Fluoxetine 20mg Capsules

One hard capsule contains 22.36 mg of fluoxetine hydrochloride equivalent to 20 mg of fluoxetine base.

For excipients, see 6.1

Capsule, hard.

Fluoxetine capsules are blue and white, and marked 'S 136'

Fluoxetine is indicated for the treatment of major depressive episodes.

For oral administration in adults.

For major depressive episodes, a dose of 20 mg/day is recommended, and a maximum daily dose should not exceed 80 mg/day.

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

Patients with renal or liver disease:

In cases of liver dysfunction or renal failure (GFR 10-50 ml/min), the dose should be reduced, e.g. to 20 mg every second day.

Children: Fluoxetine capsules are not indicated for use in children. Fluoxetine efficacy and safety have not been studied in children below the age of 18

Elderly: there are not enough data available on fluoxetine efficacy and safety in this population, therefore caution is recommended when increasing the dose which should rarely exceed 40 mg and should not exceed 60 mg.

Fluoxetine is contraindicated in patients with a known hypersensitivity to fluoxetine or to any of the excipients.

Concurrent treatment of fluoxetine with irreversible non-selective and B selective monoamine oxidase inhibitors (MAOIs) is contraindicated and could result in severe sometimes fatal disorders (see section 4.5).

Fluoxetine should normally not be used concomitantly with reversible and A selective MAOIs (see section 4.5).

For combination of fluoxetine and other antidepressants, see section 4.5.

Fluoxetine should not be administered to patients with severe renal failure (GFR <10ml/min).

Fluoxetine should not be used in patients with unstable or uncontrolled epilepsy.

Fluoxetine should not be used in nursing mothers (see section 4.6).

Special Warning

Withdrawal reactions have been reported in association with selective serotonin reuptake inhibitors (SSRIs). Symptoms typically include nausea, paraesthesia, headache, anxiety and dizziness. Avoid abrupt discontinuation of treatment.

In patients receiving fluoxetine in combination with tryptophan, adverse reactions, including agitation, gastrointestinal disorders and restlessness have been reported.

Rarely prolonged bleeding time and/or haemorrhagic manifestations may occur (e.g., ecchymosis, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings)(see section 4.8 Undesirable Effects).

Caution should be exercised in patients concomitantly treated with oral anticoagulants, drugs which have an effect on platelet function (e.g., NSAIDs, acetylsalicylic acid), or other drugs that may increase risk of bleeding. Caution is also required in patients with previous bleeding abnormalities.

Precautions for Use

Fluoxetine should be used with caution in patients with epilepsy. Patients should be treated and monitored sufficiently before initiation of fluoxetine (see also section 4.5). Treatment should be stopped in patients who develop fits or seizures. Prolonged seizures in patients who were also receiving electroconvulsive therapy (ECT) have been infrequently reported.

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

In some patients, a serotonin syndrome has been observed which can be life-threatening. Medication should be stopped and supporting measures taken.

Due to limited clinical information, caution should be taken when treating patients with cardiovascular disease or recently recovered from a myocardial infarct.

Initiation and cessation of fluoxetine treatment may affect glycaemic homeostasis. In diabetic patients, glycaemic monitoring should be reinforced and insulin and/or oral hypoglycaemic dosage may need to be adjusted.

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

In some cases, inappropriate secretion of antidiuretic hormone has been reported (see also section 4.8).

Fluoxetine has not shown evidence of potentiating the effects of alcohol. However, as during other CNS medicinal product treatment, alcohol use should be avoided.

Fluoxetine should be used with great caution in patients with hepatic insufficiency since the half-lives of fluoxetine and norfluoxetine are prolonged.

Fluoxetine should be used with great caution in patients with renal insufficiency since the half-life of norfluoxetine is prolonged (see also section 4.3).

The medicinal product should be prescribed in small quantities in order to reduce the risk of overdosing with the product.

Contraindicated combination

Irreversible non-selective and B selective MAOIs (see section 4.3).

