Oxactin Capsules 20mg

1. Name Of The Medicinal Product

Fluoxetine Capsules 20mg.

Oxactin Capsules 20mg.

2. Qualitative And Quantitative Composition

Fluoxetine 20mg present as 22.4mg Fluoxetine hydrochloride Ph.Eur.

3. Pharmaceutical Form

Hard gelatin capsule.

4. Clinical Particulars

4.1 Therapeutic Indications

1) For the treatment of symptoms of depressive illness with or without associated symptoms of anxiety, especially where sedation is not required.

2) For bulimia nervosa; for the reduction of binge-eating and purging activity.

3) For the treatment of obsessive-compulsive disorder.

4.2 Posology And Method Of Administration

Posology

Depressive illness with or without associated symptoms of anxiety has a recommended dose of 20mg per day in adults and the elderly.

Obsessive-compulsive disorder has a recommended initial dose of 20mg per day in adults and the elderly.

Bulimia nervosa has a recommended dose of 60mg per day in adults and the elderly.

The maximum recommended dose for all conditions is 60mg per day.

The use of fluoxetine in children is not recommended because safety and efficacy have not been established.

Fluoxetine is not recommended for patients with severe renal failure (GFR <10 ml/min). A lower dose (e.g. alternate day dosing) is recommended for patients with significant hepatic dysfunction or mild to moderate renal failure (GFR 10-50 ml/min).

Method of Administration

For oral administration. The capsules are to be swallowed whole with a drink of water and taken at the same time each day.

4.3 Contraindications

Hypersensitivity to fluoxetine or any of the other ingredients in the formulation.

Patients suffering from severe renal failure (GFR <10 ml/min) should not be administered fluoxetine, as chronic administration may cause accumulation of the drug in the body.

Fluoxetine can be excreted into human breast milk. Therefore concentration of fluoxetine can be transferred in women suckling children.

At least 14 days should elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) and the initiation of fluoxetine treatment (see section 4.5). Fluoxetine should not be co-administered with MAOIs.

4.4 Special Warnings And Precautions For Use

Special care should be taken with patients suffering from renal (GFR 10-50 ml/min) and/or hepatic impairment. Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. Therefore, in these patients a lower dose e.g. alternate day dosing is recommended.

In patients with diabetes, fluoxetine may alter glycaemic control resulting in hypoglycaemia during treatment and hyperglycaemia when treatment is discontinued. Hence, insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Fluoxetine administration should be stopped in any patient who develops seizures. Fluoxetine should not be administered to patients with unstable epilepsy or receiving ECT treatment. Those patients with controlled epilepsy should be carefully monitored.

Patients suffering from acute cardiac disease should be closely monitored.

Serotonin Syndrome is recognised in association with selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine. This is very rare and may develop when insufficient time has elapsed between stopping the administration of MAOIs and starting treatment with SSRIs (see section 4.5).

Fluoxetine may cause weight loss that is undesirable in underweight depressed patients.

Allergic reactions, displayed as angioneurotic oedema, urticaria and rashes may occur. If any such allergic reactions occur and a cause cannot be assigned, then fluoxetine administration should be stopped.

Patients being treated for depression should be monitored closely in order to reduce the possibility of an inherent suicide attempt. The improvement provided by fluoxetine may not occur until after the first two or more weeks from initiating treatment.

Do not administer fluoxetine if patient enters a manic phase.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which fluoxetine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine oxidase inhibitor (MAOI) medicines should be stopped at least 14 days before starting treatment with fluoxetine. These drugs include phenelzine, tranylcypromine and isocarboxazid. MAOI medicines should not be taken until at least five weeks has elapsed from discontinuing fluoxetine treatment. The period of time to elapse between ceasing fluoxetine and starting MAOI should be longer if chronic and/or high doses of fluoxetine have been administered. This elapse in time is to prevent serious and sometimes fatal reactions displayed as hyperthermia, rigidity, myoclonus, autonomic instability causing fluctuation in vital signs and changes in mental status. These are symptoms of Serotonin Syndrome. Dantrolene may benefit patients experiencing such reactions.

