Fomepizole (Monograph)

Brand name: Antizol
Drug class: Antidotes
- Alcohol Dehydrogenase Inhibitor
ATC class: V03AB34
VA class: AD900
Chemical name: 4-Methyl-1H-pyrazole
Molecular formula: C₄H₆N₂
CAS number: 7554-65-6

Introduction

Antidote for ethylene glycol or methanol intoxication; an alcohol dehydrogenase inhibitor.

Uses for Fomepizole

Ethylene Glycol or Methanol Intoxication

Treatment of known or suspected ethylene glycol (e.g., antifreeze) or methanol intoxication; use alone or in combination with hemodialysis. (See General under Dosage and Administration.)

Not a substitute for standard therapeutic measures (e.g., fluid and electrolyte therapy, correction of metabolic abnormalities [e.g., acidosis]). (See General under Dosage and Administration.)

Appears to be as effective as IV alcohol therapy in preventing development of ethylene glycol-associated metabolic acidosis and renal toxicity. However, may be technically less difficult to administer and monitor than IV alcohol therapy because fomepizole has a more prolonged and less variable rate of elimination (i.e., longer duration of action), has less potential for adverse effects (e.g., CNS depression, hypoglycemia), and does not require plasma concentration monitoring.

For treatment of ethylene glycol intoxication, the American Academy of Clinical Toxicology (AACT) and some clinicians recommend use of fomepizole rather than alcohol in cases involving ingestion of multiple substances with CNS depressant activity, in patients with altered consciousness, in critically ill patients with an anion gap metabolic acidosis of unknown etiology and potential exposure to ethylene glycol, in settings in which intensive-care and laboratory facilities to monitor alcohol therapy are unavailable, and in patients who have contraindications to the use of alcohol therapy (e.g., history of alcoholism).

Has been used with success alone or in combination with hemodialysis for the treatment of ethylene glycol intoxication in a few infants^{† [off-label]} and children^{† [off-label]}. May have advantages over alcohol therapy in young children as fomepizole lacks the risk of hypoglycemia, obtundation, and hypothermia associated with alcohol therapy; however, insufficient data to establish relative efficacy of fomepizole and alcohol for this use in children.

Related/similar drugs

Antizol

Fomepizole Dosage and Administration

General

• Initiate therapy immediately upon suspected ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in the urine, or if serum ethylene glycol or methanol concentration >20 mg/dL.

• Consider hemodialysis (in addition to fomepizole therapy) if ethylene glycol or methanol concentration ≥50 mg/dL; otherwise, closely monitor acid-base balance and institute hemodialysis when metabolic acidosis develops. Hemodialysis may be required if severe or worsening metabolic acidosis, acute renal failure, azotemia, and/or anuria occurs. (See Dosage in Patients Requiring Hemodialysis under Dosage and Administration.)

• Treat metabolic acidosis, acute renal failure (ethylene glycol intoxication), ARDS, visual disturbances (methanol intoxication), and hypocalcemia as needed. Supportive therapy (e.g., sodium bicarbonate, potassium and calcium supplementation, oxygen, fluid therapy) may be necessary. (See Adequate Patient Evaluation and Monitoring under Cautions.)

Administration

IV Administration

For compatibility information, see Compatibility under Stability.

Administer by slow IV infusion (after proper dilution); must not be administered undiluted or by rapid IV injection. (See Local Effects under Cautions.)

Dilution

Use strict aseptic technique since drug product contains no preservative.

Withdraw appropriate dose of fomepizole concentrate and add to at least 100 mL of sterile 0.9% sodium chloride or dextrose 5% injection.

Rate of Administration

Infuse diluted solution over 30 minutes. (See Local Effects under Cautions.)

Dosage

Pediatric Patients

Ethylene Glycol Intoxication† [off-label]

IV

Dosage not established; however, in a limited number of case reports, infants and children 8 months to 13 years of age received the same dosages as those recommended for adults.

Adults

Ethylene Glycol or Methanol Intoxication

IV

Loading dose: 15 mg/kg.

Maintenance dosage: 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until serum ethylene glycol or methanol concentrations are undetectable or have decreased to <20 mg/dL, and patient is asymptomatic with a normal arterial blood pH value.

Dosage in Patients Requiring Hemodialysis

Loading dose: 15 mg/kg.

Maintenance dosage: Generally similar to usual adult maintenance dosage; however, because fomepizole is dialyzable, adjust dosage/schedule before, during, and immediately upon completion of hemodialysis (see Table 1).

Example 1: Patient is given a loading dose of 15 mg/kg. Hemodialysis starts 1 hour after loading dose and lasts for 6 hours. Four hours after initiation of hemodialysis, patient would receive a dose of 10 mg/kg. Because length of time between last fomepizole dose and end of hemodialysis is 2 hours, patient should receive a dose of 5 mg/kg at the end of hemodialysis. Administer fomepizole every 12 hours thereafter until ethylene glycol or methanol concentration is <20 mg/dL and patient is asymptomatic with normal pH.

