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METHENAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Methenamine (hexamethylenetetramine) is a tertiary amine formed by reacting aqueous formaldehyde with liquid or gaseous ammonia. It is most commonly used as a urinary antibacterial agent.

Specific Substances

    1) 1,3,5,7-Tetraazatricyclo(3.3.1.1(3,7))decane
    2) 1,3,5,7-Tetraazaadamantane
    3) Aminoform
    4) Ammoform
    5) Cystamin
    6) Cystogen
    7) Formamine
    8) Formin
    9) Hexamethylenamine
    10) Hexamethylenetetramine
    11) Hexamethylenetetraamine
    12) Hexamine
    13) Hexilmethylenamine
    14) HMT
    15) HMTA
    16) Methenamine
    17) Methenamine hippurate
    18) Methenamine mandelate
    19) Methenamine sulfosalicylate
    20) Uritone
    21) Urotropin
    22) Molecular formula: C6-H12-N4
    23) CAS 100-97-0
    24) CAS 74734-16-0
    1.2.1) MOLECULAR FORMULA
    1) METHENAMINE HIPPURATE: C15H21N5O3

Available Forms Sources

    A) FORMS
    1) PHARMACEUTICAL
    a) Methenamine hippurate is available as 1 g tablet (Prod Info Urex(TM) oral tablets, 2006).
    b) Methenamine mandelate is available as 500 mg and 1000 mg tablets (Prod Info methenamine mandelate oral tablets, 2009).
    2) INDUSTRIAL
    a) In industry, methenamine is present in the form of colorless crystals or granules or powder. As a hygroscopic, white, crystalline solid, it has a slight ammoniacal odor (Trochimowicz et al, 1994; Budavari, 1996; S Sweetman , 2000). This substance is classified by DOT as a flammable solid, with label required.
    B) SOURCES
    1) Methenamine is formed by reacting aqueous formaldehyde with liquid or gaseous ammonia (Trochimowicz et al, 1994).
    C) USES
    1) PHARMACEUTICAL
    a) Methenamine hippurate is used for the prophylaxis or suppressive treatment of frequently recurring urinary tract infections caused by susceptible bacteria when long-term therapy is needed (Prod Info Urex(TM) oral tablets, 2006). Methenamine mandelate is used for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections (Prod Info methenamine mandelate oral tablets, 2009).
    2) INDUSTRIAL
    a) The manufacture of phenolic resins is the major industrial use of methenamine (Lewis, 1996). It is also used in the rubber industry to prevent vulcanized rubber from blocking and as an accelerator; in adhesives, coatings, and sealing compounds; as a curing agent for thermosetting resins; in foundry mold castings as part of binder resins; as a corrosion inhibitor for steel; as a dye fixative; in fire logs and briquettes for camping; in the preservation of hides; as a stabilizer for lubricating and insulating oils; with sodium phenate and sodium hydroxide as absorber of poisonous gases; and as an antimicrobial food additive (Budavari, 1996; Trochimowicz et al, 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Methenamine is a urinary antibacterial agent. Methenamine hippurate is used for the prophylaxis or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is needed. Methenamine mandelate is used for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections. INDUSTRIAL: The manufacture of phenolic resins is the major industrial use of methenamine. It is also used in the rubber industry to prevent vulcanized rubber from blocking and as an accelerator; in adhesives, coatings, and sealing compounds; as a dye fixative; in fire logs and briquettes for camping; and as an antimicrobial food additive.
    B) PHARMACOLOGY: Methenamine exhibits antibacterial activity by the conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component also has some antibacterial activity and acts to keep the urine acidic.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects following therapeutic use appear to be mild, reversible, and occur infrequently. Most common effects reported are gastrointestinal intolerance (eg, abdominal pain, nausea, vomiting, and diarrhea). Rash, crystalluria, increased liver enzymes, and hypersensitivity reactions may also occur after therapeutic use.
    E) WITH POISONING/EXPOSURE
    1) Overdose reports in the literature are limited. Gastrointestinal upset may occur following overdoses of either salt form of methenamine. Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks). An overdose in a child resulted in hemorrhagic cystitis, mild metabolic acidosis, elevated BUN, and lower urinary tract irritation.
    2) Methenamine in industrial settings, is an irritant to the skin, eyes, and mucous membranes. When heated to decomposition, it emits toxic fumes of formaldehyde and oxides of nitrogen. It is combustible when exposed to heat or flame. Rash and skin inflammation have been reported following occupational exposures. Blisters with oozing have been reported in more severe cases. Eye and mucous membrane irritation has been reported following industrial exposures to vapors or dust. Industrial exposure to vapors may result in asthma-like reactions in previously sensitized individuals.
    0.2.20) REPRODUCTIVE
    A) Methenamine has been classified as FDA pregnancy category C. Methenamine crossed the placental barrier in humans. No significant differences were reported in fetuses of women who received methenamine during pregnancy compared with those who did not receive any medication. No reproductive adverse effects were reported in the offspring of dogs or rabbits that were given methenamine. Methenamine passes into breast milk of lactating women; however, adverse effects to the infant have not been reported.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer reports no carcinogenic potential. However, although causality has not been established, methenamine was implicated as a possible cause of increased skin and gastrointestinal cancers in workers who handled methenamine in a factory setting.