Drug interactions may exist with flecainide, encainide, vinblastin, carbamazepine and tricyclic antidepressants as they are metabolised by the same hepatic cytochrome P450 2D6 isoenzyme system, as fluoxetine. Therefore, concomitant therapy with such drugs, particularly those with a narrow therapeutic index or treatment within five weeks from ceasing fluoxetine, should be initiated at or adjusted to the low end of their dose range.

Tryptophan may cause agitation, restlessness and gastro-intestinal symptoms when taken in combination with fluoxetine.

Concomitant treatment with phenytoin can cause an increase in plasma phenytoin concentration and clinical symptoms of toxicity.

Drugs active on the central nervous system, especially lithium administered together with fluoxetine may result in lithium toxicity. Therefore, lithium levels should be monitored in concomitant therapy.

Hyponatraemia (including serum sodium below 110 mmol/l) may result when fluoxetine is administered in association with diuretics. This condition can be reversed if fluoxetine is discontinued.

Dynamic interactions between fluoxetine and the herbal remedy St John's Wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects.

No clinically significant drug interactions are known when fluoxetine is administered concomitantly with warfarin, chlorothiazide, secobarbital, tolbutamide or ethanol. With the latter, fluoxetine does not appear to increase the effects of alcohol.

Concomitant use of fluoxetine may result in increased anticoagulant activity and haemorrhagic risk. The prothrombin time and INR level should be checked more frequently and if necessary the doses should be adjusted.

Since fluoxetine is tightly bound to plasma protein, the concomitant use of fluoxetine with another highly protein-bound medicinal product may cause a shift in plasma concentrations of either product, thus potentially resulting in an adverse effect.

4.6 Pregnancy And Lactation

In animal studies, fluoxetine has not demonstrated teratogenic effects or fetotoxicity but studies were limited by maternal toxicity.

There is limited experience of the use of fluoxetine during pregnancy in humans, with suggested increase in incidence of miscarriages. Fluoxetine can be excreted into human breast milk and cause irritability in the infant.

Some epidemiological studies suggest an increased risk of cardiovascular defects associated with the use of fluoxetine during the first trimester. The mechanism is unknown. Overall the data suggest that the risk of having an infant with a cardiovascular defect following maternal fluoxetine exposure is in the region of 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Fluoxetine should not be prescribed during pregnancy and lactation unless considered essential by the physician.

4.7 Effects On Ability To Drive And Use Machines

As fluoxetine is a psychoactive drug it has the potential to impair judgement and/or co-ordination. Therefore, patients should be cautioned before driving a car, operating machinery or performing hazardous work while taking this drug.

4.8 Undesirable Effects

Fluoxetine can cause a variety of side-effects affecting the body as a whole and within specific systems of the body. A patient may present a fever and asthenia. Frequent side-effects to the digestive system (gastrointestinal tract) include nausea, diarrhoea, vomiting, dyspepsia, abdominal pain, constipation, dry mouth and appetite loss. Less frequent is abnormal liver function.

The nervous system responses are shown as headache, insomnia, drowsiness, dizziness, dyskinesia, nervousness, anxiety, tremor, fatigue, asthenia, seizures, convulsions and hypomania or mania behaviour may be evident. Sexual dysfunction, with decreased libido and delayed orgasm may be experienced. Voluntary movement impairment, movement disorders including worsening of pre-existing movement disorders and neuroleptic malignant syndrome-like events may be experienced. Hyponatraemia may develop (usually in the elderly), which may be due to inappropriate antidiuretic hormone secretion. This condition should be considered in all patients who develop drowsiness, confusion or convulsions while taking fluoxetine.

Pulmonary events have rarely been reported, including inflammatory processes of varying histopathology and/or fibrosis. Respiratory system responses are shown as dyspnoea, which may be the only preceding symptom, and pharyngitis.

Hypersensitivity reactions, with the development of skin rashes, angioneurotic oedema, urticaria and other allergic reactions have been reported. The development of rashes may be the first symptoms of serious systemic reactions, possibly related to vasculitis.

Patients may experience sweating, arthralgia, myalgia, serum sickness, anaphylactoid reactions, weight loss and hair loss.

Abnormal bleeding has been reported, but association with fluoxetine has not been confirmed.

Fluoxetine may cause changes in blood sugar. Also, abnormal liver function tests have been reported.

