Esperal®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESPERALÒ (ESPERALÒ)

Composition:

Active substance: disulfiram;

1 tablet contains 500 mg of disulfiram;

Excipients: magnesium stearate, povidone K30, sodium carmellose, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physicochemical properties: cream-white, round tablets with a crosswise dividing line on one side and an engraving "ESPERAL" on the other.

Pharmacotherapeutic group. Agents used in alcohol dependence.

ATC code N07B B01.

Pharmacological properties.

Pharmacodynamics.

Disulfiram inhibits the activity of many enzymes. Inhibition of acetaldehyde dehydrogenase leads to increased concentration of acetaldehyde, a metabolite of ethanol, which causes unpleasant symptoms such as intense facial flushing, nausea, vomiting, discomfort, tachycardia, and arterial hypotension.

Pharmacokinetics.

After oral administration, disulfiram is rapidly absorbed, but not completely (from 70 to 90%). It is rapidly metabolized: converted into diethyldithiocarbamate, which is then excreted as glucuronide or transformed into diethylamine and carbon disulfide. Part of the carbon disulfide is exhaled via the lungs. The remaining portion is metabolized and excreted in urine.

Clinical Characteristics.

Indications.

Adjuvant therapy for the prevention of relapse in alcohol dependence.

Contraindications.

Hypersensitivity to disulfiram or any component of the medicinal product and to thiuram compounds. Severe hepatic insufficiency. Epilepsy. Renal insufficiency. Severe respiratory insufficiency. Diabetes mellitus. Psychoneurological disorders. Cardiovascular disorders. Consumption of alcoholic beverages or medicinal products containing alcohol within the last 24 hours.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended.

Alcohol (as beverage or excipient). Development of disulfiram-like reaction (flushing, warmth sensation, vomiting, tachycardia). Consumption of alcoholic beverages and medicinal products containing alcohol must be avoided while the drug is still present in the body. In such cases, guidance should be based on data regarding elimination half-life.

Isoniazid. Behavioral disturbances and impaired motor coordination.

Metronidazole. Risk of acute psychotic episodes or confusion, which resolve after discontinuation of the drug.

Phenytoin (by extrapolation and fosphenytoin). Significant and rapid increase in plasma phenytoin levels with signs of toxicity (due to inhibition of metabolism). If combination therapy cannot be avoided, clinical monitoring and measurement of plasma phenytoin levels during and after disulfiram treatment are required.

Medicinal products of the 5-nitroimidazole group (metronidazole, ornidazole, secnidazole, tinidazole). Transient psychotic disorder, confusion.

Hepatotoxic medicinal products. Concomitant use with disulfiram should be avoided due to the potential risk of liver damage.

Warfarin (and other anticoagulants by extrapolation of data). Enhanced anticoagulant effect with oral administration and increased risk of bleeding (due to reduced hepatic metabolism).

Theophylline. Disulfiram inhibits the metabolism of theophylline. Therefore, theophylline dosage should be adjusted (reduced dose), guided by clinical signs and plasma levels of the drug.

Benzodiazepines. Disulfiram may potentiate the sedative effects of benzodiazepines by inhibiting their oxidative metabolism (particularly for chlordiazepoxide and diazepam). The benzodiazepine dose should be adjusted based on clinical signs.

Tricyclic antidepressants. Potentiation of the disulfiram reaction.

Combinations requiring caution when used concomitantly.

Vitamin K antagonists. Increased effect of vitamin K antagonists and elevated risk of bleeding. International normalized ratio (INR) should be monitored more frequently. The dose of vitamin K antagonist should be adjusted during disulfiram treatment and for 8 days after its discontinuation.

Combinations to be taken into account.

Cocaine. Disulfiram may inhibit cocaine metabolism, leading to a pronounced increase in plasma cocaine concentration and an increased risk of QT interval prolongation.

Disulfiram should be used with caution in patients who use cocaine.

Special precautions for use.

Use of disulfiram as monotherapy.

Cases of severe hepatotoxicity leading to the need for liver transplantation or resulting in fatal outcomes have been reported. If warning signs appear (asthenia, anorexia, nausea, vomiting, abdominal pain or jaundice), a thorough medical examination must be performed immediately and liver function tests assessed (see section "Adverse reactions").

Cases of confusion, neuropsychiatric disorders, psychotic disorders and hallucinations have been reported during treatment with disulfiram. Physicians should inform patients about the risk of developing psychotic disorders and hallucinations, even if they have never experienced such problems before. Physicians should monitor for the development of psychiatric symptoms and advise patients and caregivers to seek immediate medical attention if psychiatric symptoms occur during treatment (see section "Adverse reactions").

Use of disulfiram with alcohol.

Patients must be informed about the risk of developing the disulfiram (Antabuse) reaction (see section "Interaction with other medicinal products and other forms of interaction") when the drug is used concomitantly with alcoholic beverages, even in small amounts. Patients should be cautious about the alcohol content in certain other medicinal products (especially oral solutions), food products, and when using perfumery and cosmetic products such as aftershaves and perfumes.

Unpleasant symptoms (flushing, erythema, nausea and vomiting, general malaise, tachycardia and hypotension) develop within 10 minutes after alcohol consumption and may last from 30 minutes to several hours.

