VA Class:AM550
Methenamine is a synthetic urinary antibacterial agent that is chemically unrelated to other currently available anti-infectives.
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.100, 101, 102
Methenamine hippurate or methenamine mandelate should be used only after the urinary tract infection has been eradicated by other appropriate anti-infectives.100, 101 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).100, 102
Efficacy of methenamine therapy should be monitored by periodic urine cultures.100, 101 Antibacterial effects of methenamine are maximal when urine pH is 5.5 or less.102 Urinary pH should be monitored during methenamine therapy and supplementary acidification used, if required.101, 102 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.100, 101, 102
Reconstitution and Administration
Methenamine hippurate and methenamine mandelate are administered orally.100, 101, 102
Care should be taken to ensure that urine is acidic during methenamine hippurate or methenamine mandelate therapy.100, 101, 102 Antibacterial effects are maximal when urine pH is 5.5 or less.102, 102 Alkalinizing food and medication should be restricted,101, 102 and supplemental acidification instituted if needed.100, 101, 102
Methenamine is commercially available as methenamine hippurate and methenamine mandelate; dosage is expressed in terms of the salt.100, 101, 102
Prophylaxis or Suppression of Urinary Tract Infections
The usual dosage of methenamine hippurate for adults and children older than 12 years of age is 1 g twice daily (morning and night).100, 101 Children 6-12 years of age may receive 0.5-1 g of methenamine hippurate twice daily (morning and night).100, 101 Dosage for children younger than 6 years of age has not been established.
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.102 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.102 Some clinicians recommend that children receive 50 mg/kg daily in 3 divided doses.
Adverse effects have been reported in less than 3.5% of patients receiving methenamine hippurate.100, 101 The most frequent adverse effects are GI disturbances including nausea,100, 101 vomiting,100 diarrhea, abdominal cramps, and anorexia. GI disturbances also have been reported with methenamine mandelate.102
Dysuria and microscopic or, rarely, gross hematuria have been reported in patients receiving methenamine hippurate or methenamine mandelate.100, 101, 102 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)100, 101 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.102 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.100 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.100
Hypersensitivity reactions, including rash,100, 101, 102 pruritus,100 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.100, 101 (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.102
Methenamine hippurate and methenamine mandelate are contraindicated in patients with renal insufficiency;100, 101, 102 methenamine hippurate also is contraindicated in patients with severe hepatic insufficiency100, 101 or severe dehydration.100, 101
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).102
Hiprex® tablets contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.101 Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.101
The manufacturers recommend that periodic liver function tests be performed in patients receiving methenamine hippurate, especially in those with hepatic impairment.100, 101 Patients with preexisting hepatic insufficiency may have adverse effects from the small amounts of ammonia and formaldehyde that are produced following administration of methenamine.100 Acute hepatic failure may occur in some patients.100
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.101 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.101 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.101 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).101 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.101
Methenamine hippurate has been used in children without unusual toxicity.100 Adverse effects have been reported in about 1% of children receiving the drug.100
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.101 Other reported clinical experience has not revealed differences in responses between geriatric and younger adults.101
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.101
Mutagenicity and Carcinogenicity
There was some evidence of mutagenicity when methenamine was evaluated using the Ames Salmonella /mammalian microsome test.100
There was no evidence of carcinogenicity in long-term oral studies in rats and mice (1.25 g/kg daily).100 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).100
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using methenamine hippurate have not revealed evidence of harm to the fetus.100, 101 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.100 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.100, 101, 102
