1. Name Of The Medicinal Product
Fluoxetine 20mg Capsules
2. Qualitative And Quantitative Composition
Each capsule contains Fluoxetine 20mg as fluoxetine hydrochloride (22.4mg). For excipients, see Section 6.1
3. Pharmaceutical Form
Hard capsule.
Size 3. Capsule cap is light green opaque . Capsule body is standard yellow opaque. Markings are “F20”.
4. Clinical Particulars
4.1 Therapeutic Indications
Depression. Fluoxetine is indicated for the treatment of the symptoms of depressive illness, with or without associated anxiety symptoms, especially where sedation is not required.
Obsessive-compulsive disorder.
Bulimia nervosa: Fluoxetine is indicated for the reduction of binge-eating and purging activity.
4.2 Posology And Method Of Administration
For oral administration to adults only.
Depression with or without associated anxiety symptoms-adults and the elderly: A dose of 20mg/day is recommended.
Obsessive-compulsive disorder: 20mg/day to 60mg/day. A dose of 20mg/day is recommended as the initial dose. Although there may be an increased potential of side-effects at higher doses, a dose increase may be considered after several weeks if there is no response.
Bulimia nervosa-adults and the elderly: A dose of 60mg/day is recommended.
Children : The use of Fluoxetine in children is not recommended, as safety and efficacy have not been established .
A lower or less frequent dose should be considered in patients with hepatic impairment, concurrent diseases, or who are taking multiple medications (see “4.4 Special Warnings and Precautions for Use” and “4.5 interactions with other Medicinal products and other forms of Interaction”)
When dosing is stopped, fluoxetine will persist in the body for weeks. This should be borne in mind when starting or stopping treatment. Dosage tapering is unnecessary in most patients.
4.3 Contraindications
Hypersensitivity to fluoxetine or the ingredients of the preparation.
Fluoxetine should not be administered to patients with severe renal failure (GFR<10 ml/min) because accumulation may occur in these patients during chronic treatment.
Usage in nursing mothers: Fluoxetine should not be prescribed to nursing mothers .
Monoamine oxidase inhibitors: Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI selegiline and the reversible MAOI (RIMA), maclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.
Some cases presented with features resembling serotonin syndrome (which may resemble, and be diagnosed as, neuroleptic malignant syndrome).
Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delerium and coma.
Therefore, fluoxetine should not be used in combination with a MAOI or RIMA or within 14 days of discontinuing treatment with a MAOI or RIMA.
Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting a MAOI or RIMA.If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.
Fluoxetine should not be used in patients with unstable or uncontrolled epilepsy.
4.4 Special Warnings And Precautions For Use
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.
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.
Rash and allergic reactions - Rash, anaphylactoid events and progressive systemic events, sometimes serious (involving skin, kidney, liver or lung), have been reported .Upon the appearance of rash or of other allergic phenomena for which an alternative aetiology cannot be identified, Fluoxetine should be discontinued.
Seizures - Fluoxetine should be discontinued in any patients who develop seizures. Fluoxetine should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. Fluoxetine should be discontinued if there is an increase in seizure frequency.
ECT - there have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Hepatic/renal function - Fluoxetine is extensively metabolised by the liver and excreted in the kidneys. Fluoxetine should be used with caution in patients with significant hepatic dysfunction or mild to moderate renal failure (GFR 10-50 ml/min). A lower dose, eg.alternate day dosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20mg per day for 2 months, patient with severe renal failure(GFR<10 ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.
Cardiac disease - Clinical experience in acute cardiac disease is limited, therefore caution is advisable. However, the ECG of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed.
Weight loss - Weight loss may occur in patients taking fluoxetine, which may be undesirable in underweight depressed patients. Only rarely have depressed or bulimic patients been discontinued for weight loss when treated with fluoxetine. Weight loss is usually proportional to baseline body weight. In clinical trials for depression, weight loss in patients who were normal or below normal weight was generally considered clinically insignificant.
Diabetes - In patients with diabetes, treatment with fluoxetine may alter glycaemic control. Hypoglycaemia has occured during therapy with fluoxetine and hyperglycaemia has developed following discontinuation.
