Fomepizole Waymade 1 g/ml concentrate for solution for infusion

Fomepizole Waymade is indicated as an antidote for ethylene glycol (antifreeze) poisoning in patients who have ingested, or are suspected of having ingested, ethylene glycol.

Treatment of Fomepizole Waymade should be continued until ethylene glycol levels falls below 200 mg/L (3.2 millimol/L).

Posology

The treatment should begin whenever ethylene glycol poisoning is suspected, as early as possible after its ingestion, even in the absence of signs of toxicity.

In the absence of ethylene glycol assay, ethylene glycol poisoning should be suspected on the following criteria:

- patient's history;

- osmolar gap > 20 mOsm/kg H20;

- metabolic acidosis with anion gap > 16 mmol/l (presence of high levels of glycolates); - calcium oxalate crystals in the urine.

An assay for plasma ethylene glycol should be performed at admission, but this determination should not delay start of treatment with fomepizole. Plasma ethylene glycol levels should be monitored every 12 to 24 hours.

Dosage depends on plasma ethylene glycol concentration and renal function:

- patients with normal renal or mild to moderate impaired renal function as assessed by serum creatinine (100 to 265 mmol/l) in whom hemodialysis is not required:

Administration should be performed by slow intravenous infusion, over 30 to 45 minutes, given as follows: infusion of a loading dose of 15 mg/kg followed by doses every 12 hours until ethylene glycol levels has been reduced below 0.2 g/l (3.2 mmol/l).

The number of maintenance doses and the dose after 48 hours will depend on initial concentration and the time course of the ethylene glycol levels.

Generally, 4 to 5 maintenance doses are recommended for initial ethylene glycol levels between 3 to 6 g/l (48 to 96 mmol/l) and 1 to 3 maintenance doses are recommended for initial ethylene glycol levels between 0.35 to 1.5 g/l (5.6 to 24 mmol/l).

-patients with severe impaired renal function as assessed by serum creatinine (> 265 mmol/l)

Hemodialysis is indicated in combination with fomepizole.

A loading dose of 15 mg/kg is infused over 30 to 45 minutes, followed by 1 mg/kg/hour continuous infusion for the entire duration of the hemodialysis.

The dosage of fomepizole during continuous venovenous hemodiafiltration, another mode of extracorporal elimination, is not known.

Hemodialysis and fomepizole administration should be discontinued when the metabolic acidosis is corrected and plasma ethylene glycol levels have been reduced below 0. 2 g/l (3.2 mmol/l).

- Hemodialysis should also be initiated under at least one of the following features in combination with fomepizole:

- arterial pH < 7.10;

- drop in arterial pH > 0.05 resulting in a pH outside the normal range despite bicarbonate infusion;

- inability to maintain arterial pH > 7.30 despite bicarbonate therapy;

- decrease in serum bicarbonate concentration of more than 5 mmol/l despite bicarbonate therapy;

- rise in serum creatinine by > 90 mmol/l (1 mg/dl).

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 experience is limited and based on similar weight-adjusted doses.

Patients with impaired liver function:

No clinical data are available.

Method of administration

Fomepizole Waymade, concentrate for solution for infusion, is to be diluted before use (see section 6.6). The diluted solution should be administered by slow intravenous infusion.

Hypersensitivity to the active substance or to other pyrazoles or to any of the excipients listed in section 6.1.

Previous treatment of ethylene glycol poisoning with ethanol does not preclude the use of fomepizole. Nevertheless, the combination of ethanol and fomepizole is usually not recommended. (See section 4.5.)

Minor hypersensitivity reactions have been reported in a few patients (rash, hypereosinophilia). These symptoms should be monitored.

Management should be modified in case of a major hypersensitivity reaction (angioedema, bronchospasms, anaphylactic shock). In these cases, the fomepizole infusion should be immediately discontinued in the absence of another established cause; symptomatic treatment should start and fomepizole should not be re- administered to the patient. Treatment by ethanol should be started and hemodialysis considered

Ethylene glycol poisoning in its severe forms is expressed by metabolic acidosis (anion gap > 16 mmol/l), convulsive coma and renal failure.

