What is fomepizole used for in the treatment of poisoning?

What is Fomepizole?

Fomepizole is a competitive inhibitor of alcohol dehydrogenase used as the first-line antidote for ethylene glycol and methanol poisoning, preventing the formation of toxic metabolites that cause metabolic acidosis, renal failure, blindness, and death. 1

Mechanism of Action

Fomepizole works by blocking alcohol dehydrogenase, the enzyme responsible for converting ethylene glycol and methanol into their toxic metabolites 1:

• Ethylene glycol poisoning: Prevents conversion to glycolate and oxalate, which cause metabolic acidosis and acute kidney injury 1
• Methanol poisoning: Prevents conversion to formic acid, which causes metabolic acidosis and visual disturbances including blindness 1
• Binding affinity: Fomepizole has >8000 times greater affinity for alcohol dehydrogenase compared to ethanol 2
• Target plasma concentration: 100-300 µmol/L (8.6-24.6 mg/L) ensures adequate inhibition of alcohol dehydrogenase 1

Clinical Indications

Fomepizole is FDA-approved for 1:

• Confirmed ethylene glycol or methanol poisoning
• Suspected ethylene glycol or methanol ingestion
• Use alone or in combination with hemodialysis

Standard Dosing Protocol

Loading dose: 15 mg/kg IV over 30 minutes 3, 1

Maintenance dosing 3:

• 10 mg/kg IV every 12 hours for four doses
• Then 15 mg/kg IV every 12 hours thereafter (due to autoinduction of metabolism)
• Continue until ethylene glycol/methanol concentration <30 mg/dL

Dosing During Extracorporeal Treatment

Critical adjustment required: Fomepizole is dialyzable and requires dose modification during hemodialysis 4, 3, 5:

• During intermittent hemodialysis: Increase frequency to every 4 hours 5
• During CRRT: Reduce maintenance dose by 50% (5 mg/kg every 12 hours initially, then 7.5 mg/kg every 12 hours) 6
• Post-hemodialysis: Administer next scheduled dose at end of dialysis session 4

Advantages Over Ethanol

Fomepizole is strongly preferred over ethanol as the antidote 3:

• Simpler dosing: No need for continuous infusion rate adjustments or blood level monitoring 3
• More predictable pharmacokinetics: Eliminates variability in ADH blockade 4
• Superior safety profile: No CNS depression, dysphoria, or hypoglycemia risk 3
• Reduced medication errors: No compounding of 10% ethanol solution required 3
• Anticipated improved safety in children: Avoids ethanol-related complications in pediatric patients 3

When Hemodialysis is Still Required Despite Fomepizole

Even with fomepizole treatment, hemodialysis is indicated for 4, 5:

• Ethylene glycol concentration >50 mmol/L (>310 mg/dL) - suggested indication 4
• Anion gap >27 mmol/L - strong recommendation 4, 3
• Coma or seizures - strong recommendation 4
• Acute kidney injury (KDIGO stage 2 or 3) - strong recommendation 4
• Glycolate concentration >12 mmol/L - strong recommendation 4

The rationale: fomepizole prevents further metabolite formation but does not remove already-formed toxic metabolites or correct severe acidosis 4

Safety Profile

Fomepizole demonstrates excellent safety based on 16-year post-marketing surveillance 7:

• Adverse reactions: Only 7% of patients experienced mild, transient effects 7
• Most common side effects: Injection site pain/burning, nausea/vomiting, drowsiness, transient aminotransferase elevation 7
• No treatment discontinuations: All adverse effects were manageable without stopping therapy 7
• No fomepizole-related deaths: None of 37 fatalities in the cohort were attributed to the antidote 7

Pharmacokinetics

• Volume of distribution: 0.6-1.02 L/kg, distributes to total body water 1
• Metabolism: Primarily hepatic via cytochrome P450 to 4-carboxypyrazole (80-85% of dose) 1
• Excretion: Only 1-3.5% excreted unchanged in urine 1
• Elimination kinetics: Michaelis-Menten (saturable) initially, then first-order after autoinduction at 30-40 hours 1
• Bioavailability: Approximately 100% (oral route achieves similar levels to IV, though oral formulation not FDA-approved) 8

Critical Clinical Pearls

Early administration prevents renal injury: Patients with normal creatinine at presentation who received fomepizole early had no renal injury, even with high ethylene glycol levels 9

Glycolate concentration matters more than parent compound: Renal injury correlates with glycolate >97.7 mg/dL (12.9 mmol/L), not ethylene glycol concentration 9

Time above minimum effective concentration: Single 15 mg/kg dose maintains therapeutic levels (>10 µmol/L) for approximately 32 hours 8

Cost considerations: While fomepizole is expensive, it may reduce or eliminate need for hemodialysis when given early, potentially offsetting costs 4