Fluoxetine Hydrochloride Tablets USP 10mg Taj Pharma

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Fluoxetine Hydrochloride Tablets USP 10mg/20mg/40mg/60mg Taj Pharma

(Fluoxetine tablets)

1. Name of the medicinal product

Fluoxetine Hydrochloride Tablets USP 10mg/20mg/40mg/60mg Taj Pharma

2. Qualitative and quantitative composition

a) Fluoxetine Hydrochloride Tablets USP 10mg

Each tablet contains:
Fluoxetine hydrochloride
(equivalent to fluoxetine)                10mg
Excipients                                         q.s.

b) Fluoxetine Hydrochloride Tablets USP 20mg

Each tablet contains:
Fluoxetine hydrochloride
(equivalent to fluoxetine)                20mg
Excipients                                         q.s.

c) Fluoxetine Hydrochloride Tablets USP 40mg

Each tablet contains:
Fluoxetine hydrochloride
(equivalent to fluoxetine)                40mg
Excipients                                         q.s.

d) Fluoxetine Hydrochloride Tablets USP 60mg

Each tablet contains:
Fluoxetine hydrochloride
(equivalent to fluoxetine)                60mg
Excipients                                         q.s.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets.

4. Clinical particulars

4.1 Therapeutic indications

Adults:

Major depressive episodes.

Obsessive-compulsive disorder.

Bulimia nervosa: Fluoxetine is indicated as a complement of psychotherapy for the 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 therapy after 4–6 sessions. Antidepressant medication should be offered to a child or young person with moderate to severe depression only in combination with a concurrent psychological therapy.

4.2 Posology and method of administration

Posology

Adults

Major depressive episodes

Adults and the elderly:

The recommended dose is 20mg 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 (OCD)

Adults and the elderly:

The recommended dose is 20mg 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 20mg, the dose may be increased gradually up to a maximum of 60mg.

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 10mg/day given as 2.5ml of the fluoxetine 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 20mg/day. Clinical trial experience with daily doses greater than 20mg 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 every second day) should be considered in patients with hepatic impairment (see section 5.2), or in patients where concomitant medication has the potential for interaction with fluoxetine (see section 4.5).

Withdrawal symptoms seen on discontinuation of fluoxetine: Abrupt discontinuation should be avoided. When stopping 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 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.

The Tablets and oral solution forms are bioequivalent.

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

Electroconvulsive Therapy (ECT)

There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.

Tamoxifen

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

Akathisia/psychomotor restlessness

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

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Hepatic/Renal Function

Fluoxetine is extensively metabolized 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 <10 ml/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 Withdrawal symptoms seen on discontinuation of fluoxetine, 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.

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, 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 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, 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 toxicity have 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).

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, 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).

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 the region of 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

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).

Breast-feeding

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.

Fertility

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

Human case reports with some SSRI’s 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

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, 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

1. 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.

1. 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).

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

behavior, 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

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

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

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 also 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.

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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors,

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 serotonergic; dopaminergic; histaminergic1; muscarinic; and GABA receptors.

Clinical efficacy and safety

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

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

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

Bulimia nervosa: In short term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria for bulimia nervosa, fluoxetine 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.

PreMenstrual 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 : Clinical trials in children and adolescents aged 8 years and above have been conducted versus placebo. Fluoxetine, at a dose of 20mg, 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.

Effects on growth, see sections 4.4 and 4.8: After 19 weeks of treatment, paediatric subjects treated with fluoxetine in a clinical trial gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo.

In a retrospective matched control observational study with a mean of 1.8 years of exposure to fluoxetine, paediatric subjects treated with fluoxetine had no difference in growth adjusted 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 gastro-intestinal tract after oral administration. The bioavailability is not affected by food intake.

Distribution

Fluoxetine is extensively bound to plasma proteins (about 95%) and it is widely distributed (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 by the polymorphic enzyme CYP2D6. Fluoxetine is primarily metabolised by the liver to the active metabolite norfluoxetine (desmethyl fluoxetine), by desmethylation.

Elimination

The elimination half-life of fluoxetine is 4 to 6 days and for norfluoxetine 4 to16 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 healthy elderly when compared to younger subjects

Paediatric population:

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

Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine 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 healthy volunteers.However, after repeated administration, an increase in steady-state plateau of plasma concentrations may be observed.

