Prescription Required
Manufacturer
COUNTY/ALVOGEN
SKU
43199002001

methenamine hipp 1 gm tablet (generic hiprex)

Generic
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Uses

Urinary Tract Infections

Methenamine hippurate or methenamine mandelate is used for prophylaxis or suppression of recurrent urinary tract infections (bacteriuria), especially when long-term therapy is considered necessary.

Methenamine hippurate or methenamine mandelate should be used only after the urinary tract infection has been eradicated by other appropriate anti-infectives. Methenamine is not effective in systemic bacterial infections and has no effect on bacteria in blood or tissues outside the urinary tract. Methenamine hippurate and methenamine mandelate should not be used alone in the treatment of acute parenchymal infections causing systemic symptoms (e.g., chills, fever).

Efficacy of methenamine therapy should be monitored by periodic urine cultures. Antibacterial effects of methenamine are maximal when urine pH is 5.5 or less. Urinary pH should be monitored during methenamine therapy and supplementary acidification used, if required. Supplementary acidification may be achieved by dietary regulation and/or concomitant administration of acidifying agents (e.g., ammonium chloride, ascorbic acid, methionine). This is particularly important when the causative organisms are urea-splitting strains of Proteus or Pseudomonas which increase urinary pH.

Dosage and Administration

Reconstitution and Administration

Methenamine hippurate and methenamine mandelate are administered orally.

Care should be taken to ensure that urine is acidic during methenamine hippurate or methenamine mandelate therapy. Antibacterial effects are maximal when urine pH is 5.5 or less. Alkalinizing food and medication should be restricted, and supplemental acidification instituted if needed.

Dosage

Methenamine is commercially available as methenamine hippurate and methenamine mandelate; dosage is expressed in terms of the salt.

Prophylaxis or Suppression of Urinary Tract Infections

Methenamine Hippurate

The usual dosage of methenamine hippurate for adults and children older than 12 years of age is 1 g twice daily (morning and night). Children 6-12 years of age may receive 0.5-1 g of methenamine hippurate twice daily (morning and night). Dosage for children younger than 6 years of age has not been established.

Methenamine Mandelate

The usual dosage of methenamine mandelate for adults and children older than 12 years of age is 1 g 4 times daily, after meals and at bedtime. Children 6-12 years of age should receive 500 mg of methenamine mandelate 4 times daily and children younger than 6 years of age should receive 18.4 mg/kg 4 times daily. Some clinicians recommend that children receive 50 mg/kg daily in 3 divided doses.

Cautions

Adverse Effects

Adverse effects have been reported in less than 3.5% of patients receiving methenamine hippurate. The most frequent adverse effects are GI disturbances including nausea, vomiting, diarrhea, abdominal cramps, and anorexia. GI disturbances also have been reported with methenamine mandelate.

Dysuria and microscopic or, rarely, gross hematuria have been reported in patients receiving methenamine hippurate or methenamine mandelate. Bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have occurred following administration of higher than recommended dosages of methenamine or its salts (8 g daily for 3-4 weeks) and are probably due to high concentrations of formaldehyde in the urinary tract. Dysuria may be controlled by reducing dosage and/or reducing acidification of the urine. Rarely crystalluria has been reported with methenamine mandelate in patients with reduced urinary flow rates. In chronic toxicity studies in dogs and rats receiving oral methenamine in a dosage of 50-200 mg/kg daily and 0.8-6.4 g/kg daily, respectively, gastric and bladder irritation occurred with some hemorrhagic sites and ulceration. Methenamine hippurate has been administered to rats for 12 months and to monkeys for 6 months at dosages equivalent to twice the usual recommended human dosage without evidence of adverse effects.

Hypersensitivity reactions, including rash, pruritus, urticaria, and stomatitis, have been reported rarely in patients receiving methenamine hippurate or methenamine mandelate.

Transient elevations in serum AST (SGOT) and ALT (SGPT) concentrations have been reported in some patients receiving methenamine hippurate.(See Cautions: Precautions and Contraindications.)

Other adverse effects reported rarely with methenamine salts are headache, dyspnea, generalized edema, tinnitus, and muscle cramps.

Precautions and Contraindications

Methenamine mandelate is contraindicated in patients with known hypersensitivity to the drug.

