Fomepizole is a competitive inhibitor of alcohol dehydrogenase. It is FDA-approved for the treatment of ethylene glycol and methanol poisoning. The drug must be diluted and administered by intravenous infusion over 30 minutes; administration as an undiluted intravenous bolus is associated with venous irritation and phlebosclerosis. If given with hemodialysis, which should be considered in addition to fomepizole in patients with renal failure, worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration 50 mg/dL or greater, the dosing frequency must be increased as fomepizole is dialyzable. Assess treatment success by monitoring blood gases, pH, electrolytes, BUN, creatinine, urinalysis, ethylene glycol concentrations (serum and urine) or methanol concentrations (serum), hepatic enzymes, and white blood cell counts.
General Administration Information
For storage information, see specific product information within the How Supplied section.
NOTE: If ethylene glycol or methanol poisoning is left untreated, the natural progression of the poisoning leads to accumulation of toxic metabolites, including glycolic and oxalic acids (ethylene glycol intoxication) and formic acid (methanol intoxication). These metabolites can induce metabolic acidosis, nausea, vomiting, seizures, stupor, coma, calcium oxaluria, acute tubular necrosis, blindness, and death. The diagnosis of these poisonings may be difficult because ethylene glycol and methanol concentrations diminish in the blood as they are metabolized to their respective metabolites. Hence, both ethylene glycol and methanol concentrations and acid base balance, as determined by serum electrolyte (anion gap) or arterial blood gas analysis, should be frequently monitored and used to guide treatment.
NOTE: Hemodialysis should be considered to remove ethylene glycol, methanol, and the toxic metabolites in patients with high ethylene glycol or methanol concentrations (50 mg/dL or more), significant metabolic acidosis, or renal failure.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Fomepizole solidifies at temperatures less than 25 degrees C (77 degrees F). If the solution has become solid in the vial, the solution should be liquefied by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of the solution.
Intravenous Administration
NOTE: DO NOT use polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) while diluting or administering the product. Fomepizole can interact with polycarbonate, and compromise the integrity of the syringe or needle components containing polycarbonate.
Dilution:
-Using sterile technique, withdraw the appropriate dose from the vial with a non-polycarbonate containing syringe.
-Dilute the solution with at least 100 mL of sterile 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
-Mix well.
-Storage: The diluted solution is stable for at least 24 hours when stored refrigerated or at room temperature; DO NOT use beyond 24 hours. The product does not contain preservatives; therefore sterile conditions must be maintained. Do not use solution showing haziness, particulate matter, precipitation, discoloration, or leakages.
Intravenous infusion:
-Infuse the entire contents intravenously over 30 minutes.
-Due to the development of venous irritation, DO NOT administer undiluted or as a bolus injection.
Among the most frequently reported adverse events with fomepizole therapy during clinical trials were those affecting the central nervous system, including headache (14%), dizziness (6%), and increased drowsiness (6%). Approximately 3% or fewer patients reported lightheadedness, seizures, agitation, feeling drunk, feeling hungover, facial flushing, vertigo, nystagmus, anxiety, "felt strange", and decreased environmental awareness.
Among the most frequently reported adverse events with fomepizole therapy during clinical trials were those gastrointestinal in nature, including nausea (11%) and a bad or metallic taste (6%). Approximately 3% or fewer patients reported abdominal pain, vomiting, diarrhea, dyspepsia, pyrosis (heartburn), anorexia, and transient transaminitis.
During clinical trials, 78 patients and 63 subjects received fomepizole. Adverse reactions that at least 3% of these patients and subjects reported include hiccups, pharyngitis, fever, abnormal smell, speech disturbances, visual impairment or disturbances, transient blurred vision, a roaring sound in the ear, lumbalgia, back pain, and anuria.