Example 2: Patient is given a loading dose of 15 mg/kg. Hemodialysis starts 7 hours after loading dose and lasts for 45 minutes. Patient would receive a dose of 10 mg/kg prior to initiation of hemodialysis. Because length of time between the last fomepizole dose and end of hemodialysis is <1 hour, patient should receive a 10 mg/kg dose 12 hours after the dose given prior to initiation of hemodialysis. Administer fomepizole every 12 hours thereafter until ethylene glycol or methanol concentration is <20 mg/dL and the patient is asymptomatic with normal pH.

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decrease in renal function.

Cautions for Fomepizole

Contraindications

• Known severe hypersensitivity to fomepizole or other pyrazoles.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Mild rash and eosinophilia reported.

Monitor for manifestations of an allergic reaction.

Major Toxicities

Hepatic Effects

Transient increases in serum transaminase concentrations reported following repeated dosing.

Monitor hepatic enzyme concentrations during therapy.

Hematologic Effects

Eosinophilia reported following repeated dosing.

Monitor WBC counts during therapy.

Local Effects

Vein irritation and phlebosclerosis reported following rapid (i.e., <30 minutes) IV infusion or IV injection (i.e., over 5 minutes) of a 25-mg/mL solution.

General Precautions

Adequate Patient Evaluation and Monitoring

Frequently monitor arterial blood gases, pH, electrolytes, BUN, creatinine, and urinalysis to determine response to therapy.

Frequently monitor serum and urine ethylene glycol concentrations and monitor for presence of urinary oxalate crystals in patients with ethylene glycol intoxication. In patients with methanol intoxication, monitor serum methanol concentrations.

Perform ECG because acidosis and electrolyte imbalances can affect the cardiovascular system. Electroencephalography also may be required in comatose patients.

Monitor hepatic enzyme (i.e., serum transaminase) concentrations and WBC counts. (See Major Toxicities under Cautions.)

Concomitant Use with Alcohol

Consider potential interaction with alcohol, which often is ingested concomitantly by patients with ethylene glycol intoxication or used initially in the treatment of ethylene glycol or methanol intoxication. (See Alcohol under Interactions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not know whether fomepizole is distributed into milk. Caution if used in nursing women.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy not established.

Common Adverse Effects

Headache, nausea, dizziness, increased drowsiness, bad/metallic taste.

Drug Interactions

Metabolized by mixed-function oxidases (cytochrome P-450 system). Potent inducer of CYP-mediated drug elimination; induces own metabolism.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes: Potential pharmacokinetic interaction; however, no studies to date.

Specific Drugs

Fomepizole Pharmacokinetics

Absorption

Bioavailability

Immediately and completely bioavailable following IV administration.

Distribution

Extent

Rapidly distributes to total body water following IV infusion.

Not known whether fomepizole is distributed into milk.

Elimination

Metabolism

Metabolized in the liver.

Induces own metabolism; elimination rate increases after about 30–40 hours.

Elimination Route

Excreted in urine mainly as metabolites; only 1–3.5% of administered dose excreted in urine as unchanged drug.

Fomepizole is dialyzable.

Half-life

Not determined, but varies with dose.

Special Populations

Pharmacokinetics not studied in patients with hepatic or renal impairment or in geriatric patients.

Stability

Storage

Parenteral

Injection Concentrate for IV Infusion

20-25°C. Fomepizole concentrate solidifies at temperatures <25°C. If solidification occurs, pass vial under warm water or hold vial in the hand to liquify solution before dilution. Solidification does not affect efficacy, safety, or stability of fomepizole.

Following dilution with 0.9% sodium chloride or 5% dextrose injection, stable for ≥24 hours when refrigerated or stored at controlled room temperature (20–25°C). However, because product contains no preservatives, manufacturer recommends using within 24 hours after dilution.

Discard if solutions become hazy, discolored, or contain a precipitate or if they exhibit leakage.

Compatibility

Parenteral

Solution Compatibility1

Actions

• Competitively inhibits alcohol dehydrogenase, the enzyme that catalyzes the oxidation of alcohol to acetaldehyde and the initial steps in the metabolism of ethylene glycol and methanol to toxic metabolites.

• Blocks metabolism of ethylene glycol (main component of most antifreezes and coolants) to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are toxic metabolites principally responsible for the metabolic acidosis and renal damage associated with ethylene glycol intoxication. Lethal dose of ethylene glycol in humans is approximately 1.4–1.6 mL/kg (about 100 mL in an adult); however, as little as 30 mL may be fatal.

• Blocks metabolism of methanol (main component of windshield wiper fluid) to formaldehyde, which undergoes subsequent oxidation to yield formic acid. Formic acid is principally responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity, potential blindness) associated with methanol intoxication. Lethal dose of pure methanol in humans is approximately 1–2 mL/kg; however, permanent blindness and death reported with as little as 0.1 mL/kg (6–10 mL in adults).

• Fomepizole has approximately 8000 or 80,000 times greater affinity for alcohol dehydrogenase than alcohol or methanol, respectively.

Advice to Patients

• Risk of hypersensitivity reactions.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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