Fomepizole

Why this drug is interesting

Ethylene glycol and methanol are, in themselves, not much more toxic than ethanol. What kills is what alcohol dehydrogenase does to them: ethylene glycol becomes glycolate and then oxalate, producing severe metabolic acidosis and calcium oxalate crystal nephropathy; methanol becomes formate, which destroys the optic nerve. Block the enzyme and the parent alcohol is simply excreted, largely unchanged.

Fomepizole is a clean competitive inhibitor of that enzyme, with far higher affinity than ethanol, no sedation, no need for level monitoring of the antidote itself, and no ethanol infusion to titrate on a busy ward. It is one of the most rational antidotes in existence.

Pharmacology

Mechanism

Fomepizole (4-methylpyrazole) competitively inhibits alcohol dehydrogenase, the first enzyme in the metabolic pathway of both toxic alcohols. Ethanol works the same way, by being a preferred substrate — which is why an ethanol infusion was the traditional antidote and why an intoxicated patient who drinks antifreeze may present late and relatively well.

The advantages over ethanol are practical rather than mechanistic: no CNS depression, no need for hourly blood ethanol levels, no hypoglycaemia in children, predictable pharmacokinetics and a fixed dosing schedule.

Dialysability

Fomepizole is removed by haemodialysis, which is why the dialysis regimen is a continuous infusion rather than intermittent boluses.

When to start

"Treatment should begin whenever ethylene glycol poisoning is suspected, as early as possible after ingestion, even in the absence of signs of toxicity."¹ An ethylene glycol assay should be sent on admission but must not delay treatment, and levels should then be monitored every 12 to 24 hours.

In the absence of an assay, the label lists the criteria on which poisoning should be suspected:¹

• The patient's history
• Osmolar gap > 20 mOsm/kg H₂O
• Metabolic acidosis with an anion gap > 16 mmol/L (reflecting high glycolate)
• Calcium oxalate crystals in the urine

Dosing

Normal to moderately impaired renal function, no dialysis

Slow intravenous infusion over 30 to 45 minutes, given 12-hourly until the ethylene glycol concentration is below 0.2 g/L (3.2 mmol/L):¹

The number of maintenance doses depends on the initial concentration: generally 4–5 maintenance doses for initial ethylene glycol levels of 3–6 g/L (48–96 mmol/L), and 1–3 maintenance doses for 0.35–1.5 g/L (5.6–24 mmol/L).¹ This band applies to patients with serum creatinine of 100–265 µmol/L or better.

Severe renal impairment or dialysis

Where serum creatinine exceeds 265 µmol/L, haemodialysis is indicated in combination with fomepizole. The regimen changes:¹

• Loading dose 15 mg/kg over 30–45 minutes, then
• 1 mg/kg/hour by continuous infusion for the entire duration of the haemodialysis.

Both dialysis and fomepizole are stopped when the metabolic acidosis is corrected and the ethylene glycol level is below 0.2 g/L (3.2 mmol/L).¹ The dose during continuous venovenous haemodiafiltration is not known.

When to dialyse

Haemodialysis should also be initiated, in combination with fomepizole, if any one of the following is present:¹

• Arterial pH < 7.10
• A fall in arterial pH > 0.05 taking it outside the normal range despite bicarbonate
• Inability to maintain arterial pH > 7.30 despite bicarbonate
• A fall in serum bicarbonate of more than 5 mmol/L despite bicarbonate therapy
• A rise in serum creatinine of more than 90 µmol/L (1 mg/dL)

Special populations

• Elderly — limited experience; adjust to renal function as above.¹
• Children — no pharmacokinetic data; clinical experience is limited and based on similar weight-adjusted doses.¹
• Hepatic impairment — no clinical data.¹

Administration, safety and interactions

Contraindications

Hypersensitivity to fomepizole, to other pyrazoles, or to any excipient.¹

Fomepizole and ethanol

Prior treatment with ethanol does not preclude fomepizole. Nevertheless the combination is not recommended: concurrent use reduces the elimination rate of both substances, and although fomepizole's clinical efficacy appears unimpaired, the label advises against it for safety reasons.¹ In practice, if ethanol has been started and fomepizole becomes available, this is a conversation with the poisons service rather than a simple switch.

