Details About Overdose or Poisoning Generic Salt :: Fomepizole 4 Methylpyrazole, 4 MP
Fomepizole (4-Methylpyrazole, 4-MP)
Drug Pharmacology ::
Fomepizole(4-methylpyrazole) is a potent competitive inhibitor of alcoholdehydrogenase, the first enzyme in the metabolism of ethanol and otheralcohols. Fomepizole can prevent the formation of toxic metabolitesafter methanol or ethylene glycol ingestion. Furthermore, earlytreatment with fomepizole for ethylene glycol or methanol poisoning(before the presence of a significant acidosis) may obviate the needfor dialysis. Since the introduction of fomepizole, most patients withethylene glycol or methanol poisoning probably will be treated withthis drug instead of ethanol, particularly in cases involving smallchildren, patients taking disulfiram, patients with alteredconsciousness and ingestion of multiple substances, patients withpancreatitis or active liver disease, and hospitals lacking laboratorysupport to perform rapid ethanol levels (for monitoring treatment).Economic models have suggested that fomepizole may be morecost-effective than ethanol despite the high acquisition cost offomepizole.
Fomepizoleis eliminated mainly via zero-order kinetics, but P-450 metabolism canundergo autoinduction within 2–3 days. The drug is dialyzable. It iswell absorbed and has been used successfully with PO administration butis not approved by this route in the United States.
Drug Indications ::
Indications are similar to those for ethanol (see Ethanol): suspected or confirmed methanol (methyl alcohol; see Methanol) or ethylene glycol (see Ethylene Glycol and Other Glycols) poisoning with one or more of the following:
Areliable history of ingestion of a toxic dose but no available bloodconcentration measurements (when used empirically, allows a 12-hour”window” after one dose to assess the patient);
Metabolic acidosis and an unexplained elevated osmolar gap (see Serum osmolality and osmolar gap); or
Serum methanol or ethylene glycol concentration 20 mg/dL.
Othersubstances that are metabolized by alcohol dehydrogenase to toxicmetabolites include propylene glycol, diethylene glycol, triethyleneglycol, glycol ethers (eg, ethylene glycol ethyl ether, ethylene glycolbutyl ether), and 1,4-butanediol. The criteria for fomepizole therapyand evidence for improved outcomes are lacking for all thesesubstances. However, case reports of poisonings from some of theseother glycols (eg, propylene glycol, diethylene glycol) have suggestedbenefit when fomepizole therapy is coupled with dialysis to remove thepotentially toxic parent compound and concomitantly prevent theformation of toxic metabolites.
E. Disulfiramreaction (or risk of): to halt progression or production ofacetaldehyde, assuming that ethanol is still present (based on casereports).
Drug Contra-Indications ::
III. Contraindications. History of allergy to the drug or to other pyrazoles.
Drug Adverse Effects ::
IV. Adverse effects
Venous irritation and phlebosclerosis after intravenous injection of the undiluted product.
Headache,nausea, and dizziness are the most commonly reported side effects. Lesscommon effects are vomiting, tachycardia, hypotension, feeling ofinebriation, rash, fever, and eosinophilia.
Transient non-dose-dependent elevation of hepatic transaminases has been reported after multiple doses.
Althoughsafety and effectiveness in children have not been established by themanufacturer, fomepizole has been used successfully and reported forpediatric poisonings (as young as 8 months).
E. Use in pregnancy. FDAcategory C (indeterminate). Has been used in pregnant patients withoutimmediate adverse effects on the mother or fetus (see Table III–1).
Drug Lab Interactions ::
Drug or laboratory interactions
Drugsor chemicals metabolized by alcohol dehydrogenase (eg, chloral hydrate,ethanol, isopropyl alcohol) will also have impaired elimination.Fomepizole and ethanol mutually inhibit each other’s metabolism.
Drugsor chemicals metabolized by cytochrome P-450 enzymes may compete withfomepizole for elimination. Also, induction of P-450 activity by thesedrugs or by fomepizole may alter metabolism.
Drug Dose Management ::
Dosage and method of administration. Note:The interval between the initial dose and subsequent maintenance doses,12 hours, provides an opportunity to confirm the diagnosis withlaboratory testing.
Initial dose. Givea loading dose of 15 mg/kg (up to 1 g). Dilute in at least 100 mL ofnormal saline or 5% dextrose and infuse intravenously slowly over 30minutes. (Oral administration may be considered for patients lacking IVaccess.) Patients > 100 kg may receive a loading dose of 1500 mg(one vial) to avoid wastage from opening a second vial of fomepizole.However, it is unknown if sufficient enzyme blockade will be achievedin all patients, and additional doses are recommended if there isevidence of a worsening acidosis. Note: The drug maysolidify at room temperature and should be inspected visually prior toadministration. If there is any evidence of solidification, hold thevial under a stream of warm water or roll between the hands.
Maintenance therapy. Give10 mg/kg every 12 hours for four doses, then increase to 15 mg/kg (tooffset increased metabolism resulting from autoinduction) untilmethanol or ethylene glycol serum levels are below 20 mg/dL.
Adjustment for hemodialysis. To offset loss of fomepizole during dialysis, increase the frequency of dosing to every 4 hours. (Note:With newer high-flux hemodialysis equipment, fomepizole half-lifeaverages 1.7 hours compared with 3 hours with standard dialysis.)
Drug Chemical Formulations ::
Parenteral. Fomepizole (Antizol, Jazz Pharmaceuticals): 1 g/mL in 1.5-mL vials, prepackaged in tray packs containing four vials.
The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is four vials. Note:Jazz Pharmaceuticals has announced that it will replace free of chargeany expired vials of fomepizole if returned within 6 months of theexpiration date.