Consumer medicine information

Antizol

Fomepizole

BRAND INFORMATION

Brand name

Antizol Concentrated injection

Active ingredient

Fomepizole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Antizol.

What is in this leaflet

This leaflet answers some of the common questions people ask about Antizol. It does not contain all the information that is known about Antizol.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you being given Antizol against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet.

You may need to read it again.

What Antizol is used for

Antizol belongs to a group of medicines called antidotes.

Antizol is used to treat ethylene glycol and methanol poisoning.

Antizol helps to restore your blood levels of ethylene glycol and/or methanol to normal.

Your doctor may have administered this medicine for another reason.

Your doctor will explain why you are being treated with Antizol and tell you what dose you are being given.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

Ask your doctor if you have any questions about why Antizol has been administered to you.

Antizol is not addictive.

This medicine is available only with a doctor’s prescription

Before you are given Antizol

When you must not be given it

You must not be given Antizol if you have been drinking alcohol excessively.

You should not be given Antizol if you have ever experienced an anaphylactic reaction with Antizol or other pyrazoles.

Antizol should not be used if the expiry date (EXP) printed on the pack has passed.

Before you use it

Tell your doctor if you are pregnant or planning to become pregnant

The effect of ANTIZOL in pregnant women is not known. Therefore the use of ANTIZOL in pregnant women is not recommended.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known whether ANTIZOL passes into breast milk. If you are breast feeding, your doctor may advise you to stop breastfeeding while you are using this medicine.

Taking other medicines

Antizol can significantly reduce the rate of elimination of ethanol and vice versa. For this reason, you should not be given Antizol if you have been drinking alcohol to excess.

Antizol may interact with medicines that increase or decrease the effect of phenytoin, carbamazepine, cimetidine, ketoconazole and other similar medicines, although this has not been studied.

How Antizol is given

Antizol is given as a slow intravenous infusion into a vein.

Antizol must only be given by a doctor or nurse.

Your doctor will decide what dose and for how long you will receive Antizol. This depends on your condition and other factors.

To begin treatment, 15 mg/kg of Antizol is given as a slow intravenous infusion over 30 minutes.

Your serum levels of ethylene glycol and/or methanol will be monitored during the treatment.

If you are given too much

The doctor giving you Antizol will be experienced in administration of antidotes, so it is unlikely that you will be given an overdose.

However, if you are accidentally given an overdose of Antizol, you may have nausea, dizziness or vertigo. These are usually short-lived.

Your doctor has information on how to recognise and treat an overdose. Ask your doctor if you have any concerns.

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are being given Antizol.

Antizol helps most people with ethylene glycol and/or methanol intoxication, but it may have unwanted side effects in a few people.

If you are over 65 years of age you may have an increased chance of getting side effects.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

If you have any questions, please talk to your doctor, nurse or pharmacist.

Tell your doctor, pharmacist, or nurse if you notice any of the following and they worry you:

  • Hangover
  • Light-headedness
  • Dizziness
  • Feeling drunk
  • Facial flush
  • Speech/visual disturbances, including temporary blurred vision
  • Abdominal pain
  • Fever
  • Back pain
  • Pain or burning along the length of a vein
  • Vein being hard and cord like
  • Fainting
  • Seizures
  • Nausea or vomiting
  • Diarrhoea
  • Indigestion
  • Heartburn
  • Decreased appetite
  • Agitation/anxiety
  • Pharyngitis
  • Rash
  • Abnormal smell
  • Roar in ear
  • Headache
  • Drowsiness
  • Bad or metallic taste
  • Cough
  • Vertigo
  • Sweating or feeling of warmth
  • Rapid involuntary eye movements
  • Heart rate increase or decrease
  • Blood pressure increase or decrease
  • Confusion

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • Signs of kidney problems such as painful urination, difficulty urinating or lower back pain
  • Signs of anaemia such as paleness, coldness, clamminess or fatigue
  • Easy bruising

The above list includes serious side effects, which may require medical attention.

