AHFS Class:

• Methanol or ethylene glycol poisoning 91:04.08

Generic Name(s):

• Fomepizole

Fomepizole, an alcohol dehydrogenase inhibitor,1,2,3,4,5,6,7,8,10,11,12,13,14,16,18 blocks the metabolism of ethylene glycol to glycoaldehyde.1,2,4,9,11,15,17

Ethylene Glycol or Methanol Intoxication

Fomepizole is used alone or in combination with hemodialysis in the treatment of known or suspected ethylene glycol (antifreeze) or methanol intoxication.1,2,11,14,16,23,34,35 Because fomepizole only blocks the formation of toxic metabolites of ethylene glycol (e.g., glycolate, oxalate) or methanol (e.g., formic acid), the drug is not a substitute for standard therapeutic measures for these intoxications, including appropriate fluid and electrolyte therapy and correction of metabolic abnormalities (e.g., acidosis); hemodialysis also should be considered in patients with high plasma ethylene glycol or methanol concentrations (e.g., 50 mg/dL or greater)1,14,23 and may be required in those with severe or worsening metabolic acidosis and/or renal failure.1,2,3,4,5,8,11,14,15,16,17,22,25,26,27,28

While IV or oral alcohol is commonly used for ethylene glycol or methanol intoxication principally because of its availability (at least for oral use), low cost, and effectiveness as an alcohol dehydrogenase inhibitor,14,23,24,25 prospective studies of alcohol therapy for this use are lacking.22,24,25 Therapy with IV alcohol requires frequent monitoring and readjustment of dosage to maintain therapeutic effects because of unpredictable and variable pharmacokinetics,14,22,23,24 and limited data suggest that therapeutic concentrations of alcohol may not block the formation of toxic metabolites at very high plasma ethylene glycol concentrations.25,36 Although studies directly comparing the safety and efficacy of fomepizole and alcohol therapy in humans are lacking, limited data in animals suggest that IV administration of these drugs inhibits to a similar degree the development of metabolic acidosis and renal toxicity associated with ethylene glycol intoxication.1,4,19 Therapy with fomepizole may be technically less difficult to administer and monitor since the drug has a more prolonged and less variable rate of elimination (i.e., longer duration of action) than alcohol, has less potential for adverse effects such as CNS depression or hypoglycemia,1,2,3,4,5,7,11,22,25 and does not require plasma concentration monitoring.21,22,24 The American Academy of Clinical Toxicology (AACT) and some clinicians currently recommend the use of fomepizole rather than alcohol in cases of ethylene glycol intoxication involving ingestion of multiple substances with CNS depressant activity, in patients with altered consciousness, in critically ill patients with an anion gap metabolic acidosis of unknown etiology and potential exposure to ethylene glycol, in settings in which intensive-care and laboratory facilities to monitor alcohol therapy are unavailable, and in patients who have contraindications to the use of alcohol therapy (e.g., history ofalcoholism).24,25,26,27

Ethylene Glycol Intoxication

Adults

Evidence of clinical benefit of fomepizole in the management of ethylene glycol intoxication is based principally on data from prospective, uncontrolled trials in a limited number of adults, most of whom had severe intoxication and underwent dialysis, and retrospective analysis of a few patients who had normal renal function and received oral or IV fomepizole alone without hemodialysis.1,11,22,25,27 Although the relationship between fomepizole and plasma glycolate and urinary oxalate concentrations was confounded by the use of hemodialysis and the presence of substantial blood alcohol concentrations in many patients studied prospectively, observations during the postdialysis period when blood alcohol concentrations were low suggested that fomepizole alone was effective in preventing increases in plasma glycolate concentrations in these patients.1,11 Use of fomepizole early in the course of ethylene glycol intoxication (i.e., in patients with normal serum creatinine concentrations) has been shown to prevent renal injury by inhibiting the formation of toxic metabolites; renal function has decreased further in patients who had elevated serum creatinine concentrations (1.5-3.3 mg/dL) and more severe acidosis prior to initiation of fomepizole treatment.22,28 Toxicokinetic analysis of data from one prospective study suggests that serum creatinine concentration at initiation of fomepizole therapy, rather than plasma ethylene glycol concentration, may be more useful for predicting the rate at which ethylene glycol is eliminated from the body and the need for hemodialysis.28 Some clinicians have suggested that patients with uncomplicated ethylene glycol intoxication (i.e., no metabolic acidosis or impaired renal function) may be successfully treated with fomepizole therapy alone, even when plasma ethylene glycol concentrations exceed 50 mg/dL.22,25,27,33 However, the AACT states that if fomepizole is used alone in patients with high plasma ethylene glycol concentrations, acid-base balance should be monitored closely and hemodialysis instituted if metabolic acidosis develops.25