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.102 One manufacturer of methenamine hippurate states that safety during the last trimester is suggested, but not definitely proven.101
The effects of methenamine during labor and delivery are unknown and there are no recognized uses for the drug during labor or delivery.100
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.100
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.100
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.100, 101, 102
Formaldehyde interferes with fluorometric procedures for determination of urinary catecholamines and vanillylmandelic acid (VMA), causing erroneously high results.102
Formaldehyde causes falsely decreased urine estriol concentrations by reacting with estriol when acid hydrolysis techniques are used; estriol determinations which use enzymatic hydrolysis are unaffected by formaldehyde.101, 102
Formaldehyde causes falsely elevated 17-hydroxycorticosteroid concentrations when the Porter-Silber method is used and falsely decreased 5-hydroxyindoleacetic acid (5HIAA) concentrations by inhibiting color development when nitrosonaphthol methods are used.102
Limited information is available on the acute toxicity of methenamine hippurate or methenamine mandelate. Dogs and rats have received up to 600 mg/kg of methenamine hippurate administered IV in a single dose without evidence of toxic effects.100
If overdosage occurs, absorption of the drug should be minimized by immediately inducing emesis or by gastric lavage, followed by administration of activated charcoal.100 Adequate hydration should be maintained and oral or parenteral fluids forced to tolerance.100
The antibacterial effects of methenamine hippurate or methenamine mandelate depend on conversion of methenamine to formaldehyde in an acid medium (acidic urine).100, 101, 102 Formaldehyde is a nonspecific antibacterial agent which is usually bactericidal in action. The acid portions of methenamine salts (hippuric acid, mandelic acid) have some nonspecific antibacterial activity and may enhance the liberation of formaldehyde from methenamine in vivo by maintaining urinary acidity.100, 101, 102
Formaldehyde is active against both gram-positive and gram-negative bacteria including Enterobacter , Escherichia coli , Klebsiella , Proteus , Pseudomonas aeruginosa , Staphylococcus aureus , S. epidermidis , and Enterococcus faecalis (formerly Streptococcus faecalis ).
Because formaldehyde, hippuric acid, and mandelic acid have nonspecific antibacterial activity, resistance does not usually develop during prolonged therapy with methenamine hippurate or methenamine mandelate.
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.
Methenamine crosses the placenta.100 The drug is distributed into milk.100
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.
Methenamine is a synthetic antibacterial agent that is chemically unrelated to other currently available anti-infectives. Methenamine occurs as colorless, lustrous crystals or a white, crystalline powder, is practically odorless, and has solubilities of approximately 0.67 g/mL in water and 80 mg/mL in alcohol at 25°C. The pKa of methenamine is 4.8. Methenamine hippurate, which contains approximately 44% methenamine and 56% hippuric acid, occurs as a white, crystalline powder and is freely soluble in water and in alcohol. Methenamine mandelate, which contains approximately 48% methenamine and 52% mandelic acid, occurs as a white, practically odorless, crystalline powder which has a sour taste. Methenamine mandelate is very soluble in water and has a solubility of approximately 100 mg/mL in alcohol at 25°C.
Methenamine hippurate tablets and methenamine mandelate tablets should be stored at 15-30°C100, 101, 102 in tight, light-resistant containers.102 Methenamine salts should be protected from excessive heat.
The methenamine component of methenamine hippurate and methenamine mandelate is hydrolyzed by acids to formaldehyde and ammonia.100, 101, 102 Methenamine is incompatible with most alkaloids and some metallic salts including ferric, mercuric, and silver salts. The drug is darkened by ammonium salts and alkalies.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 1 g* | Hiprex® (with povidone and tartrazine; scored) | |
Methenamine Hippurate Tablets | ||||
Urex® (with povidone; scored) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 500 mg | Mandelamine® Hafgrams® (with povidone and polyethylene glycol) | |
1 g | Mandelamine® (with povidone and polyethylene glycol) | Warner Chilcott |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
100. Vatring. Urex® (methenamine hippurate) prescribing information. Wytheville, VA; 2004 Aug.
101. Sanofi-Aventis. Hiprex® (methenamine hippurate) prescribing information. Bridgewater, NJ; 2006 Mar.
102. Warner Chilcott. Mandelamine® (methenamine mandelate) prescribing information. Rockaway, NJ; 2006 Oct.