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.

6. Pharmaceutical particulars

6.1 List of excipients

Tablets contents:

Cellulose, microcrystalline

Crospovidone, Silica, colloidal anhydrous

Maize starch, Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Fluoxetine Tablets are available in blister pack and HDPE bottle pack with polypropylene closure.

Blister pack: 5, 7, 10, 14, 20, 28, 30, 56 and 60 Tabletss, hard

Bottle pack: 28 and 500 Tabletss, hard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

                                                                                                                                                                    Rx Only

                                                             Fluoxetine Hydrochloride Tablets USP 10mg/20mg/40mg/60 mg Taj Pharma

(Fluoxetine tablets)

PACKAGE LEAFLET: INFORMATION FOR THE USER

EIGHT IMPORTANT THINGS YOU NEED TO KNOW ABOUT FLUOXETINE

Fluoxetine treats depression and anxiety disorders.

Like all medicines it can have unwanted effects. It is therefore important that you and your doctor weigh up the benefits of treatment against the possible unwanted effects, before starting treatment.

Fluoxetine is not for use in children and adolescents under 18. See section 2, Use in children and adolescents aged 8 to 18 years.

Fluoxetine won’t work straight away. Some people taking antidepressants feel worse before feeling better. Your doctor should ask to see you again a couple of weeks after you first start treatment. Tell your doctor if you haven’t started feeling better. See section 3, How to take Fluoxetine film-coated tablets.

Some people who are depressed or anxious think of harming or killing themselves. If you start to feel worse, or think of harming or killing yourself, see your doctor or go to a hospital straight away. See section 2.

Don’t stop taking Fluoxetine without talking to your doctor. If you stop taking Fluoxetine suddenly or miss a dose, you may get withdrawal effects. See section 3 for further information

If you feel restless and feel like you can’t sit or stand still, tell your doctor. Increasing the dose of Fluoxetine may make these feelings worse. See section 4, Possible side-effects.

Taking some other medicines with Fluoxetine can cause problems. You may need to talk to your doctor. See section 2, Taking other medicines.

If you are pregnant or planning to get pregnant, talk to your doctor. See section 2, Pregnancy and breastfeeding.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor or
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet:

1. What Fluoxetine film-coated tablets are and what they are used for
2. What you need to know before you take Fluoxetine film-coated tablets
3. How to take Fluoxetine film-coated tablets
4. Possible side effects
5. How to store Fluoxetine film-coated tablets
6. Contents of the pack and other information

1.What Fluoxetine film-coated tablets are and what they are used for

Fluoxetine belongs to a group of medicines called selective serotonin reuptake inhibitor (SSRI) antidepressants.

This medicine is used to treat the following conditions:

Adults:

• Major depressive episodes
• Obsessive-compulsive disorder
• Bulimia nervosa: Fluoxetine is used alongside psychotherapy for the reduction of binge-eating and purging

Children and adolescents aged 8 years and above:

Moderate to severe major depressive disorder, if the depression does not respond to psychological therapy after 4-6 sessions. Fluoxetine should be offered to a child or young person with moderate to severe major depressive disorder only in combination with psychological therapy.

How Fluoxetine works

Everyone has a substance called serotonin in their brain. People who are depressed or have obsessive- compulsive disorder or bulimia nervosa have lower levels of serotonin than others. It is not fully understood how Fluoxetine and other SSRIs work but they may help by increasing the level of serotonin in the brain.

Treating these conditions is important to help you get better. If it’s not treated, your condition may not go away and may become more serious and more difficult to treat.

You may need to be treated for a few weeks or months to ensure that you are free from symptoms.

2. What you need to know before you take Fluoxetine film-coated tablets Do not take Fluoxetine if you are:

• allergic to fluoxetine or any of the other ingredients of this medicine (listed in section 6). If you develop a rash or other allergic reactions (like itching, swollen lips or face or shortness of breath), stop taking the tablets straight away and contact your doctor immediately.
• taking other medicines known as non-selective monoamine oxidase inhibitors or reversible monoamine oxidase inhibitors type A (MAOIs), since serious or even fatal reactions can occur. Examples of such MAOIs include medicines used to treat depression such as nialamide, iproniazide, moclobemide, phenelzine, tranylcypromine, isocarboxazid, toloxatone and also linezolid (an antibiotic) and methylthioninium chloride also called methylene blue (used to treat medicinal or chemical induced methaemogobinaemia).

