Apo-Fluoxetine

Fluoxetine hydrochloride.

Each capsule contains fluoxetine hydrochloride 10 mg or 20 mg, respectively.

Therapeutic Classification: Antidepressant/Antiobsessional/Antibulimic Agent.
Pharmacology: The antidepressant, antiobsessional and antibulimic actions of fluoxetine are presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. At clinically relevant dose, fluoxetine blocks the uptake of serotonin into human platelets. Antagonism of muscarinic, histaminergic and alpha-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects classical tricyclic antidepressant drugs. In vitro receptor binding studies have demonstrated that fluoxetine binds to these and other membrane receptors (opiate, serotonergic (5-HT1, 5-HT2), adrenergic (1, 2, B) and dopaminergic) much less potently than do the tricyclic drugs.
Pharmacokinetics: Fluoxetine is well absorbed after oral administration. In man, following a single 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/ml are observed after 6 to 8 hours. Capsule and oral solution dosage forms of fluoxetine are bioequivalent. Foods does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food.
Fluoxetine is extensively metabolized in the liver to norfluoxetine and other unidentified metabolites. The pharmacological activity of norfluoxetine, which is formed by desmethyl metabolite is similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of fluoxetine. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
A two-way, single-dose, randomized, crossover bioavailability study using 18 normal male volunteers was conducted to evaluate the relative bioavailability of APO-FLUOXETINE 20 mg and Prozac 20 mg capsules (manufactured by Eli Lilly Inc.). The mean pharmacokinetics parameters obtained are listed as follows: (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Clinical Issues Related To Metabolism/Elimination: The complexity of fluoxetine's metabolism has several consequences which may potentially affect its clinical use.
Accumulation And Slow Elimination: The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) results in significant accumulation during chronic use. After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1 + 33.4 ng/mL and norfluoxetine 129 + 42.0 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single dose studies, presumably because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days.
Steady state plasma levels were attained after 4 to 8 weeks on continuous drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years exhibited, on average, plasma concentrations similar to those seen among patients treated for 4 to 5 weeks.
Similarly because of the long half-lives of fluoxetine and norfluoxetine, it may take up to 1 to 2 months for the active drug substances to disappear from the body, this is of potential consequences in the withdrawal of fluoxetine (see Warnings).
Age: The disposition of single doses of fluoxetine in healthy elderly subjects (greater than 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases.
The effects of age upon the metabolism of fluoxetine have been investigated in a subset of 260 elderly, but otherwise healthy, depressed patients (mean age: 67.4 years, range 60 to 85 years) who received 20 mg fluoxetine for 6 weeks. The mean plasma concentrations were found to be 89.5 + 53.6 ng/mL for fluoxetine and 119 + 51.3 ng/mL for norfluoxetine.
Protein Binding: Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and other highly protein bound drugs has not been fully evaluated, but may be important (see Warnings).
Liver Diseases: As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease, norfluoxetine elimination half-life was also delayed, with a mean duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution (see Warnings and Dosage & Administration).
Renal Disease: In single dose studies, the pharmacokinetics of fluoxetine and norfluoxetine were similar among subjects with all levels of impaired renal function including anephric patients on chronic hemodialysis. However, with chronic administration, additional accumulation of fluoxetine or its metabolites [possibly including some not frequent dose is advised (see Warnings)].
The efficacy of fluoxetine was established in 6- and 5-week placebo-controlled trials in depressed outpatients (≥18 years of age), who met the DSM-III criteria for major depressive disorder.
Two-6-weeks placebo-controlled clinical trials in depressed elderly patients, who met the DSM-III-R criteria for major depressive disorder (mean age 67.4 years, range 60 to 85 years) have shown fluoxetine, 20 mg/day, to be effective.

