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Description

Fluoxetine hydrochloride is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, Fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl- 3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the molecular formula of C17H18F3NO●HCl. Its molecular weight is 345.79. The structural formula is:

Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.

Each capsule contains Fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol) or 20 mg (64.7 µmol) of Fluoxetine. In addition, each capsule also contains the following inactive ingredients: colloidal silicon dioxide, D & C Red 28, D & C Red 33, D & C Yellow 10, F D & C Blue 1, gelatin, magnesium stearate, maize (corn) starch, microcrystalline cellulose, pregelatinised maize starch, sodium lauryl sulphate and titanium dioxide.

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 α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) 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

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, tablet 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 by 1 to 2 hours, which is probably not clinically significant. Thus, Fluoxetine may be administered with or without food.

Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of Fluoxetine is bound in vitro to human serum proteins, including albumin and α-glycoprotein. The interaction between Fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see  PRECAUTIONS).

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.

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.

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 P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. 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 four active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) 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 TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see  Drug Interactionsunder  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 to 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 Fluoxetine.

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 with 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 with 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  PRECAUTIONSand  DOSAGE AND ADMINISTRATION).

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 with 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 Illnessunder  PRECAUTIONSand  DOSAGE AND ADMINISTRATION).

Geriatric pharmacokinetics

The disposition of single doses of Fluoxetine in healthy elderly subjects (>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.

Pediatric pharmacokinetics (children and adolescents)

Information related to the pharmacokinetics in pediatric patients is approved for Eli Lilly and Company’s Fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Clinical Trials

Major Depressive Disorder

Adult

The efficacy of Fluoxetine for the treatment of patients with major depressive disorder (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine 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 (N=671, randomized) comparing Fluoxetine 20 mg and placebo have shown Fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with major depressive disorder. In these studies, Fluoxetine 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 ≤8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Fluoxetine (12%) and placebo (9%).

A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Fluoxetine 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Fluoxetine 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 depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking Fluoxetine compared to those on placebo.

Pediatric (children adolescents)

Information related to clinical trials of Fluoxetine in the treatment of major depressive disorder in pediatric patients is approved for Eli Lilly and Company’s Fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Obsessive Compulsive Disorder

The effectiveness of Fluoxetine 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 Fluoxetine 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 Fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with 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 two 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:

Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

Information related to clinical trials of Fluoxetine in the treatment of OCD in pediatric patients is approved for Eli Lilly and Company’s Fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Bulimia Nervosa

The effectiveness of Fluoxetine 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 or 60 mg/day of Fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed Fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these three 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 three studies, Fluoxetine 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 versus placebo was present as early as Week 1 and persisted throughout each study. The Fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these three studies, the treatment effect, as measured by differences between Fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from one to two episodes per week for binge-eating and two to four 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.

In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Fluoxetine 60 mg/day, were randomized to continuation of Fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.

Panic Disorder

The effectiveness of Fluoxetine in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia.

Study 1 (N=180 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.

Study 2 (N=214 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

Indications and Usage

Major Depressive Disorder

Fluoxetine is indicated for the treatment of major depressive disorder.

The efficacy of Fluoxetine was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see  CLINICAL TRIALS).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

The effects of Fluoxetine in hospitalized depressed patients have not been adequately studied.

The efficacy of Fluoxetine 20 mg once daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial.

Information related to the efficacy of Fluoxetine in the treatment of major depressive disorder in children and adolescents is approved for Eli Lilly and Company’s Fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

The usefulness of the drug in adult and pediatric patients receiving Fluoxetine for extended periods should be reevaluated periodically.

Obsessive Compulsive Disorder

Fluoxetine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of Fluoxetine was established in 13-week trials with obsessive-compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see  CLINICAL TRIALS).

OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are egodystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

The effectiveness of Fluoxetine in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see  DOSAGE AND ADMINISTRATION).

Information related to the efficacy of Fluoxetine in the treatment of OCD in children and adolescents is approved for Eli Lilly and Company’s Fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Bulimia Nervosa

Fluoxetine is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa.

The efficacy of Fluoxetine was established in 8- to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least three bulimic episodes per week for 6 months (see  CLINICAL TRIALS).

The efficacy of Fluoxetine 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Fluoxetine 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see  CLINICAL TRIALS). Nevertheless, the physician who elects to use Fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see  DOSAGE AND ADMINISTRATION).

