Olanzapine and Fluoxetine

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 )] Abnormal 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, fatique, 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 Par Pharmaceutical at 1-800-828-9393 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 consisting of 2547 patients with treatment resistant depression, depression episodes associated with Bipolar 1 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 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 1 Disorder and Treatment Resistant Depression — Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine HCl 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 HCl (incidence of at least 1% for olanzapine and fluoxetine HCl 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 , Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder and Treatment Resistant Depression — In short-term studies, the most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine HCl -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 use were generally similar to those seen in short-term studies. Weight gain, hyperlipidemia, and hyperglycemia were observed in olanzapine and fluoxetine-treated patients throughout the study. Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder and Treatment Resistant Depression — Table 16 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence of at least 2% for olanzapine and fluoxetine HCl and twice or more than for placebo). The olanzapine and fluoxetine HCl -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-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 HCl 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 HCl group than in the placebo group. One case of decreased libido led to discontinuation in the olanzapine and fluoxetine HCl group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the olanzapine and fluoxetine HCl 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 dysfunction with olanzapine and fluoxetine 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 HCl 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-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. 4 Stuttering was only studied in oral and long acting injection (LAI) olanzapine formulations Children andAdolescent Patients(aged10to 17years)witha Diagnosis of Bipolar Depression The information below is derived from asingle, 8-week, randomized, placebo-controlledclinical trial investigating olanzapine and fluoxetine for thetreatment of bipolarI depression in patients 10 to 17 years of age. Adverse Reactions Associated with Discontinuation of Treatment in the single pediatric study – Overall, 14% of the 170 patients in the olanzapine and fluoxetine group discontinued to adverse reactions compared to 5.9% of the 85 patients for placebo. Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine ( incidence of a least 1% for olanzapine and fluoxetine 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 (incidence of at least 2% for olanzapine and fluoxetine 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 (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-treated patients [see Warnings and Precautions ( 5.11 ) ] . The mean standing pulse rate of olanzapine and fluoxetine treated patients was reduced by 0.7 beats/min. Laboratory Changes — In olanzapine and fluoxetine clinical studies, (including treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction), olanzapine and fluoxetine was 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 HCl. In the olanzapine and fluoxetine HCl -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 HCl 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 HCl-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 or discontinued olanzapine and fluoxetine. 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 HCl-treated patients and infrequently in clinical trials of olanzapine-treated patients. QT Interval Prolongation – In patients treated with olanzapine and fluoxetine QT C F≥450 msec for males and QTcF≥470 msec for females has been reported frequently (≥1%). The incidence of QT C F>500 msec associated with olanzapine and fluoxetine 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-treated patients (5.17 msec) in the one clinical study directly comparing olanzapine and fluoxetine 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 for treatment of bipolar 1 depression in patients 10 to 17 years of age, the following was observed: Vital Signs – In the olanzapine and fluoxetine 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 or equal to 7% occurred in 52.4% of the olanzapine and fluoxetine 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 group and none of the placebo group. Laboratory Changes - Olanzapine and Fluoxetine was accociated 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 7.7%) 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 and adverse event potentially associated with elevated prolactin; these events included dysmenorrhea, galactorrhea, and ovulation disorder. QT Interval Prolongation – Olanzapine and Fluoxetine was associated with a statistically significant 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, fluoxetine, or olanzapine therapy include the following: Olanzapine and fluoxetine capsules: rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Fluoxetine : aplastic anemia, cholestatic jaundice, 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, 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). 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.