Treatment with Fluoxetine should only be started at least 2 weeks after discontinuation of an irreversible MAOI (for instance tranylcypromine).

However, treatment with fluoxetine can be started the following day after discontinuation of certain reversible MAOIs (for instance moclobemide, linezolid, methylthioninium chloride (methylene blue)).

Do not take any MAOIs for at least 5 weeks after you stop taking Fluoxetine. If Fluoxetine has been prescribed for a long period and/or at a high dose, a longer interval needs to be considered by your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking Fluoxetine if any of the following applies to you:

• heart problems;
• appearance of fever, muscle stiffness or tremor, changes in your mental state like confusion, irritability and extreme agitation; you may suffer from the so-called “serotonin syndrome” or “neuroleptic malignant syndrome”. Although this syndrome occurs rarely it may result in potentially life threatening conditions; contact your doctor immediately, since Fluoxetine might need to be
• mania now or in the past; if you have a manic episode, contact your doctor immediately because Fluoxetine might need to be discontinued;
• history of bleeding disorders or appearance of bruises or unusual bleeding;
• ongoing treatment with medicines that thin the blood (see ‘Other medicines and Fluoxetine’);
• epilepsy or fits. If you have a fit (seizures) or experience an increase in seizure frequency, contact your doctor immediately; Fluoxetine might need to be discontinued;
• ongoing ECT (electro-convulsive therapy);
• ongoing treatment with tamoxifen (used to treat breast cancer) (see ‘Other medicines and Fluoxetine’);
• starting to feel restless and cannot sit or stand still (akathisia). Increasing your dose of Fluoxetine may make this worse;
• diabetes (your doctor may need to adjust your dose of insulin or other antidiabetic treatment);
• liver problems (your doctor may need to adjust your dosage);
• low resting heart-rate and/or if you know that you may have salt depletion as a result of prolonged severe diarrhoea and vomiting (being sick) or usage of diuretics (water tablets);
• ongoing treatment with diuretics (water tablets), especially if you are elderly;
• glaucoma (increased pressure in the eye).
• medicines like Fluoxetine (so called SSRIs/SNRIs) may cause symptoms of sexual dysfunction (see section 4). In some cases, these symptoms have continued after stopping

Thoughts of suicide and worsening of your depression or anxiety disorder.

If you are depressed and/or have anxiety disorders you can sometimes have thoughts of harming or killing yourself. These may be increased when first starting antidepressants, since these medicines all take time to work, usually about two weeks but sometimes longer.

You may be more likely to think like this:

• If you have previously had thoughts about killing or harming
• If you are a young adult. Information from clinical trials has shown an increased risk of suicidal behaviour in adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant.

If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away.

You may find it helpful to tell a relative or close friend that you are depressed or have an anxiety disorder, and ask them to read this leaflet. You might ask them to tell you if they think your depression or anxiety is getting worse, or if they are worried about changes in your behaviour.

Children and adolescents aged 8 to 18 years:

Patients under 18 have an increased risk of side-effects such as suicide attempt, suicidal thoughts and hostility (predominantly aggression, oppositional behaviour and anger) when they take this class of medicines. Fluoxetine should only be used in children and adolescents aged 8 to 18 years for the treatment of moderate to severe major depressive episodes (in combination with psychological therapy) and it should not be used to treat other conditions.

Additionally, only limited information concerning the long-term safety of Fluoxetine on growth, puberty, mental, emotional and behavioural development in this age group is available. Despite this, and if you are a patient under 18, your doctor may prescribe Fluoxetine for moderate to severe major depressive episodes, in

combination with psychological therapy, because he/she decides that this is in your best interests. If your doctor has prescribed Fluoxetine for a patient under 18 and you want to discuss this, please go back to your doctor. You should inform your doctor if any of the symptoms listed above develop or worsen when  patients under 18 are taking Fluoxetine.

Fluoxetine should not be used in the treatment of children under the age of 8 years.