If any of the following happen, tell your doctor or nurse immediately, or go to emergency department at your nearest hospital:

  • Signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; selling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin

Some people may get other side effects while being given Antizol that are not present on this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After being given Antizol

Storage

Antizol will be stored in the pharmacy ward.

Product is for single use in one patient only. Discard any residue.

The injection is kept in a cool, dry place, protected from light, where the temperature stays below 25­°C.

Product Description

What Antizol looks like

Antizol is a clear to yellow liquid at room temperature. It may present as a solid at lower temperatures.

Ingredients

Each vial of Antizol contains 1.5 g of fomepizole. The vials are packed under nitrogen but do not contain any other excipients.

Sponsor

In Australia

AFT Pharmaceuticals Pty Ltd
113 Wicks Road
North Ryde
NSW 2113

In New Zealand

AFT Pharmaceuticals Ltd,
Auckland.

Australian Registration Number AUST R 263913

This leaflet was prepared in November 2016

BRAND INFORMATION

Brand name

Antizol Concentrated injection

Active ingredient

Fomepizole

Schedule

S4

 

Name of the medicine

Fomepizole.

Excipients.

Fomepizole injection does not contain any excipients.

Description

Molecular formula: C4H6N2. Molecular weight: 82.1 g mol-1. Chemical name: Fomepizole (4-methylpyrazole). CAS registry number 7554-65-6.
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 g/mol. It is a clear to yellow liquid at room temperature. Its melting point is 25°C and it may present as a solid at room temperature. Fomepizole is soluble in water in water and very soluble in ethanol, diethyl ether, and chloroform. Each vial contains 1.5 mL (1 g/mL) of fomepizole. It is supplied sterile. Fomepizole injection does not contain any excipients.

Pharmacology

Mechanism of action.

Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyses the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyses 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, and oxalate. Glycolate and oxalate are the metabolic by-products primarily responsible for the metabolic acidosis and renal damage seen 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 yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g. decreased visual activity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1-2 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 micromol/L. In animal studies, fomepizole has been shown to inhibit the formation of toxic metabolites of ethylene glycol and methanol, to reverse acidosis and to prevent mortality and ethylene-glycol induced renal damage.
Fomepizole in the range of 100 to 300 micromol/L (8.6 - 24.6 mg/L) has been targeted to assure adequate plasma concentrations in humans for the effective inhibition of alcohol dehydrogenase.
In healthy volunteers, oral doses of fomepizole (10 - 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 Interactions with Other Medicines).

Pharmacokinetics.

The plasma half-life of fomepizole varies with dose, even in patients with normal renal function (GFR ≥90 mL/min/1.73 m2), 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 1.02 L/kg.

Metabolism.

In healthy volunteers, only 1 - 3.5% of the administered dose of fomepizole (7-20 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 - 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.
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 - 40 hours. After enzyme induction, elimination follows first-order kinetics.

Excretion.

The elimination of fomepizole is best characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations [100 - 300 micromol/L, 8.2 - 24.6 mg/L]. Fomepizole and its metabolites are renally excreted.
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 - 40 hours. After enzyme induction, elimination follows first-order kinetics.