Undesirable effects constituting the symptoms of Serotonin Syndrome consist of hyperthermia, muscle rigidity, myoclonus, instability of various autonomic nervous system functions such as cardiovascular, sweating, respiratory and/or gastrointestinal effects and in addition, changes in mental status which may, in severe or untreated cases, progress to delirium, coma and even death.

A number of other undesirable effects have been reported, however no causal relationship with fluoxetine has been established. These include aplastic anaemia, thrombocytopenia, thrombocytopenic purpura, gastrointestinal haemorrhage, hyperprolactinaemia, immune-related haemolytic anaemia, cerebrovascular accident, confusion, ecchymoses, eosinophilic pneumonia, pancreatitis, pancytopenia, vaginal bleeding after drug withdrawal, suicidal ideation and violent behaviour.

Cases of suicidal ideation and suicidal behaviours have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4).

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

4.9 Overdose

Deaths from an overdose of fluoxetine are rare and therefore rarely reported. The most common symptoms reported in overdosage are CNS excitation (agitation, restlessness, hypomania, insomnia, fever), nausea, vomiting, tachycardia, seizures and a rise in blood pressure.

There is no known specific antidote for fluoxetine overdose.

Symptomatic supportive measures should be taken, including establishing an airway, monitoring cardiac and vital signs. The monitoring time should be extended for patients who have taken a tricyclic antidepressant with or after fluoxetine administration.

Patients experiencing seizures that fail to cease, may respond to diazepam. Dialysis, forced diuresis, haemoperfusion and exchange transfusion provide little benefit due to the wide distribution of fluoxetine in tissue.

Activated charcoal with sorbitol may be used and may be as or more effective than emesis or lavage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Fluoxetine is a bicyclic monoamine. It acts as a selective inhibitor of serotonin reuptake in the presynastic nerve-endings. The ATC code is N06A B03.

In vitro studies have demonstrated a significant reduction in the uptake by brain tissue of 5-hydroxytryptamine (serotonin) after pre-treatment with fluoxetine. In vivo studies where 30mg/day fluoxetine for one week and thereafter 20mg/day for 13 consecutive days was administered reduced endogenous levels of serotonin in blood platelets and uptake of labelled serotonin were decreased to about 20% and 25% of baseline values, respectively.

5.2 Pharmacokinetic Properties

Peak plasma concentrations are reached six to eight hours after oral administration, this is delayed in the presence of food by approximately three to four hours. Fluoxetine has an elimination half-life (t_½) of one to three days after acute administration, which may be increased to four to six days after chronic administration. Steady state plasma concentrations are only achieved after continuous dosing for weeks.

Metabolism occurs primarily by the hepatic cytochrome P450 2D6 isoenzyme system though there are non-saturable pathways. The active metabolite is norfluoxetine with a mean half-life of 9.3 days (4-16 days) after multiple dosing. Steady state plasma concentrations are reached after continuous dosing for weeks. Fluoxetine has a large volume of distribution.

There is approximately 90-95% binding to plasma proteins.

5.3 Preclinical Safety Data

Acute toxicity of fluoxetine in mouse, rat, cat, dog, monkey and guinea pig is low with some differences between species. The acute effects in rodent and non-rodents are convulsions, tremors, dysnoea and anorexia.

Chronic toxicity studies have shown inducible reversible phospholipidosis, similiar to that observed with other amphiphilic cationic substances (e.g. amiodarone, imipramine). The clinical relevance of this effect has not been established. However, this should be taken into consideration, should respiratory disorders occur.

All the doses associated with the teratogenicity in animals were maternally toxic and several times the recommended maximum dose in humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Contains: lactose, cellulose, magnesium stearate, colloidal silica

Capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172), quinoline yellow (E104), indigo carmine (E132).

6.2 Incompatibilities

None known.

6.3 Shelf Life

48 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

200μm polyvinylchloride coated with 40g/m² PVDC/20μm aluminium blister pack of 28, 30, 56, 60, 90 and 98 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN UK

8. Marketing Authorisation Number(S)

PL 06831/0067

9. Date Of First Authorisation/Renewal Of The Authorisation

05/07/1999 / 02/03/2009

10. Date Of Revision Of The Text

10/08/2010