Antabuse® tablets 200 mg.

Disulfiram tablets 200 mg.

Each tablet contains 200 mg disulfiram.

Tablets.

Alcohol deterrent compound. Disulfiram may be indicated as an adjuvant in the treatment of carefully selected and co-operative patients with drinking problems. Its use must be accompanied by appropriate supportive treatment.

Adults and elderly patients only:

It is recommended that treatment with Disulfiram should be initiated only in a hospital or specialised clinic and by physicians experienced in its use. The patient should have adequate social and family support to avoid ingestion of alcohol. Suitable patients should not have ingested alcohol for at least 24 hours and must be warned that a Disulfiram-alcohol reaction is potentially dangerous.

On the first day of treatment, the patient should be given no more than 4 tablets of Disulfiram in one dose (800 mg). The next day the patient should take 3 tablets followed on the third day by 2 tablets and on the fourth and fifth days by 1 tablet. Subsequently, daily dosing should continue at 1 or half a tablet daily for as long as advised by the physician but no longer than six months without review.

In the routine management of the alcoholic it is not recommended to carry out an alcohol challenge test. If the clinician feels an alcohol challenge test is essential for the success of the therapy, full information of the procedure and risks of this test can be obtained from the company. As severe reactions can occur any alcohol challenge should be carried out in specialised units by physicians acquainted with the procedure. Full resuscitation facilities must be immediately available.

Children:

Not applicable.

• Presence of cardiac failure,

• coronary artery disease,

• previous history of CVA,

• hypertension,

• severe personality disorder,

• suicidal risk or psychosis.

• consumption of alcohol (see section 4.4, 4.5 and 4.8)

• hypersensitivity to disulfiram or to any of the excipients.

Caution should be exercised in the presence of renal failure, hepatic or respiratory disease, diabetes mellitus, hypothyroidism, cerebral damage and epilepsy.

Alcohol must not be consumed during treatment and for up to 14 days after discontinuation, as disulfiram prevents the metabolism of ethanol, causing acetaldehyde to accumulate in the body. This can result in a “disulfiram-alcohol reaction” causing adverse effects as listed in section 4.8).

Before initiating treatment it is advised that appropriate examinations should be carried out to establish the suitability of the patient for treatment. Patients must be warned of the unpredictable and potentially severe nature of a Disulfiram-alcohol reaction as, in rare cases deaths have been reported following the drinking of alcohol by patients receiving Disulfiram. Certain foods, liquid medicines, remedies, tonics, toiletries, perfumes and aerosol sprays may contain sufficient alcohol to elicit a Disulfiram-alcohol reaction and patients should be made aware of this. Caution should also be exercised with low alcohol and “non-alcohol” or “alcohol-free” beers and wines, which may provoke a reaction when consumed in sufficient quantities. All personnel involved in the administration of Disulfiram to the patient know that Disulfiram should not be given during a drinking episode.

Disulfiram blocks the metabolism of alcohol and leads to an accumulation of acetaldehyde in the blood stream. For full details of the disulfiram-alcohol reaction please refer to section 4.8.

The intensity of the Disulfiram-alcohol reaction may be increased by amitriptyline. Chlorpromazine while decreasing certain components of the Disulfiram-alcohol reaction may increase the overall intensity of the reaction.

Disulfiram inhibits the metabolism of certain benzodiazepines such as chlordiazepoxide and diazepam enhancing their sedative effect. The interaction is not indicated for oxazepam. Benzodiazepines may reduce the disulfiram-alcohol reaction.

Disulfiram inhibits the metabolism of many drugs which are converted in the liver (such as phenytoin, theophylline and warfarin) and thereby enhances efficacy. Dose adjustment may be necessary.

Animal studies have indicated similar inhibition of metabolism of pethidine, morphine and amphetamines.

A few case reports of increase in confusion and changes in affective behaviour have been noted with the concurrent administration of metronidazole, isoniazid or paraldehyde.

Potentiation of organic brain syndrome and choreoatphetosis following pimozide have occurred very rarely.

Disulfiram inhibits the oxidation and renal excretion of rifampicin.

Pregnancy: The use of Disulfiram in the first trimester of pregnancy is not advised. The risk/benefit ratio in assessing adverse effects of alcoholism in pregnancy should be taken into account when considering the use of Disulfiram in pregnant patients.

There have been rare reports of congenital abnormalities in infants whose mothers have received Disulfiram in conjunction with other medicines.

Lactation: Should not be used. No information is available on whether Disulfiram is excreted in breast milk. Its use during breast feeding is not advised especially where there is a possibility of interaction with medicines that the baby may be taking.