Other medicines and Fluoxetine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines

Do not take Fluoxetine with:

• Certain irreversible, non-selective monoamine oxidase inhibitors (MAOIs), some used to treat depression. Irreversible, non-selective MAOIs must not be used with Fluoxetine as serious or even fatal reactions (serotonin syndrome) can occur (see section “Do not take Fluoxetine”). Treatment with Fluoxetine should only be started at least 2 weeks after discontinuation of an irreversible, non- selective MAOI (for instance tranylcypromine). Do not take any irreversible, non-selective MAOIs for at least 5 weeks after you stop taking Fluoxetine. If Fluoxetine has been prescribed for a long period and/or at a high dose, a longer interval than 5 weeks may need to be considered by your doctor.
• metoprolol when used for heart failure; there is an increased risk of your heart beat becoming too slow.Fluoxetine may affect the way the following medicines work (interaction):
• tamoxifen (used to treat breast cancer); because Fluoxetine may change the blood levels of this drug, resulting in the possibility of a reduction in the effect of tamoxifen, your doctor may need to consider prescribing a different antidepressant
• monoamine oxidase inhibitors A (MAOI-A) including moclobemide, linezolid (an antibiotic) and methylthioninium chloride (also called methylene blue, used for the treatment of medicinal or chemical product induced methemoglobinemia): due to the risk of serious or even fatal reactions (called serotonin syndrome). Treatment with fluoxetine can be started the day after stopping treatment with reversible MAOIs but the doctor may wish to monitor you carefully and use a lower dose of the MAOI-A
• mequitazine (for allergies); because taking this drug with Fluoxetine may increase the risk of changes in the electrical activity of the
• phenytoin (for epilepsy); because Fluoxetine may influence the blood levels of this drug, your doctor may need to introduce phenytoin more carefully and carry out check-ups when given with Fluoxetine.
• lithium, selegiline, St. John’s Wort, tramadol (a painkiller), triptans (for migraine) and tryptophan; there is an increased risk of mild serotonin syndrome when these drugs are taken with Fluoxetine. Your doctor will carry out more frequent check-ups.
• medicines that may affect the heart’s rhythm, e.g. 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 or certain antihistamines (astemizole, mizolastine), because taking one or more of these drugs with Fluoxetine may increase the risk of changes in the electrical activity of the
• Anti-coagulants (such as warfarin), NSAID (such as ibruprofen, diclofenac), aspirin and other medicines which can thin the blood (including clozapine, used to treat certain mental disorders). Fluoxetine may alter the effect of these medicines on the blood. If Fluoxetine treatment is started or stopped when you are taking warfarin, your doctor will need to perform certain tests, adjust your dose and check on you more
• cyproheptadine (for allergies); because it may reduce the effect of
• drugs that lower sodium levels in the blood (including, drug that causes increase in urination, desmopressin, carbamazepine and oxcarbazepine); because these drugs may increase the risk of sodium levels in the blood becoming too low when taken with
• anti-depressants such as tricyclic anti-depressants, other selective serotonin reuptake inhibitors (SSRIs) or bupropion, mefloquine or chloroquine (used to treat malaria), tramadol (used to treat severe pain) or anti-psychotics such as phenothiazines or butyrophenones; because Fluoxetine may increase the risk of seizures when taken with these
• flecainide, propafenone, nebivolol or encainide (for heart problems), carbamazepine (for epilepsy), atomoxetine or tricyclic antidepressants (for example imipramine, desipramine and amitriptyline) or risperidone (for schizophrenia); because Fluoxetine may possibly change the blood levels of these medicines, your doctor may need to lower their dose when administered with Fluoxetine.

Fluoxetine with food, drink and alcohol

• You can take Fluoxetine with or without food, whatever you
• You should avoid alcohol while you are taking this

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Talk to your doctor as soon as possible if you’re pregnant, if you might be pregnant, or if you’re planning to become pregnant.

In babies whose mothers took fluoxetine during the first few months of pregnancy, there have been some studies describing an increased risk of birth defects affecting the heart. In the general population, about 1 in 100 babies are born with a heart defect. This increased to about 2 in 100 babies in mothers who took fluoxetine.

When taken during pregnancy, particularly in the last 3 months of pregnancy, medicines like fluoxetine may increase the risk of a serious condition in babies, called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If this happens to your baby you should contact your midwife and/or doctor immediately.

