1 NAME OF THE MEDICINAL PRODUCT

Gerozac 60 mg hard capsules Capsules, Hard

4.1 Therapeutic indications

Gerozac 60 mg capsules are indicated for:

Adults:
Major depressive episodes.
Obsessive-compulsive disorder.
Bulimia nervosa:  Fluoxetine Gerozac is indicated as a complement of psychotherapy for the reduction of binge-eating and purging activity.

4.2 Posology and method of administration

All indications:

Adults: The recommended dose may be increased or decreased.  Doses above 80 mg/day have not been systematically evaluated.

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

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. 

Paediaric population
Children and adolescents aged 8 years and above (moderate to severe major depressive episode):
Treatment should be initiated and monitored under specialist supervision. The starting dose is 10 mg/day given as 2.5 ml of a fluoxetine liquid formulation. Dose adjustments should be made carefully, on an individual basis, to maintain the patient at the lowest effective dose.

Elderly: Caution is recommended when increasing the dose, and the daily dose should generally not exceed 40 mg. Maximum recommended dose is 60 mg/day.

Hepatic impairment:
A lower or less frequent dose (e.g. 20 mg every second day) should be considered in patients with hepatic impairment (see section 5.2),  or in patients where concomitant medication has the potential for interaction with fluoxetine (see section 4.5).

Withdrawal symptoms seen on discontinuation of Fluoxetine Gerozac: Abrupt discontinuation should be avoided. When stopping treatment with Fluoxetine Gerozac 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 section sections 4.4 and section 4.8). 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.

Method of administration

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

4.4 Special warnings and precautions for use

It is important that the prescriber discusses carefully the risks and benefits of treatment with the child/young person and/or their parents.

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.

Cardiovascular effects:
Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the postmarketing period (see sections 4.5, 4.8 and 4.9).

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia, hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment), or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes (see section 4.5).

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment should be withdrawn and an ECG should be performed.

Irreversible non-selective Monoamine Oxidase Inhibitors (e.g. iproniazid):
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible non-selective monoamine oxidase inhibitor (MAOI).

These cases presented with features resembling serotonin syndrome (which may be confounded with (or diagnosed as) neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a 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 delirium and coma.

Therefore, fluoxetine is contra-indicated in combination with an irreversible non-selective MAOI (see section 4.3).

Because of the two weeks-lasting effect of the latter, treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting an irreversible, non-selective MAOI.

Serotonin syndrome or neuroleptic malignant syndrome-like events:
On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularly when given in combination with other serotonergic (among others L-tryptophan) and/or neuroleptic drugs (see section 4.4). As these syndromes may result in potentially life-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

Mania:
Antidepressants should be used with caution in patients with a history of mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase.

Haemorrhage:
There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRI’s.  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 bleedings) have been reported rarely.  Caution is advised in patients taking SSRIs, particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA’s, aspirin, NSAID’s) or other drugs that may increase risk of bleeding as well as in patients with a history of bleeding disorders (see section 4.5).

Seizures:
Seizures are a potential risk with antidepressant drugs.  Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures.  Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency.  Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored (see section 4.5).

Electroconvulsive therapy (ECT):
There have been rare reports of prolonged seizures in patients on Fluoxetine receiving ECT treatment, therefore caution is advisable.

Tamoxifen:
Fluoxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, fluoxetine should whenever possible be avoided during tamoxifen treatment (see section 4.5).

Akathisia/psychomotor restlessness:
The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental

Diabetes:
In patients with diabetes, treatment with an SSRI 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.

Hepatic/renal function:
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.  When given fluoxetine 20 mg per day for 2 months, patients with severe renal failure (GFR < 10 ml/mm) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.

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:
Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures.  Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored (see section 4.5).

Electroconvulsive therapy (ECT):
There have been rare reports of prolonged seizures in patients on Fluoxetine receiving ECT treatment, therefore caution is advisable.

Mania:
Antidepressants should be used with caution in patients with a history of mania/hypomania.  As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase.

Hepatic/renal function:
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.  When given fluoxetine 20mg per day for 2 months, patients with severe renal failure (GFR < 10 ml/mm) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.

Tamoxifen:
Fluoxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, fluoxetine should whenever possible be avoided during tamoxifen treatment (see section 4.5).

Cardiovascular effects:
Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period (see sections 4.5, 4.8 and 4.9).

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia, hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment).

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment should be withdrawn and an ECG should be performed.

Weight loss:
Weight loss may occur in patients taking fluoxetine but is usually proportional to baseline body weight. 

