Antizol

Name: Antizol

Adverse Effects

>10%

Headache (14%)

Nausea (11%)

1-10%

Bad/metallic taste (6%)

Dizziness (6%)

Drowsiness (6%)

Venous irritation

Transient elevations in LFTs (AST)

Backache

Nystagmus

Fever

Abdominal pain

<1%

Rash

Eosinophilia

Fomepizole Dosage

Fomepizole is injected into a vein through an IV. A healthcare provider will give you this injection.

You may be given other medicines and IV fluids as part of your treatment.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving fomepizole. Your blood and urine will also need to be tested often during treatment, and your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

You will also be watched for any effects of the poisoning, such as problems with vision, breathing, or urination.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Because you will receive fomepizole in a clinical setting, you are not likely to miss a dose.

Overdose

Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 50 and 100 mg/kg doses of Antizol (fomepizole) (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 (fomepizole) is dialyzable, and hemodialysis may be useful in treating cases of overdosage.

How is Antizol (fomepizole)given?

Fomepizole is injected into a vein through an IV. A healthcare provider will give you this injection.

You may be given other medicines and IV fluids as part of your treatment.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving fomepizole. Your blood and urine will also need to be tested often during treatment, and your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

You will also be watched for any effects of the poisoning, such as problems with vision, breathing, or urination.

Uses for Antizol

Ethylene Glycol or Methanol Intoxication

Treatment of known or suspected ethylene glycol (e.g., antifreeze) or methanol intoxication; use alone or in combination with hemodialysis.1 2 11 14 16 23 34 35 (See General under Dosage and Administration.)

Not a substitute for standard therapeutic measures (e.g., fluid and electrolyte therapy, correction of metabolic abnormalities [e.g., acidosis]).1 14 23 (See General under Dosage and Administration.)

Appears to be as effective as IV alcohol therapy in preventing development of ethylene glycol-associated metabolic acidosis and renal toxicity.1 4 19 However, may be technically less difficult to administer and monitor than IV alcohol therapy because fomepizole has a more prolonged and less variable rate of elimination (i.e., longer duration of action), has less potential for adverse effects (e.g., CNS depression, hypoglycemia),1 2 3 4 5 7 11 22 25 and does not require plasma concentration monitoring.21 22 24

For treatment of ethylene glycol intoxication, the American Academy of Clinical Toxicology (AACT) and some clinicians recommend use of fomepizole rather than alcohol in cases involving ingestion of multiple substances with CNS depressant activity, in patients with altered consciousness, in critically ill patients with an anion gap metabolic acidosis of unknown etiology and potential exposure to ethylene glycol, in settings in which intensive-care and laboratory facilities to monitor alcohol therapy are unavailable, and in patients who have contraindications to the use of alcohol therapy (e.g., history of alcoholism).24 25 26 27

Has been used with success alone or in combination with hemodialysis for the treatment of ethylene glycol intoxication in a few infants† and children†.29 30 31 32 May have advantages over alcohol therapy in young children as fomepizole lacks the risk of hypoglycemia, obtundation, and hypothermia associated with alcohol therapy;25 31 however, insufficient data to establish relative efficacy of fomepizole and alcohol for this use in children.1 25

Antizol Dosage and Administration

General

  • Initiate therapy immediately upon suspected ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances,1 26 34 or oxalate crystals in the urine,1 24 25 26 30 or if serum ethylene glycol or methanol concentration >20 mg/dL.1

  • Consider hemodialysis (in addition to fomepizole therapy) if ethylene glycol or methanol concentration ≥50 mg/dL;1 14 23 otherwise, closely monitor acid-base balance and institute hemodialysis when metabolic acidosis develops.25 Hemodialysis may be required if severe or worsening metabolic acidosis, acute renal failure, azotemia, and/or anuria occurs.1 2 3 4 5 8 11 14 15 16 17 22 25 26 27 28 b (See Dosage in Patients Requiring Hemodialysis under Dosage and Administration.)

  • Treat metabolic acidosis, acute renal failure (ethylene glycol intoxication), ARDS, visual disturbances (methanol intoxication), and hypocalcemia as needed.1 4 8 10 Supportive therapy (e.g., sodium bicarbonate, potassium and calcium supplementation, oxygen, fluid therapy) may be necessary.a b (See Adequate Patient Evaluation and Monitoring under Cautions.)

Administration

IV Administration

For compatibility information, see Compatibility under Stability.

Administer by slow IV infusion (after proper dilution); must not be administered undiluted or by rapid IV injection.1 (See Local Effects under Cautions.)

Dilution

Use strict aseptic technique since drug product contains no preservative.b

Withdraw appropriate dose of fomepizole concentrate and add to at least 100 mL of sterile 0.9% sodium chloride or dextrose 5% injection.1 b

Rate of Administration

Infuse diluted solution over 30 minutes.1 (See Local Effects under Cautions.)