Children

Although the manufacturer states that safety and efficacy of fomepizole therapy in pediatric patients have not been established,1 the drug has been used with success alone or in combination with hemodialysis in a few infants and children with ethylene glycol intoxication† .29,30,31,32 Some clinicians state that in addition to ease of administration,31 fomepizole may have advantages over alcohol in young children with ethylene glycol intoxication in that fomepizole lacks the risk of hypoglycemia, obtundation, and hypothermia associated with alcohol therapy.25,31 However, data currently are insufficient to establish the relative efficacy of fomepizole and alcohol in the treatment of ethylene glycol intoxication in children.1,25

Methanol Intoxication

Evidence of clinical benefit of fomepizole in the management of methanol intoxication is based principally on data from a prospective, uncontrolled clinical trial in 11 adults, 7 of whom had severe intoxication and underwent hemodialysis.1,23 In this study, 98% of patients had plasma fomepizole concentrations exceeding those documented to inhibit alcohol dehydrogenase (0.8 mcg/mL), and plasma formic acid concentrations decreased in all patients treated with the drug.23 Simultaneous resolution of metabolic acidosis and improvements in mental status and manifestations of visual disturbances also occurred.23 None of the patients whose visual acuity was evaluated appeared to have any decrements in visual acuity related to methanol intoxication.23 However, only 3 of 11 patients had decreased visual acuity at initial examination as a result of methanol intoxication, and visual examinations could not be performed in 4 other patients, 3 of whom were hospitalized in a comatose state with severe methanol intoxication.23 While fomepizole alone appeared to prevent metabolism of methanol to formic acid in this study, the median plasma half-life of methanol in patients who did not undergo dialysis was 54 hours, suggesting that patients with very high plasma methanol concentrations may require hemodialysis to avoid prolonged hospitalization.23

Other Considerations

Clinicians should consider that fomepizole-induced inhibition of alcohol dehydrogenase may reduce the elimination of alcohol, which often is ingested concomitantly by patients with ethylene glycol intoxication or used initially in the treatment of ethylene glycol or methanol intoxication.1,2,4,5,7,22,23,24,25,26,33 Likewise, alcohol may reduce the elimination of fomepizole by the same mechanism.1,2,4,5,7,25

Other Uses

Fomepizole reportedly has been used in a limited number of patients for the treatment of diethylene glycol intoxication†, and propylene glycol intoxication†, for the prevention of disulfiram interaction with alcohol†, and for suppression of acetaldehyde accumulation in patients sensitive to alcohol† .25

Administration

Fomepizole is administered by IV infusion.1

Commercially available fomepizole for injection concentrate must be diluted prior to IV administration; the drug must not be given undiluted or by rapid IV injection .1 For IV infusion, the manufacturer recommends diluting the drug in at least 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 The diluted solution of fomepizole should be infused over a period of 30 minutes; more rapid infusion of a 25-mg/mL solution of fomepizole has resulted in vein irritation and phlebosclerosis.1,16,21

Solutions of fomepizole prepared in 5% dextrose injection or 0.9% sodium chloride injection are stable for at least 24 hours when stored at a controlled room temperature of 20-25°C or when refrigerated at 2-8°C.1 Because of the risk of microbial contamination in products without preservatives, the manufacturer recommends that the solutions be used within 24 hours after preparation.1

Fomepizole for injection concentrate solidifies at temperatures less than 25°C.1 If the fomepizole solution has solidified in the vial, the solution should be liquefied by passing the vial under warm water or by holding the vial in the hand.1 Solidification does not affect the efficacy, safety, or stability of fomepizole.1

As with all parenteral products, diluted solutions of fomepizole should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 Fomepizole solutions should be discarded if they are hazy, discolored, or contain a precipitate or if they exhibit leakage.1

Fomepizole is contraindicated in patients with a documented history of serious hypersensitivity to the drug or other pyrazoles.1,8,11,21 Patients receiving fomepizole should be monitored for manifestations of an allergic reaction; if a severe hypersensitivity reaction occurs, fomepizole should be discontinued immediately.1

Dosage

Fomepizole therapy should be initiated immediately upon suspected ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances,1,26,34 or oxalate crystals in the urine,1,24,25,26,30 or if the serum ethylene glycol or methanol concentration exceeds 20 mg/dL.1

For the treatment of ethylene glycol or methanol toxicity, the recommended initial dose of fomepizole in adults is 15 mg/kg, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until serum ethylene glycol or methanol concentrations have decreased to less than 20 mg/dL and the patient is asymptomatic and has a normal arterial blood pH value.1,22,23,25,26 All fomepizole doses should be administered by slow IV infusion over 30 minutes.1 (See Dosage and Administration: Administration.)

