Acetaminophen overdose, adjunctive agent:
Note: Consultation with a clinical toxicologist or poison control center is highly recommended to determine if fomepizole therapy is indicated; routine use is not recommended (Ref). Dosing is based on use in ethylene glycol and methanol toxicity, as well as preclinical data in healthy volunteers who received supratherapeutic doses of acetaminophen (Ref).
IV: Limited data available: 15 mg/kg, followed by 10 mg/kg every 12 hours as needed. A single loading dose is often described in case reports; however, additional doses may be reasonable based on patient presentation and severity (Ref). The duration of therapy should be determined in consultation with a clinical toxicologist or poison control center (Ref).
Ethylene glycol or methanol toxicity:
Note: Fomepizole therapy should begin immediately upon suspicion of ethylene glycol or methanol ingestion. Consultation with a clinical toxicologist or poison control center is highly recommended to determine if fomepizole therapy is indicated.
IV: 15 mg/kg (loading dose), followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours 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 altered kidney function.
Note: Hemodialysis should be considered as an adjunct to fomepizole in patients with kidney failure, significant or worsening metabolic acidosis, or ethylene glycol or methanol concentrations ≥50 mg/dL (Ref). The following dosing adjustments should be used for any patient receiving hemodialysis regardless of kidney 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:
Intermittent hemodialysis: During intermittent hemodialysis, administer fomepizole every 4 hours. Alternatively, a continuous IV infusion of 1 mg/kg/hour may be considered (Ref).
CRRT: During CRRT, administer fomepizole every 8 hours. Alternatively, a continuous IV infusion of 0.5 mg/kg/hour may be considered (Ref).
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 to 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).
Fomepizole is metabolized in the liver. Specific dosage adjustments have not been determined in patients with hepatic impairment.
Specific studies have not been conducted in elderly patients.
(For additional information see "Fomepizole: Pediatric drug information")
Note: Fomepizole therapy should begin immediately upon suspicion of ethylene glycol or methanol ingestion. Consultation with a clinical toxicologist or poison control center is highly recommended to determine if fomepizole therapy is indicated.
Ethylene glycol or methanol toxicity; patient not requiring hemodialysis: Limited data available; consider consultation with a clinical toxicology or poison control center:
Infants, Children, and Adolescents: IV: Initial: 15 mg/kg loading dose; followed by 10 mg/kg every 12 hours for 4 doses; then 15 mg/kg every 12 hours until ethylene glycol or methanol concentrations have been reduced to <20 mg/dL and patient is asymptomatic with normal pH (Ref). Note: For severe toxicity requiring concomitant hemodialysis, see "Dosing: Altered Kidney Function: Pediatric."
Infants, Children, and Adolescents (limited data available) (Ref): 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 (Ref). The following dosage 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 <6 hours since last fomepizole dose: Do not administer dose upon beginning dialysis.
If ≥6 hours since last fomepizole dose: Administer next scheduled dose upon beginning dialysis.
During hemodialysis: Administer every 4 hours. Alternatively, a loading dose of 10 to 20 mg/kg followed by a continuous infusion 1 to 1.5 mg/kg/hour during hemodialysis has been described in case reports (Ref).
Upon completion of hemodialysis; dependent upon the time between the last dose and the end 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 <1 hour since last fomepizole dose: Do not administer a dose at the end of hemodialysis.
If 1 to 3 hours since last fomepizole dose: Administer 1/2 of the next scheduled dose at the end of hemodialysis.
If >3 hours since last fomepizole dose: Administer the next scheduled dose at the end of hemodialysis.
Maintenance dose off hemodialysis: Administer every 12 hours starting from the time last dose administered.
Fomepizole is metabolized in the liver. Specific dosage adjustments have not been determined in patients with hepatic impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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%, postmarketing and/or case reports: Hypersensitivity reaction (mild; mild rash, eosinophilia)
Hypersensitivity to fomepizole, other pyrazoles, or any component of the formulation
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 to 7.3), worsening metabolic acidosis, or ethylene glycol or methanol concentrations ≥50 mg/dL.
• Isopropanol (isopropyl alcohol) poisoning: Fomepizole should not be administered in known isopropanol ingestions as the toxicity of isopropanol is predominantly due to the parent alcohol; inhibiting the metabolism of isopropanol may result in prolonged CNS depression, hypotension, or respiratory depression (Bekka 2001; Kraut 2018).
Other warnings/precautions:
• Administration: Should not be given undiluted or by bolus injection. Avoid using polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) during dilution or administration; fomepizole may interfere with the integrity of polycarbonate products.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Generic: 1.5 g/1.5 mL (1.5 mL)
Yes
Solution (Antizol Intravenous)
1 g/mL (per mL): $1,233.20
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Antizol: 1 g/mL (1.5 mL)
Generic: 1 g/mL (1.5 mL)
IV: All doses should be administered as a slow IV infusion (IVPB) over 30 minutes. Avoid using polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) during administration.
Parenteral: IV: Infuse as a diluted solution over 30 minutes; rapid infusion at a concentration of 25 mg/mL has been associated with vein irritation and phlebosclerosis. Avoid using polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) during administration.
Ethylene glycol or methanol toxicity: Treatment of known or suspected 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).
Acetaminophen overdose (adjunctive agent)
Fomepizole may be confused with omeprazole
None known.
There are no known significant interactions.
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).
It is not known if fomepizole is excreted in breast milk. The manufacturer recommends that caution be exercised when administering fomepizole to nursing women.
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
The manufacturer recommends concentrations concentrations of 8.2 to 24.6 mg/L (SI: 100 to 300 micromole/L) to achieve enzyme inhibition of alcohol dehydrogenase; according to practice guidelines, serum fomepizole concentrations of ≥0.8 mg//L (SI: 10 micromole/L) provide constant inhibition of alcohol dehydrogenase (Barceloux 1999; Barceloux 2002). However, fomepizole concentrations are generally not available.
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.
When used as adjunctive treatment for acetaminophen overdose, fomepizole is theorized to be protective during the injury phase as well as promote hepatocyte regeneration (Akakpo 2021; Akakpo 2022; Kang 2020). Fomepizole, via CYP2E1 inhibition, may attenuate the formation of N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen that contributes to hepatocellular injury (Akakpo 2018; Kang 2020). In addition, fomepizole may inhibit c-Jun N-terminal kinase, thereby preventing amplification of mitochondrial damage by limiting mitochondrial oxidant stress and hepatocellular death after NAPQI has already been generated (Akakpo 2018; Akakpo 2019).
Onset of effect: Peak effect: Maximum: 1.5 to 2 hours.
Absorption: Oral: Readily absorbed.
Distribution: Vd: 0.6 to 1.02 L/kg; rapidly into total body water.
Protein binding: Negligible.
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 to 40 hours.
Half-life elimination: Varies with dose and duration. After 96 hours of administration, the self-induction of fomepizole metabolism results in a shortened half-life of 1.5 to 2 hours (McMartin 2012).
Excretion: Urine (1% to 3.5% as unchanged drug and metabolites).
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