Antizol (Page 2 of 3)

General

Antizol 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 Antizol at a concentration of 25 mg/mL.

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

Laboratory Tests

In addition to specific antidote treatment with Antizol, 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 Antizol dosing.

Drug Interactions

Oral doses of Antizol (10-20 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 Antizol (by approximately 50%) by the same mechanism.

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

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 WP2uvr A 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.

Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with fomepizole. It is also not known whether Antizol can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Antizol 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 Antizol 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.

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 Antizol® (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 Antizol and were as follows:

Body as a Whole: Abdominal pain, fever, multiorgan system failure, pain during Antizol 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

OVERDOSAGE

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

Antizol is dialyzable, and hemodialysis may be useful in treating cases of overdosage.

DOSAGE AND ADMINISTRATION

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 Antizol, 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 Antizol

Begin Antizol 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 Antizol 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.

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