018936s064lbl.pdf

NDA 18-936/S-064Approved Labeling EnclosurePage 1 ENCLOSURE
[Note: Below is the Agency’s final labeling for Prozac to incorporate the new
pediatric major depressive disorder and obsessive compulsive disorder changes
to the Prozac labeling.]
PROZAC®
FLUOXETINE HYDROCHLORIDE
DESCRIPTION
Prozac® (fluoxetine hydrochloride) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (SarafemTM, fluoxetinehydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C H F NO•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 Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin,silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 mg and 20 mgPulvules also contain F D & C Blue No. 1, and the 40 mg Pulvule also contains F D & C BlueNo. 1 and F D & C Yellow No. 6.
Each tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol) of fluoxetine.
The tablets also contain microcrystalline cellulose, magnesium stearate, crospovidone,hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. Inaddition to the above ingredients, the 10 mg tablet contains F D & C Blue No. 1 aluminum lake,and polysorbate 80.
The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 µmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water,and sucrose.
Prozac Weekly capsules, a delayed release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules alsocontain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres,talc, titanium dioxide, triethyl citrate, and other inactive ingredients.
NDA 18-936/S-064Approved Labeling EnclosurePage 2 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 clinicallyrelevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin intohuman platelets. Studies in animals also suggest that fluoxetine is a much more potent uptakeinhibitor of serotonin than of norepinephrine.
Antagonism of muscarinic, histaminergic, and α -adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classicaltricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptorsfrom 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, tablet, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, althoughit may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus,fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayedrelease formulation, contain enteric-coated pellets that resist dissolution until reaching a segmentof the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset ofabsorption of fluoxetine 1 to 2 hours relative to the immediate release formulations.
Protein Binding--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 notbeen 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 uptakeinhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer iseliminated 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 formedby demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selectiveinhibitor 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 metabolitesexcreted 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 "poormetabolizers" of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a studyinvolving labeled and unlabeled enantiomers administered as a racemate, these individualsmetabolized 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 NDA 18-936/S-064Approved Labeling EnclosurePage 3 metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared withnormal metabolizers, the total sum at steady state of the plasma concentrations of the four activeenantiomers was not significantly greater among poor metabolizers. Thus, the netpharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-IID6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves asteady-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, involves the P450IID6 system, concomitanttherapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead todrug 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 andchronic administration), leads to significant accumulation of these active species in chronic useand delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosingat 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL andnorfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations offluoxetine were higher than those predicted by single-dose studies, because fluoxetine'smetabolism is not proportional to dose. Norfluoxetine, however, appears to have linearpharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multipledosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to5 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 onindividual patient characteristics, previous dosing regimen, and length of previous therapy atdiscontinuation). This is of potential consequence when drug discontinuation is required or whendrugs are prescribed that might interact with fluoxetine and norfluoxetine following thediscontinuation of Prozac.
Weekly Dosing—Administration of Prozac Weekly once-weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared toonce daily dosing (for fluoxetine: 24% [daily] to 164% [weekly] and for norfluoxetine: 17%[daily] to 43% [weekly]). Plasma concentrations may not necessarily be predictive of clinicalresponse. Peak concentrations from once-weekly doses of Prozac Weekly capsules offluoxetine are in the range of the average concentration for 20 mg once-daily dosing. Averagetrough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than theconcentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations ofeither once-daily or once-weekly dosing are in relative proportion to the total doseadministered. Average steady state fluoxetine concentrations are approximately 50% lowerfollowing the once-weekly regimen compared to the once-daily regimen.
Cmax for fluoxetine following the 90 mg dose was approximately 1.7 fold higher than the Cmax value for the established 20 mg once daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90 mg once weekly dose and the last 20 mg oncedaily dose were separated by one week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transitionthe next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be NDA 18-936/S-064Approved Labeling EnclosurePage 4 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 astudy of cirrhotic patients, with a mean of 7.6 days compared to the range of 2 to 3 days seen insubjects without liver disease; norfluoxetine elimination was also delayed, with a mean durationof 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. Thissuggests 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 shouldbe used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal Disease--In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasmaconcentrations comparable to those seen in patients with normal renal function. While thepossibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levelsin patients with severe renal dysfunction, use of a lower or less frequent dose is not routinelynecessary in renally impaired patients (see Use in Patients with Concomitant Illness underPRECAUTIONS and DOSAGE AND ADMINISTRATION).
Age—Geriatric Pharmacokinetics--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 normalsubjects. However, given the long half-life and nonlinear disposition of the drug, a single-dosestudy 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 butotherwise healthy depressed patients (≥ 60 years of age) who received 20 mg fluoxetine for 6weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events wasobserved in those elderly patients.
Pediatric Pharmacokinetics (Children and Adolescents)--Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18)diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine20 mg/day was administered for up to 62 days. The average steady-state concentrations offluoxetine in these children were 2-fold higher than in adolescents (171 ng/mL and 86 ng/mL,respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 ng/mL and 113 ng/mL, respectively). These differences canbe almost entirely explained by differences in weight. No gender-associated difference influoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetineplasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18)diagnosed with major depressive disorder.
Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range ofconcentrations observed in the adult population. As in adults, fluoxetine and norfluoxetineaccumulated extensively following multiple oral dosing; steady-state concentrations wereachieved within 3 to 4 weeks of daily dosing.
Major Depressive Disorder—Daily Dosing: NDA 18-936/S-064Approved Labeling EnclosurePage 5 Adult--The efficacy of Prozac for the treatment of patients with major depressive disorder (≥ 18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac wasshown to be significantly more effective than placebo as measured by the Hamilton DepressionRating Scale (HAM-D). Prozac was also significantly more effective than placebo on theHAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.
Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg, and placebo have shown Prozac 20 mg daily, to be effective in the treatment of elderly patients (≥ 60 yearsof age) with major depressive disorder. In these studies, Prozac produced a significantly higherrate of response and remission as defined respectively by a 50% decrease in the HAM-D scoreand a total endpoint HAM-D score of < 8. Prozac was well tolerated and the rate of treatmentdiscontinuations 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 ofmajor depressive disorder by DSM-III-R criteria) by the end of an initial 12-week opentreatment phase on Prozac 20 mg/day. These patients (N=298) were randomized tocontinuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), astatistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis ofmajor depressive disorder for 2 weeks or a modified HAMD-17 score of > 14 for 3 weeks)was observed for patients taking Prozac compared to those on placebo.
Pediatric (Children and Adolescents)--The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to<13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled clinical trials.
In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score frombaseline to endpoint than did placebo.
Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness Weekly dosing for maintenance/continuation treatment: A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorderwho had responded (defined as having a modified HAMD-17 score of < 9, a CGI-Severityrating of < 2, and no longer meeting criteria for major depressive disorder) for 3 consecutiveweeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once-daily. Thesepatients were randomized to double-blind, once-weekly continuation treatment with ProzacWeekly, Prozac 20 mg once-daily, or placebo. Prozac Weekly once-weekly and Prozac 20 mgonce daily demonstrated superior efficacy (having a significantly longer time to relapse ofdepressive symptoms) compared to placebo for a period of 25 weeks. However, theequivalence of these two treatments during continuation therapy has not been established.
Obsessive Compulsive Disorder—Adult--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 dayschedule, 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 NDA 18-936/S-064Approved Labeling EnclosurePage 6 mean reductions of approximately 4 to 6 units on the YBOCS total score, compared to a 1-unitreduction for placebo patients. In Study 2, patients receiving Prozac experienced meanreductions of approximately 4 to 9 units on the YBOCS total score, compared to a 1-unitreduction for placebo patients. While there was no indication of a dose response relationship foreffectiveness in Study 1, a dose response relationship was observed in Study 2, with numericallybetter responses in the two higher dose groups. The following table provides the outcomeclassification by treatment group on the Clinical Global Impression (CGI) improvement scale forStudies 1 and 2 combined: Outcome Classification (%) on CGI Improvement Scale forCompleters in Pool of Two OCD Studies Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
Pediatric (Children and Adolescents)--In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD,patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. Thedose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response andtolerability. Prozac produced a statistically significantly greater mean change from baseline toendpoint than did placebo as measured by the Children’s Yale-Brown Obsessive CompulsiveScale (CY-BOCS).
Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of 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 meetingDSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/dayof Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozacdose of 60 mg/day (once a day) or placebo. Patients in these three studies had moderate tosevere bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 perweek and 5 to 9 per week, respectively. In these three studies, Prozac 60 mg, but not 20 mg,was statistically significantly superior to placebo in reducing the number of binge-eating andvomiting episodes per week. The statistically significantly superior effect of 60 mg vs placebowas present as early as Week 1 and persisted throughout each study. The Prozac relatedreduction in bulimic episodes appeared to be independent of baseline depression as assessed bythe Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, asmeasured by differences between Prozac 60 mg, and placebo on median reduction frombaseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per weekfor binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to NDA 18-936/S-064Approved Labeling EnclosurePage 7 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 oftreatment, for the majority, the benefit was a partial reduction in the frequency of binge-eatingand 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 Prozac60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to52 weeks of observation for relapse. Response during the single-blind phase was defined byhaving achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapseduring the double-blind phase was defined as a persistent return to baseline vomiting frequencyor physician judgement that the patient had relapsed. Patients receiving continued Prozac60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weekscompared with those receiving placebo.
Panic Disorder—The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adultoutpatients who had a primary diagnosis of panic disorder (DSM-IV), with or withoutagoraphobia.
Study 1 (N = 180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/dayon the basis of clinical response and tolerability. A statistically significantly greater percentage ofProzac-treated patients were free from panic attacks at endpoint than placebo-treated patients,42% vs. 28%, respectively.
Study 2 (N = 214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day onthe basis of clinical response and tolerability. A statistically significantly greater percent ofProzac-treated patients were free from panic attacks at endpoint than placebo-treated patients,62% vs. 44%, respectively.
INDICATIONS AND USAGE
Major Depressive Disorder--Prozac is indicated for the treatment of major depressive Adult--The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to theDSM-III (currently DSM-IV) category of major depressive disorder (see Clinical Trials underCLINICAL PHARMACOLOGY).
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 dailyfunctioning, and includes at least five of the following nine symptoms: depressed mood; loss ofinterest 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 Prozac in hospitalized depressed patients have not been adequately studied.
The efficacy of Prozac 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.