Depression: APO-FLUOXETINE (fluoxetine hydrochloride) may be indicated for the symptomatic relief of depressive illness.
Bulimia Nervosa: Fluoxetine hydrochloride has been shown to significantly decrease binge-eating and purging activity when compared with placebo treatment.
Obsessive-Compulsive Disorder: Fluoxetine hydrochloride has been shown to significantly reduce the symptoms of obsessive-compulsive disorder in double blind placebo controlled studies.
The obsessions of compulsions must be experienced as intrusive, markedly distressing, time consuming or interfering significantly with the persons social or occupational function.
The efficacy of fluoxetine hydrochloride in hospitalized patients has not been studied.
The effectiveness of fluoxetine in long-term use (i.e. for more than 5 to 6 weeks in depression, for more than 16 weeks in bulimia nervosa, or for more than 13 weeks in obsessive compulsive disorder), has not been systemically evaluated in controlled trials. Therefore, the physician who elects to use APO-FLUOXETINE for extended periods should periodically re-evaluate the long-term usefulness of the drug of the individual patient.

Since it may take up to four or five weeks to reach steady-state plasma levels of APO-FLUOXETINE (fluoxetine hydrochloride), sufficient time should be allowed to elapse before dosages is gradually increased. Higher dosages are usually associated with an increased incidence of adverse reactions.
Depression: Initial Adult Dosage: The usual initial dosage is 20 mg administered once daily in the morning. A gradual dose increase should be considered only after a trial period of several weeks if the expected clinical improvement does not occur. Dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is limited.
Use in the Elderly: Fluoxetine was evaluated in depressed elderly patients only at a dosage of 20 mg/day. A lower or less frequent dosage may be effective and should be considered in elderly patients with concurrent disease or on multiple medications.
Use in Children: The safety and effectiveness of fluoxetine in patients below the age of 18 years have not been established.
Bulimia Nervosa: Adult Dosage: The recommended dosage is 60 mg per day, although studies show that lower doses may also be effecacious. Electrolyte levels should be assessed prior to initiation of treatment.
Obsessive-Compulsive Disorder: A dose range of 20 mg/day to 60 mg/day is recommended for the treatment of obsessive-compulsive disorder.
For any indication, the total fluoxetine dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is very limited.
During maintenance therapy, the dosage should be kept at the lowest effective level.
A lower or less frequent dosage should be used in patients with renal and/or hepatic impairment and in those on multiple medications.

During the clinical trials, there were two deaths among approximately 38 reports of acute overdose with fluoxetine, either alone or in combination with other drugs and/or alcohol. One death involved a combined overdose with approximately 1800 mg of fluoxetine and an undetermined amount of maprotiline were 4.57 mg/L and 4.18 mg/L, respectively.
A second death involved 3 drugs yielding plasma concentrations as follows: fluoxetine, 1.93 mg/L; norfluoxetine, 1.10 mg/L; codeine, 1.80 mg/L; temazepam 3.80 mg/L.
One other patient who reportedly took up to 3000 mg of fluoxetine experienced two grand mal seizures that remitted spontaneously without specific treatment. Since vomiting occurred, the amount of drug absorbed may have been less than that ingested.
In the postmarketing phase, there have been 16 confirmed reports of overdose of fluoxetine taken alone. The amount of drug ingested has varied from 80 mg to 2000 mg and the patients have ranged in age from 13 to 51 years. There have been no deaths in this group of patients, some of whom were treated vigorously absence of serious adverse events with the exception of a 13 year old male who ingested 1880 mg and experienced two brief seizures but thereafter had an uneventful recovery.
Since introduction, reports of death attributed to overdosage of fluoxetine alone have been rare.
Symptoms: Nausea and vomiting were prominent in overdoses involving higher fluoxetine doses. Other prominent symptoms of overdose included agitation, restlessness, hypomania and other signs of CNS excitation, including seizures.
Treatment: Establish and maintain an airway, incure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.
Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures. Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures which fail to remit spontaneously may respond to diazepam.
There are no specific antidotes for APO-FLUOXETINE (fluoxetine hydrochloride).
Due to large volume of distribution of APO-FLUOXETINE, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre on the treatment of any overdosage.

APO-FLUOXETINE (fluoxetine hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.
Monoamine Oxidase Inhibitors: There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, APO-FLUOXETINE should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping APO-FLUOXETINE before starting an MAOI. Limited reports suggest that orally administered cyproheptadine or intravenously administered dantrolene (Dantrium) may benefit patients experiencing such reactions.

