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SUMMARYOFPRODUCTCHARACTERISTICS

1. NAMEOFTHEMEDICINALPRODUCT

FluoxetinMylan 20 mg Dispersible Tablets

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Each dispersible tablet contains fluoxetine hydrochloride equivalent to 20 mg of fluoxetine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICALFORM

Dispersible tablet.

An oval, normal convex, white tabletdebossed “FL|20” on one side and “G” on the other.

The score line is not intended for breaking the tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Major depressive episodes.

Obsessive-compulsive disorder.

Bulimia nervosa: Fluoxetin Mylan is indicated as a complement of psychotherapyforthe reduction of binge-eating and purging activity.

Children and adolescents aged 8 years and above:

Moderate to severe major depressive episode, if depression is unresponsive to psychological therapyafter4-6 sessions. Antidepressant medication should be offered to a child or young person with moderate to severe depression only in combination with concurrent psychological therapy.

4.2 Posology and method of administration

Posology

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 therapyand thereafter as judged clinicallyappropriate. Although there maybe an increased potential for undesirable effects at higher doses, in some patients with insufficient response to 20 mg, the dose maybe increased gradually up to a maximum of 60 mg (see section 5.1). Dosage adjustments should be made carefullyon 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 patients 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 maybe increased graduallyup 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 therearenosystematic 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 carefullyon 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-termefficacy(more than 24 weeks) has not been demonstrated in OCD.

Bulimia nervosa

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

All indications

Adults:

The recommended dose maybe increased or decreased. Doses above 80 mg/dayhave not been systematicallyevaluated.

Paediatric population

Children and adolescents aged 8 years and above (moderate to severe major depressive episode):

Treatment mustbe initiated and monitored under specialist supervision. The starting dose is 10 mg/daygiven as a fluoxetine liquid formulation. Dose adjustments must be made carefully, on an individual basis, to maintain the patient at the lowest effective dose. After one to two weeks, the dose maybe increasedto20 mg/day. Clinical trial experience with dailydoses 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.

Hepatic impairment

A lower or less frequent dose (e.g. 20 mg everysecondday) should be considered in patients with hepatic impairment (see section 5.2), or in patients where concomitant medication has the potential for interaction with Fluoxetin Mylan (see section 4.5).

Withdrawal symptoms seen on discontinuation of fluoxetine

Abrupt discontinuation should be avoided. Whenstopping treatment with fluoxetine 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 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previouslyprescribed dose maybe considered. Subsequently, the physicianmaycontinue decreasing the dose, but at a more gradual rate.

Method of administration

For oral administration.

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

When dosing is stopped, active drug substances will persist in the bodyfor weeks. This should be borne in mind when starting or stopping treatment.

4.3 Contraindications

Hypersensitivityto the active substance or to anyof the excipients listed in section 6.1.

Fluoxetine is contraindicated in combination with irreversible, non-selective MAOI (e.g. iproniazid) (see sections 4.4 and 4.5).

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

4.4 Special warnings and precautions for use

Paediatricpopulation -children and adolescents under 18 years of age:

Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility(predominantly aggression, oppositional behaviour and anger) were more frequentlyobserved in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. Fluoxetin Mylanshouldonlybe used in children and adolescentsaged8to18years 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 theappearance of suicidal symptoms. In addition, onlylimited 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 (seesection 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 possibilityofadelayinpubertycannot be ruled out (see sections 4.8 and 5.3). 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 hypomaniawerecommonlyreported (see section 4.8). Therefore, regular monitoring for the occurrence of mania/hypomania is recommended. Fluoxetine should be discontinued in anypatiententering a manic phase.

It is important that the prescriber discusses carefullythe 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 maynot occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience with all antidepressant therapies that the risk of suicide mayincrease 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 maybe 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 historyof suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, areknown to beat a 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 yearsold.

Close supervision of patients and in particular those at high risk should accompanydrug therapy especiallyinearlytreatment and following dose changes.