NDA 18-936/S-064Approved Labeling EnclosurePage 8 The efficacy of Prozac Weekly once-weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks followingopen-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basisprovides the same level of protection from relapse as that provided by Prozac 20 mg daily (seeClinical Trials under CLINICAL PHARMACOLOGY).
Pediatric (Children and Adolescents)--The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatientswhose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of majordepressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).
The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically.
Obsessive-Compulsive Disorder—Adult--Prozac 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 orcompulsions cause marked distress, are time-consuming, or significantly interfere with social oroccupational 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 ofobsessive-compulsive disorder (see Clinical Trials under 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, andintentional behaviors (compulsions) that are recognized by the person as excessive orunreasonable.
The effectiveness of Prozac 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 useProzac for extended periods should periodically reevaluate the long-term usefulness of the drugfor the individual patient (see DOSAGE AND ADMINISTRATION).
Pediatric (Children and Adolescents)--The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see Clinical Trials under CLINICAL PHARMACOLOGY).
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, i.e., at least three bulimic episodes per week for 6 months(see Clinical Trials under CLINICAL PHARMACOLOGY).
The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a NDA 18-936/S-064Approved Labeling EnclosurePage 9 placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY).
Nevertheless, the physician who elects to use Prozac for extended periods should periodicallyreevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE ANDADMINISTRATION).
Panic Disorder—Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence ofunexpected panic attacks, and associated concern about having additional attacks, worry aboutthe implications or consequences of the attacks, and/or a significant change in behavior relatedto the attacks.
The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see Clinical Trials underCLINICAL PHARMACOLOGY).
Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., adiscrete period of intense fear or discomfort in which 4 or more of the following symptomsdevelop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, oraccelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breathor smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominaldistress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear ofdying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes.
The effectiveness of Prozac in long-term use, that is, for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac forextended periods should periodically reevaluate the long-term usefulness of the drug for theindividual patient (DOSAGE AND ADMINISTRATION).
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 rapidfluctuations of vital signs, and mental status changes that include extreme agitation progressing todelirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidaseinhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then startedon 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 14days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite havevery long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine hasbeen prescribed chronically and/or at higher doses [see Accumulation and Slow Eliminationunder CLINICAL PHARMACOLOGY]) should be allowed after stopping Prozac beforestarting an MAOI.
Thioridazine—Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS).
WARNINGS
Rash and Possibly Allergic Events--In US 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 rashand/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, NDA 18-936/S-064Approved Labeling EnclosurePage 10 carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mildtransaminase elevation. Most patients improved promptly with discontinuation of fluoxetineand/or adjunctive treatment with antihistamines or steroids, and all patients experiencing theseevents 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 consideredto have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that wasconsidered variously to be a vasculitis or erythema multiforme. Other patients have had systemicsyndromes suggestive of serum sickness.
Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, theymay be serious, involving the lung, kidney, or liver. Death has been reported to occur inassociation 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 precedingsymptom.
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 underlyingimmunologic basis for these events has not been identified. Upon the appearance of rash or ofother possibly allergic phenomena for which an alternative etiology cannot be identified, Prozacshould be discontinued.
Potential Interaction with Thioridazine—In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose ofthioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in theslow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylationis felt to depend on the level of cytochrome P450IID6 isozyme activity. Thus, this studysuggests that drugs which inhibit P450IID6, such as certain SSRIs, including fluoxetine, willproduce 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 ofthioridazine metabolism (see CONTRAINDICATIONS).
PRECAUTIONS
GeneralAnxiety and Insomnia--In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placeboreported anxiety, nervousness, or insomnia.
In US placebo-controlled clinical trials for OCD, 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 60mg, and in 9% and 5% of patients treated with placebo.
NDA 18-936/S-064Approved Labeling EnclosurePage 11 Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary eventassociated with discontinuation) in US 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, 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 major depressive disorder, 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 patientstreated with placebo. However, only rarely have patients discontinued treatment with Prozacbecause of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS).
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 patientdiscontinued treatment with Prozac because of anorexia (see also Pediatric Use underPRECAUTIONS).
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 (decreasedappetite). Patients treated with Prozac, 60 mg, on average lost 0.45 kg compared with a gain of0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight changeshould be monitored during therapy.
Activation of Mania/Hypomania--In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% ofpatients treated with placebo. Activation of mania/hypomania has also been reported in a smallproportion of patients with Major Affective Disorder treated with other marketed drugseffective in the treatment of major depressive disorder (see also Pediatric Use underPRECAUTIONS).
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 reportedmania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinicaltrials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see alsoPediatric Use under PRECAUTIONS).
Seizures--In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patientstreated with Prozac and 0.2% of patients treated with placebo. No patients reportedconvulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozacclinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentageappears to be similar to that associated with other marketed drugs effective in the treatment ofmajor depressive disorder. Prozac should be introduced with care in patients with a history ofseizures.
Suicide--The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high risk patients shouldaccompany initial drug therapy. Prescriptions for Prozac should be written for the smallestquantity of capsules consistent with good patient management, in order to reduce the risk ofoverdose.