Laboratory Monitoring

    A) Monitor serum electrolytes, renal function, and urinalysis after significant overdose.
    B) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with severe respiratory symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after overdose of methenamine. Hemorrhagic cystitis is probably caused by methenamine converting to formaldehyde in acid urine. Maintaining dilute and slightly alkaline urine (pH 7 or higher) may prevent this complication. Hydrate to maintain urine output of 1 to 2 mL/kg/hr. Consider urinary alkalinization in patients with hematuria or urinary tract irritation.
    C) DECONTAMINATION
    1) PREHOSPITAL: INGESTION: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. OCULAR: Irrigate exposed eyes with water. DERMAL: Remove contaminated clothes, follow with copious irrigation. INHALATION: Humidified oxygen.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENTS
    1) Should not be required in overdose cases. In case of occupational inhalational exposure, aggressive airway management in patients with any indication of upper airway injury is recommended.
    E) ANTIDOTE
    1) None.
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is not recommended given the low toxicity of this drug.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with severe respiratory distress should also be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected methenamine overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Methenamine and its salts are readily absorbed. The methenamine component of methenamine hippurate tablets is hydrolyzed to formaldehyde in acidic urine. Vd: 0.56 L/kg. After administration of a single 1-gram oral dose of methenamine hippurate, 90% of the methenamine component is excreted in the urine within 24 hours. Elimination half-life: 4.3 hr
    K) DIFFERENTIAL DIAGNOSIS
    1) Exposure to another irritant.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Overdose information is very limited. A child developed hemorrhagic cystitis following an overdose of about 8 g. Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks).
    B) THERAPEUTIC DOSES: METHENAMINE HIPPURATE: ADULTS: 1 gram twice daily. CHILDREN: OVER 12 YEARS: 1 gram twice daily. 6 TO 12 YEARS: 1 gram or one-half of a tablet (0.5 g) twice daily. METHENAMINE MANDELATE: ADULTS: 1 gram 4 times daily. CHILDREN: OVER 12 YEARS: 1 gram 4 times daily. 6 TO 12 YEARS: 500 mg 4 times daily. LESS THAN 6 YEARS: 250 mg per 30 pounds body weight 4 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Methenamine is a urinary antibacterial agent. Methenamine hippurate is used for the prophylaxis or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is needed. Methenamine mandelate is used for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections. INDUSTRIAL: The manufacture of phenolic resins is the major industrial use of methenamine. It is also used in the rubber industry to prevent vulcanized rubber from blocking and as an accelerator; in adhesives, coatings, and sealing compounds; as a dye fixative; in fire logs and briquettes for camping; and as an antimicrobial food additive.
    B) PHARMACOLOGY: Methenamine exhibits antibacterial activity by the conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component also has some antibacterial activity and acts to keep the urine acidic.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects following therapeutic use appear to be mild, reversible, and occur infrequently. Most common effects reported are gastrointestinal intolerance (eg, abdominal pain, nausea, vomiting, and diarrhea). Rash, crystalluria, increased liver enzymes, and hypersensitivity reactions may also occur after therapeutic use.
    E) WITH POISONING/EXPOSURE
    1) Overdose reports in the literature are limited. Gastrointestinal upset may occur following overdoses of either salt form of methenamine. Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks). An overdose in a child resulted in hemorrhagic cystitis, mild metabolic acidosis, elevated BUN, and lower urinary tract irritation.
    2) Methenamine in industrial settings, is an irritant to the skin, eyes, and mucous membranes. When heated to decomposition, it emits toxic fumes of formaldehyde and oxides of nitrogen. It is combustible when exposed to heat or flame. Rash and skin inflammation have been reported following occupational exposures. Blisters with oozing have been reported in more severe cases. Eye and mucous membrane irritation has been reported following industrial exposures to vapors or dust. Industrial exposure to vapors may result in asthma-like reactions in previously sensitized individuals.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Eye and mucous membrane irritation has been reported following industrial exposures to vapors or dust (Lewis, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Methenamine mandelate suspension contains a vegetable oil base. Aspiration of this, particularly in elderly, dysphagic patients may result in a lipoid pneumonitis (HSDB , 2001).
