INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo PROTHIADEN 25 mg : Capsules
PROTHIADEN 75 mg: Tablets

SCHEDULING STATUS
Schedule 5

PROPRIETARY NAME
(and dosage form)

PROTHIADEN 25 mg : Capsules
PROTHIADEN 75 mg: Tablets

COMPOSITION
25 mg Capsule: Each gelatin capsule contains 25 mg Dothiepin hydrochloride.
75 mg Tablet: Each sugar-coated tablet contains 75 mg Dothiepin hydrochloride.

PHARMACOLOGICAL CLASSIFICATION
A 1.2 Psychoanaleptics (antidepressants).

PHARMACOLOGICAL ACTION
Dothiepin Hydrochloride is a tricyclic antidepressant which has anxiolytic properties. The descriptive chemical name is 3-(6H-dibenzo(b,e)-thiepin-11-ylidene)propyldimethylamine hydrochloride.
Dothiepin is readily absorbed from the gastro-intestinal tract, and extensively demethylated by first pass metabolism in the liver to its primary active metabolite, northiaden.
Dothiepin is excreted in the urine, mainly in the form of metabolites; small amounts are also excreted in the faeces. Dothiepin and its metabolites have a half-life of 19-33 hours. Dothiepin is also excreted in breast-milk.

INDICATIONS
Treatment of major depressive disorders in adults and in depression associated with anxiety.

CONTRA-INDICATIONS
Safety in pregnancy and lactation has not been established.
PROTHIADEN should not be given concurrently or within 14 days of treatment with MAO inhibitory medicine.
It is inadvisable to use catecholamine-containing local anaesthetics in patients receiving PROTHIADEN.
It is inadvisable to give PROTHIADEN to patients with recent myocardial infarction or a cardiac arrhythmia.

WARNINGS:
Patients with heart block.
This medicine should at all times be kept out of reach of children as even small doses may be fatal to them.
At the time of initiation of therapy patients should be advised not to drive a motor vehicle, climb dangerous heights or operate dangerous machinery, for at least several days. In these situations impaired decision making could lead to accidents.

DOSAGE AND DIRECTIONS FOR USE
It may be two to four weeks from the start of treatment before there is an improvement in the patient's depression; the subject should be monitored closely during this period. The anxiolytic effect may be observed within a few days of treatment.

Adults:
Dosage may vary widely depending on the individual patients and conditions. It is preferable to use the smaller dose for the first few days. In certain circumstances, i.e. in hospital use, PROTHIADEN has been given at dosages up to 225 mg daily. The usual dosage range is 75 mg to 150 mg daily.

Mild to moderate depression:
Take one 75 mg tablet at night, or one 25 mg capsule three times a day.

Moderate to severe depression:
Take two 75 mg tablets at night or two 25 mg capsule three times a day, or take 75 mg at night plus one 25 mg capsule three times a day.

Elderly:
The recommended initial dose for the elderly is 50 - 75 mg daily. Half the normal maintenance dose may be adequate.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side-effects include dry mouth, metallic taste, constipation, occasionally leading to paralytic ileus, urinary retention, pupillary dilatation with blurred vision and disturbances in accommodation, palpitations, tachycardia and impotence. Other side-effects of dothiepin include drowsiness but sometimes nervousness and insomnia, headache, peripheral neuropathy tremor, orthostatic hypotension, occasionally hypertension, dizziness, sweating, weakness and fatigue, ataxia, epileptiform seizures, occasional extrapyramidal symptoms including speech difficulties, tinnitis, stomatitis and gastric irritation with nausea and vomiting. The risks of central nervous system depression are greater when administered together with other central nervous system depressants e.g. alcohol and barbiturates. Confusion or delirium may occur, particularly in the elderly. Anorexia with mass loss, or mass gain, sometimes with inappropriate appetite (carbohydrate craving) may occur. Allergic skin reactions and photosensitisation have been reported and, less frequently cholestatic jaundice, hepatitis (including altered liver function) and blood disorders, including eosinophilia, bone-marrow depression, thrombocytopenia, leucopenia and agranulocytosis.
Dothiepin has an adverse effect on the myocardium and can cause conduction defects and cardiac arrhythmias; an increased risk of sudden death has been suspected in cardiac patients receiving tricyclic antidepressants.
Endocrine effects associated with dothiepin therapy include changes in libido, interference with sexual function, gynaecomastia and breast enlargement and galactorrhoea. Changes in blood sugar concentrations may also occur, and, very occasionally, inappropriate secretion of antidiuretic hormone.

