Oral fomepizole administration to treat ethylene glycol and methanol poisonings: advantages and limitations

To the Editor:

We read with great interest the study by Marraffa and co-workers (1) demonstrating in 10 healthy volunteers similar pharmacokinetic parameters for fomepizole administered either intravenously or orally. Fomepizole was rapidly and almost completely absorbed orally. Its blood levels were nearly identical and the time above the currently accepted minimum effective concentration of 10 μmol/L was not significantly different between both routes, encouraging and strongly supporting effectiveness of oral fomepizole administration in poisoned patients.

However, to our best knowledge, only very few poisoned patients were treated in this manner (2–4) despite significant advantages: potential pharmacoeconomic benefits, greater patient comfort, and easier management in case of mass poisoning outbreak or absence of local facilities to perform and monitor intravenous infusion.

Here, we report our experience with oral treatment of toxic alcohol poisonings, based on a 10-year retrospective analysis conducted in our intensive care unit in Paris, which aimed to evaluate fomepizole safety. Over this period, 18 ethylene glycol-poisoned patients [13 M/3 F: age, 31 years (27–51), median (25–75% percentiles)] were treated either orally [N = 7: serum ethylene glycol concentrations, 16 mg/dL (6–70); maximum concentration, 150 mg/dL], intravenously (N = 8) or both (N = 3), whereas nine methanol-poisoned patients [8 M/1 F: age, 46 years (38–55)] were treated either orally (N = 1: serum methanol concentration, 10 mg/dL) or intravenously (N = 8). Only two patients treated orally had positive prefomepizole plasma ethanol concentrations (60 and 73 mg/dL, respectively). Two different preparations containing either 4-methylpyrazole hydrochloride or sulfate were used in 22 and 78% of patients, respectively.

None of the poisoned patients treated with oral fomepizole developed further complications, including renal failure, blindness, or neurological sequelae, although, as shown in the Table 1, oral route was preferentially used by the attending physicians in significantly less severe poisonings. Among the patients treated with oral fomepizole, three with serum ethylene glycol concentrations of >20 mg/dL and undetectable ethanol concentrations had uneventful outcome. Side-effects either possibly or definitely related to fomepizole were observed in five patients. Two patients treated with intravenous fomepizole suffered from painful inflammation at the injection site. Two orally treated patients developed mild transient eosinophilia (840 and 720/mm³) and one a generalized pruritus skin rash on day 2, whereas none reported an unpleasant taste in the mouth.

Table 1.  Characteristics of the patients intoxicated with either ethylene glycol or methanol and treated with fomepizole by either oral or intravenous route

	Oral fomepizole (N = 8)	Intravenous fomepizole (N = 16)	p
Ethylene glycol/methanol poisoning	7/1	8/8	0.1
Plasma ethylene glycol concentration (mg/dL)	16 (6–70)	82 (42–332)	0.08
Plasma methanol concentration (mg/dL)	10	72 (24–104)	ND
Anion gap (mmol/L)	12.2 (9.6–16.7)	22.5 (17.9–34.6)	0.001
Serum creatinine concentration (μmol/L)	84 (61–90)	81 (64–145)	0.9
Loading fomepizole dose (mg/kg)	11.4 (7.2–15.0)	10.1 (9.1–12.9)	0.7
Total fomepizole dose (mg/kg)	20.4 (12.6–46.9)	23.6 (12.8–38.5)	0.7
Number of administration	2 (2–5)	4 (2–5)	0.6
Hemodialysis	0/8	6/14	0.06
Hospital stay duration (days)	2 (1–3)	6 (4–8)	<0.001
Outcome		2 blindness and 1 death

ND, not determined.

Data are represented as median (25–75% percentiles). Comparisons were performed using Mann–Withney and exact Fischer tests, as requested. Significance level was set at p = 0.05.

Although preliminary, our data clearly support the assumption of the efficiency and safety of oral fomepizole in early presentations of ethylene glycol poisonings. Thus, based on this series, we may advice that asymptomatic adult patients referred to the emergency department for evaluation after ingesting a potentially toxic quantity of ethylene glycol may safely and efficiently receive oral fomepizole, thereby providing enough time according to the hospital facilities, to obtain the serum concentration of the involved alcohol as delayed treatment may be deleterious (5). Our data also support the safety of oral fomepizole in methanol exposure, with limited evidence of efficiency, however. One must note that although in two patients oral administration was through a nasogastric tube, vomiting, drowsiness, or stupor should clearly limit this route. As in three of our patients with initial gastrointestinal symptoms, the oral route was only used after initial intravenous administration, once the patient's initial condition improved.

Exact information from patients regarding oral fomepizole palatability was limited in this retrospective study although patient's compliance did not appear to be compromised. In this series, the manufactured preparation for infusion of fomepizole sulfate (Fomepizole AP-HP^®, 5 mg/mL) was directly administered either orally or using a nasogastric tube. However, because of possible disagreeable flavor, we may advice in the future to dilute fomepizole solution in orange juice to improve its acceptance.

By contrast, in life-threatening poisonings requiring critical care, we believe that the intravenous route should be the only recommended one as fomepizole pharmacokinetics using oral administration have not yet been definitively assessed in these patients. Furthermore, severely poisoned patients may present significant alterations in gastrointestinal absorption, therefore compromising the rapid achievement of effective fomepizole concentrations in blood. Thus, further studies are still needed to evaluate fomepizole concentrations after repeated oral doses as well as the maintenance of effective concentrations in case of adjunctive hemodialysis, before ascertaining the effectiveness and safety of the oral route in more severely poisoned patients.

Acknowledgments

The authors thank Alexandra Chronopoulos, MD, FRCPC, Intensive Care and Internal Medicine, Hôtel-Dieu de Lévis, Québec, Canada, for her helpful review of this manuscript.