1 INDICATIONS AND USAGE Olanzapine and fluoxetine capsules are indicated for the treatment of: Acute depressive episodes in Bipolar I Disorder [see Clinical Studies ( 14.1 )] .

Treatment resistant depression (Major Depressive Disorder in patient who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) [see Clinical Studies ( 14.2 )] .

Olanzapine and fluoxetine capsules combine olanzapine, an atypical antipsychotic and fluoxetine, a selective serotonin reuptake inhibitor, indicated for treatment of: Acute Depressive Episodes Associated with Bipolar I Disorder ( 1 ) Treatment Resistant Depression ( 1 )

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 )] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Neuroleptic Malignant syndrome (NMS) [see Warnings and Precautions ( 5.3 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.4 )] Hyperglycemia [see Warnings and Precautions ( 5.5 )] Dyslipidemia [see Warnings and Precautions ( 5.5 )] Weight Gain [see Warnings and Precautions ( 5.5 )] Serotonin Syndrome [see Warnings and Precautions ( 5.6 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.7 )] Allergic Reactions and Rash [see Warnings and Precautions ( 5.8 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.9 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.10 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.11 )] Falls [see Warnings and Precautions ( 5.12 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Seizures [see Warnings and Precautions ( 5.15 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.16 )] Hyponatremia [see Warnings and Precautions ( 5.17 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.18 )] Body Temperature Dysregulation [see Warnings and Precautions ( 5.19 )] QT Prolongation [see Warnings and Precautions ( 5.20 )] Anticholinergic (antimuscarinic) Effects [see Warnings and Precautions ( 5.21 )] Hyperprolactinemia [see Warnings and Precautions ( 5.22 )] Discontinuation Adverse Reactions [see Warnings and Precautions ( 5.25 )] Sexual Dysfunction [see Warnings and Precautions ( 5.26 )] Most common adverse reactions (≥5% and at least twice that for placebo) in adults: sedation, weight increased, appetite increased, dry mouth, fatigue, edema, tremor, disturbance in attention, blurred vision.

Children and adolescents: sedation, weight increased, appetite increased, tremor, triglyceride increased, hepatic enzymes increased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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.

The data in the tables represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed.

A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adults — The information below is derived from a clinical study database for olanzapine and fluoxetine capsules consisting of 2547 patients with treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction with approximately 1085 patient-years of exposure.

The conditions and duration of treatment with olanzapine and fluoxetine capsules varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or long-term exposure.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine capsule group discontinued due to adverse reactions compared with 4.4% of the 477 patients for placebo.

Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine capsules (incidence of at least 1% for olanzapine and fluoxetine capsules and greater than that for placebo) using MedDRA Dictionary coding were weight increased (2%) and sedation (1%) versus placebo patients which had 0% incidence of weight increased and sedation.

Commonly Observed Adverse Reactions in Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — In short-term studies, the most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine capsules (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine capsule-controlled database) using MedDRA Dictionary coding were: disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, vision blurred, and weight increased.

Adverse reactions reported in clinical trials of olanzapine and fluoxetine in combination are generally consistent with treatment-emergent adverse reactions during olanzapine or fluoxetine monotherapy.

In a 47-week maintenance study in adults with treatment resistant depression, adverse reactions associated with olanzapine and fluoxetine capsule use were generally similar to those seen in short-term studies.

Weight gain, hyperlipidemia, and hyperglycemia were observed in olanzapine and fluoxetine capsule -treated patients throughout the study.

Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression — Table 16 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine capsules (incidence of at least 2% for olanzapine and fluoxetine capsules and twice or more than for placebo).

The olanzapine and fluoxetine capsule-controlled column includes patients with various diagnoses while the placebo column includes only patients with bipolar depression and major depression with psychotic features.

