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

Logo REZAK (capsules)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

REZAK (capsules)

COMPOSITION
Each capsule contains fluoxetine hydrochloride equivalent to 20 mg
fluoxetine

PHARMACOLOGICAL CLASSIFICATION
A 1.2 Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION
Pharmacodynamics
The antidepressant and anti-obsessive-compulsive action of fluoxetine is presumed to be linked to its inhibition of central nervous system (CNS) neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets.
Pharmacokinetics
Because of the long elimination half-life of the parent drug (4 to 6 days) and its major active metabolite norfluoxetine (4 to 16 days), changes in dose will not be fully reflected in plasma for several weeks (approximately 4 half-lives). This is to be taken into consideration during dose titration or cessation of treatment.

INDICATIONS
Major depressive episodes
i.e. single episode and recurrent depression with associated anxiety.
Bulimia nervosa
REZAK
has been shown to significantly decrease binge-eating and purging activity.
Obsessive-compulsive disorder
REZAK
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 functioning.

CONTRAINDICATIONS
Hypersensitivity to fluoxetine.
REZAK should not be administered to patients with severe renal failure (GFR < 10 mL/min) because accumulation may occur in these patients during chronic treatment.
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 state 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 are then started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with a MAOI, or within 14 days of discontinuing therapy with a MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting a MAOI.
Usage in pregnancy
Safety in pregnancy has not been established.
Breast-feeding mothers
The safety of fluoxetine has not been established in lactating women.
Paediatric use
Safety and efficacy in children has not been established.

WARNINGS
Serotonin Syndrome
A serotonin syndrome, which may be confused with the neuroleptic malignant syndrome may occur with the use of fluoxetine. This syndrome is characterised by the clustering of clinical features of changes in mental state (confusion, disorientation, agitation) and neuromuscular activity (myoclonus, hyper-reflexia, tremor, rigidity, incoordination), in combination with auto-immune dysfunction (especially fever, sweating, diarrhoea). The serotonin syndrome has been seen in temporal association with the use of mono-amine oxidase inhibitors and with other serotonergic medication but may occur in the absence of any concomitant medication. Fluoxetine should be stopped immediately as serious morbidity and death may follow the serotonin syndrome.

Rash and possibly allergic events
Upon the appearance of rash or of other possibly allergic phenomena fluoxetine should be discontinued.
Rash, anaphylactoid events, and progressive systemic events, sometimes serious and involving skin, kidney, liver or lung has been reported in patients taking fluoxetine.

INTERACTIONS
REZAK
should not be used concomitantly with monoamine oxidase inhibitors (see CONTRAINDICATIONS).
Medicines metabolised by cytochrome P450IID6 isoenzyme:
Because fluoxetine has the potential to inhibit the cytochrome P450IID6 isoenzyme, therapy with medications that are predominantly metabolised by the P450IID6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving such a medicine, the need for decreased dose of the original medication should be considered.
Altered anti-coagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increased bleeding, have been reported uncommonly when fluoxetine is co-administered with warfarin. As is prudent in concomitant use of warfarin with many other medicines, patients using warfarin should receive careful coagulation monitoring when fluoxetine is initiated or stopped.
Caution is advised if the concomitant administration of fluoxetine and central nervous system active agents, including lithium, is required. There have been reports of both increased and decreased lithium levels when used concomitantly with fluoxetine. Lithium levels should be monitored.
Changes in blood levels of phenytoin, carbamazepine, haloperidol, clozapine, diazepam, alprazolam, imipramine and desipramine, and in some cases clinical manifestations of toxicity have been observed. Consideration should be given to using conservative titration schedules of the concomitant medicine and monitoring of clinical status.
There have been greater than two-fold increases of previously stable plasma levels of other antidepressants when fluoxetine has been administered in combination with these agents.
Patients receiving fluoxetine in combination with tryptophan have been reported to experience adverse reactions, including agitation, restlessness and gastro-intestinal distress.
The long elimination half-lives of fluoxetine and its active metabolite should be borne in mind (see Pharmacokinetics) when considering pharmacodynamic or pharmacokinetic medicine interactions, or the potential consequence when medicines are prescribed which might interact with either substance following the discontinuation of fluoxetine.
The half-life of concurrently administered diazepam may be prolonged.
Fluoxetine is bound to plasma protein and concurrent administration may alter plasma concentrations of other plasma protein bound agents e.g. warfarin, digitoxin or conversely, fluoxetine binding may be changed by other agents.
Electroconvulsive therapy (ECT): There have been reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

PREGNANCY AND LACTATION
Usage in pregnancy
Safety in pregnancy has not been established.
Breast-feeding mothers
The safety of fluoxetine has not been established in lactating women.

DOSAGE AND DIRECTIONS FOR USE
For oral administration to adults only.
A major depressive episode
A dose of 20 mg/day is recommended, preferably in the morning. Doses above 80 mg/day are not recommended.
Bulimia nervosa
A dose of 60 mg/day is recommended.
Obsessive-compulsive disorder
A dose of 20 to 60 mg/day is the recommended dose for the treatment of obsessive-compulsive disorder.
REZAK may be administered with or without food.