Allergic Reactions (Rash and Accompanying Events): During premarketing testing of more than 5600 patients given fluoxetine, approximately 4% developed a rash and/or urticaria. Among these cases, almost a third were withdrawn from the treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with these allergic reactions include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely.
In premarketing clinical trials, two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events, possible related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver.
Anaphylactoid events, including bronchospasm, angioedema and urticaria along and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or other possible allergic phenomena for which an alternative etiology cannot be identified, APO-FLUOXETINE (fluoxetine hydrochloride) should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.
Implications of the Long Elimination Half-Life of Fluoxetine: Because of the long elimination half-lives of fluoxetine and its major active metabolite nor-fluoxetine, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see Actions and Dosage & Administration). Even when dosing is stopped, active drug substance will persist in the body for weeks due to the long elimination half-lives of fluoxetine and norfluoxetine. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following discontinuation of APO-FLUOXETINE.
Anxiety and Insomnia: During premarketing clinical trials, anxiety, nervousness and insomnia were reported by 10 to 15% of patients treated with fluoxetine. These symptoms led to discontinuation of the drug in 5% of the patients.
Weight Change: Significant weight loss, especially in underweight depressed patients, may be an undesirable result of treatment with APO-FLUOXETINE (fluoxetine hydrochloride).
Mania/Hypomania: During premarketing clinical trials in a patient population comprised primarily of unipolar depressives, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. The incidence in a general patient population which might also include bipolar depressives is unknown. The likelihood of hypomania or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.
Seizures: APO-FLUOXETINE should be used with caution in patients with a history of convulsive disorders. The incidence of seizures associated with fluoxetine during clinical trials did not appear to differ from that reported with other marketed antidepressants; however, patients with a history of convulsive disorders were excluded from these trials.
Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.
Hypokalemia: Self-induced vomiting often leads to hypokalemia which may lower seizure threshold and/or may lead to cardiac conduction abnormalities. Electrolyte levels of bulimic patients should be assessed prior to initiation of treatment.
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management.
Concomitant Illness: Clinical experience with fluoxetine in patients with concomitant systemic illness is limited and it should be used cautiously in such patients, especially those with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnosis were systemically excluded from premarketing clinical studies. Retrospective evaluation of EKG's in some of these studies showed no conduction abnormalities that resulted in heart block. The mean heart rate was reduced by approximately 3 beats/minute.
APO-FLUOXETINE should be given with caution to patients suffering from anorexia and only if the expected benefits (e.g. co-morbid depression) markedly outweigh the potential weight reducing effect of the drug.
In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrent by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Since fluoxetine is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. However, until an adequate number of patients with severe renal impairment have been evaluated in the course of chronic treatment, fluoxetine should be used with caution in such patients.
Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired liver function including cirrhosis, a lower or less frequent dose should be used in such patients.
Hyponatremia: Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when fluoxetine was discontinued. Although these cases were complex with varying possible etiologies, some were possible due to the syndrome of inappropriate antidiuretics hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.
Platelet Function: There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role.
Cognitive and Motor Performance: Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with APO-FLUOXETINE does not affect them adversely.
Use in Pregnancy & Lactation: Safe use of fluoxetine during pregnancy and lactation has not been established. Therefore it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweigh the possible hazards to the child or fetus. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/ml. The concentration in the mother's plasma as 295.0 ng/mL. No adverse effects on the infant were reported.
Use in Children: Safety and effectiveness in patients below the age of 18 have not been established.
Use in the Elderly: Evaluation of patients over the age of 60 who received fluoxetine 20 mg daily, revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. These data are, however, insufficient to rule out possible age-related differences during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs.

Safe use of fluoxetine during pregnancy and lactation has not been established. Therefore it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweigh the possible hazards to the child or fetus. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/ml. The concentration in the mother's plasma as 295.0 ng/mL. No adverse effects on the infant were reported.

