Fluoxetine Capsules 20 mg.

Each capsule contains fluoxetine 20 mg as fluoxetine hydrochloride.

Capsule.

Hard gelatin capsule, size 3.

Capsule cap is light green opaque. Capsule body is light green opaque.

Capsule contains an almost white powder. Capsule is marked “F20”.

For the treatment of symptoms of depressive illness, with or without anxiety symptoms, especially when sedation is not required; obsessive-compulsive disorder, and for the symptoms of bulimia nervosa in adults.

Fluoxetine may be administered as a single or divided dose, during or between meals.

Adults and the elderly:

Depression: The recommended dose is 20mg daily.

Obsessive-compulsive disorder: The recommended initial dose is 20mg daily, thereafter up to 60mg daily may be prescribed after several weeks if a positive response is not obtained with the initial dose.

Bulimia nervosa: The recommended dose is 60mg daily.

Unwanted effects may be more evident at higher doses.

Patients with renal or hepatic dysfunction:

A lower dose, or alternate day dosing, is recommended for patients with hepatic dysfunction or mild to moderate renal failure (i.e. with a glomerular filtrate rate of between 10ml and 50ml per minute). Fluoxetine is contra-indicated in patients with severe renal failure as accumulation may occur in this group during chronic treatment.

Children:

Fluoxetine Capsules 20mg are not recommended for children.

Steady state plasma levels of fluoxetine are only achieved after continued dosing for several weeks. When the patient stops taking fluoxetine the drug will also persist in the body for several weeks.

Method of administration: oral.

Withdrawal symptoms seen on discontinuation of SSRI

Abrupt discontinuation should be avoided. When stopping treatment with fluoxetine the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 Special warnings and precautions for use and 4.8 Undesirable effects). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Fluoxetine is contra-indicated in the following circumstances:

- hypersensitivity to fluoxetine or any of the other ingredients,

- in breast-feeding mothers,

- in unstable or uncontrolled epilepsy,

- in severe renal failure (i.e. GFR <10ml/minute), or

- if the patient has been taking monoamine oxidase inhibitors (MAOIs) within the past 2 weeks due to the “serotonin syndrome", see section 4.5. Interactions.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suiciderelated 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 suiciderelated events. In addition, these conditions may be comorbid 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 suiciderelated 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 metaanalysis of placebocontrolled 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.

If a rash or other allergic reaction such as urticaria or angioneurotic oedema occurs, fluoxetine should be discontinued, unless an alternative cause can be identified.

Fluoxetine must be discontinued in patients who start having seizures. Fluoxetine should be avoided in patients suffering with unstable epilepsy. Patients with controlled epilepsy should be carefully monitored as prolonged seizures have been reported in this group.

A lower dose, e.g. alternate day dosing, is recommended in patients with significant hepatic impairment or mild to moderate renal failure (GFR 10-50ml/minute) as fluoxetine is extensively metabolised hepatically and excreted renally.

Caution is advised in patients with acute cardiac disease as clinical experience is limited.

Fluoxetine may cause weight loss which may not be desirable in underweight patients who are depressed, although only rarely has fluoxetine been discontinued in patients with depression or bulimia due to this.

Fluoxetine may alter blood glucose control in patients with diabetes. Hypoglycaemia has occurred during treatment with fluoxetine. Hyperglycaemia has developed after discontinuation of fluoxetine. Diabetic patients taking insulin with or without other hypoglycaemic therapy may need to have their dosages of insulin and/or hypoglycaemic drugs adjusted.

Psychosis and mood shift towards manic phase have been reported which may require discontinuation of treatment.

Abrupt discontinuation of treatment should be avoided. Withdrawal reactions have been reported in association with selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, common symptoms include headache, dizziness, paraesthesia, anxiety and nausea. The majority of symptoms experienced on withdrawal of SSRIs are non-serious and self limiting.

There is little clinical experience of concurrent administration of SSRI's and electroconvulsive therapy (ECT), therefore caution is advised.

There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRI's. Caution is advised in patients taking SSRI's, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and NSAID's) as well as in patients with a history of bleeding disorders.

The long elimination time needs to be borne in mind when considering drug interactions.

Fluoxetine binds to plasma protein and concurrent administration may alter plasma concentrations of other plasma protein-bound drugs, or vice versa. In tests, no drug interaction of clinical significance was observed between fluoxetine and chlorothiazide, ethanol, tolbutamide or secobarbital.

Monoamine oxidase inhibitors: at least 14 days should elapse between discontinuation of monoamine oxidase inhibitors (MAOIs) and initiation of treatment with Fluoxetine Capsules. Conversely, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of therapy with an MAOI. NB this period should be longer if fluoxetine has been prescribed chronically or at higher doses. The serotonin syndrome, i.e. 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) have been reported with concomitant use of MAOIs and fluoxetine or when fluoxetine had been recently discontinued and an MAOI started. Some patients developed features resembling neuroleptic malignant syndrome in which case cyproheptadine or dantrolene may be beneficial.

CNS active drugs such as lithium should be administered with caution with fluoxetine. Reports have been made of both increased and decreased lithium levels and also of lithium toxicity. Levels of lithium should be monitored.

As fluoxetine is metabolised by the hepatic cytochrome CY3PA and P450IID6 isoenzymes, co-administration of other drugs similarly metabolised may lead to drug interactions. Drugs such as flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants which have a narrow therapeutic index should be started at a low dose when taken at the same time as fluoxetine or within 5 weeks of stopping fluoxetine. More than 2-fold increases in previously stable plasma levels of tricyclic antidepressants have been seen when fluoxetine has been concomitantly administered.

