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Logo APO-FLUOXETINE 20 mg CAPSULES

SCHEDULING STATUS:
Schedule 5

PROPRIETARY NAME
(and dosage form):

APO-FLUOXETINE 20 mg CAPSULES

COMPOSITION:
Each capsule contains
Fluoxetine Hydrochloride 22.4 mg equivalent to 20 mg of Fluoxetine.

PHARMACOLOGICAL CLASSIFICATION:
A 1.2 Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION:
The anti-depressant, anti-obsessional compulsive actions of fluoxetine are presumed to be linked to its ability to inhibit the CNS neuronal uptake of serotonin. At clinically relevant doses, fluoxetine blocks the uptake of serotonin into human platelets.
Pharmacokinetics:
The parent drug has an elimination half life of two to three days and the major active metabolite norfluoxetine has an elimination half life of 7 to 9 days. As a result of these long half-lives, changes in dosage regimen will not be reflected in the plasma for approximately four half-lives. This must be taken into consideration during dosage titration or cessation of treatment.

INDICATIONS:
1. MAJOR DEPRESSIVE EPISODES
This includes a single episode or recurrent depression with associated anxiety.
2. BULIMIA NERVOSA
Fluoxetine hydrochloride has been shown to significantly decrease binge-eating and purging activity.
3. OBSESSIVE COMPULSIVE DISORDER
Fluoxetine is indicated for the treatment of obsessive-compulsive disorder. The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming or interfering significantly with the person’s social or occupational function.

CONTRA-INDICATIONS:
APO-FLUOXETINE (fluoxetine hydrochloride) is contra-indicated in patients with known hypersensitivity to the agent.
Monoamine oxidase inhibitors:
There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and then started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.
Therefore, APO-FLUOXETINE should not be used in combination with MAOI, or within 14 days of discontinuing therapy with MAOI.
Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping APO-FLUOXETINE before starting an MAOI.
Patients with severe renal failure (GFR < 10 mL/min) should not be prescribed APO-FLUOXETINE as during chronic treatment accumulation of fluoxetine may occur.
Use in Pregnancy and nursing mothers: The safety of fluoxetine in pregnancy and lactation has not been established.
Use in Children: Safety and efficacy in children has not yet been established.

WARNINGS:
ALLERGIC REACTIONS (Rash and Accompanying Events)
Upon the appearance of rash or other possible allergic phenomena for which an alternative etology cannot be identified APO-FLUOXETINE (fluoxetine hydrochloride) should be discontinued.