Note:
Elderly patients are more prone to all these effects and therapy should be initiated at lower than standard doses in the elderly.

Special Precautions:
(a) Psychosis may be activated in schizophrenic patients.
(b) Caution should be observed with patients suffering from a depressive phase of manic depressive psychosis, as occasionally hypomania or mania can be precipitated in such patients. Use is not recommended in mania. Patients with suicidal tendencies should be carefully supervised during treatment.
(c) In elderly male patients suffering from prostatism urinary retention may be precipitated.
(d) In patients suffering from cardiac disease special caution should be observed because of the occasional problems of tachycardia, dysrhythmias, orthostatic hypotension and other unwanted effects on blood pressure, aggravation of conduction disturbances, and electrocardiographic abnormalities. Regular cardiological and electrocardiographic examination is advised.
(e) Epilepsy may be aggravated.
(f) The medicine should usually not be given to patients receiving other central nervous system depressants, e.g. barbiturates and to patients receiving monoamine oxidase inhibitors only after a suitable interval (the drugs may be given together if the dosages are carefully controlled, preferably in hospital). The pressor effects of the direct acting sympathomimetic agents, adrenaline and noradrenaline, are enhanced, and the use of local anaesthetics containing these vasoconstrictors should be avoided as hypertensive reactions may occur. The simultaneous administration of anticholinergic agents may be dangerous. The hypotensive effect of certain antihypertensive agents may be reduced.
(g) Narrow-angle glaucoma may be aggravated.
(h) Withdraw treatment if allergic skin reactions appear.
(i) Should be used with caution in patients with hyperthyroidism or with impaired liver function or a history of urinary retention or constipation.
(j) Blood sugar concentrations may be altered in diabetic patients.
(k) The effects of Prothiaden are influenced by drugs that affect their metabolism. Barbiturates and other enzyme inducers such as anti-epileptics increase their metabolism while neuroleptics, cimetidine, methylphenidate and possibly oestrogens and oral contraceptives reduce it.
(l) It is recommended that antidepressants should be withdrawn gradually.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms of overdosage are excitement and restlessness with antimuscarinic effects, including dry mouth, dilated pupils, tachycardia, urinary retention and intestinal stasis. Severe symptoms include unconsciousness, convulsions and myoclonus, hyperreflexia, hypotension and respiratory and cardiac depression. Cardiac arrhythmias may be life-threatening, and may recur some days after apparent recovery.
There are no specific antidotes for PROTHIADEN and other analogous antidepressants so that the immediate treatment for overdosage should be physical induction of emesis in conscious patients, followed in all cases by general support of respiration and blood circulation. If the overdose is known to have been taken within the previous four hours gastric lavage and aspirations should be undertaken; in unconscious patients with no cough reflex the lungs should be protected with a cuffed endotracheal tube.
Haemodialysis is not recommended as this type of antidepressant is largely protein-bound. Within 18 hours there should be signs of recovery as the patient metabolizes the drug. Sinus tachycardia may be observed but unless a specific dysrhythmia occurs no treatment is necessary.
Hyperexcitability may lead to convulsions which could overload the myocardium.
During recovery the patient should rest quietly until any cardiac abnormalities have resolved.

IDENTIFICATION
25 mg Capsule: A red/brown capsule overprinted P 25 in white for sale in pharmacy.
A red/brown capsule which may or may not be overprinted will be available in Government institutions only.
75 mg Tablet: A round, biconvex, polished tablet with a red sugar coat overprinted P 75 in white for sale in pharmacy.
A round, biconvex, polished tablet with a red sugar coat which may or may not be overprinted will be available in Government institutions only.

PRESENTATION
25 mg Capsules:         Amber glass bottle containing 100 capsules.
75 mg Tablets:         Calendar Pack: Cartons containing 28 blister packed tablets.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
PROTHIADEN 25 mg Capsules:         F/1.2/161
PROTHIADEN 75 mg Tablets:         K/1.2/3

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Knoll Pharmaceuticals S.A. (Pty) Ltd.
P.O. Box 3030
Halfway House 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
4 December 1992       

                989832
        Davbar Dbn.
Updated on this site: October 1999

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