Insulin and/or oral hypoglyceamic dosage may need to be adjusted.
Haemorrhage - There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g.gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleeding) have been reported rarely. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders.
Mania - Fluoxetine should be used with caution in patients with a history of mania/hypomania. Fluoxetine should be discontinued in any patient entering a manic phase.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Monoamine oxidase inhibitors - (see contra-indications)
CNS active medication - Changes in blood levels of carbamazepine, haloperidol, clozapine, diazepam, alprazolam, lithium, phenytoin and cyclic antidepressants (e.g. imipramine and desipramine) have been observed. In some cases, manifestations of toxicity have occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical studies.
Lithium and Tryptophan– There have been reports of enhanced effects when SSRIs have been taken with lithium or tryptopham and therefore the concomitant use of Fluoxetine with these drugs be undertaken with caution.
Drugs predominantly metabolised by P450IID6 isoenzyme system– Because fluoxetine's metabolism (like tricyclic anti-depressants and other selective serotonin antidepressants) involves the hepatic cytochrome P450IID6 isoenzyme system, concomitant therapy with drugs also metabolized by this enzyme system may lead to drug interactions. Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a narrow therapeutic index (such as flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants), should be initiated at or adjusted to the low end of their dose range. This will also apply if fluoxetine has been taken in previous 5 weeks.
Plasma protein bound drugs - Fluoxetine is bound to plasma protein and concurrent administration may alter plasma concentrations of other plasma protein bound drugs or conversely fluoxetine. In formal testing, no drug interaction of clinical significance has been observed between fluoxetine and chlorothiazide, ethanol, secobarbital and tolbutamide.
Warfarin - 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 concominant use of warfarin with many drugs, patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped (see Haemorrhage)
Electroconvulsive therapy (ECT) - There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.
Alcohol - The combination of Fluoxetine and alcohol is not advisable. However, in formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol.
Serotonergic drugs - Co-administration with serotonergic drugs (e.g.; tramadol, sumatriptan) may lead to an enhancement of 5-HT associate effects.
St John's Wort - In common with other SSRIs, pharmacodynamic interactions between fluoxetine and herbal remedy, St John's Wort (Hypericum perforatum) may occur, which may result in an increase of undesirable effects.
General - The long elimination half-lives should be borne in mind when considering pharmacodynamic or pharmacokinetic drug interactions.
4.6 Pregnancy And Lactation
Pregnancy - The safety of fluoxetine in human pregnancy has not been established. Treatment with fluoxetine should only be considered if deemed necessary by the physician.
Lactation - Fluoxetine should not be prescribed to nursing mothers.
In one breast milk sample the concentration of fluoxetine, plus norfluoxetine, was 70.4 ngml, compared to 295.0 ngml in mother's plasma. No adverse effects on the infant were noted. In another infant the plasma level of fluoxetine was 340 ngml and 208 ngml of norfluoxetine on the second day of breast feeding from a mother on fluoxetine. This infant developed crying, sleep disturbance, vomiting and watery stools.
Labour and delivery –The effect of fluoxetine on labour and delivery in humans is unknown.
4.7 Effects On Ability To Drive And Use Machines
Although fluoxetine has been shown not to affect psychomotor performance in healthy volunteers, any psychoactive drug may impair judgement or skills. Therefore patients should be cautioned that their ability to perform potentially hazardous tasks (e.g. driving, operating machinery) may be impaired.
4.8 Undesirable Effects
Cardiovascular disorders: Postural hypotension
Disorders of eye: Abnormal vision
Gastrointestinal Disorders: Nausea; vomiting; dry mouth; diarrhoea; dyspepsia; dysphagia; taste perversion; anorexia.
General disorders: Insomnia; dizziness; fatigue; chills; serotonin syndrome; photosensitivity; drowsiness; alopecia; yawning; vasodilation; hypersensitivity reactions including pruritus, rash, urticaria, vasculitis, serum sickness-like, angioedema and anaphylactoid reactions.
