Attention, chocolate lovers: You may not be able to help yourselves. Swiss and British scientists have linked the widespread love of chocolate to a chemical "signature" that may be programmed into our metabolic systems.
Read more health news
PROZAC®
FLUOXETINE CAPSULES, USP
FLUOXETINE ORAL SOLUTION, USP
FLUOXETINE DELAYED-RELEASE CAPSULES, USP
WARNING
Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short–term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Prozac or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short–term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Prozac is approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, Pediatric Use.)
DESCRIPTION
Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) 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 empirical 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 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– and 20–mg Pulvules also contain FD&C Blue No. 1, and the 40–mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6.
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 also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients.
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
CLINICAL TRIALS
Major Depressive Disorder
Obsessive Compulsive Disorder
Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 13–week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once–a–day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM–III–R), with mean baseline ratings on the Yale–Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1–unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared 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 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined:
Prozac | ||||
Outcome Classification | Placebo | 20 mg | 40 mg | 60 mg |
Worse | 8% | 0% | 0% | 0% |
No change | 64% | 41% | 33% | 29% |
Minimally improved | 17% | 23% | 28% | 24% |
Much improved | 8% | 28% | 27% | 28% |
Very much improved | 3% | 8% | 12% | 19% |
Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
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. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale–Brown Obsessive Compulsive Scale (CY–BOCS).
Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.
Bulimia Nervosa
The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8–week and one 16–week, multicenter, parallel group studies of adult outpatients meeting DSM–III–R criteria for bulimia. Patients in the 8–week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16–week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge–eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge–eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The Prozac–related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge–eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge–eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge–eating and purging.
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 Prozac 60 mg/day, were randomized to continuation of Prozac 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 Prozac 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 Prozac 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. Prozac 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 Prozac–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. 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 on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac–treated patients were free from panic attacks at endpoint than placebo–treated patients, 62% versus 44%, respectively.
INDICATIONS AND USAGE
Major Depressive Disorder
Prozac is indicated for the treatment of major depressive disorder.
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 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 5 of the following 9 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 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.
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 following open–label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once–weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see CLINICAL TRIALS).
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 outpatients whose diagnoses corresponded most closely to the DSM–III–R or DSM–IV category of major depressive disorder (see CLINICAL TRIALS).
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 or compulsions cause marked distress, are time–consuming, or significantly interfere with social or occupational functioning.
The efficacy of Prozac was established in 13–week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM–III–R category of OCD (see CLINICAL TRIALS).
OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego–dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.
The effectiveness of Prozac in long–term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo–controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long–term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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).
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 3 bulimic episodes per week for 6 months (see CLINICAL TRIALS).
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 placebo–controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long–term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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 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 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).
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 Prozac 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 Prozac for extended periods should periodically reevaluate the long–term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
General
Information for Patients
Laboratory Tests
Drug Interactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Labor and Delivery
The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast–milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.
Pediatric Use
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 pediatric outpatients ages 8 to ≤18 (see CLINICAL TRIALS).
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).
The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <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 CLINICAL PHARMACOLOGY).
The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine–treated, 190 placebo–treated) were generally similar to that observed in adult studies with fluoxetine. The longer–term adverse event profile observed in the 19–week major depressive 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–treatedpatients and in 0 out of 190 (0%) placebo–treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine–treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence 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, 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, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer–term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine.
(See WARNINGS, Clinical Worsening and Suicide Risk.)
Significant toxicity, including myotoxicity, long–term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures.
In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine–induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1–0.2, 1–2, and 5–10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3–0.8, 1–8, and 3–20 times, respectively, pediatric exposure at the MRD.
A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral span and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis.
In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus–maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.
Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac in a child or adolescent must balance the potential risks with the clinical need.
Geriatric Use
US 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 geriatric patients has been established (see CLINICAL TRIALS). For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
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 administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.
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 individuals who experienced, at least once, a treatment–emergent adverse event of the type uled. An event was considered treatment–emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.
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 patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug 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 2 enumerates the 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 1 of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non–US controlled trials. Table 3 enumerates treatment–emergent adverse events that occurred in 2% or more patients treated with Prozac and 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 controlled clinical trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.