Reactions upon alcohol intake may occur for up to 2 weeks after discontinuation of disulfiram treatment. More severe reactions have been reported, including cardiac arrhythmias, angina attacks, cardiovascular collapse, myocardial infarction, sudden death, respiratory depression, and neurological manifestations (confusion, encephalopathy and seizures).

Disulfiram is not recommended to be used with the following substances:

• alcoholic beverages and medicinal products containing alcohol;
• isoniazid;
• metronidazole;
• phenytoin, fosphenytoin (see section "Interaction with other medicinal products and other forms of interaction").

Precautions for use.

This medicinal product should be used only after a thorough medical examination (general physical examination and laboratory tests). Liver function tests, including measurement of transaminase levels, should be performed prior to initiating disulfiram treatment (see section "Contraindications"), and then at regular intervals, at least once a month, particularly during the first 3 months of treatment. If transaminase levels increase to three times above the upper limit of normal, the drug must be discontinued immediately and permanently. Close monitoring of patients is required until liver function parameters return to normal.

Disulfiram should be used with caution in patients with nickel-induced eczema due to an increased risk of developing hepatitis (see section "Adverse reactions").

Disulfiram should never be administered to patients without their knowledge.

The use of disulfiram is not recommended during pregnancy, regardless of gestational age, or in women of childbearing potential who are not using contraception (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not provided conclusive evidence, and clinical data are insufficient.

Therefore, disulfiram is not recommended for use during pregnancy, regardless of gestational age, or in women of childbearing potential who do not use contraception.

The development of a disulfiram (Antabuse) reaction upon concomitant use of the drug with alcohol may have serious consequences for the fetus.

Breastfeeding. The use of this medicinal product during breastfeeding is not recommended.

Ability to affect reaction speed when driving vehicles or operating other machinery. Driving vehicles or operating machinery may be hazardous due to the risk of drowsiness at the beginning of treatment.

Dosage and Administration.

The medication is intended for oral administration. The recommended dose for adults is 1 tablet per day. The tablet should be taken with water (half a glass), in the morning with breakfast, after abstaining from alcohol consumption for at least 24 hours. The duration of treatment is determined individually by a physician.

Children. There is no experience with the use of the drug for the treatment of children.

Overdose.

Symptoms. Overdose with disulfiram alone may cause neurological disorders: extrapyramidal syndrome, disorders of consciousness (coma, seizures, confusion, and encephalopathy). Treatment is symptomatic.

Overdose of disulfiram in combination with alcohol may result in coma or confusion syndrome, cardiovascular failure, sometimes with neurological complications.

Treatment is symptomatic.

Adverse Reactions

Adverse effects have been classified by frequency according to the following criteria: ≥ 1/10 – very common; ≥ 1/100 to < 1/10 – common; ≥ 1/1000 to < 1/100 – uncommon; ≥ 1/10,000 to < 1/1000 – rare; < 1/10,000 – very rare; frequency not known (cannot be estimated from available data).

Adverse effects associated with disulfiram use

Gastrointestinal disorders

Common: dysgeusia

Frequency not known: nausea, vomiting, stomach pain, diarrhea; unpleasant breath odor (halitosis); unusual fecal odor.

Hepatic disorders

Frequency not known: elevated transaminase levels are commonly observed. Cases of hepatitis (predominantly cytolytic) have been reported: in some severe cases, hepatitis has been associated with liver failure or fulminant hepatitis, which may necessitate liver transplantation or may be fatal (see section "Special precautions").

Nervous system disorders

Very common: headache

Common: somnolence

Rare: polyneuropathy

Frequency not known: optic neuritis, memory loss, seizures, encephalopathy, which is usually reversible upon discontinuation of treatment.

Vascular disorders

Frequency not known: arterial hypertension.

Psychiatric disorders

Frequency not known: confusion, neuropsychiatric disorders, psychotic disorders, and hallucinations.

Skin and subcutaneous tissue disorders

Frequency not known: allergic dermatitis.

General disorders and administration site conditions

Very common: asthenia.

Adverse effects associated with concomitant use of disulfiram and alcohol

Nervous system disorders

Frequency not known: neurological symptoms (confusion, encephalopathy, and seizures).

Cardiac disorders

Frequency not known: tachycardia, cardiac rhythm disturbances, angina attacks, myocardial infarction, sudden death.

Vascular disorders

Frequency not known: facial flushing, arterial hypotension, cardiovascular collapse.

Respiratory, thoracic and mediastinal disorders

Frequency not known: respiratory depression.

Gastrointestinal disorders

Frequency not known: vomiting, nausea.

Skin and subcutaneous tissue disorders

Frequency not known: erythema.

General disorders and administration site conditions

Frequency not known: malaise.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children. No special storage conditions required.

Packaging. No. 20: 20 tablets in a bottle, 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Sofarimes – Indústria Química e Farmacêutica, S.A.

Manufacturer's address.

Alto De Colaride, Avenida das Industrias, Agualva-Cacem, 2735-213, Portugal /

Alto De Colaride, Avenida das Industrias, Agualva-Cacem, 2735-213, Portugal.

Marketing Authorization Holder.

Neuraxpharm Arzneimittel GmbH, Germany