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Fomepizole

Pronunciation

(foe ME pi zole)

Index Terms

  • 4-Methylpyrazole
  • 4-MP

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Antizol: 1 g/mL (1.5 mL)

Generic: 1 g/mL (1.5 mL); 1.5 g/1.5 mL (1.5 mL)

Brand Names: U.S.

  • Antizol

Pharmacologic Category

  • Antidote

Pharmacology

Fomepizole competitively inhibits alcohol dehydrogenase, an enzyme which catalyzes the metabolism of ethanol, ethylene glycol, and methanol to their toxic metabolites. Ethylene glycol is metabolized to glycoaldehyde, then oxidized to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are responsible for metabolic acidosis and renal damage. Methanol is metabolized to formaldehyde, then oxidized to formic acid. Formic acid is responsible for metabolic acidosis and visual disturbances.

Absorption

Oral: Readily absorbed

Distribution

Vd: 0.6-1.02 L/kg; rapidly distributes into total body water

Metabolism

Hepatic to 4-carboxypyrazole (80% to 85% of dose), 4-hydroxymethylpyrazole, and their N-glucuronide conjugates; following multiple doses, induces its own metabolism via CYP oxidases after 30-40 hours

Excretion

Urine (1% to 3.5% as unchanged drug and metabolites)

Onset of Action

Peak effect: Maximum: 1.5-2 hours

Half-Life Elimination

Has not been calculated; varies with dose

Protein Binding

Negligible

Use: Labeled Indications

Ethylene glycol or methanol poisoning: Treatment of methanol or ethylene glycol poisoning alone or in combination with hemodialysis

Note: Fomepizole is the preferred antidote for known or suspected ethylene glycol poisoning or methanol poisoning. If fomepizole is unavailable or if the patient is intolerant to fomepizole, ethanol therapy may be considered. Ethanol as an antidote is effective in the management of methanol and ethylene glycol poisoning (Thanacoody 2016; Zakharov 2015); however, ethanol is associated with a higher incidence of adverse events and medication errors (Bestic 2009; Lepik 2009; Lepik 2011).

Contraindications

Hypersensitivity to fomepizole, other pyrazoles, or any component of the formulation

Dosing: Adult

Note: Fomepizole therapy should begin immediately upon suspicion of ethylene glycol or methanol ingestion.

Ethylene glycol and methanol toxicity: IV: Loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations have been reduced to <20 mg/dL and patient is asymptomatic with normal pH. Note: For severe toxicity requiring concomitant hemodialysis, see dosage adjustment in renal impairment.

Dosing: Geriatric

Specific studies have not been conducted in elderly patients.

Dosing: Pediatric

Ethylene glycol and methanol toxicity (off-label use): Safe and efficacious use in this patient population for ethylene glycol and methanol intoxication has been reported (Baum 2000; Benitez 2000; Boyer 2001; Brown 2001; De Brabander 2005; Detaille 2004; Fisher 1998). Consider consultation with a clinical toxicologist or poison control center. Refer to adult dosing.

Dosing: Renal Impairment

Note: Hemodialysis should be considered as an adjunct to fomepizole in patients with renal failure, significant or worsening metabolic acidosis, or ethylene glycol or methanol concentrations ≥50 mg/dL. The following dosing adjustments should be used for any patient receiving hemodialysis regardless of renal function.

Prior to the start of hemodialysis:

To determine if the patient requires a dose of fomepizole at the start of hemodialysis, determine when the last dose was administered.

If the last dose of fomepizole was given <6 hours ago, do not administer another dose upon beginning hemodialysis.

If the last dose of fomepizole was given ≥6 hours ago, administer next scheduled dose upon beginning hemodialysis.

During hemodialysis: During hemodialysis, administer fomepizole every 4 hours. Alternatively, a loading dose of 10-20 mg/kg followed by 1-1.5 mg/kg/hour continuous infusion during hemodialysis has been described in case reports (Jobard, 1996).

Upon completion of hemodialysis:

To determine if the patient requires a dose of fomepizole at the time of completion of hemodialysis, determine when the last dose was administered.

If the last dose of fomepizole was given <1 hour ago, do not administer a dose at the end of hemodialysis.

If the last dose of fomepizole was given 1-3 hours ago, administer one-half of the next scheduled dose at the end of hemodialysis.

If the last dose of fomepizole was given >3 hours ago, administer the next scheduled dose at the end of hemodialysis.

Maintenance dose when off hemodialysis: Administer fomepizole every 12 hours (starting 12 hours from last dose administered).

Dosing: Hepatic Impairment

Fomepizole is metabolized in the liver. Specific dosage adjustments have not been determined in patients with hepatic impairment.

Reconstitution

Prior to administration, dilute in at least 100 mL 0.9% sodium chloride or dextrose 5% water for injection. Although, it is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservatives.

Administration

All doses should be administered as a slow intravenous infusion (IVPB) over 30 minutes.

Storage

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); fomepizole solidifies at temperatures <25°C (77°F). If solution becomes solid in the vial, it be should be carefully warmed by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of the drug. Diluted solution should be used within 24 hours and may be stored at room temperature or under refrigeration.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Central nervous system: Headache (14%)

Gastrointestinal: Nausea (11%)

1% to 10% (≤3% unless otherwise noted):

Cardiovascular: Bradycardia, facial flushing, hypotension, phlebitis, shock, tachycardia

Central nervous system: Dizziness (6%), drowsiness (6%), metallic taste (≤6%), agitation, altered sense of smell, anxiety, seizure, speech disturbance, vertigo

Dermatologic: Skin rash

Gastrointestinal: Unpleasant taste (≤6%), abdominal pain, decreased appetite, diarrhea, heartburn, hiccups, vomiting

Genitourinary: Anuria

Hematologic & oncologic: Anemia, disseminated intravascular coagulation (DIC), eosinophilia, lymphangitis

Hepatic: Increased liver enzymes

Local: Application site reaction, inflammation at injection site, pain at injection site

Neuromuscular & skeletal: Back pain

Ophthalmic: Nystagmus, transient blurred vision, visual disturbance

Respiratory: Pharyngitis

Miscellaneous: Fever, multi-organ failure

<1% (Limited to important or life-threatening): Hypersensitivity reaction (mild; mild rash, eosinophilia)

Warnings/Precautions

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; metabolized in the liver.

• Renal impairment: Use with caution in patients with renal impairment; fomepizole and its metabolites are excreted in the urine. Hemodialysis should be considered as an adjunct to fomepizole in patients with renal failure, significant acidosis (pH <7.25-7.3), worsening metabolic acidosis, or ethylene glycol or methanol concentrations ≥50 mg/dL.

Special populations:

• Pediatric: Pediatric administration is not FDA approved; however, safe and efficacious use in this patient population for ethylene glycol and methanol intoxication has been reported (Baum, 2000; Benitez, 2000; Boyer, 2001; Brown, 2001; De Brabander, 2005; Detaille, 2004; Fisher, 1998). Consider consultation with a clinical toxicologist or poison control center.

Other warnings/precautions:

• Administration: Should not be given undiluted or by bolus injection.

Monitoring Parameters

Ideally, fomepizole plasma concentrations should be monitored; however, fomepizole concentrations are generally not available.

Use these parameters to monitor the response to fomepizole: Plasma (preferred)/urinary ethylene glycol or methanol concentrations, urinary oxalate (ethylene glycol), plasma (preferred)/urinary osmolality, renal/hepatic function, serum electrolytes, arterial blood gases; anion and osmolar gaps, resolution of clinical signs and symptoms of ethylene glycol or methanol intoxication

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey, 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or nausea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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