no evidence of harm to the fetus. There are no adequate and well-controlled
studies in pregnant women. UREX (methenamine hippurate) should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor and Delivery. UREX (methenamine hippurate) has no recognized use during labor and delivery,
and its effects during these processes are unknown.
Nursing Mothers. Methenamine is excreted in human milk. Because of the
potential for serious adverse reactions in nursing infants, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use (See DOSAGE AND ADMINISTRATION).