What is methenamine?

What is Methenamine?

Methenamine is a urinary antiseptic agent that works by converting to formaldehyde in acidic urine, providing bacteriostatic activity against urinary pathogens without promoting antibiotic resistance. 1

Chemical Composition and Formulation

• Methenamine hippurate is the hippuric acid salt of methenamine (hexamethylenetetramine), with a molecular weight of 319.37 and chemical formula C15H21N5O3. 1
• Each tablet contains 1 gram of methenamine hippurate, along with inactive ingredients including magnesium stearate, povidone, and saccharin sodium. 1
• An alternative formulation exists as methenamine mandelate, which is dosed at 1 gram every 6 hours. 2

Mechanism of Action

• Methenamine is hydrolyzed to ammonia and formaldehyde in acidic urine, with formaldehyde acting as a denaturant of proteins and nucleic acids responsible for antibacterial activity. 3
• The antimicrobial activity depends on three critical factors: urinary concentration of methenamine, urine pH, and bladder dwell time. 3
• Urinary pH must be maintained below 6.0 (ideally below 5.5) to achieve bactericidal concentrations of formaldehyde. 3, 2
• Unlike conventional antibiotics, acquired resistance does not develop to formaldehyde, making it advantageous in the era of antimicrobial resistance. 2

FDA-Approved Indications

• Methenamine hippurate is indicated for prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is considered necessary. 1
• This drug should only be used after eradication of the active infection by other appropriate antimicrobial agents. 1
• It is approved for use in patients aged 12 years and older. 3, 2

Clinical Efficacy Evidence

Patients Without Renal Tract Abnormalities

• Methenamine demonstrates significant benefit in patients with intact bladder anatomy, showing a relative risk of 0.24 for symptomatic UTI compared to placebo. 2, 4
• A study demonstrated 73% reduction in UTIs compared to placebo (p<0.01). 2
• Methenamine is noninferior to antibiotic prophylaxis, with recurrence rates of 34.2% versus 63.2% for placebo. 3, 2

Patients With Renal Tract Abnormalities

• Methenamine does not appear effective in patients with neuropathic bladder or renal tract abnormalities (RR 1.54 for symptomatic UTI, RR 1.29 for bacteriuria). 4
• Methenamine should not be used routinely in patients with long-term intermittent catheterization (A-II evidence) or long-term indwelling urethral/suprapubic catheters (A-III evidence). 3, 2

Recommended Patient Populations

Primary Indications

• Postmenopausal women with recurrent UTIs as an alternative to prophylactic antibiotics. 3, 2
• Women aged 18 years and older with recurrent UTIs who have intact bladder anatomy and fully functional bladders without incontinence. 3, 2
• Patients after gynecologic surgical procedures who are catheterized for no more than 1 week (C-I evidence). 3, 2

Contraindicated Populations

• Patients with spinal cord injury (limited efficacy demonstrated in this population). 3, 2
• Patients with long-term catheterization or significant renal dysfunction. 3, 2

Dosing and Administration

• Standard adult dosing: Methenamine hippurate 1 gram twice daily (morning and evening). 2
• Alternative formulation: Methenamine mandelate 1 gram every 6 hours. 2
• Adherence to the twice-daily regimen is essential, as 12-hour dosing intervals are required for optimal formaldehyde concentrations. 5

Urinary Acidification Requirements

• Maintaining urinary pH below 6.0 is crucial for effectiveness, though the best method to achieve this remains unclear. 2
• Ascorbic acid in dosages up to 4 grams per day shows no significant effect on mean urinary pH; dosages as high as 12 grams per day or more frequent administration may be required. 3, 2
• Ammonium chloride might be more effective for urinary acidification than ascorbic acid. 3

Duration of Therapy

• Recommended duration is 6-12 months for prevention of recurrent UTIs in women. 2
• Prophylaxis may need continuation beyond the initial 6-12 month period if recurrent UTIs persist as a clinical problem. 2
• For short-term prophylaxis (1 week or less), there is significant reduction in symptomatic UTI (RR 0.14). 4

Safety Profile and Adverse Effects

• Methenamine has a low rate of adverse events and is well-tolerated. 2, 6
• The most common side effect is nausea, which is rare. 2
• Better tolerability profile compared to nitrofurantoin. 2
• No concerning safety signals regarding stroke, venous thromboembolism, or malignancies. 3

Antimicrobial Resistance Considerations

• A 2-fold increase in antimicrobial-resistant bacteria was observed in patients receiving antimicrobial drugs other than methenamine for prophylaxis. 3
• The ALTAR trial showed 72% of participants taking daily antibiotics demonstrated E. coli resistance versus 56% in the methenamine arm (p=0.05). 2
• Methenamine does not select for resistant organisms due to its formaldehyde-based mechanism. 3, 5

Clinical Pitfalls and Important Caveats

• Methenamine is NOT effective for treating active UTIs—only for prophylaxis after infection clearance. 1
• Efficacy may be compromised in patients with renal dysfunction due to inadequate urine concentration and bladder dwell time. 7
• Patients should seek immediate medical attention if symptoms do not resolve within 4 weeks or recur within 2 weeks. 2
• Routine post-treatment urinalysis or urine cultures are NOT indicated for asymptomatic patients. 2