It is preferable not to use this treatment during pregnancy unless the potential benefit outweighs the potential risk. Thus, you and your doctor may decide to gradually stop taking Fluoxetine while you are pregnant or before being pregnant. However, depending on your circumstances, your doctor may suggest that it is better for you to keep taking Fluoxetine.

Caution should be exercised when used during pregnancy, especially during late pregnancy or just before giving birth since the following effects have been reported in new born children: irritability, tremor, muscle weakness, persistent crying, and difficulty in sucking or in sleeping.

Breast-feeding

Fluoxetine is excreted in breast milk and can cause side effects in babies. You should only breast-feed if it is clearly necessary. If breast-feeding is continued, your doctor may prescribe a lower dose of fluoxetine.

Fertility

Fluoxetine has been shown to reduce the quality of sperm in animal studies. Theoretically, this could affect fertility, but impact on human fertility has not been observed as yet.

Driving and using machines

Psychotropic drugs such as Fluoxetine may affect your judgment or co-ordination. Do not drive or use machinery until you know how Fluoxetine affects you.

3. How to take Fluoxetine film-coated tablets

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Do not take more tablets than your doctor tells you.

Swallow the tablets with a drink of water.

Adults:

The recommended dose is:

• Depression: The recommended dose is 20 mg daily. Your doctor will review and adjust your dosage if necessary within 3 to 4 weeks of the start of treatment. If required, the dosage can be gradually increased up to a maximum of 60 mg daily. The dose should be increased carefully to ensure that you receive the lowest effective dose. You may not feel better immediately when you first start taking your medicine for depression. This is usual because an improvement in depressive symptoms may not occur until after the first few weeks. Patients with depression should be treated for at least 6
• Bulimia nervosa: The recommended dose is 60 mg
• Obsessive-compulsive disorder: The recommended dose is 20 mg daily. Your doctor will review and adjust your dosage if necessary after 2 weeks of treatment. If required, the dosage can be gradually increased up to a maximum of 60 mg daily. If no improvement is noted within 10 weeks, your doctor will reconsider your

Use in children and adolescents aged 8 to 18 years with depression:

Treatment should be started and be supervised by a specialist. The starting dose is 10 mg/day. After 1 to 2 weeks, your doctor may increase the dose to 20 mg/day. The dose should be increased carefully to ensure that you receive the lowest effective dose. Lower weight children may need lower doses. If there is a satisfactory response to treatment, your doctor will review the need for continuing treatment beyond 6 months. If you have not improved within 9 weeks, your doctor will reassess your treatment.

Elderly:

Your doctor will increase the dose with more caution and the daily dose should generally not exceed 40 mg. The maximum dose is 60 mg daily.

Liver impairment:

If you have a liver problem or are using other medication that might affect Fluoxetine, your doctor may decide to prescribe a lower dose or tell you to use Fluoxetine every other day.

If you take more Fluoxetine than you should

• If you take too many tablets, go to your nearest hospital emergency department (or casualty) or tell your doctor straight
• Take the pack of Fluoxetine with you if you

Symptoms of overdose include: nausea, vomiting, seizures, heart problems (like irregular heart beat and cardiac arrest), lung problems and change in mental condition ranging from agitation to coma.

If you forget to take Fluoxetine

• If you miss a dose, do not worry. Take your next dose the next day at the usual time. Do not take a double dose to make up for a forgotten
• Taking your medicine at the same time each day may help you to remember to take it

If you stop taking Fluoxetine

• Do not stop taking Fluoxetine without asking your doctor first, even when you start to feel better. It is important that you keep taking your
• Make sure you do not run out of

You may notice the following effects (withdrawal effects) when you stop taking Fluoxetine: dizziness; tingling feelings like pins and needles; sleep disturbances (vivid dreams, nightmares, inability to sleep); feeling restless or agitated; unusual tiredness or weakness; feeling anxious; nausea/vomiting (feeling sick or being sick); tremor (shakiness); headaches.

Most people find that any symptoms on stopping Fluoxetine are mild and disappear within a few weeks. If you experience symptoms when you stop treatment, contact your doctor.

When stopping Fluoxetine, your doctor will help you to reduce your dose slowly over one or two weeks – this should help reduce the chance of withdrawal effects.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine.

