Prozac (Fluoxetine)

PROZAC®

Lilly

Fluoxetine HCl

Antidepressant – Antiobsessional – Antibulimic

Action And Clinical Pharmacology: The antidepressant, antiobsessional, and antibulimic actions of fluoxetine are presumed to be linked to its ability to selectively inhibit the neuronal reuptake of serotonin. At clinically relevant doses fluoxetine blocks the uptake of serotonin into human platelets. Antagonism of muscarinic, histaminergic and a1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects of 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 (a1, a2, b) and dopaminergic] much less potently than do the tricyclic drugs.

Pharmacokinetics: Fluoxetine is well absorbed after oral administration. In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The capsule and oral solution dosage forms of fluoxetine are bioequivalent. Food 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 demethylation of fluoxetine appears to be similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of Prozac. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

Clinical Issues Related to Metabolism/Elimination: Variability in Metabolism: The metabolism of fluoxetine, like that of a number of other compounds, including tricyclic antidepressants and some selective serotonin reuptake inhibitors, involves the P450IID6 system. Concomitant therapy with fluoxetine and the aforementioned drugs may lead to clinically significant drug interactions (see Precautions, Drug Interactions).

Accumulation and Slow Elimination: The relatively slow elimination of fluoxetine and its active metabolite, norfluoxetine, results in significant accumulation of these active moieties in chronic use. Therefore, it may take up to 1 to 2 months for the active drug substance(s) to disappear from the body. This persistence of active moieties is important to keep in mind when fluoxetine is discontinued, or when drugs that are predicted to interact with fluoxetine are to be administered soon after its discontinuation (see Warnings, Implications of the long elimination half-life of fluoxetine and Precautions, Drug Interactions).

Kinetic Data: After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1±33.4 ng/mL and of norfluoxetine 129±42.0 ng/mL have been observed. Plasma concentrations of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) were higher than those predicted by single dose studies. Norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-lives after a single dose and multiple dose were 8.6 days and 9.3 days respectively.

Steady-state plasma levels are attained after 4 to 5 weeks of 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 at the same dose.

Age: 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 yr, range 60 to 85 yr) who received 20 mg fluoxetine for 6 weeks. Mean plasma concentrations were found to be 89.5±53.6 ng/mL for fluoxetine and 119±51.3 ng/mL for norfluoxetine. However, the effects of concomitant illness and/or concomitant drugs have not been evaluated.

Protein Binding: Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and other highly protein bound drugs has not been evaluated, but may be important (see Precautions).

Liver Disease: In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged, with a mean of 7.6 days compared to a range of 2 to 3 days seen in healthy subjects; norfluoxetine half-life was also prolonged, with a mean of 12 days compared to a range of 7 to 9 days in healthy subjects. Fluoxetine should therefore be used with caution in patients with liver disease (see Precautions and Dosage).

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 yet identified) may occur in patients with severely impaired renal function and the use of a lower or less frequent dose is advised (see Precautions).

Clinical Trials: The efficacy of fluoxetine was established in 5- and 6-week placebo-controlled clinical trials in depressed outpatients (18 years of age), who met the DSM-III-R criteria for major depressive disorder.

Two, 6-week 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 Prozac, 20 mg/day, to be effective.

Indications And Clinical Uses: Depression: For the symptomatic relief of depressive illness.

Bulimia Nervosa: Fluoxetine has been shown to significantly decrease binge-eating and purging activity when compared with placebo treatment.

Obsessive-Compulsive Disorder: Fluoxetine has been shown to significantly reduce the symptoms of obsessive-compulsive disorder in double-blind, placebo-controlled clinical trials.

The obsessions or compulsions must be experienced as intrusive, markedly distressing, time-consuming, or interfering significantly with the person’s social or occupational functioning.

The efficacy of fluoxetine in hospitalized patients has not been adequately 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 systematically evaluated in controlled trials. Therefore, the physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: In patients with known hypersensitivity to the drug.

MAO 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 MAO inhibitor and in patients who have recently discontinued fluoxetine and then started on a MAO inhibitor. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with a MAO inhibitor or within a minimum of 14 days of discontinuing therapy with a MAO inhibitor. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting a MAO inhibitor. Limited reports suggest that i.v. administered dantrolene or orally administered cyproheptadine may benefit patients experiencing such reactions.

Manufacturers’ Warnings In Clinical States: Allergic Reactions (Rash and Accompanying Events): During premarketing testing of more than 5 600 patients given fluoxetine, approximately 4% developed a rash and/or urticaria. Among these cases, almost a third were withdrawn from 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 2 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 leukocytoclastic vasculitis, and the other severe desquamation that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.