4 CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOI) : Because of the risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with Olanzapine and Fluoxetine Capsules or within 5 weeks of stopping treatment with Olanzapine and Fluoxetine Capsules. Do not use Olanzapine and Fluoxetine Capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Olanzapine and Fluoxetine Capsules in a patient who is being treated with linezolid or intravenous methylene blue. (4.1) Pimozide : Do not use. Risk of QTinterval prolongation ( 4.2 , 5.20, 7.7, 7.8 ) Thioridazine : Do not use. Risk of QT interval prolongation. Do not use thioridazine within 5 weeks of discontinuing Olanzapine and Fluoxetine Capsules (4.2 , 5.20, 7.7 , 7.8 ) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine or within 5 weeks of stopping treatment with olanzapine and fluoxetine is contraindicated because of an increased risk of sertotonin syndrome. The use of olanzapine and fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.6 ) ]. Starting olanzapine and fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. [ see Dosage and Administration (2.5 ) andWarning and Precautions ( 5.6 )]. 4.2 Other Containdications Pimozide – [see Warnings and Precautions ( 5.20 ) and Drug Interactions ( 7.7 ), ( 7.8)] Thioridazine – [see Warnings and Precautions ( 5.20 ) and Drug Interactions ( 7.7 ), (7.8)] Pimozide and thioridazone prolong the QT interval. Olanzapine and Fluoxetine can increase the levels of pimozide and thioridazine prolong the QT interval. Olanzapine and Fluoxetine can increase the levels of pimozide and thioridazine inhibition of CYP2D6. Olanzapine and Fluoxetine can also prolong the QT interval.

11 DESCRIPTION Olanzapine and fluoxetine capsules USP combines an atypical antipsychotic and a selective serotonin reuptake inhibitor, olanzapine (the active ingredient in Zyprexa ® , and Zyprexa Zydis ® ) and fluoxetine hydrochloride (the active ingredient in Prozac ® , and Sarafem ® ). Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H thieno[2,3- b ] [1,5]benzodiazepine. The molecular formula is C 17 H 20 N 4 S, which corresponds to a molecular weight of 312.44. Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3‑[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride. The molecular formula is C 17 H 18 F 3 NO•HCl, which corresponds to a molecular weight of 345.79. The chemical structures are: Olanzapine is a yellow crystalline solid, which is practically insoluble in water. Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Olanzapine and fluoxetine capsules USP are available for oral administration in the following strength combinations: 3 mg/25 mg 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg Olanzapine 3 6 6 12 12 Fluoxetine base equivalent 25 25 50 25 50 Each capsule consists of gelatin, magnesium stearate, partially pregelatinized starch, titanium dioxide, and yellow iron oxide. In addition, the 3 mg/25 mg capsule also contains red iron oxide; the 6 mg/50 mg capsule also contains FD&C blue No. 2, FD&C red No. 3, and FD&C yellow No. 6; the 12 mg/25 mg capsule also contains D&C red No. 28, FD&C blue No. 1, FD&C red No. 40, and red iron oxide; and the 12 mg/50 mg capsule also contains D&C red No. 28, FD&C blue No. 1 FD&C blue No. 2, FD&C red No. 3, FD&C red No. 40, and FD&C yellow No. 6. The capsules also have printing in edible black ink which contains the following ingredients: D&C yellow No. 10, ethanol, FD&C blue No. 1, FD&C blue No. 2, FD&C red No. 40, iron oxide black, methanol, n-Butyl alcohol, propylene glycol, and shellac glaze in alcohol. This is the structure

2 DOSAGE AND ADMINISTRATION Adult Starting Dose: 6 mg olanzapine with 25 mg fluoxetine (6 mg/25 mg, once daily in the evening ( 2.1 , 2.2 ). Adult Maximum Dose: 12 mg/50 mg once daily ( 2.1 , 2.2 ) Pediatric Bipolar Depression Starting Dose: 3 mg/25 mg once daily (for ages 10 to 17 years) ( 2.1 ). Pediatric Bipolar Depression Maximum Dose: 12 mg/50 mg ( 2.1 ) Starting dose in patients predisposed to hypotensive reactions, hepatic impairment, or with potential for slowed metabolism: 3 mg/25 mg to 6 mg /25 mg. Escalate dose cautiously ( 2.3 ) 2.1 Depressive Episodes Associated with Bipolar I Disorder Adults – Administer Olanzapine and Fluoxetine Capsules once daily in the evening, generally beginning with the 6 mg/25 mg (mg olanzapine/mg equivalent fluoxetine) capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of olanzapine and fluoxetine has not been studied. Make dosage adjustments, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies ( 14 .1 )] . The safety of doses above 18 mg of olanzapine and 75 mg of fluoxetine has not been evaluated in adult clinical studies. Periodically reexamine the need for continued pharmacotherapy. Children and Adolescents (10 to 17 years of age) – Administer Olanzapine and Fluoxetine Capsules once daily in the evening, generally beginning with the 3 mg/25 mg capsule, without regard to meals, with a recommended target dose within the approved dosing range (6/25; 6/50; 12/25; 12/50 mg) [see Clinical Studies ( 14.1 )] . The safety of doses above 12 mg of olanzapine and 50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Periodically reexamine the need for continued pharmacotherapy. 