Diabetes:
In patients with diabetes, treatment with an SSRI 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.

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.

Akathisia/psychomotor restlessness:
The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Withdrawal symptoms seen on discontinuation of SSRI treatment:
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 60% of patients in both the fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the placebo group were severe in nature.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that Fluoxetine should be gradually tapered when discontinuing treatment over a period of at least one to two weeks, according to the patient's needs (see section 4.2 “Withdrawal symptoms seen on discontinuation of fluoxetine”).

Haemorrhage:
There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRI’s.  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 bleedings) have been reported rarely.  Caution is advised in patients taking SSRIs, particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA’s, aspirin, NSAID’s) or other drugs that may increase risk of bleeding as well as in patients with a history of bleeding disorders (see section 4.5).

Mydriasis:
Mydriasis has been reported in association with fluoxetine; therefore, caution should be used when prescribing fluoxetine in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.

Serotonin syndrome or neuroleptic malignant syndrome-like events:
On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of Fluoxetine, particularly when given in combination with other serotonergic (among others L-tryptophan) and/or neuroleptic drugs (see section 4.4). As these syndromes may result in potentially life-threatening conditions, treatment with Fluoxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

Irreversible non-selective Monoamine Oxidase Inhibitors (e.g. iproniazid):
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible non-selective monoamine oxidase inhibitor (MAOI).

These cases presented with features resembling serotonin syndrome (which may be confounded with (or diagnosed as) neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a 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 delirium and coma. Therefore, fluoxetine is contra-indicated in combination with an irreversible non-selective MAOI (see section 4.3).

Because of the two weeks-lasting effect of the latter, treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting an irreversible, non-selective MAOI.
Lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactase malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

QT interval prolongation: Pharmacokinetic and pharmacodynamic studies between fluoxetine and other medicinal products that prolong the QT interval have not been performed. An additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, co-administration of fluoxetine with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotic (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g.sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution (see section sections 4.4, 4.8 and 4.9).

Drugs affecting haemostasis (oral anticoagulants, whatever their mechanism, platelets antiaggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical monitoring, and more frequent monitoring of INR with oral anticoagulants, should be made. A dose adjustment during the fluoxetine treatment and after its discontinuation may be suitable (see Sections sections 4.4 and 4.8).

Other drugs metabolised by CYP2D6: Fluoxetine is a strong inhibitor of CYP2D6 enzyme, therefore concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions, notably those having a narrow therapeutic index (such as flecainide, propafenone and nebivolol) and those that are titrated, but also with atomoxetine, carbamazepine, tricyclic antidepressants and risperidone. They should be initiated at or adjusted to the low end of their dose range. This will may also apply if fluoxetine has been taken in the previous 5 weeks.

4.6 Fertility, pregnancy and lactation

Pregnancy
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, particularly 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.

Furthermore, although fluoxetine Fluoxetine can should not be used during pregnancy unless the clinical condition of the woman requires treatment with fluoxetine and justifies the potential risk to the foetus. Abrupt discontinuation of therapy should be avoided during pregnancy (see section 4.2). If fluoxetine is used during pregnancy, caution should be exercised, especially during late pregnancy or just prior to the onset of labour, since the following some other effects have been reported in neonates; irritability, tremor, hypotonia, persistant crying, difficulty in sucking or in sleeping. These symptoms may indicate either serotonergic effects or a withdrawal syndrome. The time to occur and the duration of these symptoms may be related to the long half-life of fluoxetine (4-6) days and its active metabolite, norfluoxetine (4-16 days).

Breast-feeding
Fluoxetine and its metabolite norfluoxetine, are known to be excreted in human breast milk. Adverse events have been reported in breast-feeding infants. If treatment with Fluoxetine Gerozac is considered necessary, discontinuation of breast-feeding should be considered: however, if breast-feeding is continued, the lowest effective dose of Fluoxetine fluoxetine should be prescribed.

4.8 Undesirable effects

b) Tabulated list of adverse reactions

The table below gives the adverse reactions observed with fluoxetine treatment in adult and paediatric populations. Some of these adverse reactions are in common with other SSRIs.

The following frequencies have been calculated from clinical trials in adults (n = 9297) and from spontaneous reporting.