Dosage

Pediatric Patients

Ethylene Glycol Intoxication† IV

Dosage not established;1 however, in a limited number of case reports, infants and children 8 months to 13 years of age received the same dosages as those recommended for adults.29 30 31

Adults

Ethylene Glycol or Methanol Intoxication IV

Loading dose: 15 mg/kg.1 22 23 25 26

Maintenance dosage: 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until serum ethylene glycol or methanol concentrations are undetectable or have decreased to <20 mg/dL, and patient is asymptomatic with a normal arterial blood pH value.1 22 23 25 26 b

Dosage in Patients Requiring Hemodialysis

Loading dose: 15 mg/kg.a

Maintenance dosage: Generally similar to usual adult maintenance dosage; however, because fomepizole is dialyzable, adjust dosage/schedule before, during, and immediately upon completion of hemodialysis (see Table 1).1

Example 1: Patient is given a loading dose of 15 mg/kg.a Hemodialysis starts 1 hour after loading dose and lasts for 6 hours.a Four hours after initiation of hemodialysis, patient would receive a dose of 10 mg/kg.a Because length of time between last fomepizole dose and end of hemodialysis is 2 hours, patient should receive a dose of 5 mg/kg at the end of hemodialysis.a Administer fomepizole every 12 hours thereafter until ethylene glycol or methanol concentration is <20 mg/dL and patient is asymptomatic with normal pH.a

Example 2: Patient is given a loading dose of 15 mg/kg.a Hemodialysis starts 7 hours after loading dose and lasts for 45 minutes.a Patient would receive a dose of 10 mg/kg prior to initiation of hemodialysis.a Because length of time between the last fomepizole dose and end of hemodialysis is <1 hour, patient should receive a 10 mg/kg dose 12 hours after the dose given prior to initiation of hemodialysis.a Administer fomepizole every 12 hours thereafter until ethylene glycol or methanol concentration is <20 mg/dL and the patient is asymptomatic with normal pH.a

Table 1. Fomepizole Dosing in Patients Requiring Hemodialysis

Dose at the Beginning of Hemodialysis

 

If <6 hours since last fomepizole dose

If ≥6 hours since last fomepizole dose

Do not administer dose

Administer next scheduled dose

Dose during Hemodialysis

 

Dose every 4 hours

 

Dose 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

1–3 hours

Administer half of next scheduled dose

>3 hours

Administer next scheduled dose

Maintenance Dosing off Hemodialysis

 

Give next scheduled dose 12 hours from last dose administered

 

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decrease in renal function.1 21

Cautions for Antizol

Contraindications

  • Known severe hypersensitivity to fomepizole or other pyrazoles.1 8 11 21

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Mild rash and eosinophilia reported.b

Monitor for manifestations of an allergic reaction.1

Major Toxicities

Hepatic Effects

Transient increases in serum transaminase concentrations reported following repeated dosing.b

Monitor hepatic enzyme concentrations during therapy.b

Hematologic Effects

Eosinophilia reported following repeated dosing.b

Monitor WBC counts during therapy.b

Local Effects

Vein irritation and phlebosclerosis reported following rapid (i.e., <30 minutes) IV infusion or IV injection (i.e., over 5 minutes) of a 25-mg/mL solution.1 16 21 b

General Precautions

Adequate Patient Evaluation and Monitoring

Frequently monitor arterial blood gases, pH, electrolytes, BUN, creatinine, and urinalysis to determine response to therapy.b

Frequently monitor serum and urine ethylene glycol concentrations and monitor for presence of urinary oxalate crystals in patients with ethylene glycol intoxication.b In patients with methanol intoxication, monitor serum methanol concentrations.b

Perform ECG because acidosis and electrolyte imbalances can affect the cardiovascular system.b Electroencephalography also may be required in comatose patients.b

Monitor hepatic enzyme (i.e., serum transaminase) concentrations and WBC counts.b (See Major Toxicities under Cautions.)

Concomitant Use with Alcohol

Consider potential interaction with alcohol, which often is ingested concomitantly by patients with ethylene glycol intoxication or used initially in the treatment of ethylene glycol or methanol intoxication.1 2 4 5 7 22 23 24 25 26 33 (See Alcohol under Interactions.)

Specific Populations

Pregnancy

Category C.b

Lactation

Not know whether fomepizole is distributed into milk.b Caution if used in nursing women.b

Pediatric Use

Safety and efficacy not established.b

Geriatric Use

Safety and efficacy not established.b

Common Adverse Effects

Headache, nausea, dizziness, increased drowsiness, bad/metallic taste.b

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Fomepizole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion

1 g/mL

Antizol (preservative-free)

Jazz

Antizol Description

Antizol® (fomepizole) Injection is a competitive inhibitor of alcohol dehydrogenase.

The chemical name of fomepizole is 4-methylpyrazole. It has the molecular formula C4H6N2 and a molecular weight of 82.1. The structural formula is:


It is a clear to yellow liquid at room temperature. Its melting point is 25° C (77° F) and it may present as solid at room temperature. Fomepizole is soluble in water and very soluble in ethanol, diethyl ether, and chloroform. Each vial contains 1.5 mL (1 g/mL) of fomepizole.

Precautions

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 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.

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.

What is the most important information i should know about fomepizole (antizol)?

In a poisoning situation, it may not be possible to tell your caregivers that you are pregnant or breast-feeding before you are treated with fomepizole. However, make sure any doctor caring for your pregnancy or your baby knows that you have received the medication.

Tell your caregivers at once if you have any burning, swelling, or skin changes where the medicine was injected.

To be sure this medication is helping your condition, your blood and urine will need to be tested often. This will help your doctor determine how long to treat you with fomepizole. You will also be watched for any effects of the poisoning, such as problems with vision, breathing, or urination.

What happens if i miss a dose (antizol)?

Since fomepizole is given as needed by a healthcare professional, it is not likely that you will miss a dose.

Fomepizole Pregnancy Warnings

This drug should be used during pregnancy only if clearly needed. US FDA pregnancy category: C

Animal studies have not been conducted. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

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