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Methenamine (Systemic)


VA CLASSIFICATION
Primary: AM550

Commonly used brand name(s): Hip-Rex; Hiprex; Mandelamine; Urex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—

Indications

General considerations
Nonspecific antibacterial action from formaldehyde, produced by the hydrolysis of methenamine, avoids the development of resistance. {26}

Accepted

Urinary tract infections, bacterial (prophylaxis)—Methenamine is indicated for the suppression or elimination of bacteruria associated with pyelonephritis, cystitis, and other chronic urinary tract infections. {26} Also indicated for the suppressive treatment of bacteruria in patients with neurologic diseases{06}{26}

[Urinary tract infections, bacterial (treatment) ]—Methenamine is useful in the treatment of uncomplicated lower urinary tract infections and in the suppressive treatment of urinary tract infections in patients being catheterized intermittently. {06}

—Virtually all bacteria and fungi are susceptible to the nonspecific action of free formaldehyde produced by the hydrolysis of methenamine. {01} {06}

Unaccepted
Methenamine is not recommended when urine acidification to a pH of 5.5 or below {01} {06} is contraindicated or unattainable.

Methenamine is not effective in patients with indwelling urinary catheters. {06}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Methenamine: 140.19 {18}
    Methenamine hippurate: 319.36 {18}
    Methenamine mandelate: 292.34 {18}

Mechanism of action/Effect:

Methenamine, an inactive weak base, slowly hydrolyzes in acidic urine to ammonia and the nonspecific antibacterial, formaldehyde. {20} Formaldehyde is thought to act by denaturation of protein. Urinary formaldehyde concentrations may be bactericidal or bacteriostatic, depending on urine pH (which controls the amount of formaldehyde released), volume, and flow rate. Most organisms are susceptible and resistance does not develop. Acids that dissociate from the hippurate or mandelate salt may contribute to maintenance of acidic urinary pH and liberation of formaldehyde. {24}

Absorption:

Methenamine—Rapid, but 30 to 60% hydrolyzed by gastric acid if not enteric-coated.

Methenamine hippurate—Rapid, from the gastrointestinal tract. {20}

Methenamine mandelate (enteric-coated tablets)—Absorption slightly delayed; total absorption essentially unaffected. {02}

Distribution:

Freely distributed to body tissues and fluids, but not clinically significant because methenamine does not hydrolyze at pH greater than 6.8. {22}

Vol D=Approximately 0.56 L/kg. {25}

Protein binding:

Some formaldehyde is bound to substances in the urine and the surrounding tissues.

Half-life:

Approximately 4.3 hours. {25}

Time to peak urinary formaldehyde concentration (pH 5.6)

Methenamine—0.5 to l.5 hours. {20}

Methenamine hippurate—2 hours.

Methenamine mandelate (enteric-coated tablets)—3 to 8 hours. {23}

Elimination:
    Renal; rapid.


Methenamine—
        Almost completely (90%) excreted within 24 hours; of this amount at pH 5, approximately 20% is formaldehyde. {22}

Note: Methenamine may accumulate in patients with impaired renal function. However, it does not hydrolyze in the blood (pH 7.4) and is not considered toxic. Urinary formaldehyde concentrations may be inadequate in these patients.




Hippuric acid and mandelic acid—
        40% excreted unchanged within 8 hours by glomerular filtration and tubular secretion {12}; can accumulate in patients with severely impaired renal function and may be toxic. {24}



Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Methenamine crosses the placenta. Adequate and well-controlled studies have not been done in either humans or animals. However, published reports on the use of methenamine in pregnant women have not shown an increased risk of fetal abnormalities during pregnancy. {03}

FDA Pregnancy Category C.

Breast-feeding

Methenamine is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of methenamine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


No information is available on the relationship of age to the effects of methenamine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alkalizers, urinary, such as:
Antacids, calcium- and/or magnesium-containing
Carbonic anhydrase inhibitors
Citrates
Sodium bicarbonate, or
» Diuretics, thiazide    (may cause the urine to become alkaline, thereby reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde; concurrent use is not recommended {22})


» Sulfamethizole    (in acid urine methenamine breaks down into formaldehyde, which may form an insoluble precipitate with sulfamethizole, and may also increase the danger of crystalluria; concurrent use is not recommended {11}{26})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results {05} {11}
Catecholamine, urinary and
17-hydroxycorticosteroid (17-OHCS), urinary, and
Vanillylmandelic acid (VMA), urinary    (concentrations may be falsely increased)