Table 16: Adverse Reactions: Incidence in the Short-Term Controlled Clinical Studies in Adults System Organ Class Adverse Reaction Percentage of Patients Reporting Event Olanzapine and Fluoxetine Capsule-Controlled (N=771) Placebo (N=477) Eye disorders Vision blurred 5 2 Gastrointestinal disorders Dry mouth 15 6 Flatulence 3 1 Abdominal distension 2 0 General disorders and administration site conditions Fatigue 12 2 Edema a 15 2 Asthenia 3 1 Pain 2 1 Pyrexia 2 1 Infections and infestations Sinusitis 2 1 Investigations Weight increased 25 3 Metabolism and nutrition disorders Increased appetite 20 4 Musculoskeletal and connective tissue disorders Arthralgia 4 1 Pain in extremity 3 1 Musculoskeletal stiffness 2 1 Nervous system disorders Somnolence b 27 11 Tremor 9 3 Disturbance in attention 5 1 Psychiatric disorders Restlessness 4 1 Thinking abnormal 2 1 Nervousness 2 1 Reproductive system and breast disorders Erectile dysfunction 2 1 a Includes edema, edema peripheral, pitting edema, generalized edema, eyelid edema, face edema, gravitational edema, localized edema, periorbital edema, swelling, joint swelling, swelling face, and eye swelling.

b Includes somnolence, sedation, hypersomnia, and lethargy.

Extrapyramidal Symptoms Dystonia, Class Effect for Antipsychotics — Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.

While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs.

In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with the olanzapine and fluoxetine combination.

Additional Findings Observed in Clinical Studies Sexual Dysfunction — In the pool of controlled olanzapine and fluoxetine capsule studies in patients with bipolar depression, there were higher rates of the treatment-emergent adverse reactions decreased libido, anorgasmia, erectile dysfunction and abnormal ejaculation in the olanzapine and fluoxetine capsule group than in the placebo group.

One case of decreased libido led to discontinuation in the olanzapine and fluoxetine capsule group.

In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the olanzapine and fluoxetine capsule group were less than the rates in the fluoxetine group.

None of the differences were statistically significant.

Sexual dysfunction, including 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, healthcare providers should routinely inquire about such possible side effects.

There are no adequate and well-controlled studies examining sexual dysfunction with olanzapine and fluoxetine capsule or fluoxetine treatment.

Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.

Difference Among Dose Levels Observed in Other Olanzapine Clinical Trials In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200), and 40 (N=200) mg/day of olanzapine in patients with Schizophrenia or Schizoaffective Disorder, statistically significant differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue, and dizziness.

Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Incidence of treatment-emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.

Other Adverse Reactions Observed in Clinical Studies Following is a list of treatment-emergent adverse reactions reported by patients treated with olanzapine and fluoxetine capsules 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 1/1000 patients; and rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Frequent: chills, neck rigidity, photosensitivity reaction; Rare: death 1 .

Cardiovascular System — Frequent: vasodilatation.

Digestive System — Frequent: diarrhea; Infrequent: gastritis, gastroenteritis, nausea and vomiting, peptic ulcer; Rare: gastrointestinal hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis.

Hemic and Lymphatic System — Frequent: ecchymosis; Infrequent: anemia, thrombocytopenia; Rare: leukopenia, purpura.

Metabolic and Nutritional — Frequent: generalized edema, weight loss; Rare: bilirubinemia, creatinine increased, gout.

Musculoskeletal System — Rare: osteoporosis.

Nervous System — Frequent: amnesia; Infrequent: ataxia, buccoglossal syndrome, coma, depersonalization, dysarthria, emotional lability, euphoria, hypokinesia, movement disorder, myoclonus; Rare: hyperkinesia, libido increased, withdrawal syndrome.

Respiratory System — Infrequent: epistaxis, yawn; Rare: laryngismus.

Skin and Appendages — Infrequent: alopecia, dry skin, pruritus; Rare: exfoliative dermatitis.

Special Senses — Frequent: taste perversion; Infrequent: abnormality of accommodation, dry eyes.

Urogenital System — Frequent: breast pain, menorrhagia 2 , urinary frequency, urinary incontinence; Infrequent: amenorrhea 2 , female lactation 2 , hypomenorrhea 2 , metrorrhagia 2 , urinary retention, urinary urgency, urination impaired; Rare: breast engorgement 2 .