This combination can result in severe, sometimes fatal reactions (serotonin syndrome) including sudden or progressive occurrence of the following symptoms which impose immediate discontinuation of treatment: hyperthermia, rigidity, myoclonus, tachycardia, autonomic instability, diarrhoea, and mental status changes, e.g. confusion, agitation progressing to delirium and coma.

Fluoxetine should not be used for at least 2 weeks after irreversible non-selective and B selective MAOI-medication. MAOI treatment should not be started for at least 5 weeks after cessation of fluoxetine treatment.

Inadvisable combination

Reversible and A selective MAOIs (see section 4.3).

If the combination must be used, the patient should be monitored closely and treatment initiated with the minimal dose (see also irreversible MAOIs).

Fluoxetine should not be used for at least some days after reversible and A selective MAOI-medication. MAOI treatment should not be started for at least 5 weeks after cessation of fluoxetine treatment.

Precautions for use during combination

Patients receiving stable doses of phenytoin, or carbamazepine have developed raised plasma levels of phenytoin, or carbamazepine and clinical toxicity following initiation of concomitant fluoxetine treatment.

The risk of using fluoxetine in combination with other CNS active medicinal products has not been fully evaluated. Therefore, caution is advised if the concomitant administration of fluoxetine and such medicinal products is required. Cases of lithium toxicity have been reported. When used concomitantly, lithium levels should be monitored.

There have been increases in previously stable plasma levels of other antidepressants (for example tricyclic antidepressants) and antipsychotics (e.g., Clozapine) with a potentially increased incidence of adverse effects when fluoxetine has been administered concomitantly with these agents. If necessary, doses should be adjusted. When fluoxetine is substituted by a tricyclic antidepressant, the latter should be initiated with caution due to the long half-life of fluoxetine and norfluoxetine. There are no data to show the usefulness of combination of fluoxetine and other antidepressants.

Caution is advised if the concomitant administration of fluoxetine and anticoagulants, drugs which have an effect on platelet function (e.g., NSAIDs, ticlopidine, acetylsalicylic acid), or other drugs that may increase risk of bleeding is required (see section 4.4 special warnings) The prothrombin time and INR level should be checked more frequently and if necessary the doses should be adjusted.

Generally, concomitant treatment with medicinal products known to be metabolised in the liver by cytochrome CYP 2D6, especially those with a narrow therapeutic index, should be conducted with care due to possible interaction. Lower doses of such medicinal products should therefore be considered (and for up to 5 weeks after cessation of fluoxetine treatment).

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.

In common with other SSRIs, pharmacodynamic interactions between fluoxetine and the herbal remedy St John's Wort may occur, which may result in an increase of undesirable effects.

In animal studies, fluoxetine has not demonstrated teratogenic effects or fetotoxicity but studies were limited by maternal toxicity. In humans, the number of exposed pregnancies is too low to conclude. Therefore, as a precautionary measure, fluoxetine use is not recommended during pregnancy.

Breast-feeding: Fluoxetine has been shown to pass into human milk. Therefore, breast-feeding is not recommended. See also section 4.3.

Fluoxetine may impair judgement, thinking, or motor skills. Patients should be advised to avoid driving motor vehicles or operating hazardous machinery.

Anorexia, weight loss, appetite loss, nausea, vomiting, diarrhoea, dry mouth, dyspepsia, constipation.

Headache, restlessness, insomnia, anxiety, dizziness, visual disturbance, drowsiness, confusion, tremor, sweating, sedation. Suicide and suicidal attempts (see section 4.4).

Although withdrawal reactions may occur on stopping therapy, the available preclinical and clinical evidence does not suggest that SSRIs (Selective Serotonin Reuptake Inhibitors) cause dependence. Symptoms likely to be associated with withdrawal reactions are e.g. dizziness, paraesthesia, headache, nausea and anxiety. The majority of withdrawal reactions are mild and self limiting (section 4.4).

Serotonin syndromes have exceptionally been reported (see section 4.5).

Small increases in diastolic blood pressure and tachycardia as well as bradycardia have been reported.

Rash and allergic reactions: urticaria, exceptionally Quincke edema, have been reported (see section 4.4).

