Brand names: Hiprex, Mandelamine, Urex
Drug class: Urinary Anti-infectives
VA class: AM550
CAS number: 100-97-0

Introduction

Antibacterial.^{100 101 102}

Uses for Methenamine

Urinary Tract Infections (UTIs)

Prophylaxis or suppression of recurrent UTIs (bacteriuria), especially when long-term therapy is considered necessary.^{100 101 102}

Use only after UTI has been eradicated by other appropriate anti-infectives.^{100 101}

Not effective in systemic bacterial infections and has no effect on bacteria in blood or tissues outside the urinary tract.^a Do not use alone in the treatment of acute parenchymal infections causing systemic symptoms (e.g., chills, fever).^{100 102}

Monitor efficacy by periodic urine cultures.^{100 101}

Antibacterial effects are maximal when urine pH is ≤5.5.¹⁰² Monitor urinary pH during therapy; use supplementary acidification, 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).^a This is particularly important when the causative organisms are urea-splitting strains of Proteus or Pseudomonas which increase urinary pH.^{100 101}

Methenamine Dosage and Administration

General

• Acidic urine is essential for antibacterial activity; maximum efficacy occurs when urine pH is ≤5.5.¹⁰² Restrict alkalinizing food and medication;^{101 102} use supplemental acidification if needed.^{100 101 102 a}

Administration

Oral Administration

Administer orally.^{100 101 102}

Dosage

Available as methenamine hippurate and methenamine mandelate; dosage expressed in terms of the salt.^{100 101 102}

Pediatric Patients

Prophylaxis or Suppression of Urinary Tract Infections (UTIs)

Methenamine Hippurate

Oral

Children <6 years of age: Dosage not established.^a

Children 6–12 years of age: 500 mg to 1 g twice daily (morning and night).^{100 101}

Children >12 years of age: 1 g twice daily (morning and night).^{100 101}

Methenamine Mandelate

Oral

Children <6 years of age: 18.4 mg/kg 4 times daily, (after meals and at bedtime).¹⁰²

Children 6–12 years of age: 500 mg 4 times daily (after meals and at bedtime).¹⁰²

Children >12 years of age: 1 g 4 times daily (after meals and at bedtime).¹⁰²

Alternatively, some clinicians recommend 50 mg/kg daily in 3 divided doses for children.^a

Adults

Prophylaxis or Suppression of Urinary Tract Infections (UTIs)

Methenamine Hippurate

Oral

1 g twice daily (morning and night).^{100 101}

Methenamine Mandelate

Oral

1 g 4 times daily (after meals and at bedtime).¹⁰²

Special Populations

No special population dosage recommendations at this time.^{100 101 102}

Cautions for Methenamine

Contraindications

• Known hypersensitivity to the drug.¹⁰²

• Renal insufficiency.^{100 101 102}

• Severe hepatic insufficiency^{100 101} or severe dehydration.^{100 101}

Warnings/Precautions

Warnings

Dysuria

Large doses (8 g daily for 3–4 weeks) have caused bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria.^{100 101}

Dysuria may be controlled by reducing dosage and/or reducing urine acidification.¹⁰²

Hepatic Effects

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

Transient elevations in serum AST and ALT concentrations have occurred in patients receiving methenamine hippurate.^{100 101}

Perform periodic liver function tests in patients receiving methenamine hippurate, especially in those with hepatic impairment.^{100 101} (See Hepatic Impairment under Cautions.)

Sensitivity Reactions

Tartrazine Sensitivity

Hiprex tablets contain tartrazine (FD&C yellow No. 5), which may cause allergic reactions, including bronchial asthma, in susceptible individuals.¹⁰¹ Incidence of tartrazine sensitivity is low, but it frequently occurs in patients who are sensitive to aspirin.¹⁰¹

General Precautions

Acidic Urine

Ensure that urine is maintained at an acidic pH during treatment, especially when causative organisms are urea-splitting strains of Proteus or Pseudomonas.^{100 101} (See Dosage and Administration.)

Manufacturer of methenamine mandelate states the drug is not recommended if urine acidification is contraindicated or unattainable (e.g., when some urea-splitting bacteria are present).¹⁰²

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of methenamine and other antibacterials, use only to prevent infections proven or strongly suspected to be caused by susceptible bacteria.¹⁰¹

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.¹⁰¹ In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.¹⁰¹

Specific Populations

Pregnancy

Category C.^{100 102}

One manufacturer of methenamine hippurate states that safety during the last trimester is suggested, but not definitely proven.¹⁰¹

Effects of methenamine during labor and delivery are unknown and there are no recognized uses for the drug during labor or delivery.¹⁰⁰

Lactation

Distributed into milk; discontinue nursing or the drug.¹⁰⁰

Pediatric Use

Has been used in children without unusual toxicity.¹⁰⁰

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults; clinical experience has not identified differences.¹⁰¹

Select dosage with caution, 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

Hepatic Impairment

Perform periodic liver function tests.^{100 101}

Methenamine hippurate is contraindicated in those with severe hepatic insufficiency.^{100 101}

Common Adverse Effects

GI disturbances (nausea, vomiting, diarrhea, abdominal cramps, anorexia), pruritus, rash, dysuria.^{100 101 102 a}

Drug Interactions

Specific Drugs and Laboratory Tests

Methenamine Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from the GI tract.^a About 10–30% of oral dose is hydrolyzed by gastric acidity to formaldehyde and ammonia.^a Enteric coating of methenamine mandelate tablets reduces hydrolysis in the GI tract and rate of absorption.^a

Plasma Concentrations

Following oral administration of a usual single dose to healthy fasting adults, concentrations of methenamine and formaldehyde in plasma are generally very low and antibacterial activity in plasma is negligible.^a

Distribution

Extent

Crosses the placenta.¹⁰⁰

Distributed into milk.¹⁰⁰

Elimination

Elimination Route

Within 24 hours, ≥70–90% of a single oral dose is excreted intact in the urine by glomerular filtration and tubular secretion.^a When urine is acidic, methenamine is hydrolyzed to formaldehyde and ammonia; maximum hydrolysis occurs when urine pH is ≤5.5.^a

Mandelic acid (mandelate) and hippuric acid (hippurate) are excreted in urine by glomerular filtration and tubular excretion.^{101 102}

Stability

Storage

Oral

Tablets

15–30°C^{100 101 102} in tight, light resistant containers.¹⁰²

Actions and Spectrum

• Synthetic antibacterial agent chemically unrelated to other currently available anti-infectives.^a

• Antibacterial effect of methenamine hippurate or methenamine mandelate depends on conversion of methenamine to formaldehyde in an acid medium (acidic urine).^a

• Formaldehyde is a nonspecific antibacterial agent which is usually bactericidal in action.^a 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.^a

• 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).^a

• 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.^a

Advice to Patients

• Advise patients that antibacterials (including methenamine hippurate and methenamine mandelate) should only be used for bacterial infections and not used to treat viral infections (e.g., the common cold).¹⁰¹

• Importance of completing full course of therapy, even if feeling better after a few days.¹⁰¹

• Advise patients that skipping doses or not completing the full course of 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

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or laboratory tests.^{100 101 102}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{100 101 102}

• Importance of informing patients of other important precautionary information.^{100 101 102} (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Medical Disclaimer