Nervous System disorders: headache; sleep abnormalities; anorexia; euphoria; transient abnormal movement (e.g. twitching, ataxia, tremor, myoclonus); psychomotor restlessness; seizures.
Hepato-biliary disorders: Abnormal LFT's; very rare cases of idiosyncratic hepatitis.
Musculoskeletal disorders: Arthralgia; myalgia.
Psychiatric disorders: Hallucinations; mania; confusion; agitation; anxiety; depersonalisation; panic attacks; nervousness(these symptoms may be due to underlying disease.
Suicidal ideation and suicidal behavior: Frequency not known.
Renal & Urinary disorders: Urinary retention; urinary frequency.
Reproductive disorders: Galactorrhoea; sexual dysfunction including ejaculation disorders; anorgasmy; priapism.
Skin disorders: Rash; ecchymoses; pruritus; angioedema; sweating.
Disorders of metabolism and nutrition: inappropriate ADH secretion; hyponatraemia; (including serum sodium below 10mmoll) has been rarely reported and appears to be reversible when fluoxetine is discontinued. Some cases were possibly due to syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients taking diuretics or otherwise volume depleted.
Cases of suicidal ideation and suicidal behaviours have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4)
Fluoxetine, like other selective serotonin reuptake inhibitors, has been rarely associated with withdrawal symptoms. Common symptoms include dizziness, paraesthesia, headache, anxiety, and nausea, the majority of which are mild and self-limiting. The available evidence does not such that these symptoms are due to dependence. Plasma fluoxetine and norfuoxetine concentrations decrease gradually at the conclusion of therapy, which makes dosage tapering unnecessary in most patients.
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Fluoxetine is chemically unrelated to tricyclic and tetracyclic antidepressant agents. Its is a specific serotonin (5-hydroxytryptamine,5-HT) reuptake inhibitor, whose specificity is unaltered by its major metabolite. Fluoxetine is a 50:50 mixture of two isomers which have equivalent pharmacological activity in animals. Individuals with reduced P450IID6 isoenzyme activity (3-10% of the normal human population-'poor metabolisers') were compared to normal metabolisers. The total sum at steady state of the two isomers and their active norfluoxetine metabolites was similar. Thus, net pharmacodynamic activities were essentially the same.
5.2 Pharmacokinetic Properties
Fluoxetine has a half-life of 1 to 3 days after administration. The half-life may be prolonged 4 to 6 days after chronic administration. The active metabolite, norfluoxetine, has a mean half-life of 9.3 days after multiple dosing (range 4-16 days). Steady state plasma concentrations are only achieved after continuous dosing for weeks.
When dosing is stopped, active drug substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment.
Plasma concentrations do not appear to increase without limit because, in addition to metabolism by the hepatic cytochrome P450IID6 isoenzyme system, there are non-saturable pathways. Patients receiving fluoxetine for as long as 3 years exhibited average plasma concentrations, similar to those seen among patients treated for 4 or 5 weeks.
5.3 Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
The capsule also contains:
Pregelatinised maize starch
Colloidal anhydrous silica
Magnesium stearate
Talc
The capsule shell contains:
Quinoline yellow E104
Erythrosine E127
Indigo carmine E132
Titanium dioxide E171
Gelatin
The printing ink contains:
Shellac(E904)
Black iron oxide (E172)
Soya lecithin (E322)
Antifoam DC 1510
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
2 years
6.4 Special Precautions For Storage
Do not store above 25oC. Store in the original container.
6.5 Nature And Contents Of Container
AIPVC blisters: 28 or 30 capsules/pack
HDPE bottle with snap on cap :28 or 30 capsules/pack.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Goldshield Pharmaceuticals Limited
NLA Tower
12-16 Addiscombe Road
Croydon
Surrey
CR0 0XT
United Kingdom
8. Marketing Authorisation Number(S)
PL12762/0099
9. Date Of First Authorisation/Renewal Of The Authorisation
26/01/2009
10. Date Of Revision Of The Text
26/01/2009
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