INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
APO-CLOMIPRAMINE 10
APO-CLOMIPRAMINE 25
APO-CLOMIPRAMINE 50

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

APO-CLOMIPRAMINE 10
film coated tablets
APO-CLOMIPRAMINE 25
film coated tablets
APO-CLOMIPRAMINE 50
film coated tablets

COMPOSITION:
Each film coated tablet contains 10 mg, 25 mg or 50 mg clomipramine hydrochloride.

PHARMACOLOGICAL CLASSIFICATION:
A 1.2 Psychoanaleptics (antidepressants).

PHARMACOLOGICAL ACTION:
Clomipramine hydrochloride is a tricyclic antidepressant. It has marked antimuscarinic and sedative properties and prevents the re-uptake and hence the inactivation of nonadrenaline and serotonin at nerve terminals.
Clomipramine possesses anticholinergic properties, as well as weak antihistaminic and antiserotonergic properties.

INDICATIONS:
More serious depressive conditions which can be treated with clomipramine include major depression (endogenous, unipolar, manic-depressive states, involutional melancholia and masked depression), reactive depression (neurotic depression) and secondary depression (depression associated with alcoholism, schizophrenia, parkinsonism and personality disorders, depression caused by medicines and senility with depression).

CONTRA-INDICATIONS:
Contra-indicated in heart block, cardiac arrhythmias and in the immediate recovery period after myocardial infarction.
Contra-indicated in severe liver disease.
Contra-indicated in patients with a known hypersensitivity to tricyclic antidepressants belonging to the diazepine group.
Safety in pregnancy and lactation has not been established.
Concomitant treatment with APO-CLOMIPRAMINE and MAO-inhibitors is contraindicated. Clomipramine should not be administered for a period of at least 14 days after the discontinuation of treatment with MAO-inhibitors due to the potential for severe interactions: severe hypertensive reactions, hyperpyretic crises, convulsions and fatalities have been reported.
The same caution should also be observed when administering a MAO-inhibitor after previous treatment with clomipramine.

WARNINGS:
This medicine should at all times be kept out of reach of children, as relatively small overdoses may be fatal to them.
Caution should be exercised when prescribing tricyclic antidepressants in patients with

-	cardiovascular insufficiency, atrioventricular block (grades I to III) and arrhythmias.
-	narrow-angle glaucoma.
-	disorders of micturition due to an impeded flow of urine (e.g. in diseases of the prostate).
-	a low convulsions threshold (e.g. due to brain damage of varying aetiology, epilepsy, alcoholism).
-	severe hepatic or renal disease.
-	tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma) in whom the medicine may provoke hypotensive crises.

Simultaneous treatment of patients with tricyclic antidepressants and electroconvulsive therapy should only be resorted to under careful supervision.