    B) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) Industrial exposure to vapors may result in asthma-like reactions in previously sensitized individuals (HSDB , 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal upset may occur following therapeutic doses of either salt form of methenamine (Ross & Conway, 1970). Nausea, vomiting, diarrhea, abdominal cramps, and stomatitis may occur (Prod Info Urex(TM) oral tablets, 2006; Prod Info Hiprex(R), methenamine hippurate, 1996; Prod Info Mandelamine(R), methenamine mandelate, 1996; HSDB , 2001).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal upset may occur following overdoses of either salt form of methenamine (Ross & Conway, 1970).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Elevated serum hepatic enzymes have been reported in a few patients taking methenamine hippurate in one study (Prod Info Urex(TM) oral tablets, 2006).
    b) Patients with preexisting liver disease may experience a worsening of their disease when taking high doses of methenamine due to increased ammonia production in the intestines facilitated by this drug (S Sweetman , 2000).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CRYSTALLURIA
    1) WITH THERAPEUTIC USE
    a) Methenamine therapy may result in crystalluria when urinary flow rates are reduced (Gleckman et al, 1979).
    B) DYSURIA
    1) WITH POISONING/EXPOSURE
    a) Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks) (Prod Info methenamine mandelate oral tablets, 2009; Prod Info Urex(TM) oral tablets, 2006; HSDB , 2001; Prod Info UROQID-ACID(R) NO. 2 Oral Tablet, 1999; Prod Info Hiprex(R), methenamine hippurate, 1996).
    C) HEMORRHAGIC CYSTITIS
    1) WITH POISONING/EXPOSURE
    a) Acute hemorrhagic cystitis has been reported following an accidental overdose of at least 8 grams methenamine mandelate in a 2.5-year-old boy. The patient presented to the hospital 5 days after ingestion with symptoms of severe lower urinary tract irritation, gross hematuria, and a BUN of 55 mg/dL. All symptoms resolved over a 10 day period with symptomatic therapy and the BUN returned to normal within 48 hours (Ross & Conway, 1970).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) A 2.5-year-old boy presented with a mild metabolic acidosis (bicarbonate (HCO(3)), 16) 5 days after ingesting 8 g of methenamine. The acidosis resolved 48 hours later (Ross & Conway, 1970).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH THERAPEUTIC USE
    a) Rash has been reported in 3.5% or less of patients receiving methenamine therapy (Prod Info Urex(TM) oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) Skin irritation has been reported following exposures to the vapors or solutions. Rash and skin inflammation have been reported following occupational exposures. Blisters with oozing have been reported in more severe cases (Trochimowicz et al, 1994; Lewis, 1996; HSDB , 2001).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Although uncommon, hypersensitivity reactions with anaphylaxis may occur following therapeutic dosing or inadvertent overdoses. Hypersensitivity reactions have included rash, stomatitis, pruritus, and urticaria. Some of the methenamine drug products contain FD&C Yellow No. 5 (tartrazine), which may cause hypersensitivity reactions in susceptible persons (HSDB , 2001).
    b) A fatal allergic reaction was reported in an 80-year-old man treated for a urinary tract infection with methenamine mandelate. Following methenamine therapy the patient became semi-comatose with left hemiparesis in association with a generalized rash over the entire body and leg ulcers. The rash subsequently became exfoliative and the patient's blood pressure fell to 102/76 mmHg (millimeters of mercury). The patient was noted to have confusion, slurred speech, and weakness in the left arm. Subsequently the patient died and autopsy revealed a cirrhotic liver, moderate splenomegaly, and atrophic kidneys. The authors indicated that the patient's underlying disease processes probably contributed to the methenamine adverse reaction (Joseph & Joshi, 1971).
    2) WITH POISONING/EXPOSURE
    a) Although uncommon, hypersensitivity reactions with anaphylaxis may occur following therapeutic dosing or inadvertent overdoses (HSDB , 2001).

