RiteMED Fluoxetine

RiteMED Fluoxetine 20 mg Capsule: Violet-Yellow hard gelatin capsules "4" filled with white powder.
Each capsule contains: Fluoxetine (as hydrochloride), BP 20 mg.
Excipients/Inactive Ingredients: Violet/Yellow capsules: Lactose monohydrate, cellulose microcrystalline, magnesium stearate and capsule shell consisting of sunset yellow FCF (E110), titanium oxide (E171), iron oxide yellow (E172), brilliant blue FCF (E133), erythrosine (E127) and gelatin.

Antidepressant.
Pharmacology: Pharmacokinetics: Fluoxetine is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing about 6 to 8 hours after oral dose. Systemic bioavailability does not appear to be affected by food. Fluoxetine is extensively metabolized, by demethylation, in the liver to its primary active metabolite, Norfluoxetine. Excretion is mainly via the urine. Protein binding is reported to be about 95%.
Fluoxetine used clinically is a racemic mixture consisting of R- and S-enantiomers in equal amounts. Both enantiomers are active according to animal studies, but S-Fluoxetine is eliminated more slowly.
Metabolism is believed to be mediated by cytochrome P450 isoenzyme CYP2D6 and leads to R- and S-enantiomers of Norfluoxetine with the S-enantiomer being considered as active as the parent drug, the R-enantiomer is considered to be much less active. This metabolism is subject to genetic polymorphism. While the small proportion of the population known as slow metabolizers do show a different spectrum of parent drug and metabolite, the over-all activity does not appear to be altered.
Fluoxetine is widely distributed throughout the body.
Fluoxetine has a relatively long elimination half-life of about 1 to 3 days after acute use and 4 to 6 days after long-term use; that of its metabolite, Norfluoxetine is even longer being about 4 to 16 days. These long half-lives have clinical implications. Steady-state plasma concentrations will only be attained after several weeks. Additionally, Fluoxetine and its metabolites may persist for a considerable time after treatment, and this has led to precautions concerning the subsequent use of other serotonergic drugs.
Fluoxetine and Norfluoxetine are distributed into breastmilk.
Metabolism: Although Fluoxetine is stated by the manufacturers to be metabolized by the cytochrome P450 isoenzyme CYP2D6, which is supported by studies indicating that its disposition is altered in poor metabolizers of debrisoquine (a substrate for this enzyme), others have suggested that CYP2C19, and perhaps CYP2C9, play an important role.

Fluoxetine 20 mg capsule is indicated as part of the management of generalized anxiety disorder, obsessive-compulsive disorder, panic disorders with or without agoraphobia, social phobia and post-traumatic stress disorder and as part of the management of bulimia nervosa for the reduction of associated binge-eating and purging activity, as a complement of psychotherapy. Fluoxetine is also used in the treatment of pre-menstrual dysphoric disorder.
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 and Method of Administration: For oral administration.
Major depressive episodes: The usual initial dose is 20 mg once daily, US product information recommends giving this dose in the morning. If no clinical response is seen after several weeks, the daily dose may be gradually increased, up to a maximum of 80 mg daily (60 mg in the elderly). Doses above 20 mg daily may be given in 2 divided doses, for example in the morning and at noon, or as a once daily dose.
Depression in children aged 8-years and over: Initial doses of 10 mg should be increased to 20 mg daily after 1 week (except in low-weight children when such increases should not be made for several weeks, and then only if the clinical response is insufficient). Because of the concerns about the use in children, it is use only as an adjunct to psychological therapy in children and adolescents with moderate to severe depression who have not responded to psychological therapy alone.
Bulimia nervosa: A dose of 60 mg once daily is recommended.
Obsessive-Compulsive disorder: The initial dose is 20 mg once daily increased after several weeks if there is no response to up to 60 mg daily. Up to 80 mg has been used, sometimes divided into 2 doses.
Obsessive-Compulsive disorder in children aged 7-years and over: The starting dose is 10 mg daily. In low-weight children this is increased after several weeks to 20 mg to 30 mg daily, if required. Adolescents and heavier children may be increased to 20 mg daily after 2 weeks; further increases to 60 mg daily may be made after several weeks, as necessary.
Panic disorder: Initial dose of 10 mg once daily. After a week the dose should be increased to 20 mg daily; further increases to 60 mg daily maybe considered after several weeks if no improvement is seen.
Pre-menstrual dysphoric disorder: A dose of 20 mg daily. Intermittent dosing is also permitted; for each new cycle, Fluoxetine should be started 14 days before the onset of menstruation and continued until the first full day of menstruation. Treatment may be continued for 6 months; benefits should then be re-assessed before continuing further.
Elderly: A lower or less frequent dose is recommended in elderly patients as well as patients with hepatic impairment.
Withdrawal symptoms seen on discontinuation of therapy: Although SSRIs should generally be withdrawn gradually to reduce the risk of withdrawal symptoms, the long half-life may reduce the need for dose tapering with Fluoxetine.