Patients (and caregivers of patients) should be alerted about the need to monitor for anyclinical 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,afamilyhistoryof QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia, hypomagnesemia,bradycardia,acutemyocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g. hepatic impairment) or concomitant treatment with medicinal products that may induce QT prolongation and/or Torsades 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-selectivemonoamine 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 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.

Serotoninsyndromeorneurolepticmalignantsyndrome-likeevents:

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularlywhengivenin combination with other serotonergic (among others L-tryptophan) and/or neuroleptic drugs (see section 4.4). As these syndromesmayresultinpotentiallylife-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterised byclusters 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 treatmentshould be initiated.

Mania:

Antidepressants should be used with caution in patients with a historyof mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in anypatient 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, particularlyin concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g., atypicalantipsychotics such as clozapine, phenothiazines, most TCA’s, aspirin, NSAID’s) or other drugs that mayincrease risk of bleeding as well as in patients with a historyof bleeding disorders (see section 4.5).

Seizures:

Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiouslyin patients who have a historyof 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/epilepsyand patients with controlled epilepsyshould be carefullymonitored (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, maylead 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 bya subjectivelyunpleasant or distressing restlessness and need to move, often accompanied byaninabilityto sit or stand still. This is most likelyto occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose maybe detrimental.

Diabetes:

In patients with diabetes, treatment with an SSRImayalter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulinand/ororalhypoglycaemic dosage mayneed to be adjusted.

Hepatic/renal function:

Fluoxetine is extensivelymetabolised by the liver and excreted bythe kidneys. A lower dose, e.g., alternate daydosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20 mg/dayfor 2 months, patients with severe renal failure (GFR <10 ml/min) requiringdialysis 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:

Weightlossmayoccur in patients taking fluoxetine but is usuallyproportional to baseline bodyweight.

Withdrawal symptoms seen on discontinuation of SSRI treatment:

Withdrawalsymptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials adverse reactions 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 symptomsmaybe dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensorydisturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and / or vomiting, tremor and headache are the most commonlyreported reactions. Generallythesesymptoms are mild to moderate, however, in some patients theymay be severe in intensity. Theyusuallyoccur within the first few days of discontinuing treatment. Generally, these symptoms are self-limitingandusuallyresolve within 2 weeks, though in some individuals theymaybe 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 (seesection 4.2).

Mydriasis:

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

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):

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 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.

Metoprolol usedincardiacfailure:Riskofmetoprolol adverseeventsincluding excessivebradycardia,maybeincreasedbecauseofaninhibitionofitsmetabolism byfluoxetine(seesection4.3).

Not recommended combinations

Tamoxifen:Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showinga 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 efficacyof tamoxifen has been reported with concomitant usage of some SSRIantidepressants 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 SSRItreatment 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, a 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 toxicityhave occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status.

Serotoninergic 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).

Use with triptans carries the additional risk of coronary vasoconstriction and hypertension.

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 IAand 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 sections 4.4, 4.8 and 4.9).

Drugsaffectinghaemostasis(oralanticoagulants,whatevertheirmechanism, plateletaggregation inhibitors, includingaspirinandNSAIDs):riskofincreasedbleeding. Clinicalmonitoring,andmore frequentmonitoringofINRwithoralanticoagulants, shouldbemade.Adoseadjustmentduringthe fluoxetinetreatmentandafterits discontinuationmaybesuitable(seesections4.4and4.8).

Cyproheptadine:Thereareindividualcasereportsofreducedantidepressantactivity offluoxetinewhenusedincombinationwithcyproheptadine.

Drugsinducinghyponatremia:Hyponatremiaisanundesirableeffectoffluoxetine. Useincombinationwithotheragents associatedwithhyponatremia(e.g.diuretics, desmopressin,carbamazepineandoxcarbazepine)may leadtoanincreasedrisk(seesection4.8).