1 This term represents a serious adverse event but does not meet the definition for adverse drug reactions.

It is included here because of its seriousness.

2 Adjusted for gender.

Other Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy The following adverse reactions were not observed in olanzapine and fluoxetine capsule-treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: Bruxism, dysuria, esophageal ulcer, gynecological bleeding, headache, hypotension, neutropenia, sudden unexpected death 3 and sweating.

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

They are included here because of their seriousness.

Children and Adolescent Patients (aged 10 to 17 years) with a Diagnosis of Bipolar Depression The information below is derived from a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine capsules for the treatment of bipolar I depression in patients 10 to 17 years of age.

Adverse Reactions Associated with Discontinuation of Treatment in the single pediatric study — Overall, 14.1% of the 170 patients in the olanzapine and fluoxetine capsule group discontinued due to adverse reactions compared with 5.9% of the 85 patients for placebo.

Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine capsules (incidence of at least 1% for olanzapine and fluoxetine capsules and greater than that for placebo) using MedDRA Dictionary coding were weight increased (2.9%), suicidal ideation (1.8%), bipolar disorder (1.2%), and somnolence (1.2%) versus placebo patients which had 0% incidence of weight increased, bipolar disorder, and somnolence, and a 1.2% incidence of suicidal ideation.

Adverse Reactions Occurring at an Incidence of 2% or more and greater than placebo — Table 17 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine capsules (incidence of at least 2% for olanzapine and fluoxetine capsules and twice or more than for placebo).

Table 17: Treatment-Emergent Adverse Reactions: Incidence in a 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression.

System Organ Class Adverse Reaction Percentage of Patients Reporting Event Olanzapine and Fluoxetine Capsules (N=170) Placebo (N=85) Nervous system disorders Somnolence a 24 2 Tremor 9 1 Investigations Weight increased 20 1 Blood triglycerides increased 7 2 Blood cholesterol increased 4 0 Hepatic enzyme increased b 9 1 Gastrointestinal disorders Dyspepsia 3 1 Metabolism and nutrition disorders Increased appetite 17 1 Psychiatric disorders Anxiety 3 1 Restlessness 3 1 Suicidal ideation 2 1 Musculoskeletal and connective tissue disorders Back pain 2 1 Injury, poisoning and procedural complications Accidental overdose 3 1 Reproductive system and breast disorders Dysmenorrhea 2 0 a Includes somnolence, sedation, and hypersomnia.

No lethargy was reported.

b Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, gamma-glutamyltransferase increased, and transaminases increased.

Vital Signs and Laboratory Studies Adults: Vital Signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in olanzapine and fluoxetine capsule-treated patients [see Warnings and Precautions ( 5.11 )] .

The mean standing pulse rate of olanzapine and fluoxetine capsule-treated patients was reduced by 0.7 beats/min.

Laboratory Changes — In olanzapine and fluoxetine capsule clinical studies (including treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction), olanzapine and fluoxetine capsules were associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal at baseline to abnormal at any time during the trial) compared to placebo: elevated prolactin (28% vs 5%); elevated urea nitrogen (3% vs 0.8%); elevated uric acid (3% vs 0.5%); low albumin (3% vs 0.3%); low bicarbonate (14% vs 9%); low hemoglobin (3% vs 0%); low inorganic phosphorus (2% vs 0.3%); low lymphocytes (2% vs 0%); and low total bilirubin (15% vs 4%).

As with olanzapine, asymptomatic elevations of hepatic aminotransferases [ALT, AST, and GGT] and alkaline phosphatase have been observed with olanzapine and fluoxetine capsules.

In the olanzapine and fluoxetine capsule-controlled database, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (38/698) of patients exposed to olanzapine and fluoxetine capsules compared with 0.5% (2/378) of placebo-treated patients and 4% (33/751) of olanzapine-treated patients.

