1.5 Ml Fomepizole 1000 Mg/ml Injection

Mechanism of Action: Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.

Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycolaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic by products primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg.

Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and 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 mcmol/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 mcmol/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 mcmol/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.

Special Populations:

PRECAUTIONS

General: Fomepizole injection should not be given undiluted or by bolus injection. Venous irritation and phlebosclerosis were noted in two of six normal volunteers given bolus injections (over 5 minutes) of fomepizole injection at a concentration of 25 mg/mL.

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.

Minor allergic reactions (mild rash, eosinophilia) have been reported in a few patients receiving fomepizole (see ADVERSE REACTIONS ). Therefore, patients should be monitored for signs of allergic reactions.

Laboratory Tests: 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 disturbances (methanol), and 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 anuric patient, or in patients with severe metabolic acidosis or azotemia (see DOSAGE AND ADMINISTRATION ). 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. At frequent intervals throughout the treatment, patients poisoned with ethylene glycol should be monitored for ethylene glycol concentrations in serum and urine, and the presence of urinary oxalate crystals. Similarly, serum methanol concentrations should be monitored in patients poisoned with methanol. Electrocardiography should be performed because acidosis and electrolyte imbalances can affect the cardiovascular system. In the comatose patient, electroencephalography may also be required. In addition, hepatic enzymes and white blood cell counts should be monitored during treatment, as transient increases in serum transaminase concentrations and eosinophilia have been noted with repeated fomepizole dosing.

DRUG INTERACTIONS

Drug Interactions: Oral doses of fomepizole (10 to 20 mg/kg), via alcohol dehydrogenase inhibition, significantly reduced the rate of elimination of ethanol (by approximately 40%) given to healthy volunteers in moderate doses. Similarly, ethanol decreased the rate of elimination of fomepizole (by approximately 50%) by the same mechanism.

Reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 system (e.g., phenytoin, carbamazepine, cimetidine, ketoconazole), though this has not been studied.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Carcinogenesis, Mutagenesis and Impairment of Fertility: There have been no long term studies performed in animals to evaluate carcinogenic potential.

There was a positive Ames test result in the Escherichia coli tester strain WP2uvrA and the Salmonella typhimurium tester strain TA102 in the absence of metabolic activation.

There was no evidence of a clastogenic effect in the in vivo mouse micronucleus assay.

In rats, fomepizole (110 mg/kg) administered orally for 40 to 42 days resulted in decreased testicular mass (approximately 8% reduction). This dose is approximately 0.6 times the human maximum daily exposure based on surface area (mg/m²). This reduction was similar for rats treated with either ethanol or fomepizole alone. When fomepizole was given in combination with ethanol, the decrease in testicular mass was significantly greater (approximately 30% reduction) compared to those rats treated exclusively with fomepizole or ethanol.

USE IN SPECIFIC POPULATIONS

Pregnancy: Animal reproduction studies have not been conducted with fomepizole. It is also not known whether fomepizole can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Fomepizole should be given to pregnant women only if clearly needed.

Nursing Mothers: It is not known whether fomepizole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fomepizole is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Safety and effectiveness in geriatric patients have not been established.

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.

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

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.

Storage Conditions

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.

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August 2023

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