Clinical Trials

The efficacy of fomepizole in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, U.S. clinical trials without concomitant control groups. The clinical trials described below were supplemented by open-label studies and case reports from the published literature.
An open-label, multi-dose, multi-centre, phase III pivotal trial for treatment of ethylene glycol poisoning with fomepizole has been conducted. Eligible subjects were male or female over 12 years of age who presented with a documented serum ethylene glycol concentration of >20 mg/dL (3.2 mmol/L); OR a history (or strong clinical suspicion) of ethylene glycol ingestion along with arterial pH<7.3, serum bicarbonate <20 mEq/L, osmolar gap by freezing point depression >10 mOsm/L, and/or oxalate crystals in urine; OR recent (<1 hour) documented history of a potentially toxic amount of ethylene glycol and osmolar gap >10 mOsm/L. All patients received fomepizole shortly after admission with a loading dose of 15 mg/kg body weight fomepizole followed by supplemental doses of 10 mg/kg over 30 minutes at intervals of 12 hours (or 15 mg/kg after 48 hours to compensate for increased elimination after 30 - 40 hours after multiple doses) until the serum ethylene glycol level was reduced to ≤ 20 mg/dL (3.2 mmol/L).
Fourteen of 16 patients being treated with fomepizole for ethylene glycol poisoning underwent haemodialysis because of severe intoxication (see Dosage and Administration). There were no differences in outcomes between those who did and did not undergo haemodialysis. Fomepizole levels fell faster during haemodialysis than when due to endogenous clearance alone. During haemodialysis, fomepizole levels fell at a median rate of 0.8 micromol/L/minute (range 0.27 to 4.4). In the absence of haemodialysis, levels fell at a median rate of 0.33 micromol/L/minute (range 0.1 to 0.83). Median clearance of fomepizole by dialysis was 183 mL/min (range 129 - 218 mL/min).
The results of the ethylene glycol study provide evidence that fomepizole blocks ethylene glycol metabolism mediated by alcohol dehydrogenase in the clinical setting. Plasma concentrations of toxic metabolites of ethylene glycol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by haemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol >20 mg/dL (>3.2 mmol/L), the administration of fomepizole alone blocked any rise in glycolate concentrations.
An open-label, multi-dose, multi-centre, phase III pivotal trial for treatment of methanol poisoning has been conducted. Eligible subjects were male or female patients over 12 years of age who presented with a documented serum methanol level of >20 mg/dL (> 6.24 mmol/L) OR a history (or strong clinical suspicion) of methanol intoxication and presented with at least two of the four following criteria: arterial pH<7.3, serum bicarbonate <20 mEq/L, osmolar gap by freezing point depression >10 mOsm/L, and/or recent (less than 1 hour) documented history of an ingestion of a potentially toxic amount of methanol).
All patients received fomepizole shortly after admission with a loading dose of 15 mg/kg body weight fomepizole followed by supplemental doses of 10 mg/kg at intervals of 12 hours(or 15 mg/kg after 48 hours) until the serum ethylene glycol level was reduced to ≤ 20 mg/dL (6.24 mmol/L) .
Seven of 11 patients in the trial for treatment of methanol poisoning underwent haemodialysis because of severe intoxication (see Dosage and Administration). There was no difference in outcome for these patients compared to the non-dialysis patients.
The results of the methanol study provide evidence that fomepizole blocks methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. Plasma concentrations of toxic metabolites of methanol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by haemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of methanol were >20 mg/dL (6.24 mmol/L), the administration of fomepizole alone blocked any rise in formate concentrations.

Indications

Antizol (fomepizole) is indicated for the treatment of ethylene glycol or methanol poisoning. (See Dosage and Administration).

Contraindications

Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles.
Fomepizole should not be used in patients with ethanol intoxication.
Fomepizole should not be used in patients exposed to poisons other than ethylene glycol or methanol alone or in combination (including diethylene glycol).

Precautions

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) fomepizole at a concentration of 25 mg/mL (0.3 mol/L).
Major allergic reactions (anaphylaxis) and minor allergic reactions (mild rash, eosinophilia) have been reported in a few patients receiving fomepizole (see Adverse Effects). Therefore, patients should be monitored for signs of allergic reactions.
There is a potential risk of muscle damage resulting from creatine kinase elevation with use of fomepizole.

Effects on fertility.

The effects of fomepizole on male and female fertility have not been adequately studied in animals. 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 0.1 times the human maximum daily exposure based on surface area (mg/m2). Reductions in testicular mass were significantly greater when fomepizole was given in combination with ethanol (approximately 30% reduction).

Use in pregnancy.

(Category B2)
Animal reproduction studies have not been conducted with fomepizole. It is also not known whether fomepizole can cause foetal harm when administered to pregnant women or can affect reproduction capacity. Fomepizole has been shown to cross the placenta in pregnant rats, with the concentration higher in foetal tissues that that observed in maternal serum. Fomepizole should be given to pregnant women only if clearly needed.

Use in lactation.

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 breastfeeding woman.

Paediatric use.