Methenamine hippurate and methenamine mandelate are contraindicated in patients with renal insufficiency; methenamine hippurate also is contraindicated in patients with severe hepatic insufficiency or severe dehydration.

Because care should be taken to ensure that an acid pH is maintained in urine during methenamine treatment, the manufacturer of methenamine mandelate states that the drug is not recommended if urine acidification is contraindicated or unattainable (e.g., when some urea-splitting bacteria are present).

Hiprex tablets contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.

The manufacturers recommend that periodic liver function tests be performed in patients receiving methenamine hippurate, especially in those with hepatic impairment. Patients with preexisting hepatic insufficiency may have adverse effects from the small amounts of ammonia and formaldehyde that are produced following administration of methenamine. Acute hepatic failure may occur in some patients.

To reduce development of drug-resistant bacteria and maintain effectiveness of methenamine and other antibacterials, the drug should be used only to prevent infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used. In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy. Patients should be advised that antibacterials (including methenamine) should only be used for bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with methenamine or other antibacterials in the future.

Pediatric Precautions

Methenamine hippurate has been used in children without unusual toxicity. Adverse effects have been reported in about 1% of children receiving the drug.

Geriatric Precautions

Clinical studies of methenamine hippurate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Other reported clinical experience has not revealed differences in responses between geriatric and younger adults.

Dosage for geriatric patients should be selected cautiously, usually starting at the low end of the dosage range, because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

There was some evidence of mutagenicity when methenamine was evaluated using the Ames Salmonella/mammalian microsome test.

There was no evidence of carcinogenicity in long-term oral studies in rats and mice (1.25 g/kg daily). Although there was a 50% incidence of local sarcomas following long-term subcutaneous injection of methenamine in rats also receiving formic acid, there was no evidence of carcinogenicity following 5 subcutaneous injections of methenamine (total dose 25 g/kg).

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using methenamine hippurate have not revealed evidence of harm to the fetus. A slight increase in the stillborn rate and slight impairment of weight gain and survival of live-born offspring was reported in a study in pregnant dogs using oral methenamine in dosages equivalent to the human dosage. There are no adequate and well-controlled studies to date using methenamine hippurate or methenamine mandelate in pregnant women, and the drugs should be used during pregnancy only when clearly needed.

Although safe use of methenamine or its salts during pregnancy has not been definitely established, the drugs have been used in pregnant women without adverse effects to the fetus. One manufacturer of methenamine hippurate states that safety during the last trimester is suggested, but not definitely proven.

The effects of methenamine during labor and delivery are unknown and there are no recognized uses for the drug during labor or delivery.

Fertility

Methenamine hippurate in a dosage of 800 mg/kg daily did not affect fertility in female rats; effects on male fertility have not been adequately studied.

Lactation

Because methenamine is distributed into milk and because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Sulfonamides

Formaldehyde and some sulfonamides (e.g., sulfamethizole, sulfathiazole [not commercially available in the US]) form an insoluble precipitate in acid urine; therefore, methenamine salts should not be administered concomitantly with sulfonamides.

Pharmacokinetics

Absorption

Methenamine hippurate and methenamine mandelate are readily absorbed from the GI tract. Approximately 10-30% of an oral dose of methenamine is hydrolyzed by gastric acidity to formaldehyde and ammonia. When methenamine mandelate is administered as enteric-coated tablets, the percentage of the dose hydrolyzed in the GI tract and the rate of absorption of the drug are reduced. Following oral administration of a usual single dose of methenamine or one of its salts to healthy fasting adults, concentrations of methenamine and formaldehyde in plasma are generally very low and antibacterial activity in plasma is negligible.

Distribution

Methenamine crosses the placenta. The drug is distributed into milk.

Elimination

Within 24 hours, 70-90% or more of a single oral dose of methenamine or one of its salts is excreted intact in the urine by glomerular filtration and tubular secretion. When the urine is acidic, methenamine is hydrolyzed to formaldehyde and ammonia; maximum hydrolysis occurs when urine pH is 5.5 or less.

Following oral administration of a usual single dose of methenamine or one of its salts to fasting adults, peak concentrations of formaldehyde in acidic urine average 1-85 mcg/mL and are attained within 2 hours. When a usual single dose of methenamine mandelate is administered as enteric-coated tablets to adults, peak urine concentrations of formaldehyde are usually attained within 3-8 hours.

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