While comparative efficacy of various dosages of fomepizole in the treatment of ethylene glycol or methanol intoxication have not been established in children,1 dosages used in a limited number of case reports involving infants and children 8 months to 13 years of age were the same as those recommended for adults.29,30,31

In addition to specific antidote treatment with fomepizole, management of ethylene glycol or methanol intoxication may require treatment of metabolic acidosis, acute renal failure, adult respiratory distress syndrome, visual disturbances (methanol intoxication), and hypocalcemia.1,4,8,10 Hemodialysis should be considered in addition to fomepizole therapy in patients with acute renal failure, substantial or deteriorating metabolic acidosis, or a serum ethylene glycol or methanol concentration exceeding 50 mg/dL.1 Since fomepizole is dialyzable,1,25 the frequency of dosing should be increased to every 4 hours in patients undergoing hemodialysis.1,11 Information regarding the scheduling of fomepizole doses in relation to the initiation and termination of hemodialysis is shown in the table.1

Dosage in Renal and Hepatic Impairment

The manufacturer states that the pharmacokinetics of fomepizole have not been evaluated adequately in patients with renal or hepatic impairment, nor have they been studied sufficiently in geriatric patients to determine whether the pharmacokinetics differ from those in younger individuals.1 Because fomepizole is extensively eliminated by the kidneys, the risk of toxic reactions to the drug may be greater in patients with renal dysfunction.1 In addition, since geriatric individuals are more likely to have decreased renal function, care should be taken in dosage selection for such patients.1,21

Description

Fomepizole, a synthetic pyrazole derivative, is an alcohol dehydrogenase inhibitor.1,2,3,4,5,6,7,8,10,11,12,13,14,16,18 Alcohol dehydrogenase is the enzyme that catalyzes both the oxidation of alcohol to acetaldehyde and the initial steps in the metabolism of ethylene glycol and methanol to toxic metabolites.1,4,6,7,9,11,15,16 In vitro studies have shown that fomepizole has approximately 8000 or 80,000 times greater affinity for alcohol dehydrogenase than alcohol or methanol, respectively.14 Fomepizole competitively inhibits alcohol dehydrogenase1,2,3,4,5,6,7,8,9,11,12,14,16,18 and thereby blocks the metabolism of ethylene glycol to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate, and the metabolism of methanol to formaldehyde, which undergoes subsequent oxidation to yield formic acid.1,2,4,9,11,15,17 Glycolate and oxalate are the metabolites principally responsible for the metabolic acidosis and renal damage associated with ethylene glycol intoxication, while formic acid is principally responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol intoxication.1,2,3,4,8,9,12,15,14,17,20,23,24,28 The lethal dose of ethylene glycol or methanol in humans is approximately 1.4-1.6 mL/kg (about 100 mL in an adult) or 1-2 mL/kg, respectively.1,11,20

The manufacturer states that, based on studies in monkeys of the inhibition of methanol to formate by fomepizole, plasma fomepizole concentrations of 8.6-24.6 mg/L have been targeted for ensuring effective inhibition of alcohol dehydrogenase in humans.1,21

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Orphan Medical. Antizol^® (fomepizole) injection prescribing information. Minnetonka, MN; 1997 Dec.

2. Baud FJ, Galliot M, Astier A et al. Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. N Engl J Med . 1988; 319:97-100. [PubMed 3380132]

3. Jobard E, Harry P, Turcant A et al. 4-Methylpyrazole and hemodialysis in ethylene glycol poisoning. J Toxicol Clin Toxicol . 1996; 34:373-7. [PubMed 8699550]

4. Jacobsen D, McMartin KE. Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol . 1997; 35:127-43. [PubMed 9120880]

5. Jacobsen D, McMartin K. 4-Methylpyrazole—present status. J Toxicol Clin Toxicol . 1996; 34:379-81. [PubMed 8699551]

6. Jacobsen D, Barron SK, Sebastian CS et al. Non-linear kinetics of 4-methylpyrazole in healthy human subjects. Eur J Clin Pharmacol . 1989; 37:599-604. [PubMed 2693117]