DOSAGE AND DIRECTIONS FOR USE:
Medical supervision is essential.
Dosage should be individualised according to the requirements of each patient. Treatment should be initiated at the lowest recommended dose and increased gradually.
Therapy should be initiated at doses of 25 mg 2 to 3 times daily and gradually increased by 25 mg increments, as tolerated, at 3 to 4 day intervals up to a total daily dose of 150 mg.
Therapy may also be initiated with a single dose of 50 to 100 mg at bedtime, increased by 25 mg or 50 mg as necessary to a total of 150 mg daily.
Maintenance doses are usually 50 to 100 mg daily and therapy should be continued for at least 3 months before being gradually withdrawn.
A maximum daily dose of 250 mg should not be exceeded.
Caution should be exercised in elderly and adolescent patients.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
SIDE-EFFECTS:
The most commonly observed adverse events were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness and myoclonus; genitourinary complaints, including changed libido, ejaculatory failure, impotence and micturition disorder and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain and visual changes.
Neurological - ataxia, headache, delirium, speech disorders, muscle weakness, muscle hypertonia, tinnitus, paraesthesia of the extremities, convulsions, EEG changes, hyperpyrexia, Peripheral neuropathy has been reported with other tricyclic antidepressants.
Behavioural - drowsiness, fatigue, restlessness, confusion accompanied by disorientation, anxiety states, agitation, sleep disturbances, insomnia, nightmares, aggravated depression, hypomania or manic episodes, disturbed concentration, visual hallucinations, impaired memory, aggressiveness, yawning, personalisation, activation of latent psychosis, delusions.
Cardiovascular - orthostatic hypotension with associated vertigo, sinus tachycardia, palpitations. ECG changes in patients with normal cardiac status, arrhythmias, hypertension, conduction disorders, syncope.
Haematologic- leucopenia, agranulocytosis, thrombocytopenia, eosinophilia and purpura.
Gastrointestinal - vomiting abdominal pain, diarrhoea, taste perversion, elevated transaminases, stomatitis, obstructive jaundice, hepatitis with or without jaundice.
Endocrine - weight loss, breast enlargement and galactorrhoea in the female, inappropriate antidiuretic hormone (ADH) secretion syndrome, gynecomastia in the male, changes in blood sugar levels, increase in prolactin levels, menstrual irregularity.
Allergic or toxic - allergic skin reactions (skin rash, urticaria), photosensitisation, pruritus, oedema, drug fever.
Withdrawal symptoms - abrupt cessation of treatment after prolonged administration may occasionally produce nausea, vomiting, abdominal pain, diarrhoea, insomnia, nervousness, anxiety, headache and malaise.
PRECAUTIONS:
Clomipramine hydrochloride should be administered with caution in patients with urinary retention, prostatic hypertrophy or constipation or in patients with increased intraocular pressure due to its anticholinergic properties.
Tricyclic antidepressants are known to lower the convulsive threshold and clomipramine should, therefore, be used with extreme caution in patients with a history of convulsive disorders and other predisposing factors, e.g. brain damage of varying etiology, alcoholism and concomitant use with other medicines that lower the seizure threshold.
Clomipramine hydrochloride should be ad ministered with extreme caution to patients with a history of cardiovascular disease.
Caution should be observed in prescribing Clomipramine in hyperthyroid patients or in patients receiving thyroid medication cojointly.
Depressed patients with suicidal tendencies should be carefully supervised during treatment.
Elderly patients and young children can be particularly sensitive to the side-effects and a reduced dose, especially initially, should be employed.
Blood sugar concentrations may be altered in diabetics.
Interactions:
Patients should be warned that, while taking Clomipramine, their responses to alcoholic beverages, other central nervous system depressants (e.g barbiturates, benzodiazepines or general anesthetics) or anticholinergics (e.g. atropine, biperiden, levodopa) may be exaggerated. When tricyclic antidepressants are given in combinations with anticholinergics or neuroleptics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma. Tricyclic antidepressants should not be employed in combination with anti-arrhythmic agents of the quinidine type.
Barbiturates and other enzymes inducers such as antiepileptics can increase the metabolisms of tricyclic antidepressants, resulting in lowered plasma concentrations and reduced antidepressant response. Cimetidine, methylphenidate and neuroleptics may reduce the metabolism of tricyclic antidepressants, resulting in increased plasma concentrations and accompanying toxicity.
The antihypertensive effects of bethanidine, debrisoquine, guanethidine and possibly clonidine may be reduced by tricyclic antidepressants.
Clomipramine may potentiate the cardiovascular effects of nonadrenaline or adrenaline, amphetamine, as well as nasal drops and local anaesthetics containing sympathomimetics.
Substances which activate the hepatic monooxygenase enzyme system (e.g barbiturates, phenytoin, nictoine) may lower plasma concentrations of tricyclics and so reduced their antidepressive effects.
Clomipramine should be discontinued prior to elective surgery for as long as clinically feasible, since little is known about the interaction between clomipramine and general anaesthetics.
If administered concomitantly with estrogens, the dose of clomipramine should be reduced since steroid hormones inhibit the metabolism of clomipramine.
Because clomipramine is highly bound to serum proteins, the administration of clomipramine to patients taking other medicines that are highly bound to protein (i.e. warfarin, digoxin) may cause an increase in plasma concentrations of these medicines, potentially resulting in adverse effects. Conversely, adverse reactions may result from the displacement of protein bound clomipramine by other highly bound medicines.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Signs and symptoms of overdosage and poisoning generally take the form of severe anticholinergic reactions (which set in about 1/2 to 2 hours after ingestion), central nervous system depression or excitation and cardiotoxicity.
Symptoms may include drowsiness, stupor, ataxia, dryness of the mouth, dilated pupils, vomiting, cyanosis, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements and convulsions. Hyperpyrexia, mydriasis, bowel and bladder paralysis and respiratory and cardiac depression may occur.
Patients in whom overdosage is suspected should be admitted to hospital without delay. No specific antidote is available and treatment is essentially symptomatic and supportive. Gastric lavage or aspiration should be performed promptly and administration of activated charcoal may help reduce absorption of the drug.
Forced diuresis, peritoneal dialysis and hemodialysis are unlikely to be of value. ECG monitoring is recommended.

IDENTIFICATION:
APO-CLOMIPRAMINE 10: triangular, pale yellow, film coated biconvex tablets, engraved '10' on one side and plain on the other side.
APO-CLOMIPRAMINE 25: round, pale yellow, film coated biconvex tablets, engraved '25' on one side and plain on the other side.
APO-CLOMIPRAMINE 50: round, white, film coated biconvex tablets engraved "APO'" over "50" on one side and plain on the other side.

PRESENTATION:
APO-CLOMIPRAMINE tablets are available in white, HDPE bottles or securitainers of 100, 500. or 1000.

STORAGE INSTRUCTIONS:
Store below 25°C in well-closed containers.
Protect from light.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS:
APO-CLOMIPRAMINE 10 : 31/1.2/0062
APO-CLOMIPRAMINE 25 : 31/1.2/0064
APO-CLOMIPRAMINE 50 : 31/1.2/0066

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
APOTEX S.A.
PHARMACEUTICAL INNOVATION
Reg. Prop: Acupharm (Pty) Ltd
Cnr Fleming & Watt Streets
Meadowdale Ext. 1

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
May 1997
                        P310062/64/66/2
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