Drugsloweringtheepileptogenicthreshold:Seizuresareanundesirableeffect of fluoxetine. Use incombination withotheragentswhichmay lowertheseizure threshold(forexample,TCAs,otherSSRIs, phenothiazines,butyrophenones, mefloquine, chloroquine, bupropion, tramadol) mayleadtoanincreasedrisk.

Otherdrugsmetabolised byCYP2D6:Fluoxetine isa stronginhibitorofCYP2D6 enzyme,thereforeconcomitanttherapy withdrugsalsometabolisedby thisenzyme systemmayleadtodruginteractions,notablythosehavinganarrowtherapeutic index(suchasflecainide,propafenoneandnebivolol)andthosethatare titrated,but alsowithatomoxetine,carbamazepine,tricyclic antidepressants and risperidone. Theyshould be initiated at or adjusted to the low end of their dose range. This will also applyif 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 fluoxetineduring 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 defectsofapproximately1/100 in the general population.

Epidemiological data have suggested that the use of SSRIsinpregnancy, particular in late pregnancy,mayincrease the risk of persistent pulmonaryhypertension in the newborn (PPHN).

The observed risk was approximately5 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 treatment should be avoided during pregnancy (see section 4.2). If fluoxetine is used during pregnancy caution should be exercised, especially during late pregnancyor just prior to the onset of labour since the following effects have been reported in neonates: irritability,tremor,hypotonia, persistent crying, difficultyin suckling or in sleeping. These symptomsmayindicate either serotonergic effects or a withdrawal syndrome. The time to occur and the duration of these symptomsmaybe related to the long half- life of fluoxetine (4-6days) 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 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 mayaffect sperm quality(see section 5.3).

Human case reports with some SSRIs have shown that an effect on sperm qualityis reversible. Impact on human fertilityhas not been observed so far.

4.7 Effects on ability to drive and use machines

Fluoxetine 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, anypsychoactive drug may impair judgement or skills. Patients should beadvised to avoid driving a car or operating hazardous machineryuntiltheyarereasonablycertain that their performance is not affected.

4.8 Undesirable effects

a) Summary of the safety profile

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

_{b) Tabulatedlistofadversereactions}

The table below gives the adverse reactions observed withfluoxetinetreatmentin adult and paediatricpopulations. 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.

Frequencyestimate: Verycommon(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to

<1/100) and rare (≥1/10,000 to <1/1,000).Within each frequencygrouping, 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 disorder
	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
Cardiac disorders
	Palpitations Electrocardiogram QT prolonged(QTcF ≥450 msec)8		Ventricular arrhythmia including torsades de pointes
Vascular disorders
	Flushing9	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 haemorrhage11	Oesophageal pain
Hepatobillary disorders
			Idiosyncratic hepatitis
Skin and subcutaneous tissue disorders
	Rash12 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 urination13	Dysuria	Urinary retention Micturition disorder
Reproductive system and breast disorders
	Gynaecological bleeding14 Erectile dysfunction Ejaculation disorder14	Sexual dysfunction	Galactorrhoea Hyperprolactinaemia Priapism
General disorders and administration site conditions
Fatigue16	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage
Investigations
	Weight decreased	Transaminases increased Gamma-glutamyltransferase increased

c) Description of selected adverse reactions

Suicide/suicidal thoughts or clinical worsening:

Cases of suicidal ideation and suicidal behaviours have been reported during fluoxetine therapy orearlyafter treatment discontinuation (see section 4.4)

Bone fractures:

Epidemiological studies, mainlyconducted 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.

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

d) Paediatric population (see sections 4.4 and5.1):

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

Inpaediatricclinicaltrials,suicide-relatedbehaviours(suicideattemptandsuicidalthoughts),hostility (theeventsreportedwere: anger, irritability,aggression, agitation, activationsyndrome), manicreactions,includingmaniaandhypomania(noprior episodesreportedinthesepatients) andepistaxis,werecommonlyreportedandweremorefrequentlyobservedamongchildrenandadolescentstreatedwith antidepressants compared to those treated with placebo.

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

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

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

Reporting of suspected adverse reactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.