Because of well-established comorbidity between both OCD and major depressive disorder and bulimia and major depressive disorder, the same precautions observed when treatingpatients with major depressive disorder should be observed when treating patients with OCD or NDA 18-936/S-064Approved Labeling EnclosurePage 12 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 notbe fully reflected in plasma for several weeks, affecting both strategies for titration to final doseand withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE ANDADMINISTRATION).
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 withdiseases 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 weresystematically excluded from clinical studies during the product's premarket testing. However,the electrocardiograms of 312 patients who received Prozac in double-blind trials wereretrospectively evaluated; no conduction abnormalities that resulted in heart block wereobserved. 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. Alower 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 CLINICAL PHARMACOLOGY). Use of alower or less frequent dose for renally impaired patients is not routinely necessary (seeDOSAGE 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 thedrug. As is true with many other types of medication when taken concurrently by patients withdiabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy withProzac 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 hazardousmachinery, including automobiles, until they are reasonably certain that the drug treatment doesnot affect them adversely.
Information for Patients--Physicians are advised to discuss the following issues with 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 certainthat 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 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).
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.
NDA 18-936/S-064Approved Labeling EnclosurePage 13 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 ofmajor depressive disorder, including fluoxetine and other selective uptake inhibitors of serotonin,are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relativeproportion of metabolites are altered in poor metabolizers. However, for fluoxetine and itsmetabolite the sum of the plasma concentrations of the four active enantiomers is comparablebetween poor and extensive metabolizers (see Variability in Metabolism under CLINICALPHARMACOLOGY).
Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapywith medications that are predominantly metabolized by the P450IID6 system and that have arelatively narrow therapeutic index (see list below), should be initiated at the low end of thedose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5weeks. Thus, his/her dosing requirements resemble those of "poor metabolizers." If fluoxetine isadded 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 anarrow therapeutic index represent the greatest concern (e.g., flecainide, vinblastine, andTCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentiallyassociated with elevated plasma levels of thioridazine, thioridazine should not be administeredwith fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (seeCONTRAINDICATIONS and WARNINGS).
Drugs Metabolized by Cytochrome P450IIIA4--In an in vivo interaction study involving co- administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4substrate), no increase in plasma terfenadine concentrations occurred with concomitantfluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor ofP450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as aninhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride,and midazolam. These data indicate that fluoxetine’s extent of inhibition of cytochromeP450IIIA4 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 concomitantadministration of Prozac and such drugs is required. In evaluating individual cases, considerationshould be given to using lower initial doses of the concomitantly administered drugs, usingconservative titration schedules, and monitoring of clinical status (see Accumulation and SlowElimination under CLINICAL PHARMACOLOGY).
Anticonvulsants--Patients on stable doses of phenytoin and carbamazepine have developedelevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity followinginitiation of concomitant fluoxetine treatment.
Antipsychotics--Some clinical data suggests a possible pharmacodynamic and/orpharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) andantipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed inpatients receiving concomitant fluoxetine. A single case report has suggested possibleadditive effects of pimozide and fluoxetine leading to bradycardia. For thioridazine, seeCONTRAINDICATIONS and WARNINGS.
Benzodiazepines--The half-life of concurrently administered diazepam may be prolonged insome patients (see Accumulation and Slow Elimination under Clinical Pharmacology). Co- administration of alprazolam and fluoxetine has resulted in increased alprazolam plasmaconcentrations and in further psychomotor performance decrement due to increased NDA 18-936/S-064Approved Labeling EnclosurePage 14 alprazolam levels.
Lithium--There have been reports of both increased and decreased lithium levels whenlithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increasedserotonergic effects have been reported. Lithium levels should be monitored when thesedrugs are administered concomitantly.
Tryptophan--Five patients receiving Prozac in combination with tryptophan experiencedadverse reactions, including agitation, restlessness, and gastrointestinal distress.
Monoamine Oxidase Inhibitors--See CONTRAINDICATIONS.
Other Drugs Effective in the Treatment of Major Depressive Disorder--In two studies,previously stable plasma levels of imipramine and desipramine have increased greater than 2to 10-fold when fluoxetine has been administered in combination. This influence may persistfor three weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may needto be reduced and plasma TCA concentrations may need to be monitored temporarily whenfluoxetine is coadministered or has been recently discontinued (see Accumulation and SlowElimination under CLINICAL PHARMACOLOGY, and Drugs Metabolized byP450IID6 under Drug Interactions).
Sumatriptan—There have been rare postmarketing reports describing patients withweakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan.
If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine,paroxetine, sertraline, or citalopram) is clinically warranted, appropriate observation of thepatient is advised.
Potential Effects of Co-administration of Drugs Tightly Bound to Plasma Proteins--Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient takinganother drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift inplasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects mayresult from displacement of protein bound fluoxetine by other tightly bound drugs (seeAccumulation and Slow Elimination under CLINICAL PHARMACOLOGY).
Warfarin--Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Patients receiving warfarin therapy shouldreceive 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 inpatients 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, themaximum recommended human dose [MRHD] of 80 mg on a mg/m2 basis), produced noevidence 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 rathepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinesehamster 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 thatfluoxetine had no adverse effects on fertility.
