Fluoxetine

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.

Risk of serotonin syndrome including diarrhoea, tachycardia, sweating, tremor, confusion or coma. If the concomitant use of these active substances with fluoxetine cannot be avoided, close clinical monitoring should be undertaken and the concomitant agents should be initiated at the lower recommended doses.

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.

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.

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.

Concomitant administration of fluoxetine with anticoagulants increases the risk of 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.

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.

Animal data have shown that fluoxetine may affect sperm quality. 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.

Co-administration of fluoxetine with alprazolam resulted in elevated plasma levels of alprazolam.

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

In co-administration of fluoxetine with diazepam, the half-life of co-administered diazepam may be prolonged in some patients.

Because fluoxetine binds strongly to plasma proteins, administration of fluoxetine to a patient receiving another drug that is also strongly bound to serum proteins (e.g., coumadine, digoxin) may cause changes in plasma concentrations. and potentially triggering some side effects. On the other hand, the side effects may be due to the substitution of the serum protein bound fluoxetine by other drugs, which are as strongly bound to plasma proteins.

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.

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

Changes in blood levels of phenytoin 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.

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.

Patients treated with fluoxetine in combination with tryptophan showed adverse effects, including irritability, anxiety, and gastrointestinal disorders.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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. 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).

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.

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.

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.

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.

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).

Blood and lymphatic system disorders

Rare: Thrombocytopenia, Neutropenia, Leucopenia

Immune system disorders

Rare: Anaphylactic reaction, Serum sickness

Endocrine disorders

Rare: Inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Common: Decreased appetite¹

Rare: Hyponatraemia

Psychiatric disorders

Very Common: Insomnia²

Common: Anxiety, Nervousness, Restlessness, Tension, Libido decreased³, Sleep disorder, Abnormal dreams⁴

Uncommon: Depersonalisation, Elevated mood, Euphoric mood, Thinking abnormal, Orgasm abnorma^l5, Bruxism, Suicidal thoughts and behaviour⁶

Rare: Hypomania, Mania, Hallucinations, Agitation, Panic attacks, Confusion, Dysphemia, Aggression

Nervous system disorders

Very Common: Headache

Common: Disturbance in attention, Dizziness, Dysgeusia, Lethargy, Somnolence⁷, Tremor

Uncommon: Psychomotor hyperactivity, Dyskinesia, Ataxia, Balance disorder, Myoclonus, Memory impairment

Rare: Convulsion, Akathisia, Buccoglossal syndrome, Serotonin syndrome

Eye disorders

Common: Vision blurred

Uncommon: Mydriasis

Ear and labyrinth disorders

Uncommon: Tinnitus

Cardiac disorders

Common: Palpitations, Electrocardiogram QT prolonged (QTcF ≥450 msec)8

Rare: Ventricular arrhythmia including torsades de pointes

Vascular disorders

Common: Flushing⁹

Uncommon: Hypotension

Rare: Vasculitis, Vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: Yawning

Uncommon: Dyspnoea, Epistaxis

Rare: Pharyngitis, Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis)¹⁰

Gastrointestinal disorders

Very Common: Diarrhoea, Nausea

Common: Vomiting, Dyspepsia, Dry mouth

Uncommon: Dysphagia, Gastrointestinal haemorrhage¹¹

Rare: Oesophageal pain

Hepato-biliary disorders

Rare: Idiosyncratic hepatitis

Skin and subcutaneous tissue disorders

Common: Rash¹², Urticaria, Pruritus, Hyperhidrosis

Uncommon: Alopecia, Increased tendency to bruise, Cold sweat

Rare: Angioedema, Ecchymosis, Photosensitivity reaction, Purpura, Erythema multiforme, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (Lyell Syndrome)

Musculoskeletal and connective tissue disorders

Common: Arthralgia

Uncommon: Muscle twitching

Rare: Myalgia

Renal and urinary disorders

Common: Frequent urination¹³

Uncommon: Dysuria

Rare: Urinary retention, Micturition disorder

Reproductive system and breast disorders

Common: Gynaecological bleeding¹⁴, Erectile dysfunction, Ejaculation disorder¹⁵

Uncommon: Sexual dysfunction

Rare: Galactorrhoea, Hyperprolactinaemia, Priapism

General disorders and administration site conditions

Very Common: Fatigue¹⁶

Common: Feeling jittery, Chills

Uncommon: Malaise, Feeling abnormal, Feeling cold, Feeling hot

Rare: Mucosal haemorrhage

Investigations

Common: Weight decreased

Uncommon: Transaminases increased, Gamma-glutamyltransferase increased

¹ Includes anorexia
² Includes early morning awakening, initial insomnia, middle insomnia
³ Includes loss of libido
⁴ Includes nightmares
⁵ Includes anorgasmia
⁶ Includes completed suicide, depression suicidal, intentional self-injury, self-injurious ideation, suicidal behaviour, suicidal ideation, suicide attempt, morbid thoughts, self-injurious behaviour. These symptoms may be due to underlying disease
⁷ Includes hypersomnia, sedation
⁸ Based on ECG measurements from clinical trials
⁹ Includes hot flush
¹⁰ Includes atelectasis, interstitial lung disease, pneumonitis
¹¹ Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage
¹² Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash
¹³ Includes pollakiuria
¹⁴ Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage
¹⁵ Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation
¹⁶ Includes asthenia

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.

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. It is therefore advised that when fluoxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

Paediatric population

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

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

Isolated cases of growth retardation have been reported from clinical use.

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.