4.  CLINICAL PARTICULARS

4.1 Therapeutic Indications

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.

Paediatric 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.
After one to two weeks, the dose may be increased to 20 mg/day. Clinical trial experience with daily doses greater than 20 mg is minimal. There is only limited data on treatment beyond 9 weeks.

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 Gerozac (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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Fluoxetine is contraindicated in combination with irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid) (see sections 4.4 and 4.5). 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), and in patients who have recently discontinued an SSRI and have been started on a MAOI. Treatment of Fluoxetine should only be started 2 weeks after discontinuation of an irreversible MAOI and the following day after discontinuation of a reversible MAOI-A.

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 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 irreversible, non-selective MAOIs (e.g. iproniazid) (see section 4.5). Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting a MAOI. If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.

Fluoxetine is contraindicated in combination with metoprolol used in cardiac failure (see section 4.5).

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.

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 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), 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.

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 medicinal products. 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).

Irreversible, nonselective 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 resemble and be 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 contraindicated 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. If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.

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 4.5). 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 SSRI’s, 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 medicinal products. 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).

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 manic phase.

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/day for 2 months, patients with severe renal failure (GFR<10ml/min) 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.

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 it 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 SSRI’s, 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.

Lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

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 4.5). 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.

4.5  Interaction with other medicinal products and other forms of interaction

Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind (see section 5.2) when considering pharmacodynamic or pharmacokinetic drug interactions (e.g. when switching from fluoxetine to other antidepressants).

Contraindicated combinations

Irreversible, Non-selective Monoamine Oxidase Inhibitors (e.g. iproniazid):MAOIs): (see section 4.3).
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible, nonselective 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 contraindicated 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.

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, antipsychotics (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 4.4 and 4.8). Warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped (see section 4.4, Haemorrhage).

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 does doses 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 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.

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, persistent 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).

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

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
8. Based on ECG measurements from clinical trials
9. 8. Includes hot flush
10. 9. Includes atelectasis, interstitial lung disease, pneumonitis
11. 10. Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage.
12. 11. Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash
13. 12. Includes pollakiuria
14. 13. Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage
15. 14. Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation
16. 15. Includes asthenia

5.  PHARMACOLOGICAL PROPERTIES

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-, α2, and β-adrenergic sertonergic; 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.

Bulimia nervosa: In short term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria for bulimia nervosa, 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 Pre-Menstrual Dysphoric Disorder (PMDD) diagnostic criteria according to DSM-IV. 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

Special At-risk populations

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

5.3 Preclinical safety data

There is no evidence of carcinogenicity or mutagenicity from in vitro or 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.

Juvenile animal studies
In a juvenile toxicology study in CD rats, administration of 30 mg/kg/day of fluoxetine hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and necrosis, epididymal epithelial vacuolation, immaturity and inactivity of the female reproductive tract and decreased fertility. Delays in sexual maturation occurred in males (10 and 30 mg/kg/day) and females (30 mg/kg/day). The significance of these findings in humans is unknown. Rats administered 30 mg/kg also had decreased femur lengths compared with controls and skeletal muscle degeneration, necrosis and regeneration. At 10 mg/kg/day, plasma levels achieved in animals were approximately 0.8 to 8.8-fold (fluoxetine) and 3.6 to 23.2-fold (norfluoxetine) those usually observed in paediatric patients. At 3 mg/kg/day, plasma levels achieved in animals were approximately 0.04 to 0.5-fold (fluoxetine) and 0.3 to 2.1-fold (norfluoxetine) those usually achieved in paediatric patients.

A study in juvenile mice has indicated that inhibition of the serotonin transporter prevents the accrual of bone formation. This finding would appear to be supported by clinical findings. The reversibility of this effect has not been established.

Another study in juvenile mice (treated on postnatal days 4 to 21) has demonstrated that inhibition of the serotonin transporter had long lasting effects on the behaviour of the mice. There is no information on whether the effect was reversible. The clinical relevance of this finding has not been established.

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.

6.1 List of excipients

Lactose

Maize Starch

Colloidal Anhydrous Silica

Purified Talc

Magnesium Stearate

 
Capsule Colourants

Brilliant Blue (E133)

Quinoline Yellow (E104)

Titanium Dioxide (E171)

Indigo Carmine (E132)

Erythrosine (E127)

 
Capsule Constituents

Sodium LaurilsulfateSodium Lauryl Sulphate

Anhydrous Colloidal Silica

Gelatin

 
Printing Ink

Shellac

Ethanol

Propylene Glycol

Iron Oxide Black (E172)

Water-Filtered

Ammonium Hydroxide

Potassium Hydroxide

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.

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.

Furthermore, also fluoxetine can be used during pregnancy, caution should be

exercised, especially during late pregnancy or just prior to the onset of labour since the following effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or in sleeping. These symptoms may indicate either serotoninergic 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).

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

4.8 Undesirable Effects
Addition of 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 4.1: Added indications for children and adolescents.

Section 4.2: Added posology for children and adolescents.

Section 4.4: Added warning for use in children and adolescents under 18 years of age.

Section 4.8: Added side effects for children and adolescents.

Section 5: Added pharmacological information regarding children and adolescents.