4.1. Therapeutic indications

Fluoxetine Oral Solution is indicated for the treatment of:

Major depressive episodes

Obsessive – compulsive disorder

Bulimia nervosa - Fluoxetine Oral Solution is indicated as a complement of psychotherapy for the reduction of binge eating and purging activity

4.2. Posology and method of administration

Posology

Adults

Major depressive episodes

Adults and the elderly: The recommended dose is 20 mg daily. Dosage should be reviewed and adjusted if necessary within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate. Although there may be an increased potential for undesirable effects at higher doses, in some patients, with insufficient response to 20 mg, the dose may be increased gradually up to a maximum of 60 mg (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

Obsessive-compulsive disorder

Adults and the elderly: The recommended dose is 20 mg daily. Although there may be an increased potential for undesirable effects at higher doses, in some patients, if after two weeks there is insufficient response to 20 mg, the dose may be increased gradually up to a maximum of 60 mg.

If no improvement is observed within 10 weeks, treatment with fluoxetine should be reconsidered. If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis. While there are no systematic studies to answer the question of how long to continue fluoxetine treatment, OCD is a chronic condition and it is reasonable to consider continuation beyond 10 weeks in responding patients. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose. The need for treatment should be reassessed periodically. Some clinicians advocate concomitant behavioural psychotherapy for patients who have done well on pharmacotherapy. Long- term efficacy (more than 24 weeks) has not been demonstrated in OCD.

Bulimia nervosa

Adults and the elderly: A dose of 60 mg/day is recommended. Long-term efficacy (more than 3 months) has not been demonstrated in bulimia nervosa.

All indications

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

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 the Prozep Oral Solution. 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.

Lower weight children:

Due to higher plasma levels in lower weight children, the therapeutic effect may be achieved with lower doses (see section 5.2).

For paediatric patients who respond to treatment, the need for continued treatment after 6 months should be reviewed. If no clinical benefit is achieved within 9 weeks, treatment should be reconsidered.

Elderly patients

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

Patients with 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 Prozep (see section 4.5).

Withdrawal symptoms seen on discontinuation of Prozep: Abrupt discontinuation should be avoided. When stopping treatment with Prozep the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 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.

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.

4.3. Contraindications

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

Fluoxetine is contra-indicated in combination with irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid) (see sections 4.4 and 4.5). Fluoxetine is contra-indicated in combination with metoprolol used in cardiac failure (see section 4.5).

4.4. Special warnings and precautions for use

Paediatric population - Children and adolescent under 18 years of age:

Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared with those treated with placebo. Fluoxetine should only be used in children and adolescents aged 8 to 18 years for the treatment of moderate to severe major depressive episodes and it should not be used in other indications. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, only limited evidence is available concerning long-term effect on safety in children and adolescents, including effects on growth, sexual maturation and cognitive, emotional and behavioural developments (see section 5.3).

In a 19-week clinical trial decreased height and weight gain was observed in children and adolescents treated with fluoxetine (see section 5.1). It has not been established whether there is an effect on achieving normal adult height. The possibility of a delay in puberty cannot be ruled out (see section 5.3 and 4.8). Growth and pubertal development (height, weight and TANNER staging) should therefore be monitored during and after treatment with fluoxetine. If either is slowed, referral to a paediatrician should be considered.

In paediatric trials, mania and hypomania were commonly reported (see section 4.8). Therefore, regular monitoring for the occurrence of mania/hypomania is recommended. Fluoxetine should be discontinued in any patient entering a manic phase.

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 suicidal 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 torsades 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.

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 4.5). As these syndromes may result in potentially life threatening conditions, treatment with fluoxetine should be discontinued if such events (characterized 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.

Due to the risk of serotonin syndrome, fluoxetine should not be used in combination with pethidine (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 a manic phase.

Haemorrhage: There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura, with SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g. gynaecological haemorrhages, gastro-intestinal 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 TCAs, aspirin, NSAIDs), or other drugs that may increase risk of bleeding, as well as in patients with a history of bleeding disorders (see section 4.5). SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 4.8).

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. Fluoxetine 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 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 20mg/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.

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

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).

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.

Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.

Sorbitol: This medicinal product contains 2.2 g of sorbitol in each 5 ml spoonful of fluoxetine Oral Solution which is equivalent to 0.44 g/ml. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

Benzoic acid: This medicinal product contains 2.5 mg benzoic acid in each 5ml spoonful of fluoxetine oral solution which is equivalent to 0.5 mg/ml.

Polyoxyl 40 hydrogenated castor oil: This medicinal product contains 50 mg polyoxyl 40 hydrogenated castor oil in each 5 ml spoonful of fluoxetine oral solution which is equivalent to 10mg/ml. Castor oil may cause stomach upset and diarrhoea.

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).

Contra-indicated combinations:

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, nonselective 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.

Metoprolol used in cardiac failure: risk of metoprolol adverse events, including excessive bradycardia may be increased because of an inhibition of its metabolism by fluoxetine (see section 4.3).

Not recommended combinations:

Tamoxifen: Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75 % reduction in plasma levels of one of the more active forms of the tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including fluoxetine) should whenever possible be avoided (see section 4.4).

Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol. However, the combination of SSRI treatment and alcohol is not advisable.

MAOI-A including linezolid and methylthioninium chloride (methylene blue): Risk of serotonin syndrome including diarrhoea, tachycardia, sweating, tremor, confusion or coma. If concomitant use of these active substances with fluoxetine cannot be avoided, close clinical monitoring should be undertaken and the concomitant agents should be initiated at the lower recommended doses (see section 4.4).

Mequitazine: risk of mequitazine adverse events (such as QT prolongation) may be increased because of an inhibition of its metabolism by fluoxetine.