Reproductive

    3.20.1) SUMMARY
    A) Methenamine has been classified as FDA pregnancy category C. Methenamine crossed the placental barrier in humans. No significant differences were reported in fetuses of women who received methenamine during pregnancy compared with those who did not receive any medication. No reproductive adverse effects were reported in the offspring of dogs or rabbits that were given methenamine. Methenamine passes into breast milk of lactating women; however, adverse effects to the infant have not been reported.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALIES
    1) In the Michigan Medicaid Surveillance study, pregnancies between 1985 and 1992 were assessed. There were 209 newborns exposed to methenamine during the first trimester. Overall, eight major defects were noted (eight expected), including one cardiovascular defect, one instance of cleft palate, one polydactyly, and one limb reduction defect (Rosa & Baum, 1995).
    B) LACK OF EFFECT
    1) According to the Collaborative Perinatal Project, there was no association between methenamine use and congenital defects in 49 pregnancies exposed during the first trimester. However, a possible association was found between methenamine use anytime in pregnancy and 12 birth defects in 299 exposures (Heinonen et al, 1977).
    2) No significant differences were reported in fetuses of women who received methenamine compared with those who did not receive any medication. Incidences of physiologic jaundice and of congenital abnormalities fell within ranges normally seen at the institution where the study was performed (Gordon, 1972).
    C) ANIMAL STUDIES
    1) DOGS: There were slightly increased rates of stillbirths, offspring survival, and weight gain impairment when pregnant dogs were given oral methenamine at doses equivalent to the human dose (Prod Info Urex(TM) oral tablets, 2006). No reproductive adverse effects were reported in the offspring of dogs fed either 600 or 1250 ppm methenamine (Trochimowicz et al, 1994).
    2) RABBITS: In rabbits given methenamine at doses that were about 3 times the human dose, there was no evidence of fetal harm (Prod Info Urex(TM) oral tablets, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified methenamine as FDA pregnancy category C (Prod Info Urex(TM) oral tablets, 2006).
    B) PLACENTAL BARRIER
    1) According to one report, methenamine crossed the placental barrier in humans. About 4 hours after a single dose, concentration levels in the umbilical cord plasma approximated the level in maternal plasma (Allgen et al, 1979).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Methenamine is excreted in human breast milk (Prod Info Urex(TM) oral tablets, 2006). Methenamine is detectable in breast milk with peak levels occurring at 1 hour postingestion; quantities are not sufficient to effect the nursing infant (Anderson, 1977).
    2) Since methenamine mandelate is about 50% mandelic acid, mandelic acid excretion should also be considered. A study in 6 mothers administered 12 g/day of mandelic acid from the first day of delivery reported variable amounts of the drug excreted in breast milk. The author estimated that the average amounts of mandelic acid excreted in the breast milk were less than 300 mg/24 hours, which were considered safe amounts of the drug for the infant (Berger, 1941).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FEMALE RATS: When female rats were given methenamine at a dose of 800 mg/kg/day, there was no evidence of adverse effects on fertility (Prod Info Urex(TM) oral tablets, 2006).
    2) MALE RATS: The effects of methenamine on fertility were not studied in male rats (Prod Info Urex(TM) oral tablets, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer reports no carcinogenic potential. However, although causality has not been established, methenamine was implicated as a possible cause of increased skin and gastrointestinal cancers in workers who handled methenamine in a factory setting.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for methenamine in humans (Prod Info Urex(TM) oral tablets, 2006).
    B) SKIN/GASTROINTESTINAL CARCINOMA
    1) Methenamine has been implicated as a possible cause of increased skin and gastrointestinal cancers in occupational workers in the rubber industry where methenamine is used as an accelerator. An exact causal relationship has not been established (Trochimowicz et al, 1994).
    3.21.4) ANIMAL STUDIES
    A) LOCAL SARCOMAS
    1) RATS: In a small study, there was a 50% incidence in local sarcomas when rats that were receiving concomitant formic acid were given subQ doses of methenamine (total dose 25 g/kg) over periods of up to 15 months (Prod Info Urex(TM) oral tablets, 2006).
    B) LACK OF EFFECT
    1) RATS, MICE: There was no evidence of carcinogenicity in rats and mice after 104 weeks and 60 weeks of oral methenamine 1.25 g/kg/day, respectively. In the same study, there was also no evidence of carcinogenicity when 5 subQ injections of 5 g/kg were given on alternating days (total dose 25 g/kg) (Prod Info Urex(TM) oral tablets, 2006). No evidence of carcinogenicity was seen in mice or rats given methenamine during their lifetime in various doses ranging from 400 mg/day for 1 year to 10,000 ppm in water for a lifetime in rats, and 50,000 ppm for 30 weeks in mice (Trochimowicz et al, 1994).

