METHENAMINE HIPPURATE (Generic for HIPREX)

Methenamine is used only for suppression and prophylaxis of frequently recurring urinary tract infections such as in patients with neurogenic bladder or in those who are intermittently catheterized. It is not a primary agent in the treatment of urinary tract infections and should only be used after eradication of the infection by other appropriate antimicrobial agents. Methenamine is available in the hippurate or mandelate salt formulation. All formulations of methenamine are contraindicated in patients with renal insufficiency, severe hepatic insufficiency, and severe dehydration.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer orally.

-Urine acidification should be instituted as necessary.
-Avoid use of drugs and foods that could alkalinize the urine.

Minor adverse reactions have been reported in < 3.5% of patients. Gastrointestinal (GI) effects of methenamine include nausea and upset stomach.

Minor adverse reactions have been reported in < 3.5% of patients. Dysuria is more likely to occur at high doses of methenamine and may be due to high levels of formaldehyde in the urinary tract; it can be accompanied by hematuria. Large doses (i.e., 8 grams daily for 3-4 weeks) may also cause increased urinary frequency, bladder irritation, and albuminuria. Reduction of dosage and acidification of urine may alleviate the condition. Crystalluria has also been reported in patients with low urine output.

Minor adverse reactions, such as rash (unspecified), have been reported in < 3.5% of patients.

In one study, there were a few instances of slightly elevated hepatic enzymes during treatment with methenamine which returned to normal during treatment. It is recommended that liver function studies be performed periodically on patients taking methenamine, especially those with liver dysfunction.

Methenamine, in all forms, is contraindicated in patients with renal impairment, renal failure, or severe dehydration because of the propensity for accumulation and subsequent toxicity.

Methenamine, in all forms, is contraindicated in patients with severe hepatic disease.

Some preparations of methenamine contain tartrazine dye. Patients known to have a tartrazine dye hypersensitivity should be treated cautiously with methenamine due to possible allergic reactions, including an acute attack of bronchial asthma. Patients allergic to aspirin may be at the greatest risk.

Methenamine should be avoided in patients with gout as it may precipitate urate crystals in the urine and may predispose these patients to the formation of uric acid stones.

The safe use of methenamine hippurate in early pregnancy is not established. In the last trimester, the safety of methenamine hippurate is suggested but not definitively proven. No adverse effects on the fetus were seen in studies in pregnant rats and rabbits. Since introduction, published reports on the use of methenamine mandelate in pregnant women have not shown an increased risk of fetal abnormalities from use during pregnancy. It is not known whether this medication can cause harm to a human fetus or affect human fertility. Since methenamine is known to cross the placental barrier, methenamine mandelate should be given to a pregnant woman only if the potential benefit outweighs the risk. This medication can interfere with tests of urine estriol in pregnancy resulting in unmeasurably low values when acid hydrolysis is used in the laboratory procedure; testing which utilizes enzymatic hydrolysis is unaffected.

Methenamine is distributed into breast milk in low concentrations; the manufacturers recommend caution. In 4 women, a mean breast-milk concentration of 50 micromol/L was reported, the authors stated that the amount in breast milk is similar to maternal plasma. Adverse effects in nursing infants have not been reported. The drug appears acceptable to use, even in a woman breast-feeding a newborn. Take into account the importance of the drug to the mother when determining the need for use. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Enterococcus sp., Escherichia coli, Proteus sp., Pseudomonas aeruginosa, Staphylococcus sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For urinary tract infection (UTI) prophylaxis when used for suppression or elimination of bacteriuria associated with recurrent urinary tract infection (UTI):
Oral dosage (methenamine mandelate):
Adults: 1 g PO 4 times daily, after meals and at bedtime. Not routinely recommended by guidelines.
Adolescents: 1 g PO 4 times daily, after meals and at bedtime.
Children 6 to 12 years: 500 mg PO 4 times daily, after meals and at bedtime.
Children younger than 6 years: 18.4 mg/kg/dose PO 4 times daily, after meals and at bedtime.
Oral dosage (methenamine hippurate):
Adults: 1 g PO twice daily. Not routinely recommended by guidelines.
Adolescents: 1 g PO twice daily.
Children 6 to 12 years: 0.5 to 1 g PO every 12 hours or 25 to 50 mg/kg/day PO divided every 12 hours.

Maximum Dosage Limits:
-Adults
4 g/day PO methenamine mandelate; 2 g/day PO methenamine hippurate.
-Geriatric
4 g/day PO methenamine mandelate; 2 g/day PO methenamine hippurate.
-Adolescents
4 g/day PO methenamine mandelate; 2 g/day PO methenamine hippurate.
-Children
6 to 12 years: 2 g/day PO methenamine mandelate; 2 g/day PO methenamine hippurate.
Younger than 6 years: 73.6 mg/kg/day PO methenamine mandelate; safety and efficacy of methenamine hippurate have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Dosage adjustments may be needed depending on the degree of hepatic impairment, but no quantitative recommendations are available. Methenamine hippurate and methenamine mandelate are contraindicated in patients with severe hepatic disease.

Patients with Renal Impairment Dosing
Methenamine hippurate and methenamine mandelate are contraindicated in patients with renal insufficiency or severe dehydration. No specific dosage adjustment guidelines are available.