A report involving cases in which Fluoxetine was taken in overdosage without other drugs found that the main symptoms were tachycardia, drowsiness, tremor and nausea and vomiting. These were considered relatively minor, and were of short duration, and supportive care was considered to be the only intervention necessary.
Treatment of overdosage with an SSRI involves appropriate symptomatic and supportive therapy. Activated charcoal may be given by mouth if the amount ingested was large and treatment is within an hour of ingestion. Dialysis, hemoperfusion, exchange transfusion, and measures to increase urine production are considered unlikely to be of benefit.
The UK Poisons Information Service considers the benefits of gastric decontamination in the management of overdosage with SSRIs to be uncertain. However, it is suggested that oral activated charcoal may be considered if this is given within 1 hour of ingestion and the quantity of SSRI exceeds the following amount: Fluoxetine: 500 mg (adult); 5 mg/kg (child).

Hypersensitivity to Fluoxetine or any of its excipients.
Diabetes mellitus: Changes in blood sugar concentrations may occur in patients with diabetes treated for depression with SSRIs.
Gastrointestinal disorders: For the opinion that the SSRIs may produce a clinically important increase in the risk of upper gastrointestinal bleeding in patients with a high risk of such bleeding.
Glaucoma: For reference to SSRIs precipitating or exacerbating symptoms of glaucoma.
Mania: Hypomania or mania has been reported with the SSRIs; it is recommended that SSRIs should be withdrawn in any patient entering a manic phase.
Surgery: In patients undergoing orthopedic surgery, the risk of perioperative blood loss was significantly increased in those taking serotonergic antidepressant (specifically clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine) when compared to those on non-serotonergic antidepressants. In addition, there was a significant increase in the need for blood transfusion during surgery in those on serotonergic antidepressants compared with those not receiving antidepressant medications.
Withdrawal: In general, withdrawal reactions tend to occur within 3 days of stopping on SSRI or related antidepressant although delay of up to 2 weeks may be noted with Fluoxetine. Common symptoms include dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety and sleep disorders. In some cases, withdrawal symptoms may be severe and disabling.

Because of their epileptogenic effect, SSRIs should be used with caution in patients with epilepsy or a history of such disorders (and should be avoided if the epilepsy is poorly controlled). Treatment should be stopped if seizures develop or when there is an increase in seizure frequency.
Care is advised in patients receiving ECT as prolonged seizures have occurred rarely. SSRIs should also be used with caution in patients with cardiac disease or a history of bleeding disorders. Although SSRIs are preferred to tricyclics for the treatment of depression in patients with diabetes, they may alter glycemic control and therefore caution is also warranted in diabetic subjects. SSRIs should be used with caution in patients with angle-closure glaucoma.
Fluoxetine should be stopped in patients who develop a rash since systemic effects, possibly related to vasculitis, have occurred in such patients. Fluoxetine undergoes hepatic metabolism and should be used with caution and in reduced doses in patients with impaired hepatic functions.
Patients should be closely monitored during early therapy until significant improvement in depression is observed because suicide is an inherent risk in depressed patients. Suicidal thoughts and behavior may also develop during early treatment with antidepressants for other disorders; the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders. If SSRIs are given for the depressive component of bipolar disorder, mania may be precipitated. Symptoms may also worsen during the initial treatment of panic disorder with SSRIs. SSRIs should generally be withdrawn gradually to reduce the risk of withdrawal symptoms although this may be unnecessary for Fluoxetine because of its long half-life.
Effects in ability to drive and use machines: While affective disorders probably adversely affect driving skill, treatment with anti-depressants can also be hazardous, although patients may be safer drivers with medication than without. Impairment of performance is largely related to sedative and antimuscarinic effects.

Pregnancy: There is incidence of minor fetal abnormalities in infants exposed to Fluoxetine during first trimester. Also, infants exposed to Fluoxetine during the third trimester experienced more perinatal complications such as prematurity, low full-term birth weight and length, and poor neonatal adaptation compared with infants exposed only during the first and second trimester.
Lactation: Antidepressants, including SSRIs (Fluoxetine, Fluvoxamine, Paroxetine and Sertraline) are drugs whose effect on nursing infants is unknown but may be of concern. In addition, it is advised that SSRIs should be avoided by the mother during breastfeeding.