2.2 Treatment Resistant Depression Administer Olanzapine and Fluoxetine Capsules once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of Olanzapine and Fluoxetine Capsules has not been studied. Adjust dosage, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with Olanzapine and Fluoxetine Capsules in a dose range of olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies ( 14.2 )] . The safety of doses above 18 mg/75 mg has not been evaluated in clinical studies. Periodically reexamine the need for continued pharmacotherapy. 2.3 Specific Populations Start Olanzapine and Fluoxetine Capsules at 3 mg/25 mg or 6 mg/25 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine and fluoxetine (female gender, geriatric age, nonsmoking status) or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine has not been systematically studied in patients >65 years of age or in patients <10 years of age [see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 , 12.4 )] . 2.4 Switching a Patient To or From a Monamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders, and initiation of therapy with olanzapine and fluoxetine. Conversely, at least 5 weeks should be allowed after stopping olanzapine and fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4.1 )]. 2.5 Use of Olanzapine and Fluoxetine Capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start olanzapine and fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4.1 ) ]. In some cases, a patient already receiving olanzapine and fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue are judged to outweigh the risks of serotonin syndrome in a particular patient, olanzapine and fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Olanzapine and Fluoxetine Capsules may be resumed 24 hours after the last dose of linezolid and intravenous methylene blue [see Warning and Precautions ( 5.6 )]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with olanzapine and fluoxetine in unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.6 )] . 2.6 Discontinuation of Treatment with Olanzapine and Fluoxetine Capsules Symptoms associated with discontinuation of fluoxetine, a component of olanzapine and fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions ( 5.25 )] .

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)

9.3 Dependence Olanzapine and fluoxetine HCl, as with fluoxetine and olanzapine, has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical studies did not reveal any tendency for 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, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of olanzapine and fluoxetine HCl (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). In studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the MRHD (20 mg) on a mg/m 2 basis.

9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence Olanzapine and fluoxetine HCl, as with fluoxetine and olanzapine, has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical studies did not reveal any tendency for 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, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of olanzapine and fluoxetine HCl (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). In studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the MRHD (20 mg) on a mg/m 2 basis.

10 OVERDOSAGE Olanzapine and Fluoxetine — During premarketing clinical studies of olanzapine and fluoxetine in combination, overdose of both fluoxetine and olanzapine were reported in 5 study subjects. Four of the 5 subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred. Adverse reactions involving overdose of fluoxetine and olanzapine in combination, and olanzapine and fluoxetine HCl, have been reported. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of >20 mg olanzapine in combination with a dose of >80 mg fluoxetine. Adverse reactions associated with these reports included somnolence (sedation), impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), arrhythmias, lethargy, essential tremor, agitation, acute psychosis, hypotension, hypertension, and aggression. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene. Olanzapine — In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia as well as a patient that experienced sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. There have been reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine. Fluoxetine — The following have been reported with fluoxetine overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, Torsade de Pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). 10.1 Management of Overdose For current information on the management of olanzapine and fluoxetine overdose, consider contacting a Certified Poison Control Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. In managing overdose, consider the possibility of multiple drug involvement. Establish and maintain an airway and ensure adequate ventilation. Commence cardiovascular monitoring immediately and include continuous electrocardiographic monitoring to detect possible arrhythmias. A specific precaution involves patients who are taking or have recently taken olanzapine and fluoxetine and may have ingested excessive quantities of a TCA (tricyclic antidepressant). In such cases, accumulation of the parent TCA and/or an active metabolite increases the possibility of serious sequelae and extends the time needed for close medical observation. Due to the large volume of distribution of olanzapine and fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote for either fluoxetine or olanzapine overdose is known

