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  • CLASSES

    Other Urinary Antiseptics

    DEA CLASS

    Rx

    DESCRIPTION

    Urinary antiinfective
    Used for suppression and prophylaxis of frequently recurring urinary tract infections
    Contraindicated in patients with renal insufficiency, severe hepatic insufficiency, and severe dehydration

    COMMON BRAND NAMES

    Hiprex, Mandelamine, Urex

    HOW SUPPLIED

    Hiprex/Mandelamine/Methenamine/Methenamine Hippurate/Methenamine Mandelate/Urex Oral Tab: 1g, 500mg

    DOSAGE & INDICATIONS

    For prophylactic or suppressive treatment of frequently recurring urinary tract infection (UTI), specifically cystitis, when long term therapy is considered necessary (i.e., neurogenic bladder).
    Oral dosage (methenamine mandelate)
    Adults and Adolescents

    1 g PO 4 times daily, after meals and at bedtime. The Infectious Diseases Society of America (IDSA) recommends that methenamine salts should not be used routinely to reduce catheter-associated bacteriuria or UTI in patients with long-term intermittent or long-term indwelling catheterization.

    Children 6 to 12 years

    500 mg PO 4 times daily.

    Children younger than 6 years

    18.4 mg/kg PO 4 times daily.

    Oral dosage (methenamine hippurate)
    Adults and Adolescents

    1 g PO twice daily. The Infectious Diseases Society of America (IDSA) recommends that methenamine salts should not be used routinely to reduce catheter-associated bacteriuria or UTI in patients with long-term intermittent or long-term indwelling catheterization.

    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

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

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

    STORAGE

    Hiprex:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Mandelamine:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Urex:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Dehydration, renal failure, renal impairment

    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.

    Hepatic disease

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

    Tartrazine dye hypersensitivity

    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.

    Gout

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Moderate

    dysuria / Early / 0-3.5
    elevated hepatic enzymes / Delayed / 0-1.0
    crystalluria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known

    Mild

    nausea / Early / 0-3.5
    rash / Early / 0-3.5
    increased urinary frequency / Early / Incidence not known

    DRUG INTERACTIONS

    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; 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.
    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; 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.
    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.
    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.
    Bendroflumethiazide; Nadolol: (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; Risedronate: (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.
    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.
    Chlorthalidone; Clonidine: (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) 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.
    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.
    Erythromycin; Sulfisoxazole: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    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.
    Hydralazine; 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; Methyldopa: (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.
    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.
    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.
    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.
    Methyclothiazide: (Moderate) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.
    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.
    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) 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) 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) 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.
    Propranolol; 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.
    Pyrimethamine; Sulfadoxine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    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.
    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.
    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.
    Sulfisoxazole: (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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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

    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.