PDR® entry for PROZAC (DISTA PRODUCTS AND ELI LILLY AND COMPANY) DESCRIPTION: Prozac® (Fluoxetine Hydrochloride) is an antidepressant for oral administration; it is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (±)-N-methyl-3-phenyl-3- ((alpha,alpha,alpha-trifluoro-p-tolyl)oxy)propylamine hydrochloride and has the empirical formula of C17H18F3NO.HCl. Its molecular weight is 345.79. (back to top) Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 micromol) or 20 mg (64.7 micromol) of fluoxetine. The Pulvules also contain F D & C Blue No. 1, gelatin, iron oxide, silicone, starch, titanium dioxide, and other inactive ingredients. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 micromol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. (back to top) ACTIONS/CLINICAL PHARMACOLOGY: Pharmacodynamics: The antidepressant, antiobsessive-compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, And Excretion: SYSTEMIC BIOAVAILABILITY--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 Pulvule 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. PROTEIN BINDING--Over the concentration range from 200 to 1,000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and alpha1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). ENANTIOMERS--Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. METABOLISM--Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other, unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. CLINICAL ISSUES RELATED TO METABOLISM/ELIMINATION--The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use. VARIABILITY IN METABOLISM--A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450IID6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-IID6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine's metabolism, like that of a number of other compounds including tricyclic and other selective serotonin antidepressants, involves the P450IID6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the tricyclic antidepressants) may lead to drug interactions (see Drug Interactions Under PRECAUTIONS). 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) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, 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 levels after prolonged dosing are similar to levels seen at 4-5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. LIVER DISEASE--As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination 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. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS And DOSAGE AND ADMINISTRATION). RENAL DISEASE--In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for two months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable to those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (See Use in Patients With Concomitant Illness Under PRECAUTIONS And DOSAGE AND ADMINISTRATION). 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 260 elderly but otherwise healthy depressed patients (>/=60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. (back to top) CLINICAL STUDIES: Clinical Trials: Depression--The efficacy of Prozac for the treatment of patients with depression (>/=18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies comparing Prozac, 20 mg, and placebo have shown Prozac, 20 mg daily, to be effective in the treatment of elderly patients (>/=60 years of age) with depression. In these studies, Prozac produced a significantly higher rate of response and remission as defined respectively by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of </=7. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of </=7 during each of the last 3 weeks of open-label treatment and absence of major depression by DSM-III-R criteria) by the end of an initial 12-week open treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depression for 2 weeks of a modified HAMD-17 score of >/= 14 for 3 weeks) was observed for patients taking Prozac compared to those on placebo. Obsessive-Compulsive Disorder--The effectiveness of Prozac for the treatment for obsessive-compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once a day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared to a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared to a 1-unit reduction for placebo patients. While there was no indication of a dose response relationship for effectiveness in Study 1, a dose response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for studies 1 and 2 combined: ----------------------------------------------------------------------------- Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies ----------------------------------------------------------------------------- Prozac ----------------------------------------------------------------------------- Outcome Classification Placebo 20 mg 40 mg 60 mg ----------------------------------------------------------------------------- Worse 8% 0% 0% 0% No Change 64% 41% 33% 29% Minimally Improved 17% 23% 28% 24% Much Improved 8% 28% 27% 28% Very Much Improved 3% 8% 12% 19% ----------------------------------------------------------------------------- Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Bulimia Nervosa--The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 mg/day or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac, 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg vs placebo was present as early as week 1 and persisted throughout each study. The Prozac related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac, 60 mg, and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. (back to top) INDICATIONS AND USAGE: Depression--Prozac is indicated for the treatment of depression. The efficacy of Prozac was established in 5- and 6-week trials with depressed outpatients (>/=18 years of age) whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The antidepressant action of Prozac in hospitalized depressed patients has not been adequately studied. The efficacy of Prozac in maintaining an antidepressant response for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving Prozac for extended periods should be reevaluated periodically (See Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY). Obsessive-Compulsive Disorder--Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; ie, the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of Prozac was established in 13-week trials with obsessive-compulsive outpatients whose diagnoses corresponded most closely to the DSM-III- R category of obsessive-compulsive disorder (see Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY). Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, ie, for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, they physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Bulimia Nervosa--Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8 to 16 week trials for adult outpatients with moderate to severe bulimia nervosa, ie, at least 3 bulimic episodes per week for 6 months (see Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY). The effectiveness of Prozac in long-term use, ie, for more than 16 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). (back to top) CONTRAINDICATIONS: Prozac is contraindicated in patients known to be hypersensitive to it. 