7 DRUG INTERACTIONS The risks of using olanzapine and fluoxetine in combination with other drugs have not been extensively evaluated in systematic studies. The drug-drug interactions sections of fluoxetine and olanzapine are applicable to olanzapine and fluoxetine HCl. 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. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] . Monoamine Oxidase Inhibitor (MAOI) : (2.4 , 2.5 , 4.1 , 5.6 , 7.1 ) Drugs Metabolized by CYP2D6 : Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.7 ) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with olanzapine and fluoxetine hydrochloride or when olanzapine and fluoxetine hydrochloride have been recently discontinued ( 5.6 , 7.7 ) CNS Acting Drugs : Caution is advised if the concomitant administration of olanzapine and fluoxetine hydrochloride and other CNS-active drugs is required ( 7.2 ) Antihypertensive Agent : Enhanced antihypertensive effect ( 7.7 ) Levodopa and Dopamine Agonists : May antagonize levodopa/dopamine agonists ( 7.7 ) Benzodiazepines : May potentiate orthostatic hypotension and sedation ( 7.6 , 7.7 ) Clozapine : May elevate clozapine levels ( 7.7 ) Haloperidol: Elevated haloperidol levels have been observed ( 7.7 ) Carbamazepine: Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity ( 7.7 ) Phenytoin : Potential for elevated phenytoin levels and clinical anticonvulsant toxicity ( 7.7 ) Alcohol : May potentiate sedation and orthostatic hypotension ( 7.7 ) Serotonergic Drugs : ( 2.4, 2.5 , 4.1 , 5.6 , 7.3) Fluvoxamine : May increase olanzapine levels; a lower dose of the olanzapine component of olanzapine and fluoxetine hydrochloride should be considered ( 7.6 ) Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin, etc.): May potentiate the risk of bleeding ( 7.4 ) Drugs Tightly Bound to Plasma Proteins: Fluoxetine may cause shift in plasma concentrations ( 7.7 ) Drugs that Prolong the QT Interval: Do not use olanzapine and fluoxetine capsules in combination with thioridazine or pimozide. Use olanzapine and fluoxetine capsules with caution in combination with other drugs that prolong the QT interval ( 4.2 , 5.20 , 7.7 , 7.8 ) 7.1 Monoamine Oxidase Inhibitors (MAOIs) [see Dosage and Administration ( 2.4 ,2.5), Contraindications ( 4.1 ), Warnings and Precautions ( 5.6 )] . 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of olanzapine and fluoxetine HCl and other CNS-active drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] . 7.3 Serotonergic Drugs [see Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4.1 ) and Warnings and Precations ( 5.6 )]. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin [see Warnings and Precautions ( 5.16 )] . Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Patients receiving warfarin therapy should be carefully monitored when olanzapine and fluoxetine HCl is initiated or discontinued. 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment [see Warnings and Precautions ( 5.15 )] . 7.6 Potential for Other Drugs to Affect Olanzapine and Fluoxetine Benzodiazepines — Co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7.7 )] . Inducers of 1A2 — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance [see Drug Interactions ( 7.7 )] . Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics [see Drug Interactions ( 7.7 )] . Inhibitors of CYP1A2 — Fluvoxamine decreases the clearance of olanzapine. This results in a mean increase in olanzapine C max following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of olanzapine and fluoxetine HCl should be considered in patients receiving concomitant treatment with fluvoxamine. The Effect of Other Drugs on Olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount [see Clinical Pharmacology ( 12.3 )] . Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on olanzapine and fluoxetine has not been evaluated. Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs. 7.7 Potential for Olanzapine and Fluoxetine HCl to Affect Other Drugs Pimozide — Concomitant use of fluoxetine and pimozide is contraindicated. Pimozide can prolong the QT interval. Olanzpaine and Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Olanzapine and Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT c prolongation. While a specific study with pimozide and olanzapine and fluoxetine have not been conducted, the potential for drug interactions or QT c prolongation warrants restricting the concurrent use of pimozide and olanzapine and fluoxetine. [See Contraindications ( 4.2 ), Warnings and Precautions ( 5.20 ), and Drug Interactions ( 7.8 )] . Carbamazepine — Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Alcohol — The coadministration of ethanol with olanzapine and fluoxetine may potentiate sedation and orthostatic hypotension [see Drug Interactions ( 7.6 )] . Thioridazine — Thioridazine should not be administered with olanzapine and fluoxetine or administered within a minimum of 5 weeks after discontinuation of olanzapine and fluoxetine, because of the risk of QT prolongation [ see Contraindications ( 4.2 ), Warnings and Precautions ( 5.20 ), and Drug Interactions ( 7.8 ) ]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine [see Contraindications (4.2 )] . Thioridazine administration produces a dose-related prolongation of the QT c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism [see Contraindications ( 4.2 )] . Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2 )] . Tricyclic Antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. In 2 fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2-to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when olanzapine and fluoxetine HCl is coadministered or has been recently discontinued [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )] . Antihypertensive Agents — Because of the potential for olanzapine to induce hypotension, olanzapine and fluoxetine HCl may enhance the effects of certain antihypertensive agents [see Warnings and Precautions ( 5.11 )] . Levodopa and Dopamine Agonists — The olanzapine component of olanzapine and fluoxetine HCl may antagonize the effects of levodopa and dopamine agonists. Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N desmethyldiazepam. When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients [see Clinical Pharmacology ( 12.3 )] . Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine. Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine. Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine. Drugs Metabolized by CYP2D6 — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme. Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, flecainide, propafenone, vinblastine, and TCAs). Drugs Metabolized by CYP3A — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A activity is not likely to be of clinical significance. Effect of Olanzapine on Drugs Metabolized by Other CYP Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium. There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking olanzapine and fluoxetine concomitantly with lithium [see Warnings and Precautions ( 5.5 )]. Drugs Tightly Bound to Plasma Proteins — The in vitro binding of olanzapine and fluoxetine HCl to human plasma proteins is similar to the individual components. The interaction between olanzapine and fluoxetine HCl and other highly protein-bound drugs has not been fully evaluated. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology ( 12.3 )] . Valproate — In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro . Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely. Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden. Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites. 7.8 Drugs that Prolong the QT Interval Do not use olanzapine and fluoxetine in combination with thioridazine or pimozide. Use olanzapine and fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine,mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.20 ), Drug Interactions ( 7.7 , 7.8 ), and Clinical Pharmacology ( 12.3 )].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of olanzapine and fluoxetine in the listed indications, is unclear. However, the combined effect of olanzapine and fluoxetine at the monoaminergic neural systems (serotonin, norepinephrine, and dopamine) could be responsible for the pharmacological effect. 12.2 Pharmacodynamics Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11 to 31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABA A , BZD, and β-adrenergic receptors (K i >10 µM). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters. 12.3 Pharmacokinetics Olanzapine and fluoxetine HCl — Fluoxetine (administered as a 60 mg single dose or 60 mg daily for 8 days) caused a small increase in the mean maximum concentration of olanzapine (16%) following a 5 mg dose, an increase in the mean area under the curve (17%) and a small decrease in mean apparent clearance of olanzapine (16%). In another study, a similar decrease in apparent clearance of olanzapine of 14% was observed following olanzapine doses of 6 or 12 mg with concomitant fluoxetine doses of 25 mg or more. The decrease in clearance reflects an increase in bioavailability. The terminal half-life is not affected, and therefore the time to reach steady state should not be altered. The overall steady-state plasma concentrations of olanzapine and fluoxetine when given as the combination in the therapeutic dose ranges were comparable with those typically attained with each of the monotherapies. The small change in olanzapine clearance, observed in both studies, likely reflects the inhibition of a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual components is expected to reasonably characterize the overall pharmacokinetics of the combination. Absorption and Bioavailability Olanzapine and fluoxetine HCl — Following a single oral 12 mg/50 mg dose of olanzapine and fluoxetine, peak plasma concentrations of olanzapine and fluoxetine occur at approximately 4 and 6 hours, respectively. The effect of food on the absorption and bioavailability of olanzapine and fluoxetine HCl has not been evaluated. The bioavailability of olanzapine given as Zyprexa ® , and the bioavailability of fluoxetine given as Prozac ® were not affected by food. It is unlikely that there would be a significant food effect on the bioavailability of olanzapine and fluoxetine HCl. Olanzapine — Olanzapine is well absorbed and reaches peak concentration approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption when olanzapine is given as Zyprexa ® . It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Fluoxetine — 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. Food does not appear to