Itallows continued monitoringof thebenefit/riskbalance of the medicinalproduct. Healthcare professionalsareaskedtoreportanysuspectedadversereactionsviathenationalreporting system listed in Appendix V.

4.9 Overdose

Symptoms

Cases of overdose of fluoxetine alone usuallyhave 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. Fatalityattributed to overdose of fluoxetine alone has been extremelyrare.

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 unlikelyto be of benefit. Activated charcoal, which maybe used with sorbitol, maybe as or more effective than emesis or lavage. In managing overdosage, consider the possibilityof 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 theyare also taking, or have recentlytaken, fluoxetine.

5. PHARMACOLOGICALPROPERTIES

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 probablyaccounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α₁-, α₂-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 bythe Hamilton Depression Rating Scale (HAM-D).In these studies, fluoxetine produced a significantlyhigher rate of response (defined bya 50 % decrease in the HAM-D score) and remission, compared to placebo.

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

Obsessive-compulsive disorder:Inshort-term trials (under 24 weeks), fluoxetine was shown to be significantlymore 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)efficacyhas not been shown.

Bulimia nervosa:In short-term trials (under 16 weeks), in out-patients fulfilling DSM-III-R- criteria for bulimia nervosa, fluoxetine 60 mg/daywas shown to be significantlymore effective than placebo for the reduction of binge eating, vomiting and purging activities. However, for long-term efficacyno 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. Inthefirststudyof continuous 20 mg dailydosingfor6cycles, improvement was observed in the primaryefficacyparameter (irritability,anxietyanddysphoria). In the second study, with intermittent luteal phase dosing (20 mgdaily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (DailyRecord of Severityof Problems score). However, definitive conclusions on efficacyand duration of treatment cannot be drawn from these studies.

Paediaric population

Majordepressiveepisodes(childrenandadolescents): Clinicaltrialsinchildrenandadolescents aged 8years andabovehave beenconductedversusplacebo.Fluoxetine,at a dose of 20 mg,has beenshowntobesignificantly moreeffectivethanplacebointwoshort-termpivotalstudies,as measuredby the reduction of Childhood Depression Rating Scale-Revised(CDRS-R) total scoresandClinicalGlobalImpressionofImprovement(CGI-I) scores.Inbothstudies,patients metcriteriaformoderatetosevereMDD(DSM-IIIorDSM-IV)atthree different evaluations by practisingchildpsychiatrists.Efficacyinthefluoxetinetrialsmay dependontheinclusionofa selectivepatientpopulation(onethathasnotspontaneously recoveredwithinaperiodof3-5 weeksandwhosedepressionpersistedinthefaceofconsiderableattention).Thereisonly limiteddataonsafetyandefficacybeyond9weeks.Ingeneral,efficacyoffluoxetinewas modest.Responserates(theprimary endpoint,definedasa30 %decreaseintheCDRS-Rscore) demonstratedastatistically significantdifferenceinoneofthetwopivotalstudies(58 %for fluoxetineversus32 %forplacebo,P=0.013;and65 %forfluoxetineversus54 %forplacebo,P =0.093).In thesetwostudies,themeanabsolutechangesinCDRS-Rfrombaselinetoendpoint were 20forfluoxetine versus 11forplacebo,P= 0.002;and 22forfluoxetineversus 15for placebo, P <0.001.

Effects on growth(children and adolescents),see section 4.4 and 4.8: After 19weeks of treatment,paediatricsubjectstreatedwithfluoxetineinaclinicaltrialgainedanaverageof1.1 cm less inheight (p=0.004)and 1.1 kg less inweight(p=0.008) thansubjects treatedwith placebo.

Inaretrospectivematchedcontrolobservationalstudywithameanof1.8 yearsofexposureto fluoxetine, paediatric subjectstreated withfluoxetinehadno difference ingrowthadjusted for expected growth in height from their matched, untreated controls (0.0 cm, p=0.9673).

5.2 Pharmacokinetic properties

Absorption

Fluoxetine is well absorbed from the gastrointestinal tract afteroral administration. The bioavailabilityisnotaffectedbyfood intake.