Genotoxicity

    A) Methenamine was evaluated for mutagenicity in the Ames Salmonella/mammalian microsome test in which 5 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537, and TA1538) and a strain of E. coli (WP2uvrA) were used. There was evidence of mutagenic activity with Salmonella typhimurium TA98 and TA100 by metabolic activation, and with TA98 without microsomal activation at a methenamine dose of 10,000 mcg/plate (Prod Info Urex(TM) oral tablets, 2006).
    B) Methenamine has been reported to be mutagenic in the Salmonella typhimurium assay, in E. coli, in Drosophila, in onion cells (Trochimowicz et al, 1994; RTECS , 2001), and in human cells (RTECS , 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, renal function, and urinalysis after significant overdose.
    B) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with severe respiratory symptoms.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function, and urinalysis after significant overdose.
    B) LABORATORY TEST INTERFERENCE
    1) Methenamine therapy or overdose may result in a spurious elevation of urinary catecholamine, 17-hydroxycorticosteroid, and vanillylmandelic acid laboratory measurements and a decrease in urinary hydroxyindoleacetic acid (Gleckman et al, 1979).
    4.1.3) URINE
    A) URINALYSIS
    1) Methenamine and its primary metabolite, formaldehyde, are excreted primarily in the urine. Although albuminuria, crystalluria, and hematuria are relatively uncommon during therapeutic use, overdoses may result in these effects (Ross & Conway, 1970).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs in all symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) One report described a chromatographic method of analyzing formaldehyde in urine via colorimetric determination, either by use of the chromotropic acid reaction or the reaction with acetylacetone and ammonia according to the Nash method. The same authors described a method for determination of methenamine in plasma, urine, amniotic fluid, and milk (Allgen et al, 1979).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with severe respiratory distress should also be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor serum electrolytes, renal function, and urinalysis after significant overdose.
    B) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with severe respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) INGESTION: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    B) OCULAR: Irrigate exposed eyes with water.
    C) DERMAL: Remove contaminated clothes, follow with copious irrigation.
    D) INHALATION: Humidified oxygen.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor serum electrolytes, renal function and urinalysis after significant overdose.
    2) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with severe respiratory symptoms.
    B) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Hemorrhagic cystitis is probably caused by methenamine converting to formaldehyde in acid urine. Maintaining dilute and slightly alkaline urine (pH 7 or higher) may prevent this complication. Hydrate to maintain urine output of 1 to 2 mL/kg/hr.
    2) Consider urinary alkalinization in patients with hematuria or urinary tract irritation. Administer a solution of 1 L D5W with 3 amps sodium bicarbonate (132 mEq) at a rate sufficient to maintain urine output of 1 to 2 mL/kg/hr. Monitor urine pH and serum potassium.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is not recommended given the low toxicity of this drug.

Abstracts

Case Reports

    A) PEDIATRIC
    1) A 2.5-year-old boy was admitted to the hospital 5 days following an inadvertent ingestion of at least 8 g of methenamine mandelate. Symptoms on admission included severe lower genitourinary tract irritation and gross hematuria. Laboratory tests on admission revealed increased serum BUN of 55 mg/dL and reduced carbon dioxide content of 16 mEq/L, both of which returned to normal within 48 hours. Urethroscopy and cystoscopy revealed increased vascularity in the vesical neck and trigone with hemorrhagic, edematous folds of mucosa in the same area. The boy was diagnosed with hemorrhagic cystitis. Treatment was symptomatic and supportive. Complete resolution of symptoms occurred within 10 days. Urine was microscopically negative and the boy was asymptomatic at a 3-month follow-up examination (Ross & Conway, 1970).