affect the systemic bioavailability of fluoxetine given as Prozac ® , although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Distribution Olanzapine and Fluoxetine — The in vitro binding to human plasma proteins of olanzapine and fluoxetine in combination is similar to the binding of the individual components. Olanzapine — Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α 1 -acid glycoprotein. Fluoxetine — 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 1 -glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated [see Drug Interactions ( 7.7 )] . Metabolism and Elimination Olanzapine and Fluoxetine HCl — Olanzapine and fluoxetine HCl therapy yielded steady state concentrations of norfluoxetine similar to those seen with fluoxetine in the therapeutic dose range. Olanzapine — Olanzapine displays linear pharmacokinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.4 )] . Following a single oral dose of 14 C-labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4’-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and CYP450-mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYP1A2, CYP2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo , because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. Fluoxetine — Fluoxetine is a racemic mixture (50/50) of R -fluoxetine and S -fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S -fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Fluoxetine is extensively metabolized in the liver to its only identified active metabolite, norfluoxetine, via the CYP2D6 pathway. A number of unidentified metabolites exist. In animal models, S -norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R - or S -fluoxetine. R -norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical Issues Related to Metabolism and Elimination The complexity of the metabolism of fluoxetine has several consequences that may potentially affect the clinical use of olanzapine and fluoxetine. Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S -fluoxetine at a slower rate and thus achieved higher concentrations of S -fluoxetine. Consequently, concentrations of S- norfluoxetine at steady state were lower. The metabolism of R -fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative nonsaturable pathways (non-CYP2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady state concentration rather than increasing without limit. Because the metabolism of fluoxetine, like that of a number of other compounds including TCAs and other selective serotonin antidepressants, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions ( 7.7 )] . Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because the metabolism of fluoxetine is not proportional to dose. However, norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. 12.4 Specific Populations Geriatric — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of olanzapine and fluoxetine may be altered in geriatric patients. Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity. In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects (≥65 years of age) than in non-elderly subjects (<65 years of age). The disposition of single doses of fluoxetine in healthy elderly subjects (≥65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Renal Impairment — The pharmacokinetics of olanzapine and fluoxetine HCl has not been studied in patients with renal impairment. However, olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. Olanzapine and fluoxetine HCl dosing adjustment based upon renal impairment is not routinely required. Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on olanzapine metabolite elimination has not been studied. In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Hepatic Impairment — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of olanzapine and fluoxetine HCl may be altered in patients with hepatic impairment. The lowest starting dose should be considered for patients with hepatic impairment [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.20 )]. Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (N=6) with clinically significant cirrhosis (Childs-Pugh Classification A and B) revealed little effect on the pharmacokinetics of olanzapine. As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely required. Race — No olanzapine and fluoxetine HCl pharmacokinetic study was conducted to investigate the effects of race. In vivo studies have shown that exposures to olanzapine are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race, therefore, are not routinely required. Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance of olanzapine in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Olanzapine and fluoxetine HCl dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of the olanzapine component [see Dosage and Administration ( 2.3 )] . Children and Adolescents (ages10to 17years) — Based on the pediatric olanzapine and fluoxetine study, steady-state olanzapine, fluoxetine, and norfluoxetine plasma concentrations were about 31%, 76%, and 38% higher, respectively, in pediatric patients with lower body weights (less than 50 kg) than in pediatric patients with high body weight (greater than or equal to 50 kg). Exposures in pediatric patients with high body weight were similar to those previously observed in adults. Dose modifications based on bodyweight are not required.