Panic Disorder

Fluoxetine is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of Fluoxetine was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see  CLINICAL TIRALS).

Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes.

The effectiveness of Fluoxetine in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see  DOSAGE AND ADMINISTRATION).

Contraindications

Fluoxetine hydrochloride 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, Fluoxetine 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  CLINICAL PHARMACOLOGY]) should be allowed after stopping Fluoxetine before starting an MAOI.

Thioridazine

Thioridazine should not be administered with Fluoxetine or within a minimum of 5 weeks after Fluoxetine has been discontinued (see  WARNINGS).

Warnings

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see  PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Fluoxetine, for a description of the risks of discontinuation of Fluoxetine).

Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

It should be noted that Eli Lilly and Company’s Fluoxetine is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with despressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Fluoxetine is not approved for use in treating bipolar depression.

In U.S. Fluoxetine clinical trials as of May 8, 1995, 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, 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 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 Fluoxetine, systemic events, possibly related to vasculitis and including lupus-like syndrome, 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, laryngospasm, 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, Fluoxetine should be discontinued.

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including Fluoxetine, will produce elevated plasma levels of thioridazine (see  PRECAUTIONS).

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with Fluoxetine-induced inhibition of thioridazine metabolism (see  CONTRAINDICATIONS).

Precautions

General

Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see  Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Fluoxetine with NSAIDs, aspirin, or other drugs that affect coagulation.

In U.S. placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Fluoxetine and in 7% of patients treated with placebo.

In U.S. placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse events associated with discontinuation (incidence at least twice that for placeboand at least 1% for Fluoxetine in clinical trials collecting only a primary event associated with discontinuation) in U.S. placebo-controlled Fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 3).

Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Fluoxetine.

In U.S. placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Fluoxetine because of anorexia or weight loss (see also  Pediatric Useunder  PRECAUTIONS).

In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with Fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Fluoxetine because of anorexia (see also  Pediatric Useunder  PRECAUTIONS).

In U.S. placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Fluoxetine 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.

In U.S. placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Fluoxetine 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 other marketed drugs effective in the treatment of major depressive disorder (see also  Pediatric Useunder  PRECAUTIONS).

In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In all U.S. Fluoxetine clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also  Pediatric Useunder  PRECAUTIONS).

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 two 6-week controlled studies in patients ³60 years of age, 10 of 323 Fluoxetine patients and 6 of 327 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.

In U.S. placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In all U.S. Fluoxetine clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Fluoxetine should be introduced with care in patients with a history of seizures.

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  CLINICAL PHARMACOLOGYand  DOSAGE AND ADMINISTRATION).

Clinical experience with Fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using Fluoxetine 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 Fluoxetine 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 Diseaseunder  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, 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.

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.

During marketing of Fluoxetine and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma Fluoxetine and norFluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see  DOSAGE AND ADMINISTRATION).

Information for patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Fluoxetine Capsules USP and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Fluoxetine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Fluoxetine Capsules USP.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Because Fluoxetine 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 cautioned about the concomitant use of Fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding.

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 (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under  CLINICAL PHARMACOLOGY).

Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme 2D6. Such individuals have been referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and TCAs. Many drugs, such as most drugs effective in the treatment of major depressive disorder, 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 four active enantiomers is comparable between poor and extensive metabolizers (see Variability in metabolism under  CLINICAL PHARMACOLOGY).

Fluoxetine, like other agents that are metabolized by CYP2D6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers. Therapy with medications that are predominantly metabolized by the CYP2D6 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 CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with Fluoxetine or within a minimum of 5 weeks after Fluoxetine has been discontinued (see  CONTRAINDICATIONSand  WARNINGS).

In an in vivo interaction study involving coadministration of Fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant Fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 CYP3A4 activity is not likely to be of clinical significance.

The risk of using Fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Fluoxetine 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  CLINICAL PHARMACOLOGY).

Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant Fluoxetine treatment.

Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between 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 pimozide and Fluoxetine leading to bradycardia. For thioridazine, see  CONTRAINDICATIONS and  WARNINGS.

The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and slow elimination under  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.

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.

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

See  CONTRAINDICATIONS.

In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2-to10-fold when Fluoxetine has been administered in combination. This influence may p

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