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common	Common	Uncommon	Rare
Blood and lymphatic system disorders
			Thrombocytopenia Neutropenia Leucopenia
Immune system disorders
			Anaphylactic reaction Serum sickness
Endocrine disorders
			Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
	Decreased appetite1		Hyponatraemia
Psychiatric disorders
Insomnia2	Anxiety Nervousness Restlessness Tension Libido decreased3 Sleep disorder Abnormal dreams4	Depersonalisation Elevated mood Euphoric mood Thinking abnormal Orgasm abnormal5 Bruxism Suicidal thoughts and behaviour6	Hypomania Mania Hallucinations Agitation Panic attacks Confusion Dysphemia Aggression
Nervous system disorders
Headache	Disturbance in attention Dizziness Dysgeusia Lethargy Somnolence7 Tremor	Psychomotor hyperactivity Dyskinesia Ataxia Balance disorder Myoclonus Memory impairment	Convulsion Akathisia Buccoglossal syndrome Serotonin syndrome
Eye disorders
	Vision blurred	Mydriasis
Ear and labyrinth disorders
	Tinnitus	Tinnitus
Cardiac disorders
	Palpitations Electrocardiogram QT prolonged (QTcF ≥450 msec)		Ventricular arrhythmia including torsade de pointes, Electrocardiogram QT prolonged
Vascular disorders
	Flushing89	Hypotension	Vasculitis Vasodilation
Respiratory, thoracic and mediastinal disorders
	Yawning	Dyspnoea Epistaxis	Pharyngitis Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis)10
Gastrointestinal disorders
Diarrhoea Nausea	Vomiting Dyspepsia Dry mouth	Dysphagia Gastrointestinal haemorrhage1011	Oesophageal pain
Hepatobillary disorders
			Idiosyncratic hepatitis
Skin and subcutaneous tissue disorders
	Rash812 Urticaria Pruritus Hyperhidrosis	Alopecia Increased tendency to bruise Cold sweat	Angioedema Ecchymosis Photosensitivity reaction Purpura Erythema multiforme Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell Syndrome)
Musculoskeletal and connective tissue disorders
	Arthralgia	Muscle twitching	Myalgia
Renal and urinary disorders
	Frequent urination913	Dysuria	Urinary retention Micturition disorder
Reproductive system and breast disorders
	Gynaecological bleeding11 14 Erectile dysfunction Ejaculation disorder10 15	Sexual dysfunction	Galactorrhoea Hyperprolactinaemia Priapism
General disorders and administration site conditions
Fatigue12	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage
Investigations
	Weight decreased	Transaminases increased Gamma-glutamyltransferase increased	Transaminases increased Gamma-glutamyltransferase increased

1. Includes anorexia
2. Includes early morning awakening, initial insomnia, middle insomnia
3. Includes loss of libido
4. Includes nightmares
5. Includes anorgasmia
6. Includes completed suicide, depression suicidal, intentional self-injury, self-injurious ideation, suicidal behaviour, suicidal ideation, suicide attempt, morbid thoughts, self-injurious behaviour. These symptoms may be due to underlying disease
7. Includes hypersomnia, sedation
7.8.  Based on ECG measurements from clinical trials
8.9. Includes hot flush
9.10. Includes atelectasis, interstitial lung disease, pneumonitis
10.11. Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage
11.12. Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash
12.13. Includes pollakiuria
13.14. Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage
14.15. Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation
15.16. Includes asthenia

c) Description of selected adverse reactions

Withdrawal symptoms seen on discontinuation of fluoxetine treatments:
Discontinuation of fluoxetine commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged (see section 4.4). It is therefore advised that when fluoxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section sections 4.2 and section 4.4).

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors, ATC code: N06AB03

Mechanism of action
Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α 2 and β-adrenergic; serotonergic; dopaminergic; histaminergic1 muscarinic; and GABA receptors.

Clinical efficacy and safety
Major depressive episodes: Clinical trials in patients with major depressive episodes have been conducted versus placebo and active controls. Fluoxetine has been shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D) In these studies, fluoxetine  produced a significantly higher rate of response (defined by a 50% decrease in the HAM-D score) and remission, compared to placebo.

Dose response: In fixed dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, it is clinical experience that uptitrating might be benefical for some patients.

Obsessive-compulsive disorder: In short-term trials (under 24 weeks), Fluoxetine fluoxetine was shown to be significantly more effective than placebo. There was a therapeutic effect at 20 mg/day, but higher doses (40 or 60 mg/day) showed a higher response rate. In long term studies (three short term studies extension phase and a relapse prevention study) efficacy has not been shown.

Bulimia nervosa: In short term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria for bulimia nervosa,  Fluoxetine  fluoxetine  60 mg/day was shown to be significantly more effective than placebo for the reduction of bingeing, vomiting and purging activities. However, for long-term efficacy no conclusion can be drawn.

