METHENAMINE HIPPURATE: 177 Adverse Event Reports & Safety Profile

DESCRIPTION Each yellow, capsule-shaped tablet contains 1 g Methenamine Hippurate, USP which is the hippuric acid salt of methenamine (hexamethylene tetramine). The tablet also contains inactive ingredients: FD&C Yellow No. 5 (tartrazine, see PRECAUTIONS ), magnesium stearate, povidone, and saccharin sodium.

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Microbiology: Methenamine hippurate tablets have antibacterial activity because the methenamine component is hydrolyzed to formaldehyde in acid urine. Hippuric acid, the other component, has some antibacterial activity and also acts to keep the urine acid. The drug is generally active against E. coli , enterococci and staphylococci. Enterobacter aerogenes is generally resistant. The urine must be kept sufficiently acid for urea-splitting organisms such as Proteus and Pseudomonas to be inhibited.

Human

Pharmacology: Within 1/2 hour after ingestion of a single 1-gram dose of methenamine hippurate tablets, antibacterial activity is demonstrable in the urine. Urine has continuous antibacterial activity when methenamine hippurate tablets are administered at the recommended dosage schedule of 1-gram twice daily.

Over

90% of methenamine moiety is excreted in the urine within 24 hours after administration of a single 1-gram dose. Similarly, the hippurate moiety is rapidly absorbed and excreted, and it reaches the urine by both tubular secretion and glomerular filtration. This action may be important in older patients or in those with some degree of renal impairment.

INDICATIONS Methenamine hippurate tablets, USP 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. To reduce the development of drug-resistant bacteria and maintain the effectiveness of methenamine hippurate tablets, USP and other antibacterial drugs, methenamine hippurate tablets, USP 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.

DOSAGE AND ADMINISTRATION 1 tablet (1.0 g) twice daily (morning and night) for adults and pediatric patients over 12 years of age. 1/2 to 1 tablet (0.5 to 1.0 g) twice daily (morning and night) for pediatric patients 6 to 12 years of age. Since the antibacterial activity of methenamine hippurate tablets, USP is greater in acid urine, restriction of alkalinizing foods and medications is desirable. If necessary, as indicated by urinary pH and clinical response, supplemental acidification of the urine should be instituted. The efficacy of therapy should be monitored by repeated urine cultures.

CONTRAINDICATIONS Methenamine hippurate tablets USP are contraindicated in patients with renal insufficiency, severe hepatic insufficiency, or severe dehydration. Methenamine preparations should not be given to patients taking sulfonamides because some sulfonamides may form an insoluble precipitate with formaldehyde in the urine.

ADVERSE REACTIONS Adverse effects of Methenamine Hippurate Tablets 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 pruritus, rash, dysuria. Children have received Methenamine Hippurate Tablets 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.

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 Methenamine Hippurate Tablets 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. Information for Patients: Patients should be counseled that antibacterial drugs including Methenamine Hippurate Tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g. the common cold).

When Methenamine Hippurate

Tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Methenamine Hippurate Tablets or other antibacterial drugs in the future.

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 Methenamine Hippurate Tablets. 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.

Drug

Interactions: The concomitant administration of methenamine hippurate and sulfamethizole or sulfathiazole is liable to result in the formation of a precipitate in the urine.

Drug/Laboratory

Test Interactions: Methenamine causes spuriously elevated urinary 17-hydroxycorticosteroid and catecholamine levels. Carcinogenesis, Mutagenesis and Impairment of Fertility: Methenamine Hippurate Tablets have 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 μg/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 1.25g/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. 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 methenamine hippurate was administered to pregnant rabbits at doses approximately 3 times human dose, revealed no evidence of harm to the fetus. There are no adequate and well-controlled studies in pregnant women.

Methenamine Hippurate

Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: Methenamine Hippurate Tablets have no recognized use during labor and delivery, and their effect during these processes is 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 ).

Drug Interactions: The concomitant administration of methenamine hippurate and sulfamethizole or sulfathiazole is liable to result in the formation of a precipitate in the urine.