NDA 18-936/S-064Approved Labeling EnclosurePage 15 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 15mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended humandose [MRHD] of 80 mg on a mg/m2 basis) throughout organogenesis. However, in ratreproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase inpup deaths during the first 7 days postpartum occurred following maternal exposure to 12mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence ofdevelopmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day duringgestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on amg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies thepotential 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 fluoxetinemay have adverse effects on the newborn, fluoxetine should be used during labor and deliveryonly 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 was70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects onthe infant were reported. In another case, an infant nursed by a mother on Prozac developedcrying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.
Pediatric Use-- The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatricoutpatients ages 8 to ≤18. (see Clinical Trials under CLINICAL PHARMACOLOGY).
The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo- controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see Clinical Trials underCLINICAL PHARMACOLOGY).
Safety and effectiveness in pediatric patients less than 8 years of age in major depressive disorder and less than 7 years of age in OCD have not been established.
Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICALPHARMACOLOGY).
The acute adverse event profiles observed in the three studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studieswith fluoxetine. The longer-term adverse event profile observed in the 19-week majordepressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated)was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS).
Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treatedpatients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patientsfrom the acute phases of the three studies combined. Consequently, regular monitoring for theoccurrence of mania/hypomania is recommended.
As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, NDA 18-936/S-064Approved Labeling EnclosurePage 16 pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004)and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetinetreatment was associated with a decrease in alkaline phosphatase levels. The safety offluoxetine treatment for pediatric patients has not been systematically assessed for chronictreatment longer than several months in duration. In particular, there are no studies that directlyevaluate the longer-term effects of fluoxetine on the growth, development, and maturation ofchildren and adolescent patients. Therefore, height and weight should be monitored periodicallyin pediatric patients receiving fluoxetine.
Geriatric Use—U.S. fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients > 65 years of age and 93 patients > 75 years of age. The efficacy in geriatricpatients has been established (see Clinical Trials under CLINICAL PHARMACOLOGY). Forpharmacokinetic information in geriatric patients see Age under CLINICALPHARMACOLOGY. No overall differences in safety or effectiveness were observed betweenthese subjects and younger subjects, and other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out. As with other SSRIs, fluoxetine has been associatedwith cases of clinically significant hyponatremia in elderly patients (see Hyponatremia underPRECAUTIONS).
Hyponatremia--Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac wasdiscontinued. Although these cases were complex with varying possible etiologies, some werepossibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Themajority of these occurrences have been in older patients and in patients taking diuretics or whowere otherwise volume depleted. In two 6-week controlled studies in patients > 60 years ofage, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serumsodium below the reference range; this difference was not statistically significant. The lowestobserved concentration was 129 mmol/L. The observed decreases were not clinicallysignificant.
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 ofabnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had acausative role.
ADVERSE REACTIONS
Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administeredProzac in panic clinical trials. Adverse events were recorded by clinical investigators usingdescriptive terminology of their own choosing. Consequently, it is not possible to provide ameaningful estimate of the proportion of individuals experiencing adverse events without firstgrouping similar types of events into a limited (i.e., reduced) number of standardized eventcategories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individualswho experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receivingtherapy following baseline evaluation. It is important to emphasize that events reported during NDA 18-936/S-064Approved Labeling EnclosurePage 17 The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patientcharacteristics and other factors differ from those that prevailed in the clinical trials. Similarly, thecited frequencies cannot be compared with figures obtained from other clinical investigationsinvolving different treatments, uses, and investigators. The cited figures, however, do provide theprescribing physician with some basis for estimating the relative contribution of drug andnondrug factors to the side effect incidence rate in the population studied.
Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo- Controlled Clinical Trials (excluding data from extensions of trials)--Table 1 enumeratesthe most common treatment-emergent adverse events associated with the use of Prozac(incidence of at least 5% for Prozac and at least twice that for placebo within at least one of theindications) for the treatment of major depressive disorder, OCD, and bulimia in US controlledclinical trials and panic disorder in US plus non-US controlled trials. Table 2 enumeratestreatment-emergent adverse events that occurred in 2% or more patients treated with Prozacand with incidence greater than placebo who participated in US major depressive disorder,OCD, and bulimia controlled clinical trials and US plus non-US panic disorder controlledclinical trials. Table 2 provides combined data for the pool of studies that are providedseparately by indication in Table 1.
NDA 18-936/S-064Approved Labeling EnclosurePage 18 MOST COMMON TREATMENT-EMERGENT
ADVERSE EVENTS: INCIDENCE IN MAJOR DEPRESSIVE DISORDER,
OCD, BULIMIA AND PANIC DISORDER PLACEBO-CONTROLLED CLINICAL
Body as a Whole
Asthenia
Cardiovascular
System
Digestive System
Nausea
Nervous System
Insomnia
Respiratory
System
Skin and
Appendages
Urogenital
System
*Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials.
†Denominator used was for males only (N = 690 Prozac major depressive disorder; N = 410 placebo major depressive disorder; N = 116 Prozac OCD; N = 43 placebo OCD; N = 14 Prozac bulimia; N = 1 placebo bulimia;N = 162 Prozac panic; N = 121 placebo panic).
NDA 18-936/S-064Approved Labeling EnclosurePage 19 INCIDENCE IN MAJOR DEPRESSIVE DISORDER, OCD, BULIMIA, and PANIC Major Depressive Disorder, OCD, bulimia, and panic Body as a Whole
Headache
Cardiovascular System
Digestive System
Nausea
Metabolic and Nutritional Disorders
Weight loss
Nervous System
Insomnia
Respiratory System
Yawn
Skin and Appendages
Sweating
Special Senses
Abnormal vision
*Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials.
†Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac ( major depressive disorder, OCD, bulimia, and panic disorder combined):abdominal pain, abnormal dreams, accidental injury, back paincough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis.
NDA 18-936/S-064Approved Labeling EnclosurePage 20 Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled clinical trials (excluding data from extensions of trials) --Table 3 liststhe adverse events associated with discontinuation of Prozac treatment (incidence at least twicethat for placebo and at least 1% for Prozac in clinical trials collecting only a primary eventassociated with discontinuation) in major depressive disorder, OCD, bulimia, and panicdisorder clinical trials, plus non-US panic disorder clinical trials.
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN MAJOR DEPRESSIVE DISORDER, OCD, BULIMIA
AND PANIC DISORDER PLACEBO-CONTROLLED CLINICAL TRIALS
*Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plusnon-US panic disorder clinical trials.
NDA 18-936/S-064Approved Labeling EnclosurePage 21 Other Adverse Events in Pediatric Patients (Children and Adolescents)--Treatment- emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142placebo-treated). The overall profile of adverse events was generally similar to that seen in adultstudies, as shown in Tables 1 and 2. However, the following adverse events (excluding thosewhich appear in the body or footnotes of Tables 1 and 2 and those for which the COSTARTterms were uninformative or misleading) were reported at an incidence of at least 2% forfluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder,epistaxis, urinary frequency, and menorrhagia.
The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo)associated with discontinuation in three pediatric placebo-controlled trials (N=418 randomized;228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% forfluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary eventassociated with discontinuation was collected.
Events Observed in Prozac Weekly Clinical Trials—Treatment-emergent adverse events inclinical trials with Prozac Weekly were similar to the adverse events reported by patients inclinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking ProzacWeekly reported diarrhea than patients taking placebo (10% vs. 3%, respectively) or takingProzac 20 mg daily (10% vs. 5%, respectively).
Male and Female Sexual Dysfunction with SSRIs--Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatricdisorder, they may also be a consequence of pharmacologic treatment. In particular, someevidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimatesof the incidence and severity of untoward experiences involving sexual desire, performance, andsatisfaction are difficult to obtain, however, in part because patients and physicians may bereluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experienceand performance, cited in product labeling, are likely to underestimate their actual incidence. Inpatients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlledclinical trials, decreased libido was the only sexual side effect reported by at least 2% of patientstaking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports inwomen taking fluoxetine of orgasmic dysfunction, including anorgasmia.
There are no adequate and well-controlled studies examining sexual dysfunction with Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use ofSSRIs, physicians should routinely inquire about such possible side effects.
Other Events Observed In Clinical Trials--Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 2above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative ormisleading; (3) those events for which a causal relationship to Prozac use was consideredremote; and (4) events occurring in only 1 patient treated with Prozac and which did not have asubstantial probability of being acutely life-threatening.
Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare eventsare those occurring in less than 1/1,000 patients.
NDA 18-936/S-064Approved Labeling EnclosurePage 22 Body as a Whole--Frequent: chest pain, chills; Infrequent: chills and fever, face edema,
intentional overdose, malaise, pelvic pain, suicide attempt; Rare: abdominal syndrome acute,hypothermia, intentional injury, neuroleptic malignant syndrome*, photosensitivity reaction.
Cardiovascular System--Frequent: hemorrhage, hypertension, palpitation; Infrequent:
angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct,postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation,bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles,heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis,thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.
Digestive System--Frequent: increased appetite, nausea and vomiting; Infrequent:
aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis,gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver functiontests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis,thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophagealulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon,hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage,salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.
Endocrine System--Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes
Hemic and Lymphatic System--Infrequent: anemia, ecchymosis; Rare: blood
dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura,thrombocythemia, thrombocytopenia.
Metabolic and Nutritional--Frequent: weight gain; Infrequent: dehydration,
generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema;Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatinephosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia,SGPT increased.
Musculoskeletal System--Infrequent: arthritis, bone pain, bursitis, leg cramps,
tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis,osteomyelitis, osteoporosis, rheumatoid arthritis.
Nervous System--Frequent: agitation, amnesia, confusion, emotional lability, sleep
disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia,buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria,hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased,myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder†, psychosis,vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia,coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia,neuritis, paralysis, reflexes decreased, reflexes increased, stupor.
Respiratory System--Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare:
apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynxedema, lung edema, pneumothorax, stridor.
Skin and Appendages--Infrequent: acne, alopecia, contact dermatitis, eczema,
maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis,herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.
Special Senses--Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis,
dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye NDA 18-936/S-064Approved Labeling EnclosurePage 23 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual fielddefect.
Urogenital System--Frequent: urinary frequency; Infrequent: abortion‡, albuminuria,
amenorrhea‡, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation‡,fibrocystic breast‡, hematuria, leukorrhea‡, menorrhagia‡, metrorrhagia‡, nocturia, polyuria,urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage‡; Rare: breastengorgement, glycosuria, hypomenorrhea‡, kidney pain, oliguria, priapism‡, uterinehemorrhage‡, uterine fibroids enlarged‡.
*Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome.
† Personality disorder is the COSTART term for designating non-aggressive objectionable Postintroduction Reports-- Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causalrelationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract,cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, acase of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported todevelop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completelyresolved over the next few months following drug discontinuation), eosinophilic pneumonia,epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest,hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia,kidney failure, misuse/abuse, movement disorders developing in patients with risk factorsincluding drugs associated with such events and worsening of preexisting movement disorders,neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism,pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a rangeof signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignantsyndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation,thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal,ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class--Prozac is not a controlled substance.
Physical and Psychological Dependence--Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While thepremarketing clinical experience with Prozac did not reveal any tendency for a withdrawalsyndrome or any drug seeking behavior, these observations were not systematic and it is notpossible to predict on the basis of this limited experience the extent to which a CNS active drugwill be misused, diverted, and/or abused once marketed. Consequently, physicians shouldcarefully evaluate patients for history of drug abuse and follow such patients closely, observingthem for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation ofdose, drug-seeking behavior).
OVERDOSAGE
Human Experience—Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths.
NDA 18-936/S-064Approved Labeling EnclosurePage 24 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae afteroverdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness,nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence,movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. Themost common signs and symptoms associated with non-fatal overdosage were seizures,somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetinehydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and whosubsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion aslow as 520 mg has been associated with lethal outcome, but causality has not been established.
Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patientscompletely recovered, 1 patient experienced renal failure, and 22 patients had an unknownoutcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’ssyndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, andpromethazine. Mixed-drug ingestion or other methods of suicide complicated all six overdosesin children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams whichwas non-lethal.
Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventriculartachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neurolepticmalignant syndrome-like events, pyrexia, stupor, and syncope.
Animal Experience--Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provideuseful insights into possible treatment strategies.
The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg respectively. Acute high oral doses produced hyperirritability and convulsions in several animalspecies.
Among six dogs purposely overdosed with oral fluoxetine, five experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standardveterinary dose of diazepam. In this short term study, the lowest plasma concentration at whicha seizure occurred was only twice the maximum plasma concentration seen in humans taking 80mg/day, chronically.
In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure wereobserved. Consequently, the value of the ECG in predicting cardiac toxicity is unknown.
Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (seeManagement of Overdose).
Management of Overdose--Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressivedisorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction ofemesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriateairway protection, if needed, may be indicated if performed soon after ingestion, or in Activated charcoal should be administered. Due to the large volume of distribution of this NDA 18-936/S-064Approved Labeling EnclosurePage 25 A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/oran active metabolite may increase the possibility of clinically significant sequelae and extend thetime needed for close medical observation (see Other Drugs Effective in the Treatment of MajorDepressive Disorder under PRECAUTIONS).
Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment ofany overdose. Telephone numbers for certified poison control centers are listed in thePhysicians' Desk Reference (PDR). DOSAGE AND ADMINISTRATION
Initial Treatment—Adult--In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 mg to 80 mg/day. Studies comparing fluoxetine 20,40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactoryresponse in major depressive disorder in most cases. Consequently, a dose of 20 mg/day,administered in the morning, is recommended as the initial dose.
A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once a day (morning) or b.i.d.
schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day.
Pediatric (Children and Adolescents)--In the, short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder,patients were administered fluoxetine doses of 10 to 20 mg/day (see Clinical Trials underCLINICAL PHARMACOLOGY). Treatment should be initiated with a dose of 10 or 20mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day.
However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after severalweeks if insufficient clinical improvement is observed.
All Patients--As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer.
As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for theelderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease oron multiple concomitant medications. Dosage adjustments for renal impairment are not routinelynecessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, andUse in Patients with Concomitant Illness under PRECAUTIONS).
Maintenance/Continuation/Extended Treatment--It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy.
Whether the dose needed to induce remission is identical to the dose needed to maintain and/orsustain euthymia is unknown.
Daily Dosing--Systematic evaluation of Prozac has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open- NDA 18-936/S-064Approved Labeling EnclosurePage 26 label acute treatment (50 weeks total) at a dose of 20 mg/day (see Clinical Trials underCLINICAL PHARMACOLOGY).
Weekly Dosing--Systematic evaluation of Prozac Weekly has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosingfollowing 13 weeks of open-label treatment with Prozac 20 mg once-daily. However,therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mggiven daily for delaying time to relapse has not been established. (see Clinical Trials underCLINICAL PHARMACOLOGY).
Weekly dosing with Prozac Weekly capsule is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see CLINICAL PHARMACOLOGY).
If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder-- Initial Treatment—Adult--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of obsessive-compulsive disorder, patients were administered fixed daily doses of 20, 40, or 60mg of fluoxetine or placebo (see Clinical Trials under CLINICAL PHARMACOLOGY). Inone of these studies, no dose response relationship for effectiveness was demonstrated.
Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initialdose. Since there was a suggestion of a possible dose response relationship for effectiveness inthe second study, a dose increase may be considered after several weeks if insufficient clinicalimprovement is observed. The full therapeutic effect may be delayed until 5 weeks of treatmentor longer.
