Fomepizole 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.

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, 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 :

Begin fomepizole 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 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.

Dosing of fomepizole :

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 Dosing in Patients Requiring Hemodialysis

Elderly patients :

Clinical experience in elderly patients is limited. The regimen has to be adjusted to the renal function (see above).

Children :

There is no available data regarding the pharmacokinetics of fomepizole in children. Clinical experienceis limited and based on

similar weight-adjusted doses.

Patients with impaired liver function :

No clinical data are available.

Administration :

Fomepizole solidifies at temperatures less than 25°C (77°F). If the fomepizole 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. Using sterile technique, the appropriate dose of fomepizole 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, like all parenteral products, should be inspected visually for particulate matter prior to administration.

Discontinuation of fomepizole Treatment :

Treatment with fomepizole 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.

General :

Fomepizole 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 at a concentration of 25 mg/mL.

Patients intoxicated with ethylene glycol must be managed for metabolic acidosis and acute

renal failure in addition to specific antidote treatment with Fomepizole Injection. Intravenous fluid

therapy and sodium bicarbonate administration are necessary supportive therapies. In

addition, potassium and calcium supplementation and oxygen administration are usually necessary. Haemodialysis is necessary in the anuric patient or in patients with severe

metabolic acidosis or azotemia, and necessitates more frequent Fomepizole Injection dosing as in 4.2 above.

There is a potential risk of muscle damage resulting from creatine kinase elevation with use of fomepizole. Medical professionals are warned of the potential risk of hypoglycaemia and/or seizures with use of fomepizole.

Treatment success may be assessed by measurements of blood gases, pH, electrolytes, blood urea, creatinine, and urinalysis, in addition to laboratory tests as indicated by individual patient conditions. Plasma and urine concentrations of ethylene glycol and presence of urinary oxalate crystals can be monitored throughout treatment to assess the status of ethylene glycol and metabolite clearance. Severe acidosis or electrolyte imbalance may necessitate appropriate cardiovascular monitoring. Electroencephalography may be indicated in the comatose patient.

Do not use polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) when diluting or administering Fomepizole Injection, 1.5 g/1.5 mL (1 g/mL). 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.

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.

Fomepizole has been shown to induce the expression of CYP2E1 and to inhibit its activity. These effects were enhanced in rats that had been exposed to ethanol. Fomepizole may also inhibit other CYP enzymes and therefore may alter the exposure to other drugs that are metabolised by CYP enzymes.

Interactions with disulfiram and medications for psychiatric disorders (anti-depressants, anxiolytics and antipsychotics) have not been established.

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.

Pregnancy

Pregnancy Category C: 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.

Lactation (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.

Fertility

No fertility studies have been performed.

The possible risks of dizziness and vertigo related to the treatment should be pointed out.

It is not advisable to drive or use machines during the first few days after treatment is discontinued.

A total of 141 patients were exposed to fomepizole during the clinical trial period, including both patients (n=78) and healthy volunteers (n=63).

Adverse events that occurred in at least 2% of patients treated with fomepizole for either methanol or ethylene glycol poisoning or at least 2% of healthy volunteers in clinical trials

Table of Adverse Reactions – Possibly, Probably, Definitely or Unknown Relationship to Fomepizole from clinical trials and literature.

*Unknown relationship to fomepizole

To report any side effect(s):
Saudi Arabia

Other GCC states /other countries

Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 50 and 100 mg/kg doses of fomepizole (at plasma concentrations of 290 to 520 μmol/L, 23.8 to 42.6 mg/L). These doses are 3 to 6 times the recommended dose. This dose-dependent CNS effect was short-lived in most subjects and lasted up to 30 hours in one subject. Fomepizole is dialyzable, and hemodialysis may be useful in treating cases of overdosage.

Pharmacotherapeutic group: Antidote, ATC code: V03AB34

Pharmacodynamics

Fomepizole is a competitive inhibitor of alcohol dehydrogenase (ADH). ADH catalyses the first stage of the metabolism of ethylene glycol in the liver. Fomepizole treatment blocks the formation of the toxic metabolites of ethylene glycol and prolongs its plasma half-life. Ethylene glycol is thus eliminated unchanged in urine and induces osmotic polyuria.

The spontaneous 4-hour plasma half-life of ethylene glycol is extended to 10-16 hours with fomepizole.

The efficacy of fomepizole in the treatment of ethylene glycol poisoning has been shown in dogs and monkeys, with loading doses of 20 and 50 mg/kg, respectively.

In healthy volunteers, pharmacological effects of fomepizole have been shown indirectly, by the demonstration of a metabolic interaction with ethanol, which is also metabolised by ADH. Doses of fomepizole ranging from 7 to 20 mg/kg are efficient both orally or intravenously.

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 glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4mL/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 2mL/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 0.1μmol/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.

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 1.02L/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 24.6mg/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.

Specific 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.

Carcinogenesis, Mutagenesis, 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.

None

None

Store below 30°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

2 mL clear USP type I glass vial sealed with 13 mm dark grey bromobutyl rubber stopper and sealed with 13 mm blue color flip-off aluminium seal.

Fomepizole Injection is available as a sterile, preservative-free solution for intravenous use, in vials containing 1.5 mL (1 g/mL) of fomepizole.

Fomepizole injection is supplied in cartons of one single use vial

For single use only. Any unused product must be discarded.

Fomepizole injection concentrate for solution for infusion, is to be diluted before use.

The concentrate should be diluted with 0.9 % sodium chloride solution or 5 % glucose solution for intravenous use.

Solutions showing haziness, particulate matter, precipitate, discoloration, or leakage should not be used.