Common Observed: In clinical trials, the most commonly observed adverse events associated with the use of fluoxetine and not seen at an equivalent incidence among placebo treated patients were: central nervous system complaints, including headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor and dizziness or lightheadedness; gastrointestinal complaints, including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.
Adverse Events Leading to Discontinuation of Treatment: Fifteen percent of approximately 4,000 patients who received fluoxetine in North American clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials in adults and elderly included: psychiatric, primarily nervousness, anxiety, and insomnia; digestive, primarily rash and pruritus.
In obsessive compulsive disorder studies, 12.1% of fluoxetine-treated patients discontinue treatment early because of adverse events. In bulimia nervosa studies, 10.2% of fluoxetine-treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidence of less than 2%, were the most frequently-reported events.
Serious Adverse Reactions: Suicidal thoughts and acts are far more common among depressed patients than in the general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed persons than in the general population. A comprehensive meta-analysis of pooled date from 17 double-blind clinical trials in patients with major depressive disorder compared fluoxetine (n=1765) with a tricyclic antidepressants (n=731) or placebo (n=569) or both. The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants.
In countries where the drug has already been marketed, the following potentially serious adverse reactions have been reported: interactions with MAO inhibitors and possibly other drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion, and grand mal seizure. Death and life-threatening events have been associated with some of these reactions, although casual relationship to fluoxetine has not necessarily been established.
Postmarketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with fluoxetine hydrochloride including allergic skin reactions.
Adverse Experience Reports: The pattern of treatment-emergent adverse experience incidence (>5%) for both fluoxetine and placebo was somewhat different in bulimia and obsessive compulsive disorder trials than in the adult and elderly depression studies, and is summarized in the following table. (See Table 3.)