Distribution

Fluoxetine is extensivelybound to plasma proteins (about 95 %) and it is widelydistributed (volume of distribution: 20 – 40 l/kg). Steady-state plasma concentrations are achieved after dosing for several weeks. Steady-state concentrations after prolonged dosing are similar to concentrations seen at 4 to 5 weeks.

Biotransformation

Fluoxetine has a non-linear pharmacokinetic profile with first pass liver effect. Maximum plasma concentration is generally achieved 6 to 8 hours after administration. Fluoxetine is extensively metabolised bythe polymorphic enzyme CYP2D6. Fluoxetine is primarily metabolised bythe liver to the active metabolite norfluoxetine (demethylfluoxetine),by desmethylation.

Elimination

The elimination half-life of 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.

Special populations

Elderly: Kinetic parameters are not altered in healthyelderlywhencomparedtoyounger subjects.

Paediatric population:The mean fluoxetine concentration in children isapproximately2-fold higher than that observed in adolescents and the mean norfluoxetine concentration 1.5-fold higher. Steady-state plasma concentrations are dependent on bodyweight and are higher in lower weight children (see section 4.2). As in adults, fluoxetine and norfluoxetine accumulated extensivelyfollowing multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of dailydosing.

Hepatic insufficiency:In case of hepatic insufficiency(alcohol cirrhosis), 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 in patients with mild, moderate or complete (anuria) renal insufficiency, kinetic parameters have not been altered when compared to healthyvolunteers. However, after repeated administration, an increase in steady- state plateau of plasma concentrations maybe observed.

5.3 Preclinical safety data

There is no evidence of carcinogenicity or mutagenicityfrom in vitro or animal studies.

Adult animal studies

Ina2-generation rat reproduction study, fluoxetine did not produce adverse effects on the mating or fertilityof rats, was not teratogenic, and did not affect growth, development, or reproductive parameters of the offspring.

The concentrations in the diet provided doses approximatelyequivalent to 1.5, 3.9, and 9.7 mg fluoxetine/kg bodyweight.

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 toxicitywere seen.

Juvenile animal studies

In a juvenile toxicologystudyin CD rats, administration of 30 mg/kg/dayof fluoxetine hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and necrosis, epididymal epithelial vacuolation, immaturityandinactivityof 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. At10 mg/kg/day, plasma levels achieved in animals were approximately0.8 to 8.8 fold (fluoxetine) and 3.6 to 23.2 fold (norfluoxetine) those usuallyobserved in paediatric patients.

At 3 mg/kg/day, plasma levels achieved in animals were approximately0.04to 0.5 fold (fluoxetine) and 0.3 to 2.1 fold (norfluoxetine) those usuallyachieved in paediatric patients.

Astudyin juvenile mice has indicated that inhibition of the serotonin transporter prevents the accrual of bone formation. This finding would appear to be supported byclinical findings. The reversibilityof this effect has not been established.

Another studyin 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.

6. PHARMACEUTICALPARTICULARS

6.1 List of excipients

Cellulose, microcrystalline

Silica, colloidal anhydrous

Maize starch

Crospovidone

Saccharin sodium

Magnesium stearate

Peppermint powder.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Polypropylene bottles with polyethylene snap closure cap containing 30, 100, 250 and 500 tablets. Or High densitypolyethylene bottles with polypropylene screw caps containing 100 and 250 tablets.

PVC/PE/PVdC/Al blister packs containing 7, 12, 14, 28 and30 tablets.

PVC/PE/PVdC/Al blister packs containing 30 (30x1) and 100 (100x1) unit-dose tablets.

Not all pack sizes maybe marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETINGAUTHORISATIONHOLDER

[To be completed nationally]

8. MARKETINGAUTHORISATIONNUMBER(S)

[To be completed nationally]

9. DATEOF FIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

[To be completed nationally]

10. DATEOFREVISIONOFTHETEXT

2016-11-11