*non-FDA-approved indication

Acetazolamide: (Major) The therapeutic action of methenamine requires an acidic urine. Acetazolamide can alkalinize the urine, thereby decreasing the effectiveness of methenamine. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Alkalinizing Agents: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Aluminum Hydroxide: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Aluminum Hydroxide; Magnesium Carbonate: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Aluminum Hydroxide; Magnesium Hydroxide: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Aluminum Hydroxide; Magnesium Trisilicate: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Amphetamine: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.

Amphetamine; Dextroamphetamine Salts: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.

Amphetamine; Dextroamphetamine: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.

Antacids: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Ascorbic Acid, Vitamin C: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH.

Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Atenolol; Chlorthalidone: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Azilsartan; Chlorthalidone: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Benzphetamine: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.

Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium Carbonate: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium Carbonate; Magnesium Hydroxide: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium Carbonate; Simethicone: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Calcium; Vitamin D: (Major) Avoid the concomitant use of calcium carbonate and methenamine. Calcium carbonate may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Chlorothiazide: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Chlorthalidone: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Citric Acid; Potassium Citrate; Sodium Citrate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Major) The therapeutic action of methenamine requires an acidic urine. Alkalinizing agents, such as citrate salts, can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Dextroamphetamine: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.

Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Food: (Moderate) Methenamine should theoretically not be administered concurrently with food or beverages that may alter urinary pH, such as milk products and most fruits. These agents may cause the urine to become alkaline and reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Orange juice is not a reliable urinary acidifier and should not be used to ensure urine acidification; citric acid may actually raise urine pH if taken in large amounts.

Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Ibritumomab Tiuxetan: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Lisdexamfetamine: (Major) Concurrent use of urinary acidifying agents, such as methenamine salts (e.g., methenamine containing urinary products) and lisdexamfetamine should be avoided if possible. Urinary acidifying agents reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. If combination therapy is necessary, adjust the lisdexamfetamine dose according to clinical response as needed.

Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Mafenide: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.

Magnesium Hydroxide: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Magnesium Salts: (Major) The therapeutic action of methenamine requires an acidic urine. Antacids containing alkalinizing agents such as sodium bicarbonate can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Methamphetamine: (Major) Methenamine and methenamine salts (e.g., methenamine; sodium acid phosphate) are urinary acidifiers, and acidic urine will significantly decrease the half-life of methamphetamine. Urinary acidifying agents increase the concentration of the ionized species of the amphetamine molecule, which increases urinary excretion.

Methazolamide: (Major) The therapeutic action of methenamine requires an acidic urine. Methazolamide can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Metolazone: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Omeprazole; Sodium Bicarbonate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Phentermine; Topiramate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.

Potassium Bicarbonate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Major) The therapeutic action of methenamine requires an acidic urine. Alkalinizing agents, such as citrate salts, can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Potassium Chloride: (Major) The therapeutic action of methenamine requires an acidic urine. Alkalinizing agents, such as citrate salts, can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Potassium Citrate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Major) The therapeutic action of methenamine requires an acidic urine. Alkalinizing agents, such as citrate salts, can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Potassium Citrate; Citric Acid: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Major) The therapeutic action of methenamine requires an acidic urine. Alkalinizing agents, such as citrate salts, can alkalinize the urine, thereby decreasing the effectiveness of methenamine by increasing the amount of non-ionized drug available for renal tubular reabsorption. Increased urine alkalinity also can inhibit the conversion of methenamine to formaldehyde, which is the active bacteriostatic form; concurrent use of methenamine and urinary alkalizers is not recommended.

Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Sodium Acetate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Sodium Bicarbonate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Sodium Citrate; Citric Acid: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Sodium Lactate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Sulfacetamide; Sulfur: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Sulfadiazine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.

Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.

Sulfasalazine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.

Sulfonamides: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.

Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Thiazide diuretics: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Topiramate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.

Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

Tromethamine: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.

Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.

In an acidic environment, methenamine is hydrolyzed to ammonia and to formaldehyde. The amount of formaldehyde released is directly proportional to the pH of the environment; greater amounts of formaldehyde are produced as pH decreases. Methenamine is commercially available in combination with hippuric acid or mandelic acid. These weak organic acids have some antibacterial activity and also act to keep the urine acidic. Plasma concentrations of either methenamine or formaldehyde are generally low. It is believed that formaldehyde denatures protein. Nearly all bacteria are sensitive to formaldehyde if a critical concentration is reached. Formaldehyde is generally bactericidal in action and is effective against a wide variety of organisms including gram-negative and gram-positive bacteria.

Methenamine is administered orally as either methenamine mandelate or methenamine hippurate. The drug crosses the placenta and is excreted into breast milk. The methenamine component is hydrolyzed in acidic urine to ammonia and formaldehyde. Proportionally less formaldehyde is released as urinary pH approaches 6 and insufficient quantities are released at pH concentrations above this level. Excretion of hippurate and mandelic acid is via tubular secretion and glomerular filtration. About 90% of a single dose is excreted within 24 hours.
Affected cytochrome P450 isoenzymes and transporters: none


-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, methenamine is well absorbed from the GI tract, regardless of the salt used. It remains inactive until it is excreted by the kidneys and concentrated in the urine.