ESPERAL Tablets Ref.[8451] Active ingredients: Disulfiram

Liver function tests (including transaminases) should be performed before disulfiram initiation (cf §4.3Contra-indications) and then periodically, in particular during the first 3 months. Should transaminases values be over 3 times the upper normal limit, disulfiram should be immediately and definitively withdrawn. Patients should then be closely monitored until the normalisation of liver function tests.

Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Patients should be informed of the risk of antabuse effect: (§4.5. Interaction with other medicinal products and other forms of interaction).

Disulfiram should be used with caution in patients with renal failure or hypothyroidism because of the possibility of an accidental disulfiram-alcohol reaction: (§4.8. Undesirable Effects).

Contraindicated combinations:

Alcohol: antabuse effect (flushing, erythema, nausea, vomiting, hypotension, tachycardia, malaise or more severe reactions (cf. §4.8 Undesirable Effects). Avoid the intake of alcoholic beverages and medications containing alcohol.

Inadvisable combinations:

Isoniazid: behaviour and coordination disturbances.

Nitro-5-imidazoles (metronidazole, ordinazole, secnidazole, tinidazole): acute delirium, confusional states.

Phenytoin: significant and rapid increase in the plasma levels of phenytoin leading to an increased risk of phenytoin toxicity (disulfiram inhibits phenytoin metabolism).

If combination cannot be avoided, clinical follow-up and monitor phenytoin plasma levels during and after treatment with disulfiram.

Hepatotoxic drugs: concomitant administration with disulfiram should be avoided because of the possibility of a hepatic injury. Combinations requiring caution :

Warfarin (and by extrapolation other oral anticoagulants): increased oral anticoagulant effect and haemorrhagic risk (decreased hepatic breakdown of warfarin). Close monitoring of the prothrombin time ratio or international normalised ratio (INR) and dosing adjustment upon beginning or stopping disulfiram.

Theophylline: disulfiram decreases the metabolism of theophylline. As a result, the dosage of theophylline should be adjusted (decrease the dosage) depending on clinical signs and plasma levels.

Benzodiazepines: disulfiram may potentialize the sedative effects of benzodiazepines by inhibiting their oxidative metabolism (especially for chlordiazepoxide and diazepam). The benzodiazepine dose should be adjusted in relation to the clinical signs.

Tricyclic antidepressants: potentialization of the antabuse effect.

Pregnancy: In view of the lack of existing clinical data on administration of this medication during pregnancy, disulfiram is contraindicated in pregnant women (§4.3. Contra-indications).

Lactation: The safe use of this drug in lactation has not been established. Therefore disulfiram is contra-indicated during lactation (§4.3 Contra-indications).

Attention should be drawn, in particular in vehicle drivers and machine operators, to the risk of somnolence associated with the use of this drug.

Due to disulfiram alone:

Gastro-intestinal disorders:

• Metallic taste in the mouth
• Unpleasant odour in patients with colostomies (attributed to carbon sulphide)

Liver disorders:

Rare cases of hepatitis, some occurring in non-alcoholic patients treated for nickel eczema, including very rare cases of fulminant hepatitis

Central Nervous system disorders:

• Polyneuritis of the lower limbs, optic neuritis
• Neuropsychiatric disorders, memory loss, confusion, asthenia
• Headache, somnolence

Dermatologic disorders:

• Skin allergies, possibly following a crossover sensitivity with rubber vulcanizers

Due to the combination of disulfiram-ethyl alcohol

flushing, erythema, nausea, vomiting, hypotension, tachycardia, malaise,
more severe reactions have been reported : cases of respiratory depression,
cardiovascular collapse, rhythm disorders or acute angina and sometimes fatal
myocardial infarct, as well as neurological disorders : cerebral oedema, meningeal
haemorrhage, convulsions

None.