base balance, as determined by serum electrolyte (anion gap) and/or arterial blood gas analysis, should be frequently monitored and used to guide treatment. treatment consists of blocking the formation of toxic metabolites using inhibitors of alcohol dehydrogenase, such as fomepizole injection, and correction of metabolic abnormalities. in patients with high ethylene glycol or methanol concentrations (> 50 mg/dl), significant metabolic acidosis, or renal failure, hemodialysis should be considered to remove ethylene glycol or methanol and the respective toxic metabolites of these alcohols. treatment with fomepizole injection begin fomepizole injection treatment immediately upon suspicion of ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in the urine, or a documented serum ethylene glycol or methanol concentration greater than 20 mg/dl. hemodialysis hemodialysis should be considered in addition to fomepizole injection in the case of renal failure, significant or worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration of greater than or equal to 50 mg/dl. patients should be dialyzed to correct metabolic abnormalities and to lower the ethylene glycol concentrations below 50 mg/dl. discontinuation of fomepizole injection treatment treatment with fomepizole injection may be discontinued when ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dl, and the patient is asymptomatic with normal ph. dosing of fomepizole injection a loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dl, and the patient is asymptomatic with normal ph. all doses should be administered as a slow intravenous infusion over 30 minutes (see administration ). dosage with renal dialysis fomepizole injection is dialyzable and the frequency of dosing should be increased to every 4 hours during hemodialysis. fomepizole injection dosing in patients requiring hemodialysis dose at the beginning of hemodialysis if < 6 hours since last fomepizole injection dose if > 6 hours since last fomepizole injection dose do not administer dose administer next scheduled dose dosing during hemodialysis dose every 4 hours dosing at the time hemodialysis is completed time between last dose and the end of hemodialysis < 1 hour do not administer dose at the end of hemodialysis 1 to 3 hours administer 1/2 of the next scheduled dose > 3 hours administer next scheduled dose maintenance dosing off hemodialysis give next scheduled dose 12 hours from last dose administered administration fomepizole injection solidifies at temperatures less than 25° c (77° f). if the fomepizole injection 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 fomepizole injection. using sterile technique, the appropriate dose of fomepizole injection should be drawn from the vial with a non-polycarbonate containing syringe and injected into at least 100 ml of sterile 0.9% sodium chloride injection or dextrose 5% injection . mix well. the entire contents of the resulting solution should be infused over 30 minutes. fomepizole injection, like all parenteral products, should be inspected visually for particulate matter prior to administration. stability fomepizole injection diluted in 0.9% sodium chloride injection or dextrose 5% injection remains stable and sterile for at least 24 hours when stored refrigerated or at room temperature. fomepizole injection does not contain preservatives. therefore, maintain sterile conditions, and after dilution do not use beyond 24 hours. solutions showing haziness, particulate matter, precipitate, discoloration, or leakage should not be used. discard unused portion.

al flush, vertigo, nystagmus, anxiety, "felt strange", decreased environmental awareness respiratory: hiccups, pharyngitis skin/appendages: application site reaction, rash special senses: abnormal smell, speech/visual disturbances, transient blurred vision, roar in ear urogenital: anuria

d visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. a lethal dose of methanol in humans is approximately 1 to 2 ml/kg. fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. the concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 µmol/l. in a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). the three animals in the untreated group became progressively obtunded, moribund, and died. at necropsy, all three dogs had severe renal tubular damage. fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication. several studies have demonstrated that fomepizole plasma concentrations of approximately 10 µmol/l (0.82 mg/l) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. based on these results, concentrations of fomepizole in humans in the range of 100 to 300 µmol/l (8.6 to 24.6 mg/l) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase. in healthy volunteers, oral doses of fomepizole (10 to 20 mg/kg) significantly reduced the rate of elimination of moderate doses of ethanol, which is also metabolized through the action of alcohol dehydrogenase (see precautions, drug interactions ). pharmacokinetics the plasma half-life of fomepizole varies with dose, even in patients with normal renal function, and has not been calculated. distribution after intravenous infusion, fomepizole rapidly distributes to total body water. the volume of distribution is between 0.6 l/kg and 1.02 l/kg. metabolism in healthy volunteers, only 1 to 3.5% of the administered dose of fomepizole (7 to 20 mg/kg oral and iv) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. in humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80 to 85% of administered dose), which is excreted in the urine. other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the n-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. excretion the elimination of fomepizole is best characterized by michaelis-menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations [100 to 300 µmol/l, 8.2 to 24.6 mg/l]. 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. after enzyme induction, elimination follows first-order kinetics. special populations geriatric fomepizole injection has not been studied sufficiently to determine whether the pharmacokinetics differ for a geriatric population. pediatric fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ for a pediatric population. gender fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ between the genders. renal insufficiency the metabolites of fomepizole are excreted renally. definitive pharmacokinetic studies have not been done to assess pharmacokinetics in patients with renal impairment. hepatic insufficiency fomepizole is metabolized through the liver, but no definitive pharmacokinetic studies have been done in subjects with hepatic disease. clinical studies the efficacy of fomepizole in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, u.s. clinical trials without concomitant control groups. fourteen of 16 patients in the ethylene glycol trial and 7 of 11 patients in the methanol trial underwent hemodialysis because of severe intoxication (see dosage and administration ). all patients received fomepizole shortly after admission. the results of these two studies provide evidence that fomepizole blocks ethylene glycol and methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. in both studies, plasma concentrations of toxic metabolites of ethylene glycol and methanol failed to rise in the initial phases of treatment. the relationship to fomepizole therapy, however, was confounded by hemodialysis and significant blood ethanol concentrations in many of the patients. nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol or methanol were > 20 mg/dl, the administration of fomepizole alone blocked any rise in glycolate or formate concentrations, respectively. in a separate french trial, 5 patients presented with ethylene glycol concentrations ranging from 46.5 to 345 mg/dl, insignificant ethanol blood concentrations, and normal renal function. these patients were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury.

entrations [100 to 300 µmol/l, 8.2 to 24.6 mg/l]. 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. after enzyme induction, elimination follows first-order kinetics.

he concentrations of ethylene glycol or methanol were > 20 mg/dl, the administration of fomepizole alone blocked any rise in glycolate or formate concentrations, respectively. in a separate french trial, 5 patients presented with ethylene glycol concentrations ranging from 46.5 to 345 mg/dl, insignificant ethanol blood concentrations, and normal renal function. these patients were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury.