Rosal

Adults:

Major depressive episodes.

Obsessive-compulsive disorder.

Bulimia nervosa: Rosal 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.

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 20mg, the dose may be increased gradually up to a maximum of 60mg. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

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

Obsessive-compulsive disorder

Adults and the elderly: The recommended dose is 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 60mg/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 80mg/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 Rosal 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.

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 40mg. Maximum recommended dose is 60mg/day.

Hepatic impairment

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

Withdrawal symptoms seen on discontinuation of Rosal: Abrupt discontinuation should be avoided. When stopping treatment with Rosal 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. 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 capsule and oral solution forms are bioequivalent.

Fluoxetine is contra-indicated in combination with irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid).

Fluoxetine is contra-indicated in combination with metoprolol used in cardiac failure.

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. Rosal 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.

In a 19-week clinical trial, decreased height and weight gain was observed in children and adolescents treated with fluoxetine. 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. 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. 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 Rosal 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.

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.

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. 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. As these syndromes may result in potentially life-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

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.

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.

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.

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.).

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.

Rosal oral solution contains sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Rosal 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.

a. Summary of the safety profile

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

b. Tabulated list of adverse reactions

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

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

Frequency estimate: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000).

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 www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 Torsades 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.

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors. ATC code: N06A B03.

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. Rosal has been shown to be significantly more effective than placebo, as measured by the Hamilton Depression Rating Scale (HAM-D). In these studies, Rosal 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 20mg/day, but higher doses (40 or 60mg/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 60mg/day was shown to be significantly more effective than placebo for the reduction of bingeing, vomiting and purging activities. However, for long-term efficacy no conclusion can be drawn.

Pre-Menstrual Dysphoric Disorder: Two placebo-controlled studies were conducted in patients meeting Pre-Menstrual Dysphoric Disorder (PMDD) diagnostic criteria according to DSM-IV. Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others. Patients using oral contraceptives were excluded. In the first study of continuous 20mg 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 (20mg 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.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).

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 (desmethylfluoxetine), 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 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. 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.

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.

Not applicable.

No special requirements.