Estriol, urinary, and
5-hydroxyindoleacetic acid (5-HIAA), urinary    (concentrations may be falsely decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Dehydration, severe, or
» Renal function impairment, severe {22}    (salts of methenamine may precipitate, causing crystalluria, in patients with a low urine output)


» Hepatic function impairment, severe {22}    (because methenamine is hydrolyzed to ammonia, it should not be given to patients with severe hepatic impairment)


Hypersensitivity to methenamine


Side/Adverse Effects

Note: Large doses of methenamine (8 grams daily for 3 to 4 weeks) have been reported to cause bladder irritation, painful and frequent urination, and gross hematuria. {04}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Skin rash

Incidence rare
    
Crystalluria or hematuria (blood in urine; lower back pain; pain or burning while urinating)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Gastrointestinal disturbance (nausea and vomiting)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Methenamine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to methenamine

Pregnancy—Methenamine crosses the placenta





Breast-feeding—Methenamine is excreted in breast milk
Other medications, especially urinary alkalinizers, thiazide diuretics, or sulfamethizole
Other medical problems, especially severe hepatic function impairment or severe renal function impairment

Proper use of this medication
» Using phenaphthazine paper or other test and dietary measures to measure and appropriately adjust urine pH; importance of maintaining acidic urine (pH 5.5 or below)

Taking after meals and at bedtime if nausea or gastrointestinal irritation occurs

Proper administration technique for dry granules, oral liquids, and enteric-coated tablets

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days


Side/adverse effects
Signs of potential side effects, especially crystalluria, hematuria, and skin rash


General Dosing Information
Urine pH should be monitored before starting and throughout therapy since the effectiveness of methenamine is increased if a pH of 5.5 or below is maintained. To check urine pH, phenaphthazine paper, which has a pH range of 4.5 to 7.5, may be used.

To maintain a urine pH of 5.5 or below, most fruits (especially citrus fruits and juices), milk and other dairy products, and other alkalinizing foods should be avoided. A protein-rich diet with liberal amounts of cranberries (especially ascorbic acid–enriched cranberry juice), plums, or prunes may be helpful. {22} If these measures do not produce a sufficiently acid urine, they may be supplemented with large doses of ascorbic acid (4 grams or more per day), arginine hydrochloride, or methionine. However, some brands of ascorbic acid may contain varying amounts of ascorbate sodium and may actually alkalinize the urine. Alternatively, ammonium chloride or sodium biphosphate may be given (caution—large doses of ammonium chloride may cause metabolic acidosis in patients with impaired renal function and may be contraindicated in patients with hepatic insufficiency).

Methenamine may be taken after meals and at bedtime to help minimize nausea or gastrointestinal irritation.

Urea-splitting organisms (e.g., Proteus mirabilis and some strains of Pseudomonas and Enterobacter ) may cause an increase in urine pH and thereby decrease the effectiveness of methenamine. Care should be taken to ensure urine acidification. {23}

If recurrent urinary tract infections are prevented by 4 grams of methenamine mandelate daily, the dose may be reduced to a maintenance level of 1 gram of the mandelate 2 times a day. However, close observation of the patient is recommended to ensure the continued effectiveness of the lower dose of medication. {02}

Methenamine may cause dysuria, which may be controlled by reducing the dose and the urinary acidification. {20}


Oral Dosage Forms

METHENAMINE HIPPURATE TABLETS USP

Usual adult and adolescent dose
Antibacterial
Oral, 1 gram two times a day, morning and evening. {04} {20}


Usual adult prescribing limits
Up to 4 grams daily.

Usual pediatric dose
Antibacterial
Children 6 to 12 years of age: 500 mg to 1 gram two times a day, morning and evening. {04} {20}

Children 12 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


1 gram (Rx) [Hiprex (scored) (tartrazine )] [Urex ( scored)]

Canada—


1 gram (Rx) [Hip-Rex (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Maintain acid urine.
   • Continue medicine for full time of treatment.


METHENAMINE MANDELATE FOR ORAL SOLUTION (Granules) USP

Usual adult and adolescent dose
Antibacterial
Oral, 1 gram four times a day, after meals and at bedtime. {11}{26}


Usual adult prescribing limits
Up to 12 grams daily.

Usual pediatric dose
Antibacterial
Children up to 6 years of age: Oral, 18.3 mg per kg of body weight four times a day, after meals and at bedtime. {11}

Children 6 to 12 years of age: Oral, 500 mg four times a day, after meals and at bedtime. {11}

Children 12 years of age and over: See Usual adult and adolescent dose.