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 are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (See Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY)) should be allowed after stopping Prozac before starting an MAOI. (back to top) WARNINGS: Rash And Possibly Allergic Events--In US fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, 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 rash include 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 1 was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, 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 possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. (back to top) PRECAUTIONS: General ANXIETY AND INSOMNIA--In US placebo-controlled clinical trials for depression, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for obsessive-compulsive disorder, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac, 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported respectively in 15% and 11% of patients treated with Prozac, 60 mg, and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation in US placebo-controlled fluoxetine clinical trials were anxiety (</=2%), insomnia (</=2%) and nervousness (</=1%) (see Table 3, below). ALTERED APPETITE AND WEIGHT--Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for depression, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss. In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia. In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac, 60 mg, and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac, 60 mg, on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. ACTIVATION OF MANIA/HYPOMANIA--In US placebo-controlled clinical trials for depression, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with marketed antidepressants. In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials, 0.7% of 10,782 patients reported mania/hypomania. SEIZURES--In US placebo-controlled clinical trials for depression, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed antidepressants. Prozac should be introduced with care in patients with a history of seizures. SUICIDE--The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high risk patients should accompany initial drug therapy. Prescriptions for Prozac should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Because of well-established comorbidiy between OCD and depression and bulimia and depression, the same precautions observed when treating patients with depression should be observed when treating patients with OCD or bulimia. THE LONG ELIMINATION HALF-LIVES OF FLUOXETINE AND ITS METABOLITES--Because of the long elimination half-lives of the parent drug and its major active metabolite, 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/CLINICAL PHARMACOLOGY And DOSAGE AND ADMINISTRATION). USE IN PATIENTS WITH CONCOMITANT ILLNESS--Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients 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 clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (See Renal Disease Under ACTIONS/CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (See DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, 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 Prozac is instituted or discontinued. INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE--Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Information For Patients--Physicians are advised to discuss the following issues with patients for whom they prescribe Prozac: Because Prozac may impair judgment, thinking, or motor 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. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs or alcohol. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant. Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests--There are no specific laboratory tests recommended. Drug Interactions--As with all drugs, the potential for interaction by a variety of mechanisms (eg, pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc) is a possibility (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY). DRUGS METABOLIZED BY P450IID6--Approximately 7% 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 debrisoquin, dextromethorphan, and tricyclic antidepressants. Many drugs, such as most antidepressants including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers (see Variability in Metabolism Under ACTIONS/CLINICAL PHARMACOLOGY). Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (see list below), 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. Thus, his/her dosing requirements resemble those of "poor metabolizers." 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. Drugs with a narrow therapeutic index represent the greatest concern (eg, flecainide, vinblastine, and tricyclic antidepressants). DRUGS METABOLIZED BY CYTOCHROME P450IIIA4--In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical significance. CNS ACTIVE DRUGS--The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY). ANTICONVULSANTS--Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. ANTIPSYCHOTICS--Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. A single case report has suggested possible additive effects of primozide and fluoxetine leading to bradycardia. BENZODIAZEPINES--The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. LITHIUM--There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. TRYPTOPHAN--Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. MONOAMINE OXIDASE INHIBITORS--See Contraindications. OTHER 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 three 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 Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY, and Drugs Metabolized by P450IID6 Under DRUG INTERACTIONS). POTENTIAL EFFECTS OF COADMINISTRATION OF DRUGS TIGHTLY BOUND TO PLASMA PROTEINS--Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (eg, Coumadin, 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 (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY). WARFARIN--Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. ELECTROCONVULSIVE THERAPY--There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Carcinogenesis, Mutagenesis, Impairment Of Fertility--There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility with Prozac. CARCINOGENICITY--The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/M2 basis), produced no evidence of carcinogenicity. MUTAGENICITY--Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. IMPAIRMENT OF FERTILITY--Two fertility studies conducted in rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/M2 basis), indicated that fluoxetine had no adverse effects on fertility. Pregnancy--Pregnancy Category C: In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/M2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup death during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/M2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/M2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/M2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor And Delivery--The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers--Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use--Safety and effectiveness in pediatric patients have not been established. Usage In The Elderly--Evaluation of patients over the age of 60 who received Prozac 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. However, these data are 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 (see Age Under ACTIONS/CLINICAL PHARMACOLOGY). Hyponatremia--Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac 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, 10 of 313 fluoxetine patients and 6 of 320 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. 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. (back to top) DRUG INTERACTIONS: As with all drugs, the potential for interaction by a variety of mechanisms (eg, pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc) is a possibility (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY). DRUGS METABOLIZED BY P450IID6--Approximately 7% 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 debrisoquin, dextromethorphan, and tricyclic antidepressants. Many drugs, such as most antidepressants including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers (see Variability in Metabolism Under ACTIONS/CLINICAL PHARMACOLOGY). Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (see list below), 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. Thus, his/her dosing requirements resemble those of "poor metabolizers." 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. Drugs with a narrow therapeutic index represent the greatest concern (eg, flecainide, vinblastine, and tricyclic antidepressants). DRUGS METABOLIZED BY CYTOCHROME P450IIIA4--In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical significance. CNS ACTIVE DRUGS--The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical