Methenamine Hippurate

Approved Indications:

• Prophylaxis of Recurrent Urinary Tract Infections (UTIs)
• Indicated for the long-term prevention of recurrent lower urinary tract infections, especially in females with chronic cystitis.
• Effective only in patients with consistently acidic urine (urine pH <5.5).

Clinically Accepted Off-label Uses:

• Adjunct in Chronic Bacteriuria Suppression
• Used in catheterized patients or those with structural abnormalities of the urinary tract where full bacterial eradication is not possible.

Route: Oral
Form: Tablets (500 mg); may be available in compounded oral solutions.

Adults:

• 1 gram (2 tablets) twice daily.

Pediatrics (≥6 years):

• 500 mg twice daily.
• Not recommended for children under 6 years.

Elderly:

• Same as adult dosing; assess renal function before initiation.

Renal Impairment:

• Contraindicated in severe renal impairment (CrCl <10 mL/min).
• Use caution in mild-to-moderate impairment; ensure adequate hydration.

Hepatic Impairment:

• Use with caution in severe hepatic disease; no specific dosage adjustment necessary.

Important Administration Notes:

• For optimal efficacy, urine pH should be maintained below 5.5.
• Co-administration with urinary acidifiers (e.g., ascorbic acid 1–4 g/day) may be recommended.
• Ensure adequate hydration to reduce the risk of crystalluria.

Methenamine is a urinary antiseptic that is hydrolyzed in acidic urine to release formaldehyde, a potent nonspecific antibacterial agent. Formaldehyde acts by denaturing bacterial proteins and nucleic acids, effectively killing a broad spectrum of urinary pathogens. The hippurate component aids in urine acidification, enhancing formaldehyde production. The drug is only effective in acidic urine (pH <5.5), where this hydrolysis occurs efficiently. No bacterial resistance to formaldehyde has been reported.

• Absorption: Rapidly and completely absorbed from the gastrointestinal tract.
• Distribution: Widely distributed; minimal systemic exposure to formaldehyde under normal conditions.
• Metabolism: Not systemically metabolized; decomposes into formaldehyde and ammonia in acidic urine.
• Elimination: Excreted unchanged in urine.
• Half-life: ~3–4 hours.
• Onset: Antibacterial activity begins once formaldehyde forms in acidic urine.

• Pregnancy:
• FDA Category C (under previous system).
• Limited human data; use only if clearly needed. Avoid in the first trimester unless benefit outweighs risk.
• Lactation:
• Small amounts may be excreted in breast milk.
• Use with caution; monitor the infant for gastrointestinal disturbances or hypersensitivity reactions.

• Class: Urinary Antiseptic
• Subclass: Formaldehyde-releasing urinary antibacterial agent

• Known hypersensitivity to methenamine or any component of the formulation
• Severe renal impairment or anuria
• Hepatic insufficiency (risk of hyperammonemia)
• Concomitant use with sulfonamides (risk of crystalluria and renal toxicity)
• Alkaline urine (e.g., due to renal tubular acidosis or infection with urea-splitting organisms)

• Urine pH must be acidic for the drug to be effective; use with acidifiers if needed.
• Hydration is essential to prevent crystalluria.
• Avoid with sulfonamides due to risk of formaldehyde-sulfonamide precipitate and renal damage.
• Monitor renal and liver function during prolonged therapy.
• Caution in hepatic disease due to potential ammonia retention.

Common:

• Gastrointestinal: Nausea, vomiting, abdominal discomfort
• Genitourinary: Dysuria, bladder irritation

Serious/Rare:

• Hematuria
• Crystalluria
• Allergic reactions: Rash, urticaria, pruritus
• Elevated liver enzymes
• Formaldehyde toxicity in renal impairment (rare)

Onset: Gastrointestinal and urinary side effects generally appear early in treatment and are dose/pH dependent.

• Sulfonamides (e.g., sulfamethoxazole):
  – Increased risk of renal toxicity and crystalluria.
• Urinary alkalinizers (e.g., sodium bicarbonate, acetazolamide):
  – Reduce effectiveness by preventing formaldehyde formation.
• Urinary acidifiers (e.g., ascorbic acid, ammonium chloride):
  – Enhance efficacy by maintaining urine pH <5.5.
• No significant CYP450 involvement.

• IDSA (2023):
  – Methenamine hippurate is recommended as a non-antibiotic option for recurrent UTI prophylaxis, especially in women with frequent episodes.
• Renewed interest in its role due to increasing antibiotic resistance.
• FDA Labeling:
  – Reinforced the need for urine acidification for efficacy.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity/Light: Store in a dry place, away from excessive heat and moisture.
• Handling: Keep in original container, tightly closed.
• Reconstitution: Not required.