Size(s) usually available:
U.S.—


1 gram (Rx) [Mandelamine (sucrose)]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Preparation of dosage form:
Contents of each packet of granules should be dissolved in 60 to 120 mL of cold water immediately prior to administration.

Auxiliary labeling:
   • Maintain acid urine.
   • Dissolve in water before taking.
   • Continue medicine for full time of treatment.

Note: Explain administration technique.
Available as dry granules for reconstitution.



METHENAMINE MANDELATE ORAL SUSPENSION USP

Usual adult and adolescent dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Usual adult prescribing limits
See Methenamine Mandelate for Oral Solution USP (Granules) .

Usual pediatric dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Strength(s) usually available
U.S.—


250 mg per 5 mL (Rx) [Mandelamine (parabens)]


500 mg per 5 mL (Rx) [Mandelamine (parabens)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing.

Auxiliary labeling:
   • Maintain acid urine.
   • Shake well.
   • Continue medicine for full time of treatment.

Note: When dispensing, include a calibrated liquid-measuring device.



METHENAMINE MANDELATE TABLETS (ENTERIC-COATED) USP

Usual adult and adolescent dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Usual adult prescribing limits
See Methenamine Mandelate for Oral Solution USP (Granules) .

Usual pediatric dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Strength(s) usually available
U.S.—


500 mg (Rx)


1 gram (Rx)

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Maintain acid urine.
   • Swallow tablets whole.
   • Continue medicine for full time of treatment.


METHENAMINE MANDELATE TABLETS USP

Usual adult and adolescent dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Usual adult prescribing limits
Up to 4 grams daily.{26}

Usual pediatric dose
See Methenamine Mandelate for Oral Solution USP (Granules) .

Strength(s) usually available
U.S.—


500 mg (Rx) [Mandelamine][Generic]


1 gram (Rx) [Mandelamine]

Canada—


500 mg (Rx) [Mandelamine]


1 gram (Rx) [Mandelamine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Maintain acid urine.
   • Swallow tablets whole.
   • Continue medicine for full time of treatment.



Revised: 03/28/2000



References
  1. Panel comments, Methenamine (Systemic), 6/20/84.
  1. Manufacturer comments, Methenamine (Systemic), 6/20/84.
  1. Mandelamine (PD). In: PDR Physicians' desk reference. 40th ed. 1986. Oradell, NJ: Medical Economics Company, 1986: 1365-66.
  1. Hiprex (Merrell Dow). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1417.
  1. Mandelamine (PD). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1570-71.
  1. Panel comments, Methenamine (Systemic), 12/23/86.
  1. USP DI 1989, VA Medication Classification System: 2472.
  1. Hiprex (Merrell Dow). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1415.
  1. Urex (Riker-3M). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1214.
  1. Hip-Rex (Riker). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 397.
  1. Mandelamine (PD). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1569.
  1. Methenamine mandelate package insert (generic), Rev 4/82, Rec 4/89.
  1. Red book 1989. Montvale, NJ: Medical Economics Data, 1989: 265.
  1. Red book 1989. Montvale, NJ: Medical Economics Data, 1989: 469.
  1. Red book 1989. Montvale, NJ: Medical Economics Data, 1989: 468-9.
  1. Mandelamine (PD). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 577.
  1. Redbook 1989, Methenamine-enteric-coated (gen), p 468.
  1. Fleeger CA, editor. USAN 1989. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1988: 348.
  1. USP Description and Solubility, 4/3/89.
  1. Urex package insert (Riker—US), Rev 10/85, Rec 2/89.
  1. USP DI 1989, USP Requirements: IV/57.
  1. AMA Drug evaluations. 6th ed. Chicago: American Medical Association, September 1986: 1182.
  1. McEvoy GK, editor. AHFS Drug information 89. Bethesda, MD: American Society of Hospital Pharmacists, 1989: 422-3.
  1. Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman's the pharmocological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 1108-9.
  1. Klinge E, et al. Pharmacokinetics of methenamine in healthy volunteers. J Antimicrob Chemother 1982; 9: 209-16.
  1. Product Information: Mandelamine® , methenamine mandelate. Warner Chilcott Laboratories, Rockaway, NJ, (PI revised 11/97) reviewed 1/2000.
  1. Product Information: Urised(R), methenamine, phenyl salicylate, methylene blue, benzoic acid, atropine sulfate, and hyoscyamine. PolyMedica, Woburn, MA reviewed 3/2000.
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