Click on icon to see table/diagram/image

The following adverse reactions were reported on at least one occasion by patients during treatment with fluoxetine either during clinical trials or after marketing. All reported events are included except those where a drug cause was remote or the event term so general as to be unhelpful. Multiple events may have been reported by a single condition, which may have preexisted. Therefore, while the following events occurred during treatment with fluoxetine, they were not necessarily caused by it.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 but at least 1/1000 patients; rare events are those occurring in less than 1/1000 patients.
Allergic or Toxic: Frequent: rash, pruritus.
Infrequent: chills and fever, urticaria, maculopapular rash.
Rare: allergic reactions, erythema multiforme, vesiculobullous rash, serum sickness, contact dermatitis, erythema nodosum, purpuric rash, leukocytoclastic vasculitis, leukopenia, thrombocytopenia, arthralgia, angioedema, bronchospasm, lung fibrosis, allergic alveolitis, larynx edema, respiratory distress.
Neurologic: Frequent: headache, tremor, dizziness or lightheadedness, asthenia.
Infrequent: abnormal gait, ataxia, akathisia, buccoglossal syndrome, hyperkinesia, hypertonia, incoordination, neck rigidity, extrapyramidal syndrome, convulsions, photophobia, myoclonus, vertigo, migraine, tinnitus, hypesthesia, neuralgia, neuropathy, acute brain syndrome.
Rare: dysarthria, dystonia, torticollis, decreased reflexes, nystagmus, paralysis, paresthesia, carpal tunnel syndrome, stupor, coma, abnormal electroencephalogram, chronic brain syndrome, dyskinesia and other movement disorders (including worsening of preexisting conditions or appearance in patients with risk factors [e.g. Parkinson's disease, treatment with neuroleptics or other drugs known to be associated with movement disorders]), neuroleptic malignant syndrome-like events.
Behavioural: Frequent: insomnia, anxiety, nervousness, agitation, abnormal dreams, drowsiness and fatigue.
Infrequent: confusion, delusions, hallucinations, manic reaction, paranoid reaction, psychosis, depersonalization, apathy, emotional lability, euphoria, hostility, amnesia, increased libido.
Rare: antisocial reaction, hysteria, suicidal ideation, violent behaviours.
Autonomic: Frequent: excessive sweating.
Infrequent: dry mouth, constipation, urinary retention, vision disturbance, diplopia, mydriasis, hot flushes.
Cardiovascular: Infrequent: chest pain, hypertension, syncope, hypotension (including postural hypotension), angina pectoris, arrhythmia, tachycardia.
Rare: bradycardia, ventricular arrhythmia, first degree AV block, bundle branch block, myocardial infarct, cerebral ischemia, cerebral vascular accident, thrombophlebitis.
Gastrointestinal: Frequent: nausea, disturbance of appetite, diarrhea.
Infrequent: vomiting, stomatitis, dysphagia, eructation, esophagitis, duodenal ulcer, stomach ulcer, mouth ulceration, hyperchlorhydria, colitis, enteritis, cholecystitis, cholelithiasis, hepatitis, hepatomegaly, liver tenderness, jaundice, increased salivation, saliva gland enlargement, tongue discolouration, fecal incontinence, pancreatitis.
Respiratory: Frequent: bronchitis, rhinitis, yawn.
Infrequent: asthma, dyspnea, hyperventilation, pneumonia, hiccups, epistaxis.
Rare: apnea, lung edema, hypoxia, pleural effusion, hemoptysis.
Endocrine: Frequent: weight loss.
Infrequent: generalized edema, peripheral edema, face edema, tongue edema, hypoglycemia, hypothyroidism, weight gain.
Rare: dehydration, gout, goitre, hyperthyroidism, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperprolactinemia, hypokalemia, hyponatremia, iron deficiency anemia, syndrome of inappropriate ADH pancytopenia, immune-related hemolytic anemia.
Dermatologic: Infrequent: acne, alopecia, dry skin, herpes simplex.
Rare: eczema, psoriasis, seborrhea, skin hypertrophy, skin discolouration, herpes zoster, fungal dermatitis, hirsutism, ecchymoses.
Musculoskeletal: Frequent: muscle pain, back pain, joint pain.
Infrequent: arthritis, bone pain, bursitis, tenosynovitis, twitching.
Rare: bone necrosis, osteoporosis, pathological fracture, chondrodystrophy, myositis, rheumatoid arthritis, muscle hemorrhage.
Urogenital: Frequent: painful menstruation, sexual dysfunction, urinary tract infection, frequent micturition.
Infrequent: abnormal ejaculation, menopause, amenorrhea, menorrhagia, ovarian disorder, vaginitis, leukorrhea, fibrocystic, breast pain, cystitis, dysuria, urinary urgency, urinary incontinence.
Rare: breast enlargement, galactorrhea, abortion, dyspareunia, uterine spasm, vaginal hemorrhage, metrorrhagia, hematuria, albuminuria, polyuria, pyuria, epididymitis, orchitis, pyelonephritis, salpingitis, urethritis, kidney calculus, urethral pain , urolithiasis.
Miscellaneous: Frequent: chills, abnormal vision.
Infrequent: amblyopia, conjunctivitis, cyst, ear pain, eye pain, jaw pain, neck pain, pelvic pain, hangover effect, malaise.
Rare: abdomen, enlarged, blepharitis, cataract, corneal lesion, glaucoma, iritis, ptosis, strabismus, deafness, taste loss, moniliasis, hydrocephalus, LE syndrome.

Combined use of fluoxetine and MAO inhibitors is contraindicated (see Contraindications).
There have been greater than 2-fold increases of previously stable plasma levels of other antidepressants when fluoxetine has been administered concomitantly.
Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.
The half-life of concurrently administered diazepam may be prolonged in some patients. Experience with the use of fluoxetine in combination with other CNS-active drugs is limited and caution is advised if such concomitant medication is required (see Warnings).
Drugs Tightly Bound to Plasma Protein: Because fluoxetine is highly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which highly bound to proteins (e.g. warfarin, digoxin) may cause a shift in plasma concentration potentially resulting in an adverse effect. Conversely, adverse effect may result from displacement of protein bound fluoxetine by other tightly bound drugs.
P450 Isoenzyme (IID6): Like other selective serotonin reuptake inhibitors, fluoxetine inhibits the specific hepatic cytochrome P450 isozyme (IID6) which is responsible for the metabolism of debrisoquine and sparteine. Although the clinical significance of this effect has not been established, inhibition of IID6 may lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme. Drugs metabolized by cytochrome P450 IID6 include the tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine), and Type 1C antiarrhythmics (e.g. propafenone and flecainide).
Dependence Liability: Fluoxetine has not been systemically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine.

To be stored in a cool dry environment.

Antidepressants

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

POM