• If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away (see Section 2).
• If you get a rash or allergic reaction such as itching, swollen lips/tongue or wheezing/shortness of breath, stop taking the tablets straight away and tell your doctor immediately.
• If you feel restless and cannot sit or stand still, you may have akathisia; increasing your dose of Fluoxetine may make you feel worse. If you feel like this, contact your doctor.
• Tell your doctor immediately if your skin starts to turn red or you develop a varied skin reaction or your skin starts to blister or peel. This is very

The most frequent sides effects (very common side effects that may affect more than 1 user in 10) are insomnia, headache, diarrhoea, feeling sick (nausea) and fatigue.

Some patients have had:

• a combination of symptoms (known as “serotonin syndrome”) including unexplained fever with faster breathing or heart rate, sweating, muscle stiffness or tremor, confusion, extreme agitation or sleepiness (only rarely);
• feelings of weakness, drowsiness or confusion mostly in elderly people and in (elderly) people taking diuretics (water tablets);
• prolonged and painful erection;
• irritability and extreme agitation;
• heart problems, such as fast or irregular heart rate, fainting, collapsing or dizziness upon standing which may indicate abnormal functioning of the heart

If you have any of the above side effects, you should tell your doctor immediately.

The following side effects have also been reported in patients taking Fluoxetine:

Common (may affect up to 1 in 10 people)

• not feeling hungry, weight loss
• nervousness, anxiety
• restlessness, poor concentration
• feeling tense
• decreased sex drive or sexual problems (including difficulty maintaining an erection for sexual activity)
• sleep problems, unusual dreams, tiredness or sleepiness
• dizziness
• change in taste
• uncontrollable shaking movements
• blurred vision
• rapid and irregular heartbeat sensations
• flushing
• yawning
• indigestion, vomiting
• dry mouth
• rash, urticaria, itching
• excessive sweating
• joint pain
• passing urine more frequently
• unexplained vaginal bleeding
• feeling shaky or chills

Uncommon (may affect up to 1 in 100 people)

• feeling detached from yourself
• strange thinking
• abnormally high mood
• orgasm problems
• thoughts of suicide or harming yourself
• teeth grinding
• muscle twitching, involuntary movements or problems with balance or co-ordination
• memory impairment
• enlarged (dilated) pupils
• ringing in the ears
• low blood pressure
• shortness of breath
• nose bleeds
• difficulty swallowing
• hair loss
• increased tendency to bruising
• unexplained bruising or bleeding
• cold sweat
• difficulty passing urine
• feeling hot or cold
• abnormal liver function test results

Rare (may affect up to 1 in 1,000 people)

• low levels of salt in the blood
• reduction in blood platelets, which increases risk of bleeding or bruising
• reduction in white blood cell count
• untypical wild behaviour
• hallucinations
• agitation
• panic attacks
• confusion
• stuttering
• aggression
• fits
• vasculitis (inflammation of a blood vessel)
• rapid swelling of the tissues around the neck, face, mouth and/or throat
• pain in the tube that takes food or water to your stomach
• hepatitis
• lung problems
• sensitivity to sunlight
• muscle pain
• problems urinating
• producing breast milk

Bone fractures – an increased risk of bone fractures has been observed in patients taking this type of medicines.

Most of these side effects are likely to disappear with continued treatment.

In children and adolescents (8-18 years) – In addition to the possible side effects listed above, Fluoxetine may slow growth or possibly delay sexual maturity. Suicide-related behaviours (suicide attempt and suicidal thoughts), hostility, mania, and nose bleeds were also commonly reported in children.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Fluoxetine film-coated tablets

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton (EXP). The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information What Fluoxetine film-coated tablets contains:
   • The active substance is fluoxetine. Each film-coated tablet contains fluoxetine hydrochloride equivalent to 10 mg fluoxetine.
   • The other ingredients are: Cellulose microcrystalline, crospovidone, silica colloidal anhydrous, maize starch (core) and polyvinyl alcohol-part. hydrolysed (E1203), titanium dioxide (E171), macrogol/peg (E1521) and talc (coating).

What Fluoxetine film-coated tablets looks like and contents of the pack

The film-coated tablets are white to off-white, film-coated, oval-shaped tablets, scored and debossed with “E” and “P” on one side and “360” on the other side.

The film-coated tablets are available in PVC/aluminium blister packs of 2, 7, 12, 14, 20, 28, 30, 50, 56, 70, 98, 100 and 500. Not all pack sizes may be marketed.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com