DOSAGE AND DIRECTIONS FOR USE:
1. MAJOR DEPRESSIVE EPISODES For the treatment of a major depressive episode: The usual initial dosage is 20 mg administered once daily in the morning. The daily dose should not exceed a maximum of 80 mg per day.
2. BULIMIA NERVOSA: The recommended dosage is 60 mg per day
3. OBSESSIVE-COMPULSIVE DISORDER: A dose range of 20 mg/day to 60 mg/day is recommended for the treatment of obsessive-compulsive disorder.
Use in the Elderly: The effect of age on the metabolisms of fluoxetine has not yet been fully established. Thus, APO-FLUOXETINE should be used cautiously in the elderly patients especially if they have a systemic illness or are taking multiple medications for concomitant diseases.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
SIDE EFFECTS:
The following side-effects have been observed:
Central Nervous System: Headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor, and dizziness or lightheadedness, decreased libido, seizures, hypomania or mania, abnormal dreams, agitation.
Gastrointestinal: Nausea, diarrhoea, dry mouth and anorexia, dyspepsia, vomiting and weight loss.
Endocrine system: Hyponatraemia (including Serum sodium lower than 110 mmol/L) and which appeared to be reversible upon discontinuation of treatment. Some cases of hyponatraemia were possible due to the syndrome of inappropriate anti-diuretic hormone (SIADH). Most reported cases have occurred in older patients taking diuretics or who were otherwise volume depleted.
Elevated serum transaminases have been reported.
Urogenital system: Sexual dysfunction (delayed or inhibited orgasm).
Respiratory system: Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis) where dyspnoea may be the only preceding symptom.
Skin and appendages: Rash and/or urticaria (See warnings), serious systemic reactions involving lungs, kidney or liver, possibly related to vasculitis have developed in patients with a rash and death has been reported, excessive sweating, serum sickness and anaphylactoid reactions have occurred.
Body as a whole: Fever, palpitations, vision disturbances.
The following side-effects have been reported with fluoxetine but a causal relationship is yet to be established: aplastic anaemia, cerebral vascular accident, confusion, dys-kinesia, ecchymoses, eosinophilic pneumonia, gastro-intestinal haemorrhage, hyperprolactinaemia, movement disorders, neuroleptic malignant syndrome-like events, pancreatitis, suicidal ideation, pancytopenia, immune related haemolytic anaemia, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after withdrawal of medication and violent behaviour.
PRECAUTIONS
Fluoxetine is not usually considered a suitable therapy for the depressive component of bipolar illness.
If a patient develops seizures, fluoxetine should be discontinued. Fluoxetine should not be administered to patients with unstable epilepsy and when administered to patients with controlled epilepsy, the patient should be carefully monitored; in patients receiving ECT treatment prolonged seizures have been reported.
Dosage reduction, for example, alternate day dosing, may be required in patients with hepatic dysfunction or mild to moderate renal failure (GFR 10 - 15 mL/min), as fluoxetine is metabolised by the liver and excreted in the urine.
Caution must be observed when administering fluoxetine to patients with acute cardiac disease as clinical experience is limited.
Caution must be observed when administering fluoxetine to underweight, depressed patients as fluoxetine may cause weight loss.
Diabetic patients receiving fluoxetine must be closely observed as fluoxetine may alter glycaemic control leading to hypoglycaemia. Dosage adjustments of oral hypoglycaemic agents and insulin may be necessary. These must be readjusted when fluoxetine therapy is discontinued.
Altered platelet function and/or abnormal laboratory results for patients receiving fluoxetine have been reported. There have also been reports of abnormal bleeding in patients receiving fluoxetine, but it is not clear whether fluoxetine is the causative agent.
As fluoxetine is a psychoactive medicine it may impair judgement or skills, although these were not affected in healthy volunteers. Patients should be warned that their ability to drive or perform hazardous tasks may be impaired.
Due to the fact that improvement of the condition may not begin for the first couple of weeks, patients should be observed during this early phase of treatment. Patients suffering from major depressive episodes are a high suicide risks and should be closely supervised.
Because of the well-established comorbidity between depression and obsessive-compulsive disorder, the same precaution that are observed when treating depressed patients should be observed when treating patients suffering from obsessive-compulsive disorder.
INTERACTIONS:
When considering drug interactions, the long half-lives of fluoxetine and norfluoxetine should be taken into consideration.
Fluoxetine concurrently administered with medicines that are also plasma protein bound may lead to an alteration in the plasma concentrations of these medicines, e.g. warfarin and digoxin or an alteration of the fluoxetine plasma concentration.
Concurrent administration of fluoxetine and diazepam may lead to an increase in the half-life of the diazepam.
Patients receiving fluoxetine and tryptophan have reported side-effects including agitation, restlessness and gastro-intestinal distress.
Stable plasma levels of other antidepressants have been reported to increase by more than two times when administered in combination with fluoxetine.
Fluoxetine and monoamine oxidase inhibitors should not be administered concurrently.
Concomitant administration of fluoxetine and other centrally acting medicines, including lithium should be cautiously monitored. Lithium levels have been reported to increase and decrease when fluoxetine is administered concomitantly.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Emesis induction or gastric lavage should be carried out. Treatment of overdosage is symptomatic and supportive. There are no specific antidotes for fluoxetine.

IDENTIFICATION:
APO-FLUOXETINE 20 mg Capsules: Ivory opaque body, green opaque cap, hard gelatine capsules printed “APO20”. White powder fill.

PRESENTATION:
APO-FLUOXETINE 20 mg Capsules are packaged in white high density polyethylene bottles of 30, 100 and 500.

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

REGISTRATION NUMBER:
30/1.2/0355

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Apotex S.A.
PHARMACEUTICAL INNOVATION
Apotex S.A. (Pty) Ltd.
Cnr Fleming and Watt Streets
Meadowdale Ext. 1

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
31 May 1996
                                P30035/2

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