Since the introduction of fluoxetine, systemic events, possibly related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.

Anaphylactoid events, including bronchospasm, angioedema, and urticaria alone 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 of other allergic phenomena for which an alternative etiology cannot be identified, fluoxetine 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 norfluoxetine, 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 Pharmacology and Dosage). 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 fluoxetine.

Precautions: 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 and the elderly, may be an undesirable result of treatment with fluoxetine.

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 hypomanic or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.

Seizures: 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 a prolonged seizure in patients on fluoxetine receiving ECT treatment.

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 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 diagnoses were systematically excluded from premarketing clinical studies. Retrospective evaluation of ECGs 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.

Fluoxetine should be given with caution to patients suffering from anorexia nervosa 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 concurrently 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 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 possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.

In a placebo-controlled, double-blind trial in elderly patients, 10 of 313 fluoxetine-treated patients and 6 of 320 placebo-treated patients had a lowering of serum sodium below the reference range. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L.

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.

Occupational Hazards: Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with fluoxetine does not affect them adversely.

Pregnancy: Safe use of fluoxetine during pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child or fetus.

Lactation: Fluoxetine and its metabolites are excreted in breast milk, and have been observed to reach high plasma levels in nursing infants. Women who are taking fluoxetine should not breast-feed unless, in the opinion of the treating physician, breast-feeding is necessary, in which case the infant should be closely monitored.

In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295 ng/mL. No adverse effects on the infant were reported. In another case, a 6-week infant, nursed by a mother on fluoxetine, developed crying, decreased sleep, vomiting and watery stools. The breast milk showed concentrations of 69 ng/mL for fluoxetine and 90 ng/mL for norfluoxetine. In the infant’s plasma, the concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 and 208 ng/mL, respectively.

Children: Safety and effectiveness in patients below the age of 18 have not been established.

Geriatrics: 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.

Drug Interactions: MAO Inhibitors: Combined use of fluoxetine and MAO inhibitors is contraindicated (see Contraindications).

Tricyclic Antidepressants: In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of tricyclic antidepressant (TCA) may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. See Pharmacology, Accumulation and Slow Elimination and Precautions, P450 and Isoenzyme (IID6).

Lithium: There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Tryptophan: Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness and gastrointestinal distress.

Diazepam: 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).

Phenytoin: In patients on stable, maintenance doses of phenytoin, plasma phenytoin concentrations increased substantially and symptoms of phenytoin toxicity appeared (nystagmus, diplopia, ataxia and CNS depression) following initiation of concomitant fluoxetine treatment.

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 is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.

Drugs Metabolized by P450 Isoenzyme (IID6): Approximately 3 to 10% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P450IID6. Such individuals have been referred to as “poor metabolizers” of drugs such as debrisoquine, dextromethorphan, sparteine, tricyclic antidepressants (e.g., nortryptiline, amitriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine) and Type 1C antiarrhythmics (e.g., propafenone and flecainide).

Conversely, approximately 90 to 97% of the normal population do not have this genetic defect, and are known as “extensive metabolizers”. Fluoxetine, like other agents that are metabolized by the P450IID6 system, inhibits the activity of this isoenzyme, and thus may make normal “extensive” metabolizers resemble “poor metabolizers”. Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (e.g., flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks.

If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P450IID6 the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern.

Dependence Liability: Fluoxetine has not been systematically 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.

Adverse Reactions: Commonly 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: CNS 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 nausea; nervous system, primarily dizziness, asthenia and headaches; skin, primarily rash and pruritus.

In obsessive compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued treatment early because of adverse events. Anxiety, and rash, at incidences of less than 2%, were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidences 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 data from 17 double blind clinical trials in patients with major depressive disorder compared fluoxetine (n=1 765) with a tricyclic antidepressant (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 causal relationship to fluoxetine has not been established.

Postmarketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with fluoxetine, 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,

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 patient and related to 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% of patients; infrequent adverse events are those occurring in less than 1% but at least 1/1 000 patients; rare events are those occurring in less than 1/1 000 patients.

Allergic or Toxic: Frequent: rash, pruritus.

Infrequent: chills and fever, urticaria, maculopapular rash.

Rare: allergic reaction, erythema multiforme, vesiculobullous rash, serum sickness, contact dermatitis, erythema nodosum, purpuric rash, leukocytoclastic vasculitis, leukopenia, thrombocythemia, 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, hypoesthesia, neuralgia, neuropathy, acute brain syndrome.

Rare: dysarthria, dystonia, torticollis, decreased reflexes, nystagmus, paralysis, paresthesia, carpal tunnel syndrome, stupor, coma, abnormal EEG, 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.