Doses above 20 mg/day may be administered on a once a day (i.e., morning) or b.i.d.
schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended, however,doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximumfluoxetine dose should not exceed 80 mg/day.
Pediatric (Children and Adolescents)--In the controlled clinical trial of fluoxetine supporting itseffectiveness in the treatment of OCD, patients were administered fluoxetine doses in the rangeof 10 to 60 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY).
In adolescents and higher weight children, treatment should be initiated with a dose of 10mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increasesmay be considered after several more weeks if insufficient clinical improvement is observed. Adose range of 20 to 60 mg/day is recommended.
In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvementis observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily dosesgreater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg.
All Patients--As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or lessfrequent dosage should also be considered for the elderly (see Geriatric Use underPRECAUTIONS), and for patients with concurrent disease or on multiple concomitantmedications. Dosage adjustments for renal impairment are not routinely necessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients withConcomitant Illness under PRECAUTIONS).
NDA 18-936/S-064Approved Labeling EnclosurePage 27 Maintenance/Continuation Treatment--While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable toconsider continuation for a responding patient. Although the efficacy of Prozac after 13 weekshas not been documented in controlled trials, patients have been continued in therapy underdouble-blind conditions for up to an additional 6 months without loss of benefit. However,dosage adjustments should be made to maintain the patient on the lowest effective dosage, andpatients should be periodically reassessed to determine the need for treatment.
Bulimia Nervosa-- Initial Treatment--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60mg, or placebo (see Clinical Trials under CLINICAL PHARMACOLOGY). Only the 60 mgdose was statistically significantly superior to placebo in reducing the frequency of binge-eatingand vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning.
For some patients it may be advisable to titrate up to this target dose over several days.
Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.
As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or lessfrequent dosage should also be considered for the elderly (see Geriatric Use underPRECAUTIONS), and for patients with concurrent disease or on multiple concomitantmedications. Dosage adjustments for renal impairment are not routinely necessary (see LiverDisease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients withConcomitant Illness under PRECAUTIONS).
Maintenance/Continuation Treatment-- Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of suchmaintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY).
Nevertheless, patients should be periodically reassessed to determine the need for maintenancetreatment.
Switching Patients to a Tricyclic Antidepressant (TCA): Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered or has been recently discontinued(see Other Drugs Effective in the Treatment of Major Depressive Disorder under DrugInteractions).
Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stoppingProzac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS).
Panic Disorder—Initial Treatment—In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to60 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Treatment should beinitiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day.
The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.
NDA 18-936/S-064Approved Labeling EnclosurePage 28 A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patientswith panic disorder.
As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be consideredfor the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrentdisease or on multiple concomitant medications. Dosage adjustments for renal impairment arenot routinely necessary (see Liver Disease and Renal Disease under CLINICALPHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS).
Maintenance/Continuation Treatment—While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it isreasonable to consider continuation for a responding patient. Nevertheless, patients should beperiodically reassessed to determine the need for continued treatment.
HOW SUPPLIED
The following products are manufactured by Eli Lilly and Company for Dista Products
Company.
Prozac® Pulvules®, USP, are available in:
The 10 mg* Pulvule is opaque green and green, imprinted with DISTA 3104 on the capand Prozac 10 mg on the body: NDC 0777-3104-02 (PU3104**) - Bottles of 100NDC 0777-3104-07 (PU3104**) - Bottles of 2000NDC 0777-3104-82 (PU3104**) - 20 FlexPak§ blister cards of 31 The 20 mg* Pulvule is an opaque green cap and off-white body, imprinted with DISTA3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU3105**) - Bottles of 30NDC 0777-3105-02 (PU3105**) - Bottles of 100NDC 0777-3105-07 (PU3105**) - Bottles of 2000NDC 0777-3105-33 (PU3105**) - (ID†100) BlistersNDC 0777-3105-82 (PU3105**) - 20 FlexPak§ blister cards of 31 The 40 mg* Pulvule is an opaque green cap and opaque orange body, imprinted withDISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU3107**) – Bottles of 30 Liquid, Oral Solution is available in:20 mg* per 5 mL with mint flavor: NDC 0777-5120-58 (MS-5120‡) - Bottles of 120 mL The following products are manufactured and distributed by Eli Lilly and Company.
NDA 18-936/S-064Approved Labeling EnclosurePage 29 NDC 0002-4006-30 (TA4006) - Bottles of 30NDC 0002-4006-02 (TA4006) - Bottles of 100 Prozac WeeklyTM Capsules are available in: The 90 mg* capsule is an opaque green cap and clear body containing discretely visiblewhite pellets through the clear body of the capsule, imprinted with “Lilly” on the cap, and“3004” and “90 mg” on the body.
NDC 0002-3004-75 (PU3004) – Blister package of 4NDC 0002-3004-99 (PU3004) – Blister package of 12 ____________________*Fluoxetine base equivalent.
**Protect from light.
†Identi-Dose® (unit dose medication, Lilly).
‡Dispense in a tight, light-resistant container.
§FlexPak (flexible blister card, Lilly).
Store at controlled room temperature, 59° to 86°F (15° to 30°C).
ANIMAL TOXICOLOGY
Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipidaccumulation in animals has been observed with many cationic amphiphilic drugs, includingfenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
Eli Lilly and Company
Indianapolis, IN 46285, USA

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