Percentage of Patients Reporting Event | ||||||||
Major Depressive Disorder |
|
|
| |||||
Body
System/ | Prozac | Placebo | Prozac | Placebo | Prozac | Placebo | Prozac | Placebo |
Body as a Whole | ||||||||
Asthenia | 9 | 5 | 15 | 11 | 21 | 9 | 7 | 7 |
Flu syndrome | 3 | 4 | 10 | 7 | 8 | 3 | 5 | 5 |
Cardiovascular | ||||||||
Vasodilatation | 3 | 2 | 5 | 2 | 1 | 1 | ||
Digestive System | ||||||||
Nausea | 21 | 9 | 26 | 13 | 29 | 11 | 12 | 7 |
Diarrhea | 12 | 8 | 18 | 13 | 8 | 6 | 9 | 4 |
Anorexia | 11 | 2 | 17 | 10 | 8 | 4 | 4 | 1 |
Dry mouth | 10 | 7 | 12 | 3 | 9 | 6 | 4 | 4 |
Dyspepsia | 7 | 5 | 10 | 4 | 10 | 6 | 6 | 2 |
Nervous System | ||||||||
Insomnia | 16 | 9 | 28 | 22 | 33 | 13 | 10 | 7 |
Anxiety | 12 | 7 | 14 | 7 | 15 | 9 | 6 | 2 |
Nervousness | 14 | 9 | 14 | 15 | 11 | 5 | 8 | 6 |
Somnolence | 13 | 6 | 17 | 7 | 13 | 5 | 5 | 2 |
Tremor | 10 | 3 | 9 | 1 | 13 | 1 | 3 | 1 |
Libido decreased | 3 | 11 | 2 | 5 | 1 | 1 | 2 | |
Abnormal | 1 | 1 | 5 | 2 | 5 | 3 | 1 | 1 |
Respiratory | ||||||||
Pharyngitis | 3 | 3 | 11 | 9 | 10 | 5 | 3 | 3 |
Sinusitis | 1 | 4 | 5 | 2 | 6 | 4 | 2 | 3 |
Yawn | 7 | 11 | 1 | |||||
Skin
and | ||||||||
Sweating | 8 | 3 | 7 | 8 | 3 | 2 | 2 | |
Rash | 4 | 3 | 6 | 3 | 4 | 4 | 2 | 2 |
Urogenital System | ||||||||
Impotence | 2 | 7 | 1 | |||||
Abnormal | 7 | 7 | 2 | 1 | ||||
Percentage of Patients Reporting Event | ||
Major Depressive Disorder, OCD, Bulimia, | ||
Body
System/ | Prozac | Placebo |
Body as a Whole | ||
Headache | 21 | 19 |
Asthenia | 11 | 6 |
Flu syndrome | 5 | 4 |
Fever | 2 | 1 |
Cardiovascular System | ||
Vasodilatation | 2 | 1 |
Digestive System | ||
Nausea | 22 | 9 |
Diarrhea | 11 | 7 |
Anorexia | 10 | 3 |
Dry mouth | 9 | 6 |
Dyspepsia | 8 | 4 |
Constipation | 5 | 4 |
Flatulence | 3 | 2 |
Vomiting | 3 | 2 |
Metabolic
and Nutritional | ||
Weight loss | 2 | 1 |
Nervous System | ||
Insomnia | 19 | 10 |
Nervousness | 13 | 8 |
Anxiety | 12 | 6 |
Somnolence | 12 | 5 |
Dizziness | 9 | 6 |
Tremor | 9 | 2 |
Libido decreased | 4 | 1 |
Thinking abnormal | 2 | 1 |
Respiratory System | ||
Yawn | 3 | |
Skin and Appendages | ||
Sweating | 7 | 3 |
Rash | 4 | 3 |
Pruritus | 3 | 2 |
Special Senses | ||
Abnormal vision | 2 | 1 |
Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic disorder placebo–controlled clinical trials (excluding data from extensions of trials) — Table 4 uls the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non–US panic disorder clinical trials.
Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined | Major Depressive Disorder | OCD | Bulimia | Panic Disorder |
Anxiety (1%) | -- | Anxiety (2%) | -- | Anxiety (2%) |
-- | -- | -- | Insomnia (2%) | -- |
-- | Nervousness (1%) | -- | -- | Nervousness (1%) |
-- | -- | Rash (1%) | -- | -- |
Other adverse events in pediatric patients (children and adolescents) — Treatment–emergent adverse events were collected in 322 pediatric patients (180 fluoxetine–treated, 142 placebo–treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine 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 3 pediatric placebo–controlled trials (N=418 randomized; 228 fluoxetine–treated; 190 placebo–treated) was mania/hypomania (1.8% for fluoxetine–treated, 0% for placebo–treated). In these clinical trials, only a primary event associated with discontinuation was collected.
Events observed in Prozac Weekly clinical trials — Treatment–emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo–controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking Prozac 20 mg daily (10% versus 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 psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo–controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine,<1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.
There are no adequate and well–controlled studies examining sexual dysfunction with fluoxetine treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Other Events Observed in Clinical Trials
Following is a ul of all treatment–emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those uled in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial 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 1/1000 patients; rare events are those occurring in less than 1/1000 patients.
Body
as a Whole — Frequent: chest
pain, chills; Infrequent: chills
and fever, face edema, intentional overdose, malaise, pelvic pain, suicide
attempt; Rare: acute
abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant
syndrome
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 function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, 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 mellitus.
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, creatine phosphokinase 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
Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, 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 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital
System — Frequent: urinary
frequency; Infrequent: abortion
Postintroduction Reports
Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal–lingual–masticatory syndrome with involuntary tongue protrusion reported to develop in a 77–year–old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, 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 factors including 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 range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), 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 the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, 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.
Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, 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. The most common signs and symptoms associated with non–fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low 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 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9–year–old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed–drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal.
Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes–type arrhythmias), hypotension, mania, neuroleptic malignant 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 provide useful 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 animal species.
Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short–term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/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 were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management 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 depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large–bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known.
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/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive 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 of any overdose. Telephone numbers for certified poison control centers are uled in the Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
Major Depressive Disorder
Obsessive Compulsive Disorder
Bulimia Nervosa
Panic Disorder
Special Populations
Discontinuation of Treatment with Prozac
Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. 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.
HOW SUPPLIED
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. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
Literature revised June 21, 2007
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.lilly.com
Supplement Patient Material Section
Medication
Guide
Antidepressant
Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts
or Actions
Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic–depressive illness) or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a ul of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
Patient Information revised June 21, 2007