During clinical trials, 78 patients and 63 subjects received fomepizole. Adverse hematologic and lymphatic reactions were reported in at least 3% of these patients and subjects, and include eosinophilia, hypereosinophilia, lymphangitis, disseminated intravascular coagulation (DIC), and anemia. Multiorgan system failure was also reported.
During clinical trials, 78 patients and 63 subjects received fomepizole. Adverse reactions of the skin and appendages, that at least 3% of these patients and subjects reported, include injection site reaction, which included pain during the injection and inflammation at the injection site, and rash (unspecified).
During clinical trials, 78 patients and 63 subjects received fomepizole. Adverse cardiovascular reactions that at least 3% of these patients and subjects reported include sinus bradycardia/bradycardia, phlebosclerosis, sinus tachycardia, phlebitis, shock, and hypotension.
Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles.
Fomepizole is classified as FDA pregnancy category C. Animal reproduction studies have not been conducted. It is also not known whether the drug can cause fetal harm or affect reproduction capacity when administered to pregnant women. Use during pregnancy only if clearly needed.
Data are limited regarding use of fomepizole during breast-feeding, and its excretion in human breast milk is unknown. According to the manufacturer, the drug should be used with caution in lactating women. However, recipients of fomepizole may not be appropriate candidates for breast-feeding because of the potential for ethylene glycol or methanol toxicity in a nursing infant. While undergoing treatment, patients should be instructed to temporarily avoid breast-feeding until the drug is cleared from the maternal system.
In addition to specific antidote treatment with fomepizole, patients intoxicated with ethylene glycol or methanol must be managed for metabolic acidosis, acute renal failure (ethylene glycol), adult respiratory distress syndrome, visual disturbance (methanol), and electrolyte imbalance (i.e., hypocalcemia). Fluid therapy and sodium bicarbonate administration are potential supportive therapies. In addition, potassium and calcium supplementation and oxygen administration are usually necessary. Hemodialysis is necessary in the patients with anuria, or in patients with severe metabolic acidosis or azotemia. Treatment success should be assessed by frequent measurements of blood gases, pH, electrolytes, BUN, creatinine, and urinalysis, in addition to other laboratory tests as indicated by individual patient conditions. Ethylene glycol plasma and urine concentrations and presence of urinary oxalate crystals should also be monitored frequently throughout treatment to assess the status of ethylene glycol and metabolite clearance. For patients poisoned with methanol, serum methanol concentrations should be monitored. Since acidosis and electrolyte imbalances can affect the cardiovascular system, electrocardiography should be performed. In the comatose patient, electroencephalography may also be required. Hepatic enzymes and white blood cell counts should be monitored during treatment, as transient increases in serum transaminase levels and eosinophilia have been noted with repeated fomepizole dosing.
Fomepizole and its metabolites are substantially excreted by the kidney and are dialyzable. The risk of toxic reactions to this drug may be increased in patients with renal impairment or renal disease. Consider hemodialysis in addition to fomepizole for patients with high ethylene glycol or methanol concentrations (50 mg/dL or more), significant metabolic acidosis, or renal failure. If used in combination with hemodialysis, the dosing frequency of fomepizole must be increased to every 4 hours.
For the treatment of ethylene glycol poisoning or methanol poisoning, either alone or in combination with hemodialysis:
Intravenous dosage:
Adults: Begin treatment immediately upon suspicion of ethylene glycol or methanol ingestion. Administer a loading dose of 15 mg/kg IV, followed by 10 mg/kg IV every 12 hours for 4 doses, then 15 mg/kg every 12 hours until ethylene glycol or methanol serum concentrations are undetectable or reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. All doses must be administered via slow IV infusion over 30 minutes. The dose increases from 10 to 15 mg/kg because fomepizole induces its own metabolism.
Adult patients requiring intermittent hemodialysis: Fomepizole is removed by hemodialysis and the dosing interval should be changed to every 4 hours during hemodialysis. A regimen for dosing during hemodialysis is as follows:
DOSE AT THE BEGINNING OF HEMODIALYSIS: If less than 6 hours since the last dose, do not administer dose. If 6 or more hours since last dose, administer next scheduled dose.
