1 INDICATIONS AND USAGE Fluoxetine tablets are indicated for the treatment of: Major Depressive Disorder (MDD).

The efficacy of fluoxetine in MDD was established in one 5 week trial, three 6 week trials, and one maintenance study in adults.

The efficacy of fluoxetine was also established in two 8 to 9 week trials in pediatric patients 8 to 18 years of age [see Clinical Studies (14.1) ].

Obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD).

The efficacy of fluoxetine in OCD was demonstrated in two 13 week trials in adults and one 13 week trial in pediatric patients 7 to 17 years of age [see Clinical Studies (14.2) ].

Binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa.

The efficacy of fluoxetine in Bulimia Nervosa was demonstrated in two 8 week trials and one 16 week trial in adults [see Clinical Studies (14.3) ].

Panic Disorder, with or without agoraphobia.

The efficacy of fluoxetine in Panic Disorder was demonstrated in two 12 week trials in adults [see Clinical Studies ( 14.4 )].

Fluoxetine tablets are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of: Major Depressive Disorder (MDD) ( 1 ) Adults: Efficacy was established in one 5 week trial, three 6-week trials, and one maintenance study (14.1) Pediatrics: Efficacy was established in two 8 to 9 week trials of patients 8 to 18 years of age (14.1 ) Obsessive Compulsive Disorder (OCD) (1) Adults: Efficacy was established in two 13 week trials (14.2) Pediatrics: Efficacy was established in one 13 week trial in patients 7 to 17 years of age (14.2) Bulimia Nervosa ( 1) Adults: Efficacy was established in two 8 week trials and one 16 week trial (14.3) Panic Disorder, with or without agoraphobia (1) Adults: Efficacy was established in two 12 week trials (14.4)

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Allergic Reactions and Rash [see Warnings and Precautions ( 5.3 )] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions ( 5.4 )] Seizures [see Warnings and Precautions ( 5.5 )] Altered Appetite and Weight [see Warnings and Precautions ( 5.6 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.7 )] Angle-closure Glaucoma [see Warnings and Precautions ( 5.8 )] Hyponatremia [see Warnings and Precautions ( 5.9 )] Anxiety and Insomnia [see Warnings and Precautions ( 5.10 )] QT Prolongation [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.13 )] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15 )] Most common adverse reactions (≥ 5% and at least twice that for placebo): abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S.

clinical trials.

In addition, there have been 425 patients administered fluoxetine in panic clinical trials.

The stated frequencies represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed.

An adverse reaction was included if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Incidence in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)—Table 2 enumerates the most common adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of MDD, OCD, and bulimia in U.S.

controlled clinical trials and Panic Disorder in U.S.

plus non-U.S.

controlled trials.

Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.

Table 2.

Most Common Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical Trials Percentage of Patients Reporting Event MDD OCD Bulimia Panic Disorder Body System/Adverse Reaction Fluoxetine (N = 1728) Placebo (N = 975) Fluoxetine (N = 266) Placebo (N = 89) Fluoxetine (N = 450) Placebo (N = 267) Fluoxetine (N = 425) Placebo (N = 342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System 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 dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn — — 7 — 11 — 1 — Skin and Appendages Sweating 8 3 7 — 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence a 2 — — — 7 — 1 — Abnormal ejaculation a — — 7 — 7 — 2 1 Note: Includes U.S.

data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S.

data for Panic Disorder clinical trials.

a = Denominator used was for males only (N = 690 fluoxetine MDD; N = 410 placebo MDD; N = 116 fluoxetine OCD; N = 43 placebo OCD; N = 14 fluoxetine Bulimia; N = 1 placebo Bulimia; N = 162 fluoxetine Panic Disorder; N = 121 placebo Panic Disorder).

— = Incidence less than 1%.

Table 3.

Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical Trials Percentage of Patients Reporting Event MDD, OCD, Bulimia, and Panic Disorder Combined Body System/Adverse Reaction Fluoxetine (N = 2869) Placebo (N = 1673) 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 Disorders 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 Note: Includes U.S.

data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S.

data for Panic Disorder clinical trials.

— = Incidence less than 1%.

Associated with discontinuation in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)—Table 4 lists the adverse reactions associated with discontinuation of fluoxetine treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S.

Panic Disorder clinical trials.

Table 4.

Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical Trials MDD, OCD, Bulimia, and Panic Disorder Combined (N = 1533) MDD (N = 392) OCD (N = 266) Bulimia (N = 450) Panic Disorder (N = 425) Anxiety (1%) — Anxiety (2%) — Anxiety (2%) — — — Insomnia (2%) — — Nervousness (1%) — — Nervousness (1%) — — Rash (1%) — — Note: Includes U.S.

data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S.

data for Panic Disorder clinical trials.

— = Incidence less than 1%.

Other adverse reactions in pediatric patients (children and adolescents)—Adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated).

The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2 and Table 3.

However, the following adverse reactions (excluding those which appear in the body or footnotes of Table 2 and Table 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 reaction (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 reaction associated with discontinuation was collected.

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 U.S.

MDD, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual adverse reaction 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.

Symptoms of sexual dysfunction occasionally persist after discontinuation of 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 adverse reactions.

Other adverse reactions observed during the premarketing evaluation of fluoxetine —Following is a list of adverse reactions reported by patients treated with fluoxetine in clinical trials.

This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients.

Body as a Whole —Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.

Cardiovascular System —Frequent: palpitation; Infrequent: arrhythmia, hypotension 1 .

Digestive System —Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.

Hemic and Lymphatic System —Infrequent: ecchymosis; Rare: petechia, purpura.

Nervous System —Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder 1 , bruxism 1 , buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions.

Respiratory System —Rare: larynx edema.

Skin and Appendages —Infrequent: alopecia; Rare: purpuric rash.

Special Senses —Frequent: taste perversion; Infrequent: mydriasis.

Urogenital System —Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding 2 .

1 MedDRA dictionary term from integrated database of placebo-controlled trials of 15,870 patients, of which 9,673 received fluoxetine.

2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage.

Adjusted for gender.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluoxetine.

Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: anosmia, aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS), 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 1 , epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest 1 , hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, hyposmia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis 1 , pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1 , thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes-type arrhythmias), vaginal bleeding, and violent behaviors 1 .

1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions.

They are included here because of their seriousness.