Behavioral: 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 behaviors.

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, disturbances of appetite, diarrhea.

Infrequent: vomiting, stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis, glossitis, melena, thirst, abnormal liver function tests.

Rare: bloody diarrhea, hematemesis, gastrointestinal hemorrhage, duodenal ulcer, stomach ulcer, mouth ulceration, hyperchlorhydria, colitis, enteritis, cholecystitis, cholelithiasis, hepatitis, hepatomegaly, liver tenderness, jaundice, increased salivation, salivary gland enlargement, tongue discoloration, 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, hypercholesteremia, hyperglycemia, hyperlipemia, hyperprolactinemia, hypokalemia, hyponatremia, iron deficiency anemia, syndrome of inappropriate ADH secretion.

Hematologic: Infrequent: anemia, lymphadenopathy, hemorrhage.

Rare: bleeding time increased, leukocytosis, lymphocytosis, thrombocytopenia, thrombocytopenic purpura, thrombocythemia, retinal hemorrhage, petechia, purpura, sedimentation rate increased, aplastic anemia, pancytopenia, immune-related hemolytic anemia.

Dermatologic: Infrequent: acne, alopecia, dry skin, herpes simplex.

Rare: eczema, psoriasis, seborrhea, skin hypertrophy, skin discoloration, 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, impotence, sexual dysfunction, urinary tract infection, frequent micturition.

Infrequent: abnormal ejaculation, menopause, amenorrhea, menorrhagia, ovarian disorder, vaginitis, leukorrhea, fibrocystic breast, 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.

Symptoms And Treatment Of Overdose: During clinical trials, there were 2 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 1 800 mg of fluoxetine and an undetermined amount of maprotiline. Plasma concentrations of fluoxetine and 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 3 000 mg of fluoxetine experienced 2 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 2 000 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 with activated charcoal in the acute phase. Furthermore, patient recoveries were remarkable in the absence of serious adverse events with the exception of a 13 year old male who ingested 1 880 mg and experienced 2 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; ensure 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 fluoxetine.

Due to the large volume of distribution of 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.

Dosage And Administration: Since it may take up to 4 or 5 weeks to reach steady state plasma levels of fluoxetine, sufficient time should be allowed to elapse before dosage is gradually increased. Higher dosages are usually associated with an increased incidence of adverse reactions.

Depression: Adults: The recommended 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/day since clinical experience with doses above 80 mg/day is very limited.

Geriatrics: 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.

Children: The safety and effectiveness of fluoxetine in patients below the age of 18 years have not been established.

Bulimia Nervosa: Adults: The recommended dosage is 60 mg/day, although studies show that lower doses may also be efficacious. 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/day since clinical experience with doses above 80 mg/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.

Switching Patients to a Tricyclic Antidepressant (TCA): Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Drug Interactions, Tricyclic Antidepressants).

Switching Patients to or from a MAO Inhibitor: At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of therapy with fluoxetine. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping fluoxetine before starting an MAO inhibitor (see Contraindications).

Availability And Storage: Capsules: 10 mg: Each green and grey capsule, printed with Lilly 3104 and Prozac 10 mg, contains: fluoxetine HCl equivalent to fluoxetine 10 mg. Nonmedicinal ingredients: silicone and starch. The capsule shell contains: benzyl alcohol, carboxymethylcellulose, edetate calcium disodium, FD&C Blue No. 1, gelatin, iron oxide black, iron oxide yellow, methylparaben, sodium, sodium lauryl sulfate, sodium propionate and titanium dioxide. Amber bottles of 100.

20 mg: Each green and white capsule, printed with Lilly 3105 and Prozac 20 mg, contains: fluoxetine HCl equivalent to fluoxetine 20 mg. Nonmedicinal ingredients: silicone and starch. The capsule shell contains: benzyl alcohol, carboxymethylcellulose, edetate calcium disodium, FD&C Blue No. 1, gelatin, iron oxide yellow, methylparaben, sodium, sodium lauryl sulfate, sodium propionate and titanium dioxide. Amber bottles of 100.

Liquid: Each 5 mL clear, colorless, syrup solution, with an odor of mint, contains: fluoxetine HCl equivalent to fluoxetine 20 mg/5 mL. Nonmedicinal ingredients: benzoic acid, glycerin, mint flavor, purified water and sucrose. Energy: 50.3 kJ (12.0 kcal)/5 mL. Amber glass bottles of 120 mL (M-5120).

Store at 15 to 25°C.

PROZAC® Lilly Fluoxetine HCl Antidepressant – Antiobsessional – Antibulimic

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