DOSE DURING HEMODIALYSIS: Administer dose every 4 hours.
DOSE AT TIME HEMODIALYSIS IS COMPLETED: If less than 1 hour between last dose and end of hemodialysis, do not administer dose. If 1 to 3 hours between last dose and end of hemodialysis, administer one-half of next scheduled dose. If more than 3 hours between last dose and end of hemodialysis, administer next scheduled dose.
MAINTENANCE DOSE OFF HEMODIALYSIS: Give next scheduled dose 12 hours from last dose administered.
Maximum Dosage Limits:
-Adults
15 mg/kg/dose IV.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Fomepizole undergoes hepatic metabolism; however, specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied. The metabolites of fomepizole are excreted renally.
Intermittent hemodialysis
Increase the dosing frequency to every 4 hours during hemodialysis.
*non-FDA-approved indication
Carbamazepine: (Minor) Carbabamezapine may decrease the actions of Fomepizole via induction of the CYP450 hepatic enzyme system. This interaction has not been studied, and its clinical significance has not been established.
Cimetidine: (Minor) In healthy volunteers, moderate oral doses of fomepizole significantly reduced the rate of elimination of ethanol by approximately 40%. Similarly, ethanol decreased the rate of elimination of fomepizole by approximately 50%. Both interactions occur via alcohol dehydrogenase inhibition. Although not studied, reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 enzyme system, like cimetidine.
Ethanol: (Major) Avoid concomitant use of fomepizole and alcohol-containing beverages. In healthy volunteers, moderate oral doses of fomepizole significantly reduced the rate of elimination of alcohol by approximately 40%. Additionally, alcohol decreased the rate of elimination of fomepizole by approximately 50%. Both interactions occur via alcohol dehydrogenase inhibition.
Ketoconazole: (Minor) Drugs that inhibit the cytochrome P450 enzyme system, such as ketoconazole, may decrease the rate of elimination of fomepizole.
Levoketoconazole: (Minor) Drugs that inhibit the cytochrome P450 enzyme system, such as ketoconazole, may decrease the rate of elimination of fomepizole.
Phenytoin: (Minor) In healthy volunteers, moderate oral doses of fomepizole significantly reduced the rate of elimination of ethanol by approximately 40%. Similarly, ethanol decreased the rate of elimination of fomepizole by approximately 50%. Both interactions occur via alcohol dehydrogenase inhibition. Although not studied, reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 enzyme system like phenytoin.
Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Ethylene glycol is metabolized to glycoaldehyde which is further oxidized to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol poisoning. The lethal dose of ethylene glycol is approximately 1.4 mL/kg. Methanol is metabolized to formaldehyde which is further oxidized to formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances associated with methanol poisoning. The lethal dose of methanol is approximately 1 to 2 mL/kg. By inhibiting alcohol dehydrogenase, fomepizole prevents the metabolism of ethylene glycol and methanol to their toxic metabolites. Since ethanol is also metabolized by this enzyme, fomepizole can also inhibit its metabolism.
Fomepizole is administered via intravenous infusion. Once in systemic circulation, fomepizole rapidly distributes to total body water with a volume of distribution between 0.6 and 1.02 L/kg. Metabolism is the major route of elimination and is characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations. With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30 to 40 hours. Following enzyme induction, fomepizole elimination follows first-order kinetics. Since fomepizole is metabolized via the P-450 enzyme system, significant drug interactions may occur, although these have not been systematically investigated. The primary metabolite is 4-carboxypyrazole (approximately 80% to 85% of an administered dose). Other metabolites observed are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. Fomepizole and its metabolites are eliminated via the urine. In healthy volunteers, only 1% to 3.5% of the administered dose was excreted unchanged in the urine. The plasma half-life varies with dose (irrespective of renal function) and has not been calculated.