ALT elevations ≥5 times ULN were observed in 2% (11/701) of olanzapine and fluoxetine capsule-treated patients, compared to 0.3% (1/379) of placebo-treated patients and 1% (11/760) of olanzapine-treated patients.

No patient with elevated ALT values experienced jaundice or liver failure, or met the criteria for Hy’s Rule.

ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine and fluoxetine capsules or discontinued olanzapine and fluoxetine capsules.

Rare postmarketing reports of hepatitis have been received in patients treated with olanzapine.

Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period in patients treated with olanzapine.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

An increase in creatine phosphokinase has been reported very rarely in olanzapine and fluoxetine capsule-treated patients and infrequently in clinical trials of olanzapine-treated patients.

QT Interval Prolongation — In patients treated with olanzapine and fluoxetine capsules QT c F≥450 msec for males and QT c F≥470 msec for females has been reported frequently (≥1%).

The incidence of QT c F>500 msec associated with olanzapine and fluoxetine capsule treatment in clinical trials has been rare and was not significantly different from the incidence associated with placebo.

The mean increase in QT c interval for olanzapine and fluoxetine capsule-treated patients (5.17 msec) in the one clinical study directly comparing olanzapine and fluoxetine capsules to placebo in adult patients was significantly greater than that for placebo-treated patients (-1.66 msec).

Children and Adolescents (aged 10 to 17 years): In a single 8-week randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine capsules for treatment of bipolar I depression in patients 10 to 17 years of age, the following was observed: Vital Signs — In the olanzapine and fluoxetine capsule-treated patients compared with placebo-treated patients, the mean orthostatic blood pressure and standing pulse rate were not significantly different between treatment groups.

Body Weight: An increase in weight greater than or equal to 7% occurred in 52.4% of the olanzapine and fluoxetine capsule group and 3.6% of the placebo group.

Weight gain greater than or equal to 15% occurred in 14.1% of the olanzapine and fluoxetine capsule group and none of the placebo group.

Laboratory Changes — Olanzapine and fluoxetine capsules were associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal or low at baseline to abnormal at any time during the trial) compared to placebo: elevated ALT (45.9% vs 2.5%); elevated AST (33.7% vs 7.6%); high fasting total cholesterol (28.9% vs 8.2%); high fasting LDL cholesterol (19.7% vs 6.5%); high fasting triglycerides (52.3% vs 27.3%), and elevated prolactin (85% vs 36%).

No patient with elevated hepatic enzyme values experienced jaundice or liver failure, or met the criteria for Hy’s Rule.

Five patients experienced an adverse event potentially associated with elevated prolactin; these events included dysmenorrhea, galactorrhea, and ovulation disorder.

QT Interval Prolongation — Olanzapine and fluoxetine capsules were associated with a statistically significantly greater mean increase in QT c F interval (8.2 msec [95% CI 6.2, 10.2]) compared with placebo.

No patients developed QT c increases ≥60 msec or QT c ≥480 msec [see Warnings and Precautions ( 5.20 )] .

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of olanzapine and fluoxetine capsules, Fluoxetine, or Olanzapine monotherapy.

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.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine and fluoxetine capsule, fluoxetine, or olanzapine therapy include the following: Olanzapine and fluoxetine capsules : rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis) Fluoxetine : anosmia, aplastic anemia, cholestatic jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS), eosinophilic pneumonia 3 , erythema multiforme, violent behavior 3 , atrial fibrillation 3 , cataract, cerebrovascular accident 3 , epidermal necrolysis, erythema nodosum, heart arrest 3 , hepatic failure/necrosis, hypoglycemia, hyposmia, kidney failure, memory impairment, optic neuritis, pulmonary hypertension, Stevens-Johnson syndrome.

Olanzapine : diabetic coma, jaundice, random triglyceride levels of ≥1000 mg/dL, restless legs syndrome, stuttering 4 , salivary hypersecretion, allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), drug reaction with eosinophilia and systemic symptoms (DRESS), fecal incontinence, somnambulism, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) .

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

They are included here because of their seriousness.

4 Stuttering was only studied in oral and long acting injection (LAI) olanzapine formulations.