Hexamine Nisshin

To reduce the development of drug-resistant bacteria and maintain the effectiveness of UREX (methenamine hippurate) and other antibacterial drugs, UREX (methenamine hippurate) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

UREX (methenamine hippurate) is indicated for prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is considered necessary. This drug should only be used after eradication of the infection by other appropriate antimicrobial agents.

One tablet (1 g) twice daily for adults and children over 12 years of age. One-half tablet or one tablet (0.5 or 1 g) twice daily for children 6 to 12 years of age.

The antibacterial activity of UREX (methenamine hippurate) is greater in acid urine. Therefore, restriction of alkalinizing foods and medications is desirable. If necessary, as indicated by urinary pH and clinical response, supplemental acidification of the urine may be instituted. The efficacy of therapy should be monitored by repeated urine cultures.

UREX (methenamine hippurate) is contraindicated in patients with renal insufficiency, severe hepatic insufficiency, or severe dehydration. It should not be used as the sole therapeutic agent in acute parenchymal infections causing systemic symptoms.

WARNINGS

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.

PRECAUTIONS

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.

Pregnancy

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).

Adverse effects of UREX (methenamine hippurate) have been reported in fewer than 3.5% of patients treated.

These reactions have included the following, in decreasing order of frequency: nausea, vomiting, and rarely puritus, rash, dysuria.

Children have received UREX (methenamine hippurate) at the recommended dosages as a prophylactic/suppressive regimen after initial treatment of acute episodes of pyuria. Side effects were encountered in only 1.1% of these children.

Immediately after ingestion of an overdose, further absorption of the drug may be minimized by inducing vomiting or by gastric lavage, followed by administration of activated charcoal. Fluids, either oral or parenteral, should be forced to tolerance.