What is Hiprex (methenamine hippurate)?

What is Hiprex (Methenamine Hippurate)?

Hiprex is a urinary antiseptic medication containing methenamine hippurate 1 gram per tablet, which works by converting to formaldehyde in acidic urine to provide bacteriostatic activity against common urinary pathogens, and is FDA-approved for prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is necessary. 1

Mechanism of Action

Methenamine hippurate functions through a unique dual-component system that distinguishes it from conventional antibiotics:

• The methenamine component is hydrolyzed to formaldehyde in acid urine, providing antibacterial activity 1
• The hippuric acid component has some antibacterial activity and acts to keep the urine acidic 1
• This formaldehyde-based mechanism does not lead to acquired bacterial resistance, unlike traditional antibiotics 2
• Antibacterial activity is demonstrable in urine within 30 minutes after ingestion of a single 1-gram dose 1
• Over 90% of the methenamine component is excreted in urine within 24 hours 1

Spectrum of Activity

The medication demonstrates effectiveness against specific urinary pathogens:

• Generally active against E. coli, enterococci, and staphylococci 1
• Enterobacter aerogenes is generally resistant 1
• Urea-splitting organisms such as Proteus and Pseudomonas require sufficiently acidic urine to be inhibited 1

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, and should only be used after eradication of the infection by other appropriate antimicrobial agents 1

Clinical Evidence for Use

Recent high-quality guidelines provide strong support for methenamine hippurate:

• A 2024 JAMA Network Open consensus statement found sufficient quality and quantity of evidence to recommend methenamine hippurate as an alternative to prophylactic antibiotics in patients with intact bladder anatomy 3
• Methenamine was found to be noninferior to antibiotics for UTI prevention in multiple randomized controlled trials 3
• One study demonstrated a 73% reduction in UTIs compared to placebo (p<0.01) 2
• In a comparative study, methenamine hippurate showed a recurrence rate of 34.2% compared to 63.2% in placebo, though less effective than trimethoprim at 10.4% 2

Standard Dosing

The recommended dose is methenamine hippurate 1 gram twice daily (morning and evening) for adults and children over 12 years of age 2, 1

Critical Requirement for Efficacy

Urinary pH must be maintained below 6.0 for optimal bactericidal formaldehyde concentrations to be achieved 2, 4

• Data are insufficient to recommend the best method to achieve low urinary pH 2
• Studies of ascorbic acid in dosages up to 4g per day have shown no significant effect on mean urinary pH; dosages as high as 12g per day may be required 2

Patient Selection Criteria

Methenamine hippurate is most appropriate for specific patient populations:

• Most effective in patients without incontinence and with fully functional bladders 2
• Recommended for patients with intact bladder anatomy 3, 2
• Should NOT be used routinely in patients with long-term intermittent or long-term indwelling urethral or suprapubic catheterization 2
• Not recommended for spinal cord injured patients due to limited efficacy in this population 2

Safety Profile and Tolerability

Methenamine hippurate has a low rate of adverse events and is well-tolerated, with the most common side effect being nausea, which is rare 2

• Better tolerated than nitrofurantoin 2
• Unlike conventional antibiotics, acquired resistance does not develop to formaldehyde 2
• The ALTAR trial showed 72% of participants taking daily antibiotics demonstrated antibiotic resistance in E. coli versus 56% in the methenamine arm (p=0.05) 2
• Contains FD&C Yellow No. 5 (tartrazine), which requires precaution in susceptible individuals 1

Duration of Treatment

Methenamine hippurate should be used for 6-12 months for the prevention of recurrent urinary tract infections 2

• Prophylaxis may need to be continued beyond the initial 6-12 month period if recurrent UTIs persist as a clinical problem 2

Important Clinical Considerations

The mechanism of action depends on adequate urine concentration and bladder dwell time, which may be compromised in renal dysfunction 4

• This drug should only be used after eradication of the infection by other appropriate antimicrobial agents 1
• Methenamine is not effective for treating acute, established infections and should be reserved for prophylaxis 5

Follow-up Recommendations

Patients should seek immediate medical attention if symptoms do not resolve within 4 weeks after treatment completion or recur within 2 weeks 2

• For patients whose symptoms do not resolve by the end of treatment or recur within 2 weeks, a urine culture with antimicrobial susceptibility testing should be performed 2
• Routine post-treatment urinalysis or urine cultures are NOT indicated for asymptomatic patients 2