Rarely, vasculitis, erythema polymorph, or exceptionally Lyell syndrome, and rare cases of fever, rash and arthralgia as in serum sickness.

Rarely prolonged bleeding time and/or haemorrhagic manifestations may occur (e.g. ecchymosis, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings).

Hyperprolactinemia with galactorrhea.

Hyponatremias have been reported. In some cases, plasma sodium was less than 100 mmol/l.

Hyponatremia may be revealed by confusion or seizures and was reversible on discontinuation of treatment. Most of the cases have been described in elderly or patients with diuretics or hypovolemia.

Rare cases of increase ALTs and exceptional cytolytic or mixed hepatitis have been reported.

Sexual dysfunction (decreased libido, delayed or inhibited orgasm).

Nausea, vomiting, seizures and signs of CNS excitations have been reported with overdose. No specific antidote is known. Appropriate elimination of ingested product and/or prevention of absorption should be performed when indicated. Management should include general symptomatic and supportive measures including a clear airway and monitoring cardiac and vital signs until stable. Extra-renal elimination techniques are likely to be of no benefit in view of the large distribution volume.

Pharmacotherapeutic group: Antidepressant

ATC code: N06 AB03

Fluoxetine is a selective competitive inhibitor of 5HT (serotonin) uptake in the presynaptic cleft and exerts little or no effect on re-uptake mechanisms for norepinephrine, dopamine or acetylcholine. The major metabolite norfluoxetine is similar in efficacy to the parent molecule.

Absorption

Fluoxetine is well absorbed from the gastrointestinal tract after oral administration. The bioavailability is not affected by food intake.

Distribution

It is highly protein bound (about 95%) and has a high volume of distribution (Vd: 20-40 l/kg).

Metabolism

Fluoxetine has a non-linear pharmacokinetic profile with first pass liver effect. Maximum plasma concentration is generally achieved 6 to 8 hours after administration. Fluoxetine is primarily metabolised by the liver to the active metabolite norfluoxetine (demethylfluoxetine), by demethylation.

Elimination

The elimination half-life of fluoxetine is about 4 days (2-7 days) and for norfluoxetine about 7-9 days (4-15 days). These long half-lives are responsible for persistence of the drug for 5-6 weeks after discontinuation (see section 4.5). Excretion is mainly (about 65%) via the kidneys. Fluoxetine is secreted into breast milk.

At-risk populations

•Elderly: Kinetic parameters are not altered in healthy elderly as compared with younger subjects.

•Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine and norfluoxetine half-lives are increased up to 7 to 12 days, respectively. This should lead to decrease the dose.

•Renal insufficiency: After single-dose administration of fluoxetine in patients with mild, moderate or complete (anuria) renal insufficiency, kinetic parameters have not been altered as compared to healthy volunteers. However, after repeated administration, an increase in steady-state plateau of plasma concentrations may be observed.

Fluoxetine was of low acute toxicity. Chronic toxicity studies have shown inducible reversible phospholipidosis, similar to that observed with other amphophilic 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. Fluoxetine did not show evidence of mutagenicity, carcinogenicity nor teratogenicity in animal studies. Fertility studies conducted in rats at dose levels of up to 9 to 12.5 mg/kg/day showed that fluoxetine had no adverse effects on fertility but that neonatal survival rate was slightly decreased (probably associated with depressed maternal food consumption and suppressed weight gain).

Dimeticone

Pregelatinised Starch

Cap

Titanium Dioxide (E171)

Erythrosine (E127)

Patent Blue V (E131)

Gelatin

Body

Titanium Dioxide (E171)

Gelatin

Capsule printing ink

Shellac

Black Iron Oxide

Propylene Glycol

Not applicable.

3 years.

Do not store above 30°C. Keep container in the outer carton.

Transparent PVC foil blister pack with aluminium foil seal and contained in cardboard cartons.

Pack size: 14, 28, 30, 70.

Not applicable.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey GU1 4YS

United Kingdom

Trading as Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey GU1 4YS, UK

PL 17780/0047

7 August 2001

30 January 2007