Fomepizole

INDICATIONS AND USAGE Fomepizole injection is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis (see DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION Do not use polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) when diluting or administering fomepizole injection. Fomepizole can interact with polycarbonate, compromising the integrity of the syringe and/or needle component containing polycarbonate. Treatment Guidelines: 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) 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 ½ 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.

ADVERSE REACTIONS The most frequent adverse events reported as drug-related or unknown relationship to study drug in the 78 patients and 63 normal volunteers who received fomepizole injection were headache (14%), nausea (11%), and dizziness, increased drowsiness, and bad taste/metallic taste (6% each). All other adverse events in this population were reported in approximately 3% or fewer of those receiving fomepizole injection and were as follows: Body as a Whole: Abdominal pain, fever, multiorgan system failure, pain during fomepizole injection, inflammation at injection site, lumbalgia/backache, hangover Cardiovascular: Sinus bradycardia/bradycardia, phlebosclerosis, tachycardia, phlebitis, shock, hypotension Gastrointestinal: Vomiting, diarrhea, dyspepsia, heartburn, decreased appetite, transient transaminitis Hemic/Lymphatic: Eosinophilia/hypereosinophilia, lymphangitis, disseminated intravascular coagulation, anemia Nervous: Lightheadedness, seizure, agitation, feeling drunk, facial 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 To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 mcmol/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.