Treatment of ethylene glycol intoxication involves prevention of the metabolism of ethylene glycol to its toxic metabolites, correction of metabolic acidosis, sufficient hydration (oral or venous if applicable) to prevent the risks of dehydration and hypernatremia and to increase urine clearance of ethylene glycol, and if necessary, removal of toxic metabolites with hemodialysis. Monitoring requires frequent measurements of plasma ethylene glycol, blood gas, pH, electrolytes, serum creatinine, urine analysis and presence of urinary oxalate crystals.

Evaluation of hepatic transaminases and blood cell counts before and one month after treatment is recommended.

Pre-existing impaired liver function requires careful monitoring of hepatic transaminases.

Fomepizole concentrate for solution for infusion, should not be given undiluted. The diluted concentrate should not be given by bolus injection.

Combination with ethanol:

Concurrent use of alcohol and fomepizole reduces the elimination rate for both substances. Although the clinical efficacy of fomepizole seems not impaired, for safety reason, the concomitant use of fomepizole with alcohol is not-recommended (See section 4.4)

Pregnancy

There are no clinical data from the use of fomepizole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fomepizole should not be used during pregnancy unless clearly necessary.

Breast-feeding

There is no information on the excretion of fomepizole in human milk. It is advised to discontinue breastfeeding temporarily during treatment with Fomepizole.

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.

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention:

Very Common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10,000, <1/1,000), Very Rare (<1/10,000), not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Dizziness, drunkenness, nausea, vertigo, headaches, nystagmus and speech disturbances have been observed for doses of 50 to 100 mg/kg in healthy volunteers.

In case of a substantial overdose, as fomepizole is dialysable, hemodialysis could be considered.

Pharmacotherapeutic group: Antidote, ATC code: V03AB34

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.

Fomepizole has a volume of distribution of approximately 0.7 l/kg. The elimination of fomepizole is non-linear and is saturable for doses ranging from 7 to 20 mg/kg. Upon repeated administration, fomepizole induces its own metabolism.

Fomepizole is almost entirely eliminated by metabolism. The principal metabolite, 4- carboxypyrazole does not have any inhibitory effect on human ADH in vitro.

The enzymes involved in the metabolism of fomepizole have not been identified. In preclinical studies, fomepizole has been shown to be both an inhibitor and an inducer of CYP450 isoenzymes. Corresponding studies have not been performed in human and the potential to affect the pharmacokinetics of drugs metabolised by CYP450 cannot be predicted.

Fomepizole and its metabolites are excreted in urine. Only 2 to 3 % of fomepizole administered is excreted unchanged in the urine.

Fomepizole is dialysable. The extraction ratio is about 0.75, and the hourly extraction ranges between 0.41 and 1.15 mg/kg/h.

Toxicity studies in animals have not demonstrated fomepizole to have any particular toxicity.

Fomepizole has shown no sign of mutagenicity or clastogenicity.

Its carcinogenic potential and its reproductive toxicity have not been studied.

With respect to reproductive toxicology no conventional studies were performed. It is known from literature that fomepizole administered intraperitoneally to mice once at day 11 of pregnancy at a dose (mg/kg/day) of 6.5 times the loading therapeutic dose induced embryotoxic (increased rate of fetal resorption) and teratogenic (increased number of anterior limb malformations) effects.

None.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial:

3 years.

After dilution

Chemical and physical in-use stability has been demonstrated in 5% dextrose and 0.9% sodium chloride solutions for 72 hours at 2 °C to 8 °C and 25°C.

From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8° C, unless dilution has taken place in controlled and validated aseptic conditions.

This medicine does not require any special storage conditions.

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

Clear type I glass vial with dark grey bromobutyl rubber stopper and blue flip-off aluminium seal packed in a carton

Fomepizole injection is supplied in carton of one single use vial containing 1.5 ml of solution.

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

Fomepizole solidifies at temperature less than 25°C. If the fomepizole solution has become solid in the vial the solution should be liquefied by running the vial under warm water or holding in the hand. Solidification does not affect the efficacy, safety or stability of fomepizole.

Avoid polycarbonate syringes or polycarbonate-containing needles (including polycarbonate filter needles) when diluting or administering fomepizole. Fomepizole can interact with polycarbonate, compromising the integrity of the syringe and/or needle component containing polycarbonate.

While using aseptic 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 5% dextrose injection. Mix well to ensure complete dissolution of fomepizole in the sodium chloride or dextrose solution. 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, whenever solution and container permit.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.