Combinations requiring caution:

Phenytoin: Changes in blood levels have been observed when combined with fluoxetine. 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 status.

Serotonergic drugs: (lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St. John's Wort (Hypericum perforatum)): There have been reports of mild serotonin syndrome when SSRIs were given with drugs also having a serotoninergic effect.Therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution, with closer and more frequent clinical monitoring (see section 4.4).

Pethidine: Cases of serotonin syndrome have been reported in patients taking pethidine concomitantly with fluoxetine (see section 4.4)

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 sections 4.4 and 4.8).

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).

Cyproheptadine: There are individual case reports of reduced antidepressant activity of fluoxetine when used in combination with cyproheptadine.

Drugs inducing hyponatremia: Hyponatremia is an undesirable effect of fluoxetine. Use in combination with other agents associated with hyponatremia (e.g. diuretics, desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk (see section 4.8).

Drugs lowering the epileptogenic threshold: Seizures are an undesirable effect of fluoxetine. Use in combination with other agents which may lower the seizure threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk.

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 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 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.

Fluoxetine 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 “Posology and method of administration”). If fluoxetine is used during pregnancy, caution should be exercised, especially during late pregnancy or just prior to the onset of labour since 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).

Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).

Breastfeeding

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 is considered necessary, discontinuation of breast-feeding should be considered; however, if breast-feeding is continued, the lowest effective dose of fluoxetine should be prescribed.

Fertility

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.

4.7. Effects on ability to drive and use machines

Prozep has no or negligible influence on the 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. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.

4.8. Undesirable effects

a. Summary of the safety profile

The most commonly reported adverse reactions in patients treated with fluoxetine were headache, nausea, insomnia, fatigue and diarrhoea. Undesirable effects may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

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) and not known (cannot be estimated from the available data).

Very Common

Common

Uncommon

Rare

Not Known

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 appetite 1

Hyponatraemia

Psychiatric disorders

Insomnia 2

Anxiety

Nervousness

Restlessness

Tension

Libido decreased 3

Sleep disorder

Abnormal dreams 4

Depersonalisation

Elevated mood

Euphoric mood

Thinking abnormal

Orgasm abnormal 5

Bruxism

Suicidal thoughts and behaviour 6

Hypomania Mania

Hallucinations

Agitation

Panic attacks

Confusion

Dysphemia

Aggression

Nervous system disorders

Headache

Disturbance in attention

Dizziness

Dysgeusia

Lethargy

Somnolence 7

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

Cardiac disorders

Palpitations

Electrocardiogram QT prolonged (QTcF ≥ 450 msec) 8

Ventricular arrhythmia including torsades de pointes

Vascular disorders

Flushing 9

Hypotension

Vasculitis

Vasodilatation

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 haemorrhage 11

Oesophageal pain

Hepato-biliary disorders

Idiosyncratic hepatitis

Skin and subcutaneous tissue disorders

Rash 12

Urticaria

Pruritus

Hyperhidrosis

Alopecia

Increased tendency to bruise

Cold sweat

Angioedema

Ecchymosis

Photosensitivity reaction

Purpura

Erythema multiforme

Stevens-Johnson syndrome

Toxic Epidermal Necrolysis (Lyell Syndrome)

Musculoskeletal and connective tissue disorders

Arthralgia

Muscle twitching

Myalgia

Renal and urinary disorders

Frequent urination 13

Dysuria

Urinary retention

Micturition disorder

Reproductive system and breast disorders

Gynaecological bleeding 14

Erectile dysfunction

Ejaculation disorder 15

Sexual dysfunction

Galactorrhoea

Hyperprolactinemia

Priapism

Postpartum haemorrhage 17

General disorders and administration site conditions

Fatigue 16

Feeling jitteryChills

Malaise

Feeling abnormal

Feeling cold

Feeling hot

Mucosal haemorrhage

Investigations

Weight decreased

Transaminases increased

Gamma- glutamyl transferase 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

8 Based on ECG measurements from clinical trials

9 Includes hot flush

10 Includes atelectasis, interstitial lung disease, pneumonitis

11 Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage

12 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 Includes pollakiuria

14 Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage

15 Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation

16 Includes asthenia

17 This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).

c. Description of selected adverse reactions

Suicide/suicidal thoughts or clinical worsening: Cases of suicidal ideation and suicidal behaviour have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4).

Bone fractures: 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 the risk is unknown.

Withdrawal symptoms seen on discontinuation of fluoxetine treatment: 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 4.2 and section 4.4).

d. Paediatric population (see sections 4.4 and 5.1):

Adverse reactions that have been observed specifically or with a different frequency in this population are described below. Frequencies for these events are based on paediatric clinical trial exposures (n = 610).

In paediatric clinical trials suicide-related behaviours (suicide attempt and suicidal thoughts), hostility (the events reported were: anger, irritability, aggression, agitation, activation syndrome), manic reactions, including mania and hypomania (no prior episodes reported in these patients) and epistaxis, were commonly reported and were more frequently observed among children and adolescents treated with antidepressants compared to those treated with placebo.

Isolated cases of growth retardation have been reported from clinical use (see also section 5.1).

In paediatric clinical trials, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.

Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual dysfunction have been reported from paediatric clinical use (see also section 5.3).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias (including nodal rhythm and ventricular arrhythmias) or ECG changes indicative of QTc prolongation to cardiac arrest (including very rare cases of Torsade de Pointes), pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been extremely rare.

Management

Cardiac and vital signs monitoring are recommended, along with general symptomatic and supportive measures. No specific antidote is known.

Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage. In managing overdosage, consider the possibility of multiple drug involvement. An extended time for close medical observation may be needed in patients who have taken excessive quantities of a tricyclic antidepressant if they are also taking, or have recently taken, fluoxetine.