Restlessness, agitation and gastro-intestinal symptoms have been reported in a small number of patients receiving fluoxetine at the same time as tryptophan.

Patients, previously stable on phenytoin, have developed raised plasma levels of phenytoin and clinical phenytoin toxicity following the start of concomitant fluoxetine therapy.

No drug interaction between fluoxetine and warfarin has been observed in formal testing. However, possible interactions have been rarely reported.

Fluoxetine does not seem to potentiate the effects of alcohol.

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

The safety of fluoxetine has not been established during pregnancy, and therefore its use is not recommended. Fluoxetine is contra-indicated in breast-feeding mothers as breast milk has been found to contain fluoxetine and norfluoxetine.

Fluoxetine does not seem to affect psychomotor performance. However, if patients find that their concentration is impaired, or they feel tired or dizzy, they should not drive or operate machines.

General: Asthenia, fever, loss of appetite, weight loss, or hair loss (usually reversible). Rare reports of hyponatraemia (including serum sodium below 110 mmol/litre) have been made which appeared to be reversible on discontinuation of fluoxetine; some cases may have been due to inappropriate ADH secretion. Most reports of hyponatraemia were associated with elderly patients, or patients taking diuretics or who were otherwise volume depleted.

Allergic reactions: see Skin and appendages.

Digestive system: dry mouth, dyspepsia, nausea, vomiting, or diarrhoea.

Hepatic system: abnormal liver function tests have been rarely reported.

Nervous system: the following effects have been reported: headache, nervousness, fatigue, drowsiness, insomnia, anxiety, tremor, dizziness, seizures, hypomania or mania, dyskinesia, movement disorders in patients with risk factors (including drugs associated with movement disorders), worsening of pre-existing movement disorders, or neuroleptic malignant syndrome-like events.

Reproductive system: decreased libido or sexual dysfunction (delayed or inhibited orgasm) may occur.

Respiratory system: pharyngitis or dyspnoea. Rare reports of pulmonary events with dyspnoea as the only preceding symptom (including various inflammatory processes and/or fibrosis) have been made.

Skin and appendages: a small percentage of patients developed rash and/or urticaria. Serious systemic reactions, possibly related to vasculitis, have developed in patients with rash, and rarely death has been reported. Hyperhidrosis, arthralgia, myalgia, serum sickness and anaphylactoid reactions have also been reported. If a rash or other allergic reaction occurs such as urticaria or angioneurotic oedema, fluoxetine should be discontinued, unless an alternative cause can be identified.

The following have been reported in association with fluoxetine but no causal relationship has been established: abnormal bleeding, anaemia (aplastic and immune-related haemolytic), cerebrovascular accident, confusion, ecchymoses, eosinophilic pneumonia, gastrointestinal haemorrhage, hyperprolactinaemia, pancreatitis, pancytopenia, purpura, thrombocytopenia, vaginal bleeding after drug withdrawal 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).

The fatal dose is not known. The effects will be potentiated by alcohol taken at the same time. Toxicity is also potentiated by tricyclic antidepressants and MAOIs.

Symptoms

Nausea, vomiting, agitation, tremor, nystagmus and drowsiness may occur. Convulsions have been reported in a small percentage of cases and may not occur until up to ten hours after ingestion. Sinus tachycardia is common. Less frequently bradycardia, hypertension and junctional rhythm may occur.

Rarely features of the "serotonin syndrome" may occur. This includes alteration of mental status, neuromuscular hyperactivity and autonomic instability. There may be hyperpyrexia and elevation of serum creatine kinase. Rhabdomyolysis is rare.

Management

Consider oral activated charcoal if more than 500 mg has been ingested by an adult or if more than 5 mg/kg has been ingested by a child within one hour. Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable.

ATC Code: N06A B03.

Fluoxetine is a specific serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor.

Fluoxetine is readily absorbed from the gastro-intestinal tract with peak plasma levels approximately 6-8 hours after oral administration, although steady state plasma concentrations do not occur until after several weeks. Fluoxetine is widely distributed throughout the body and is extensively bound to plasma proteins.

The drug is largely metabolised hepatically to its primary metabolite, norfluoxetine. Fluoxetine has an elimination half-life of about 1-6 days depending on type of administration (acute 1-3 days, chronic 4-6 days). Norfluoxetine's elimination half-life is approximately 4-16 days after multiple doses. This is of clinical significance as after the patient has stopped taking fluoxetine, the active substance and its metabolites may remain in the body for weeks. Excretion is mainly via the kidneys.

There are no preclinical data of relevance to the prescriber which are additional to that already included in the other sections of the Summary of Product Characteristics.

Pregelatinised maize starch, anhydrous colloidal silica, magnesium stearate, talc, quinoline yellow (E104), indigo carmine (E132), titanium dioxide (E171) and gelatin.

None known.

Blister packs: 24 months. HDPE bottles: 36 months.

Blister pack: Do not store above 25°C. Store in the original package.

HDPE bottle: No special storage recommendations.

i) Aluminium/PVC blister strips packed in an outer carton, or

ii) A high density polyethylene bottle with low density polyethylene snap-on cap.

Pack sizes: 28 and 30.

None.

Sandoz Limited

Woolmer Way

Bordon

Hampshire

GU35 9QE

United Kingdom

PL 04416/0330

05/03/2009

27/07/2009