Disulfiram may cause side effects such as drowsiness or fatigue. Patients should make sure they are not affected before driving or operating machinery.

Psychiatric disorders

• psychotic reactions; depression, paranoia, schizophrenia, mania.

• reduction in libido

Nervous system disorders

• drowsiness (during initial treatment)

• peripheral neuritis

• optic neuritis

• encephalopathy

Gastrointestinal disorders

• nausea

• vomiting

Hepatobiliary disorders

• hepatic cell damage

Skin and subcutaneous tissue disorders

• allergic dermatitis

General disorders and administration site conditions

• fatigue (during initial treatment)

• halitosis

Disulfiram-alcohol reaction:

Disulfiram irreversibly inhibits acetaldehyde dehydrogenase. Intake of ethanol during disulfiram therapy will lead to accumulation of acetaldehyde, which is considered the main contributing factor to the disulfiram-alcohol reaction

Disulfiram-ethanol reactions often develop within 15 minutes after exposure to ethanol; symptoms usually peak within 30 minutes to 1 hour, and then gradually subside over the next few hours. Symptoms may be severe and life-threatening.

The disulfiram- alcohol reaction is characterised by:

• Intense vasodilation of the face and neck causing flushing, increased body temperature, sweating, nausea, vomiting, pruritis, urticaria, anxiety, dizziness, headache, blurred vision, dyspnoea, palpitations and hyperventilation.

• In severe cases tachycardia, hypotension, respiratory depression, chest pain, QT prolongation, ST depression, arrhythmias, coma and convulsions may occur.

• Rare complications include hypertension, bronchospasm and methaemoglobinaemia.

Disulfiram overdose

Disulfiram alone has low toxicity. Although most patients will develop symptoms within the first 12 hours, there are case reports of clinical deterioration days after an overdose, with slow recovery and long-term sequel.

Symptoms include:

• Nausea, vomiting, abdominal pain, diarrhoea, drowsiness, delirium, hallucinations and lethargy may occur.

• Tachycardia, tachypnoea, hyperthermia and hypotension. Hypotonia may be prominent, especially in children and tendon reflexes may be reduced. Hyperglycaemia, leukocytosis, ketosis (often disproportionate to the degree of dehydration) and methaemoglobinaemia have been reported.

• In severe cases there may be cardiovascular collapse, coma and convulsions.

• Rare complications include sensorimotor neuropathy, EEG abnormalities, encephalopathy, psychosis and catatonia, which may appear several days after overdose. Dysarthria, myoclonus, ataxia, dystonia and akinesia may also occur. Movement disorders may be related to direct toxic effects on the basal ganglia.

Treatment:

Treatment should be symptomatic and observation is recommended. Supportive therapy should be available and measures may be necessary to counteract hypotension.

Gastric lavage and/or activated charcoal may be considered in cases of disulfiram overdose. Severe vomiting might occur requiring administration of intravenous fluids.

The effect of Disulfiram is primarily due to irreversible inactivation of liver ALDH. In the absence of this enzyme, the metabolism of ethanol is blocked and the intracellular acetaldehyde concentration rises. The symptoms of the Disulfiram-alcohol reaction (DAR) are due partly to the high levels of acetaldehyde. The conversion of dopamine to noradrenaline is also inhibited and the depletion of noradrenaline in the heart and blood vessels allows acetaldehyde to act directly on these tissues to cause flushing, tachycardia and hypotension.

In addition to its affect on acetaldehyde dehydrogenase, disulfiram inhibits other enzyme systems including dopamine-beta-hydroxylase (which converts dopamine and noradrenaline) and hepatic microsomal mixed function oxidases (which are responsible for the metabolism of many drugs). Disulfiram may thus potentiate the action of drugs which are metabolised by these enzymes.

Following oral administration, absorption is variable, distribution is primarily to the kidney, pancreas, liver, intestines and fat. Disulfiram is rapidly metabolised to diethyldithiocarbamic acid (DDC), is conjugated with glucuronic acid, oxidised to sulphate, methylated and decomposed to diethylamine and carbon disulphide. Excretion is primarily through the kidneys.

None.

Lactose, potato starch, povidone, microcrystalline cellulose, polysorbate 20, tartaric acid, colloidal anhydrous silica, sodium bicarbonate, maize starch, magnesium stearate.

None.

3 years.

Store below 25°C in a dry place and keep tightly closed. Protect from light.

Polyethylene container with a polyethylene screw cap tamper evident closure, pack size of 50 tablets.

Not applicable.

Actavis Group PTC ehf

Reykjavikuvegi 76-78

220 Hafnarfjordur

Iceland.

PL 30306/0036

16/08/1994

30/12/2011