7. Jacobsen D, Sebastian CS, Dies DF et al. Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans. Alcohol Clin Exp Res . 1996; 20:804-9. [PubMed 8865952]

8. Baud FJ, Bismuth C, Garnier R et al. 4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. J Toxicol Clin Toxicol . 1986; 24:463-83. [PubMed 3573122]

9. Anon. Ethylene glycol and methanol poisoning simplified. N Z Med J . 1988; 101:591.

10. Jacobsen D, Sebastian CS, Blomstrand R et al. 4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses. Alcohol Clin Exp Res . 1988; 12:516-22. [PubMed 3056073]

11. Orphan Medical. Antizol^® (fomepizole) injection product monograph. Minnetonka, MN; 1997 Dec.

12. Harry P, Turcant A, Bouachour G et al. Efficacy of 4-methylpyrazole in ethylene glycol poisoning: clinical and toxicokinetic aspects. Hum Exp Toxicol . 1994; 13:61-4. [PubMed 8198831]

13. Jacobsen D, Sebastian CS, Barron SK et al. Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med . 1990; 8:455-61. [PubMed 2212566]

14. Burns MJ, Graudins A, Aaron CK et al. Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med . 1997; 30:829-32. [PubMed 9398786]

15. Davis DP, Bramwell KJ, Hamilton RS et al. Ethylene glycol poisoning: case report of a record-high level and a review. J Emerg Med . 1997; 15:653-67. [PubMed 9348055]

16. Antidotes. In: Ellenhorn MJ, ed. Medical Toxicology Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore: Williams & Wilkins; 1997:99-100.

17. Alcohols and Glycols. In: Ellenhorn MJ, Barceloux DG, eds. Medical Toxicology Diagnosis and Treatment of Human Poisoning. New York: Elsevier Science; 1988:805-9.

18. Woolf AD, The Haitian diethylene glycol poisoning tragedy: a dark wood revisited. JAMA . 1998; 279:1215-6.

19. Grauer GF, Thrall MA, Henre BA et al. Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog. Toxicol Lett . 1987; 35:307-14. [PubMed 3824418]

20. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams & Wilkins CO; 1984:III-172-9.

21. Orphan Medical, Minnetonka, MN: Personal communication.

22. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med . 1999; 340:832-8. [PubMed 10080845]

23. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med . 2001; 344:424-9. [PubMed 11172179]

24. Jacobsen D. New treatment for ethylene glycol poisoning. N Engl J Med . 1999; 340:879-81. [PubMed 10080853]

25. Barceloux DG, Krenzelok EP, Olson K et al. American academy of clinical toxicology practice guideline on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol . 1999; 37:537-60. [PubMed 10497633]

26. Casavant MJ. Fomepizole in the treatment of poisoning. Pediatrics . 2001; 107:170-1. [PubMed 11134450]

27. Watson WA. Ethylene glycol toxicity: closing in on rational evidence based treatment. Ann Emerg Med . 2000; 36:139-41. [PubMed 10918105]

28. Sivilotti MA, Burns MJ, McMartin KE et al. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med . 2000; 36:114-125. [PubMed 10918102]

29. Baum CR, Langman CB, Oker EE et al. Fomepizole treatment of ethylene glycol poisoning in an infant. Pediatrics . 2000; 106:1489-91. [PubMed 11099610]

30. Harry P, Jobard E, Briand M et al. Ethylene glycol poisoning in a child treated with 4-methylpyrazole. Pediatrics . 1998; 102:E1. [PubMed 9724679]

31. Boyer EW, Mejia M, Woolf A et al. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics . 2001; 107:172-3. [PubMed 11134452]

32. Benitez JG, Swanson-Biearman B, Krenzelok EP. Nystagmus secondary to fomepizole administration in a pediatric patient. J Toxicol Clin Toxicol . 2000; 38:795-8. [PubMed 11192468]

33. Boron SW, Mégarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet . 1999; 354:831. [PubMed 10485727]

34. Megarbane B, Borron SW, Trout H et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med . 2001; 27:1370-8. [PubMed 11511951]

35. Girault C, Tamion F, Moritz F et al. Fomepizole (4-methylpyrazole) in fatal methanol poisoning with early CT scan cerebral lesions. J Toxicol Clin Toxicol . 1999; 37:777-80. [PubMed 10584591]

36. Davis DP, Bramwell KJ, Hamilton RS et al. Ethylene glycol poisoning: case report of a record-high level and a review. J Emerg Med . 1997; 15:653-67. [PubMed 9348055]