Adverse effects reported include dry mouth and gastrointestinal disturbances such as nausea, vomiting, dyspepsia, constipation and diarrhea. Anorexia and weight loss may also occur. Neurological adverse effects have included either anxiety, restlessness, nervousness and insomnia, or drowsiness and fatigue; headache, tremor, dizziness, seizures, hallucinations, confusion, agitation, extrapyramidal effects, depersonalization, mania, panic attacks, sexual dysfunction, and symptoms suggestive of serotonin syndrome have also occurred.
Excessive sweating, pruritus, skin rashes, alopecia, photosensitivity and urticaria have also been reported. Angioedema and anaphylactoid reactions have occurred. In some patients who have developed rashes while taking Fluoxetine, systemic hypersensitivity reactions involving the lungs, kidneys, or liver and possibly related to vasculitis, have developed; it has therefore been advised that Fluoxetine therapy should be stopped in patients who develop a skin rash. Hyponatraemia, possibly due to inappropriate secretion of antidiuretic hormone, has been associated with the use of antidepressants, particularly in the elderly. Hyperprolactenaemia and galactorrhea have occurred, as have changes in blood sugar, in patients receiving SSRIs. Arthralgia and myalgia have been reported and there have also been cases of orthostatic hypotension, yawning, urinary retention, and abnormal vision including blurred vision and mydriasis. Abnormal liver function tests have been reported rarely. SSRIs have occasionally been associated with bleeding disorders such as ecchymosis and purpura and other effects on the blood.
In overdosage nausea, vomiting and excitation of the CNS are considered to be prominent features; death has been reported.
Effects on the Blood: Abnormalities in platelet aggregation were associated with Fluoxetine given to a severely underweight patient; Fluoxetine was also suspected of being the cause of bruising in a patient whose blood clotting parameters were within normal limits. Purpura and bruising have been reported to be the commonest adverse blood effects associated with Fluoxetine, Paroxetine, or Sertraline although cases of thrombocytopenia have been recorded for all three antidepressants.
Effects on the Cardiovascular System: SSRIs are not associated with the same degree of cardiotoxicity as the tricyclic antidepressants, although orthostatic hypotension has been reported in some patients.
Effects on the Cerebrovascular System: There have been rare reports of cerebral ischaemic events associated with the use of SSRIs.
Effects on the Endocrine System: The symptoms of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia have been reported in patients receiving antidepressants. SSRI-associated hyperprolactinemia has been reported, Gynecomastia, unrelated to prolactin concentrations, was associated with the start of Fluoxetine therapy. Although SSRIs may be favored for the management of depression in patients with diabetes, there is some evidence that sertraline and fluoxetine can induce hypoglycemia.
Effects on the Eyes: Symptoms of glaucoma that developed in a patient receiving Fluoxetine subsided within 2 days of drug withdrawal. It is recommended that those with risk factor for glaucoma, such as elderly patients with a family history, should be considered for ophthalmic consultations before starting an SSRI and regularly throughout treatment.
Effects on the Gastro-intestinal Tract: A case-control study suggested that treatment with SSRIs produced a moderately increased risk of upper gastrointestinal bleeding. The risk was greatly increased if SSRIs were given with NSAIDs. This effect was considered to be clinically important for patients with a high risk of such bleeding, namely the very elderly and those with a history of previous upper gastrointestinal bleeding.
Effects on the Hair: A report on patients who had hair loss associated with the use of Fluoxetine.
Effects on the Liver: Acute hepatitis occurred in 2 patients after several months of Fluoxetine treatment.
Effects on Mental State: There is a concern that the SSRIs increased the risk of suicidal ideation, and it was concluded that the risk of suicide may increase in the early stages of treatment for depression in adults and consequently careful and frequent monitoring is important, particularly if a patient has worsening of symptoms or new symptoms after starting therapy. Although there was no clear evidence of an increased risk of self-harm or suicidal thoughts in young adults of 18-years or over, such patients have a higher background risk of suicidal behavior than older adults and consequently those treated with SSRIs should be closely monitored.
Effects on Sexual Function: Sexual dysfunction is often noted in patients with depression and may be due to their antidepressant medication or to the disease itself. Complaints include a decrease in or loss of libido, delayed ejaculation, erectile difficulty, or anorgasmia in men; loss of libido, delayed orgasm or anorgasmia have been reported in women.
Effects on the Skin: Amitriptyline and Fluoxetine have been implicated in the development of atypical cutaneous lymphoid hyperplasia; bullous pemphigoid induced by Fluoxetine has been reported.
Epileptogenic Effect: Generalized seizures have been reported in patients with no history of seizures after starting Fluoxetine therapy.
Extrapyramidal Effects: Extrapyramidal effects, such as tics and akathisia have been reported with Fluoxetine. Orofacial dystonias (teeth clenching) or dyskinesias (teeth grinding), resulting in severe damage to teeth and gums in many cases have been reported in patients receiving Fluoxetine, Fluvoxamine, Paroxetine or Sertraline.

SSRIs interact with other drugs mainly as a result of their inhibitory activity on hepatic cytochrome P450 isoenzymes. Individual SSRIs do not all exhibit the same degree of inhibition, nor do they react with the same isoenzymes. The drugs inhibited by specific SSRIs depends on the isoenzyme affected.
SSRIs should not generally be given to patients receiving MAOIs or for at least 2 weeks after their use. No treatment-free period is necessary after stopping a reversible inhibitor of monoamine oxidase type A (RIMA) and starting an SSRI. For Fluoxetine, the interval may need to be further extended if therapy has been prolonged or if high doses have been given.
Adverse effects such as the serotonin syndrome may also occur when the SSRIs are given with other drugs known to act on the same neurotransmitter, a consequence of synergistic interaction.
Antibacterials: Rapid development of delirium was reported in a patient when clarithromycin was added to existing regimen of Fluoxetine and Nitrazepam. It was suggested that this delirium was a result of increased plasma-Fluoxetine concentrations produced by the inhibition of cytochrome P450 enzymes by Clarithromycin. There have also been reports of serotonin syndrome when Linezolid was given with Fluoxetine, Sertraline, Paroxetine, and Citalopram.
Anticoagulants: SSRIs may increase the anticoagulant activity of some anticoagulants including acenocoumarol and warfarin.
Antidepressants: Combination therapy with differing classes of antidepressants has been used successfully in the treatment of drug-resistant depression. It should be emphasized, however, that such combinations may result in enhanced adverse reactions or interactions, and should be used only under expert supervision.
Anti-epileptics: Antidepressants may antagonize the activity of antiepileptics by lowering the convulsive threshold. There has been report of a serotonin syndrome developing in patient days after Fluoxetine had been added to carbamazepine therapy.
Antihistamines: Cyproheptadine given to male and female patients as treatment for sexual dysfunction induced by Fluoxetine or Paroxetine has produced re-emergence of previously controlled depressive symptoms or bulimia nervosa in some patients. Citalopram, Fluoxetine, and Fluvoxamine may increase plasma concentrations of Astemizole or Terfenadine by inhibition of their hepatic cytochrome P450 metabolism, increasing the risk of ventricular arrhythmias; use together should be avoided.
Antivirals: Plasma concentrations of Fluoxetine and other SSRIs are possibly increased by HIV-protease inhibitors, such as Ritonavir, which may inhibit metabolism of the SSRI. The serotonin syndrome has been described in a few patients given regimens that included Fluoxetine and antiretroviral-dose Ritonavir. The reaction also occurred in another patient given Fluoxetine and Efavirenz.
Anxiolytics: Fluoxetine and Fluvoxamine increase plasma concentrations of some benzodiazepines.
Beta-blockers.
Ciclosporin.
Cough suppressants: Effects with dextromethorphan.
Dopaminergics: Selegiline is an irreversible selective inhibitor of monoamine oxidase type B. Serious adverse effects have been reported when selegiline and SSRIs have been used together. In some instances, these reactions resemble the potentially fatal serotonin syndromes reported when SSRIs are given with non-selective MAOIs. SSRIs should not generally be given to patients receiving Selegiline, or at least 2 weeks after it has been stopped. Similarly, at least one week should elapse between withdrawing an SSRI and starting Selegiline; this interval should be increased to 2 weeks for Sertraline, and to 5 weeks for Fluoxetine because of their longer half-lives.
Gastro-intestinal Drug: Acute dystonia has been noted in patients given Fluoxetine, Fluvoxamine, Metoclopramide, Sertraline.
Hypnotics: for reference to visual hallucinations in patients receiving an SSRI concomitantly with Zolpidem.
Muscle relaxant: Report of QT prolongation in patients taking Fluoxetine and Cyclobenzaprine.
NSAIDs: An increased risk of upper gastrointestinal bleeding in patients taking SSRIs and NSAIDs together.
Opioid analgesics: There have also been occasional reports of the syndrome in patients given Tramadol with Citalopram, Fluoxetine or Paroxetine. Other reports of serotonin syndrome were associated with use of Pethidine and Fluoxetine.
Sibutramine: There is a risk of CNS toxicity due to synergistic serotonergic actions when an SSRI is given with Sibutramine.

Store in a dry place. Protect from light. Store at a temperature not exceeding 25°C.

Antidepressants

N06AB03 - fluoxetine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

Rx