Hypersensitivity

Minor reactions — rash, hypereosinophilia — have been reported and should be monitored. A major reaction (angioedema, bronchospasm, anaphylactic shock) requires immediate discontinuation, symptomatic treatment, no re-administration, and a switch: "Treatment by ethanol should be started and hemodialysis considered."¹

Adverse effects

Very common

Dizziness, headache¹

Common — neurological

Vertigo, convulsion, nystagmus, speech disorder

Common — other

Eosinophilia, anaemia, anxiety, agitation, visual impairment, bradycardia, tachycardia, raised blood pressure, nausea, vomiting, diarrhoea, dyspepsia, hiccups, raised transaminases, pruritus, rash, raised CK, injection site reactions

Monitoring

Frequent plasma ethylene glycol, blood gases, pH, electrolytes, serum creatinine, urinalysis and urinary oxalate crystals. Hepatic transaminases and blood counts before treatment and one month afterwards are recommended; pre-existing liver impairment requires careful transaminase monitoring.¹ Adequate hydration prevents dehydration and hypernatraemia and increases urinary clearance of the parent alcohol.

Practical use in the ED

1. Suspect it on the gaps. An unexplained high anion gap metabolic acidosis, or a raised osmolar gap, in a patient who may have drunk something. Ethylene glycol is in antifreeze and screenwash; methanol in some imported and illicit spirits and in some solvents.
2. Send the alcohol level but do not wait for it. Few UK laboratories run it on site and turnaround is typically hours to days.
3. Start fomepizole early — 15 mg/kg over 30–45 minutes, diluted, never bolus.
4. Do not give activated charcoal. Ethanol and the toxic alcohols (methanol, ethylene glycol) all carry a strong recommendation against in the 2026 CTRC guideline, red across every time column of Table 4. Figure 1 lists alcohols first among poisons "not clinically significantly adsorbable to activated charcoal".² See activated charcoal.
5. Get the renal and critical care teams involved early, before the dialysis criteria are met rather than after. The five triggers are mostly about trajectory.
6. Give supportive treatment — fluid, sodium bicarbonate for the acidosis, and in methanol poisoning, folinic acid to accelerate formate breakdown (see folinic acid); in ethylene glycol, thiamine and pyridoxine are traditionally given to divert glyoxylate away from oxalate — see pyridoxine.
7. Call NPIS on 0344 892 0111. Toxic alcohols are among the strongest indications for a poisons centre conversation in UK practice, and methanol use of fomepizole is off-label.

Critical appraisal

Fomepizole has no randomised trial against ethanol and is not going to get one. Its case rests on identical mechanism with markedly better usability, and on observational series showing that patients treated with fomepizole are less likely to require dialysis. The counter-argument has always been cost: ethanol is nearly free and fomepizole is not, and in resource-limited settings that argument is decisive.

The UK label is a decent document — the dosing table, the dialysis criteria and the osmolar/anion gap triggers are all clearly stated — but it has two visible gaps. It does not cover methanol, which is the poisoning with the most feared outcome, and it explicitly declines to give a dose for continuous venovenous haemodiafiltration, which is what most UK critical care units actually use in an unstable patient. Both are handled in practice by expert advice rather than by the label.

References

1. 1
   Fomepizole Waymade 1 g/mL concentrate for solution for infusion — Summary of Product Characteristics, Waymade plc. electronic Medicines Compendium, product 101333. Sections 4.1–4.8. Source of the ethylene-glycol-only indication, the full dosing table including the 48- and 60-hour dose ranges, the 1 mg/kg/hour dialysis regimen, the five haemodialysis triggers, the osmolar and anion gap criteria, the pyrazole contraindication, the ethanol interaction and the adverse-effect list. Verified 31 Aug 2026.
2. 2
   Hoegberg LCG, Gosselin S, Buckley NA, Wood DM, et al. Recommendations from the Clinical Toxicology Recommendations Collaborative on the administration of activated charcoal in acute oral overdose. Clinical Toxicology 2026;64(6):419–475. PubMed 41906697. Table 4 and Figure 1: ethanol and the toxic alcohols carry strong recommendations against activated charcoal. Full text read 4 Sep 2026.
3. 3
   National Poisons Information Service. TOXBASE · NPIS 0344 892 0111. Required for methanol poisoning, where UK fomepizole use is off-label, and for antidote stock location.