Usage in the elderly
The effects of age upon the metabolism of fluoxetine have not been fully explored. Thus fluoxetine should be used with caution in the elderly, particularly if they have systemic illness or are receiving multiple medications for concomitant diseases.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side Effects
The following treatment-emergent adverse events were observed:
Body as a whole
Asthenia, fever, palpitations, vision disturbances (including blurred vision and mydriasis), vasodilatation, chills, serotonin syndrome (characterised by the clustering of clinical features of changes in mental state and neuromuscular activity, in combination with autonomic nervous system dysfunction) and photosensitivity.
Digestive system
Nausea, diarrhoea, dry mouth, appetite loss, dyspepsia, vomiting, dysphagia, taste perversion and idiosyncratic hepatitis.
Anorexia and weight loss may also occur.
Nervous system
Headache, insomnia, drowsiness, anxiety and associated symptoms such as palpitations, nervousness, psychomotor restlessness, abnormal movement including twitching, ataxia, buccoglossal syndrome, myoclonus, tremor, dizziness, fatigue, somnolence, asthenia, decreased libido, seizures (see Precautions). Hypomania or mania occurred in approximately 1 % of fluoxetine-treated patients. Abnormal dreams, agitation, depersonalisation, insomnia, anorexia, impairment of concentration or thought process, and weight loss.
Respiratory system
Yawning and dyspnoea. Pulmonary events (including inflammatory processes of varying histopathology and/or fibrosis) have been reported. Dyspnoea may be the only preceding symptom.
Skin and appendages
A small percentage of patients developed rash and/or urticaria (see WARNINGS). Serious systemic events, possibly related to vasculitis, have developed in patients with rash and rarely death has been reported. Excessive sweating, serum sickness and anaphylactoid reactions have also been reported. Alopecia has been reported.
Urogenital system
Sexual dysfunction (delayed or inhibited orgasm), impotence, decreased libido, abnormalities of micturition, urinary frequency, impaired urination, priapism or prolonged erection.
Haemic and lymphatic system
Ecchymosis.
Endocrine system
Hypothyroidism, inappropriate secretion of ADH.
Hyponatraemia (including serum sodium lower than 110 mmol/L) has been reported. The hyponatraemia appeared to be reversible when fluoxetine was discontinued. Although these cases were complex with varying possible aetiologies, some were possibly due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.
Elevated serum transaminase values have occurred.
The following have been reported in association with fluoxetine, but no causal relationship has been established : Aplastic anaemia, cerebral vascular accident, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome, which resolved following discontinuation of the medicine), ecchymoses, eosinophilic pneumonia, gastro-intestinal haemorrhage, hyperprolactinaemia, movement disorders developing in patients with risk factors (including agents associated with such events) and worsening of pre-existing movement disorders, neuroleptic malignant syndrome-like events, pancreatitis, suicidal ideation, pancytopenia, immune related haemolytic anaemia, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after withdrawal of the medication and violent behaviour.
Precautions
REZAK
should be introduced cautiously in patients who have a history of seizures.
REZAK should be discontinued in any patient who develops seizures. REZAK should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. There have been reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. A lower dose e.g. alternate day dosing, is recommended in patients with significant hepatic dysfunction or mild to moderate renal failure (GFR 10-50 mL/min).
Clinical experience in acute cardiac disease is limited, therefore caution is advisable. REZAK may cause loss of mass which could be undesirable in underweight depressed patients.
In patients with diabetes, REZAK may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted when REZAK therapy is initiated or discontinued.
There have been reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role.
Although fluoxetine has been shown not to affect psychomotor performance in healthy volunteers any psychoactive drug may impair judgment, thinking or motor skills. Therefore patients should be cautioned that their ability to perform potentially hazardous tasks (e.g. driving a motor vehicle or operating machinery) may be impaired.
As improvement may not occur during the first two or more weeks of treatment, patients should be closely monitored during this period. Due to the risk of suicide in major depressive episodes, close supervision of high risk patients should accompany medication therapy.
Because of well-established co-morbidity between obsessive-compulsive disorder and depression, the same precautions observed when treating patients with depression should be observed when treating patients with obsessive-compulsive disorder.
If REZAK is given for the depressive component of bipolar disorder, mania may be precipitated.
Discontinuation of REZAK may lead to withdrawal symptoms. Common symptoms include dizziness, paraesthesia, headache, insomnia, tremor, confusion, sensory disturbances, agitation, anxiety and nausea.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See SIDE-EFFECTS AND SPECIAL PRECAUTIONS. The most prominent features are nausea, vomiting and excitation of the central nervous system.
Treatment of overdosage involves emesis induction or gastric lavage followed by symptomatic and supportive therapy.
Activated charcoal may be of benefit.
Due to the large volume of distribution of fluoxetine, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.
There are no specific antidotes for fluoxetine.

IDENTIFICATION
A hard gelatin capsule with an opaque light blue cap and opaque light turquoise blue body filled with a white to off-white powder. “FLUOXETINE 20 mg” imprinted with black ink on cap and “R148”imprinted with black ink on body.

PRESENTATION
Blister packs containing 30 capsules.

STORAGE INSTRUCTIONS
Store below 25ºC.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
34/1.2/0279

NAME AND BUSINESS ADDRESS OF HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr. Reddy’s Laboratories (Pty) Ltd.
381 Rossouw Street
Murrayfield
Pretoria
0184

DATE OF PUBLICATION OF PACKAGE INSERT
23 July 2003

New addition to this site: March 2010
Source: Pharmaceutical Industry

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