Pre-menstrual dysphoric disorder: Two placebo-controlled studies were conducted in patients meeting premenstrual Dysphoric Disorder (PMDD) diagnostic criteria according to DSMIV. Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others. Patients using oral contraceptives were excluded. In the first study of continuous 20 mg daily dosing for 6 cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety and dysphoria). In the second study, with intermittent luteal phase dosing (20 mg daily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (Daily Record of Severity of Problems score). However, definitive conclusions on efficacy and duration of treatment cannot be drawn from these studies.

Paediatric population
Major depressive episodes (children and adolescents): Clinical trials in children and adolescents aged 8 years and above have been conducted versus placebo. Fluoxetine, at a dose of 20 mg, has been shown to be significantly more effective than placebo in two short-term pivotal studies, as measured by the reduction of Childhood Depression Rating Scale-Revised (CDRS-R) total scores and Clinical Global Impression of Improvement (CGI-I) scores. In both studies, patients met criteria for moderate to severe MDD (DSM-III or DSM-IV) at three different evaluations by practising child psychiatrists. Efficacy in the fluoxetine trials may depend on the inclusion of a selective patient population (one that has not spontaneously recovered within a period of 3-5 weeks and whose depression persisted in the face of considerable attention). There is only limited data on safety and efficacy beyond 9 weeks. In general, efficacy of fluoxetine was modest. Response rates (the primary endpoint, defined as a 30% decrease in the CDRS-R score) demonstrated a statistically significant difference in one of the two pivotal studies (58% for fluoxetine versus 32% for placebo, P = 0.013; and 65% for fluoxetine versus 54% for placebo, P = 0.093). In these two studies, the mean absolute changes in CDRS-R from baseline to endpoint were 20 for fluoxetine versus 11 for placebo, P = 0.002; and 22 for fluoxetine versus 15 for placebo, P <0.001.

5.2 Pharmacokinetic properties

Elimination
The elimination half-life of Fluoxetine fluoxetine is 4 to 6 days and for norfluoxetine 4 to 16 days. These long half-lives are responsible for persistence of the drug for 5-6 weeks after discontinuation.  Excretion is mainly (about 60%) via the kidney.  Fluoxetine is secreted into breast milk.

At-risk Special populations

Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects.

Paediatric population: The mean fluoxetine concentration in children is approximately 2-fold higher than that observed in adolescents and the mean norfluoxetine concentration 1.5-fold higher. Steady-state plasma concentrations are dependent on body weight and are higher in lower weight children (see section 4.2). As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), Fluoxetine fluoxetine and norfluoxetine half-lives are increased to 7 and 12 days, respectively. A lower or less frequent dose should be considered.

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

Section 4.4:
[...]
Irreversible non-selective Monoamine Oxidase Inhibitors (e.g. iproniazid):
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a an irreversible non-selective monoamine oxidase inhibitor (MAOI).

Section 4.5:
[...]
Irreversible, Non-selective Monoamine Oxidase Inhibitors (e.g. iproniazid):
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a an irreversible non-selective monoamine oxidase inhibitor (MAOI).

Section 4.8:
"Aggression" added to the table under Rare Psychiatric disorders.

Extensive updates to SPC in line with Core Safety Profile.

Extensive updates to the SmPC in line with the brand leader and QRD template.

Section 4.6 (Pregnancy and lactation), addition of the following paragraph:
 

Animal data have shown that fluoxetine may affect sperm quality (see section 5.3).

Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

Section 5.3 (Preclinical safety data)

 

Juvenile animal studies

There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility from in vitro or juvenile animal studies.

Adult animal studies
In a 2-generation rat reproduction study, fluoxetine did not produce adverse effects on the mating or fertility of rats, was not teratogenic, and did not affect growth, development, or reproductive parameters of the offspring. The concentrations in the diet provided doses approximately equivalent to 1.5, 3.9, and 9.7 mg fluoxetine/kg body weight. Male mice treated daily for 3 months with fluoxetine in the diet at a dose approximately equivalent to 31 mg/kg showed a decrease in testis weight and hypospermatogenesis. However, this dose level exceeded the maximum-tolerated dose (MTD) as significant signs of toxicity were seen.

4.6. Pregnancy and lactation
Addition of following 2 paragraphs..

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, particularly 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.

4.8 Undesirable effects
Addition of following paragraph..

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.

Section 4.6: redundant paragraph removed.

Section 4.4. & 4.8 Addition of suicidal thoughts and behaviour warnings .

most sections updated due to renewal of licence.