Range Of Toxicity

Summary

    A) TOXICITY: Overdose information is very limited. A child developed hemorrhagic cystitis following an overdose of about 8 g. Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks).
    B) THERAPEUTIC DOSES: METHENAMINE HIPPURATE: ADULTS: 1 gram twice daily. CHILDREN: OVER 12 YEARS: 1 gram twice daily. 6 TO 12 YEARS: 1 gram or one-half of a tablet (0.5 g) twice daily. METHENAMINE MANDELATE: ADULTS: 1 gram 4 times daily. CHILDREN: OVER 12 YEARS: 1 gram 4 times daily. 6 TO 12 YEARS: 500 mg 4 times daily. LESS THAN 6 YEARS: 250 mg per 30 pounds body weight 4 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) METHENAMINE HIPPURATE
    1) 1 gram twice daily (Prod Info Urex(TM) oral tablets, 2006).
    B) METHENAMINE MANDELATE
    1) 1 gram 4 times daily (Prod Info methenamine mandelate oral tablets, 2009).
    7.2.2) PEDIATRIC
    A) METHENAMINE HIPPURATE
    1) OVER 12 YEARS: 1 gram twice daily (Prod Info Urex(TM) oral tablets, 2006).
    2) 6 TO 12 YEARS: 1 gram or one-half of a tablet (0.5 g) twice daily (Prod Info Urex(TM) oral tablets, 2006).
    B) METHENAMINE MANDELATE
    1) OVER 12 YEARS: 1 gram 4 times daily (Prod Info methenamine mandelate oral tablets, 2009).
    2) 6 TO 12 YEARS: 500 mg 4 times daily (Prod Info methenamine mandelate oral tablets, 2009).
    3) LESS THAN 6 YEARS: 250 mg per 13.6 kg body weight 4 times daily (Prod Info methenamine mandelate oral tablets, 2009).

Maximum Tolerated Exposure

    A) PEDIATRIC
    1) An inadvertent overdose of at least 8 g of methenamine mandelate resulted in hemorrhagic cystitis in a 2.5-year-old boy. Symptoms upon admission to the hospital included severe lower urinary tract irritation and gross hematuria. Abnormal laboratory tests included a BUN level of 55 mg/100 mL and carbon dioxide content of 16 mEq/L, both of which returned to normal within 48 hours. Urethroscopy and cystoscopy as well as roentgenographic studies were consistent with a diagnosis of hemorrhagic cystitis. Complete resolution of symptoms occurred within 10 days following symptomatic and supportive therapy (Ross & Conway, 1970).
    B) ADULT
    1) Dysuria, bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria have been reported following large doses of methenamine (8 g daily for 3 to 4 weeks) (Prod Info Urex(TM) oral tablets, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 569 mg/kg (RTECS, 2001)
    B) LD50- (SUBCUTANEOUS)MOUSE:
    1) 215 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Methenamine hippurate exhibits antibacterial activity by the conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component also has some antibacterial activity and acts to keep the urine acidic (Prod Info methenamine mandelate oral tablets, 2011).
    B) Methenamine hippurate is generally active against E. coli, enterococci, and staphylococci. However, enterobacter aerogenes is generally resistant to methenamine. Inhibition of urea-splitting organisms, such as Proteus and Pseudomonas, is achieved only in highly acidic urine (Prod Info Hiprex(R) oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) Methenamine is a hygroscopic, white, crystalline or powder solid, with a slight ammoniacal odor or no odor (Trochimowicz et al, 1994; Budavari, 1996), or colorless, lustrous crystals (HSDB , 2001; S Sweetman , 2000).

Ph

    A) The aqueous solution is alkaline to litmus (HSDB , 2001).

Molecular Weight

    A) METHENAMINE: 140.19 (Fleeger, 1988)
    B) METHENAMINE HIPPURATE: 319.37 (Prod Info Urex(TM) oral tablets, 2006)
    C) METHENAMINE MANDELATE: 292.34 (Fleeger, 1988)

References

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