Safety and effectiveness in paediatric patients have not been established.

Genotoxicity.

The genotoxic potential of fomepizole has only been partially investigated. Fomepizole was shown to be mutagenic in bacteria. Fomepizole did not appear to cause chromosomal aberrations in mouse micronucleus assay. The available evidence indicates that fomepizole is genotoxic.

Carcinogenicity.

There have been no long-term studies performed in animals to evaluated carcinogenic potential.

Patient management.

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 hypocalcaemia. Fluid therapy and sodium bicarbonate administration are potential 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 azotaemia (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 or methanol should be monitored.
Electrocardiography should be performed because acidosis and electrolyte imbalances can affect the cardiovascular system. 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 Antizol dosing.

Effects on the ability to drive and use machinery.

Effect of fomepizole on the ability to drive and use machinery has not been studied.

Elderly.

Fomepizole injection has not been studied sufficiently to determine whether the pharmacokinetics differ for an elderly 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.

Other.

Medical professionals are warned of the potential risk of hypoglycaemia and/or seizures with use of fomepizole.

Interactions

Oral doses of fomepizole (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 fomepizole (by approximately 50%) by the same mechanism. Fomepizole is ineffective at treating ethanol intoxication, and would conversely prolong ethanol intoxication if administered.
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.

Adverse Effects

A total of 141 patients were exposed to fomepizole during the clinical trial period, including both patients (n=78) and healthy volunteers (n=63). See Tables 1 and 2.

Post-marketing experience.

Cyanosis, anaphylactic reaction, brain herniation, drug administration error, decreased platelet count, hypoglycaemia, brain oedema, renal failure, renal necrosis, pharyngeal oedema, respiratory distress and superficial thrombophlebitis have been reported in post-market data.

Dosage and Administration

Caution.

Must be diluted prior to use.

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, if the fomepizole solution has become a 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 stability of Antizol.
Using sterile technique, the appropriate dose of fomepizole should be drawn from the vial with a 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 for particulate matter prior to administration.

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 (ethylene glycol 3.22 mmol/L, methanol 6.24 mmol/L).

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 (ethylene glycol 3.22 mmol/L, methanol 6.24 mmol/L), and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes (see Treatment guidelines).

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 (ethylene glycol 3.22 mmol/L, methanol 6.24 mmol/L), and the patient is asymptomatic with normal pH.

Haemodialysis.

Haemodialysis should be considered in addition to fomepizole in the case of renal failure (Stage 5 CKD, GFR <15 mL/min/1.73 m2), significant or worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration of greater than or equal to 50 mg/dL (ethylene glycol 8.06 mmol/L, methanol 15.61 mmol/L). Patients should be dialyzed to correct metabolic abnormalities and to lower the ethylene glycol concentrations below 50 mg/dL (ethylene glycol 8.06 mmol/L). See Table 3.

Dosage with renal dialysis.

Fomepizole injection is dialyzable and the frequency of dosing should be increased to every 4 hours during haemodialysis.
Both ethylene glycol and methanol concentrations, acid base balance[as determined by serum electrolyte (anion gap) and/or blood gas analysis], should be frequently monitored and used to guide treatment.

Overdosage

Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 50 - 100 mg/kg doses of fomepizole (at plasma concentrations of 290 - 520 micromol/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.
Fomepizole is dialyzable, and haemodialysis may be useful in treating cases of overdosage.
Contact the Poisons Information Centre (Australia telephone 131 126) for advice on the management of overdose.

Presentation

Antizol (fomepizole 1.5 g/1.5 mL injection) is supplied as a clear to yellow liquid (or solid) sterile, preservative-free solution for intravenous use in type I, 2 mL vials.
Solidification does not affect the stability of Antizol.
Each 1.5 mL vial contains 1.5 g (1 g/mL) of fomepizole.
Supplied in packages of four vials or one vial.
AUST R 263913.

Storage

Store below 25°C. Protect from light.
Contains no antimicrobial preservative. Product is for single use in one patient only. Discard any residue.
To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2-8°C for not more than 24 hours.

Poison Schedule

S4.