12.1 Mechanism of Action The mechanism of action of olanzapine and fluoxetine in the listed indications, is unclear. However, the combined effect of olanzapine and fluoxetine at the monoaminergic neural systems (serotonin, norepinephrine, and dopamine) could be responsible for the pharmacological effect.

12.2 Pharmacodynamics Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11 to 31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABA A , BZD, and β-adrenergic receptors (K i >10 µM). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters.

12.3 Pharmacokinetics Olanzapine and fluoxetine HCl — Fluoxetine (administered as a 60 mg single dose or 60 mg daily for 8 days) caused a small increase in the mean maximum concentration of olanzapine (16%) following a 5 mg dose, an increase in the mean area under the curve (17%) and a small decrease in mean apparent clearance of olanzapine (16%). In another study, a similar decrease in apparent clearance of olanzapine of 14% was observed following olanzapine doses of 6 or 12 mg with concomitant fluoxetine doses of 25 mg or more. The decrease in clearance reflects an increase in bioavailability. The terminal half-life is not affected, and therefore the time to reach steady state should not be altered. The overall steady-state plasma concentrations of olanzapine and fluoxetine when given as the combination in the therapeutic dose ranges were comparable with those typically attained with each of the monotherapies. The small change in olanzapine clearance, observed in both studies, likely reflects the inhibition of a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual components is expected to reasonably characterize the overall pharmacokinetics of the combination. Absorption and Bioavailability Olanzapine and fluoxetine HCl — Following a single oral 12 mg/50 mg dose of olanzapine and fluoxetine, peak plasma concentrations of olanzapine and fluoxetine occur at approximately 4 and 6 hours, respectively. The effect of food on the absorption and bioavailability of olanzapine and fluoxetine HCl has not been evaluated. The bioavailability of olanzapine given as Zyprexa ® , and the bioavailability of fluoxetine given as Prozac ® were not affected by food. It is unlikely that there would be a significant food effect on the bioavailability of olanzapine and fluoxetine HCl. Olanzapine — Olanzapine is well absorbed and reaches peak concentration approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption when olanzapine is given as Zyprexa ® . It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Fluoxetine — 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. Food does not appear to affect the systemic bioavailability of fluoxetine given as Prozac ® , although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Distribution Olanzapine and Fluoxetine — The in vitro binding to human plasma proteins of olanzapine and fluoxetine in combination is similar to the binding of the individual components. Olanzapine — Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α 1 -acid glycoprotein. Fluoxetine — 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 1 -glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated [see Drug Interactions ( 7.7 )] . Metabolism and Elimination Olanzapine and Fluoxetine HCl — Olanzapine and fluoxetine HCl therapy yielded steady state concentrations of norfluoxetine similar to those seen with fluoxetine in the therapeutic dose range. Olanzapine — Olanzapine displays linear pharmacokinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.4 )] . Following a single oral dose of 14 C-labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4’-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and CYP450-mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYP1A2, CYP2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo , because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. Fluoxetine — Fluoxetine is a racemic mixture (50/50) of R -fluoxetine and S -fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S -fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Fluoxetine is extensively metabolized in the liver to its only identified active metabolite, norfluoxetine, via the CYP2D6 pathway. A number of unidentified metabolites exist. In animal models, S -norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R - or S -fluoxetine. R -norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical Issues Related to Metabolism and Elimination The complexity of the metabolism of fluoxetine has several consequences that may potentially affect the clinical use of olanzapine and fluoxetine. Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S -fluoxetine at a slower rate and thus achieved higher concentrations of S -fluoxetine. Consequently, concentrations of S- norfluoxetine at steady state were lower. The metabolism of R -fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative nonsaturable pathways (non-CYP2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady state concentration rather than increasing without limit. Because the metabolism of fluoxetine, like that of a number of other compounds including TCAs and other selective serotonin antidepressants, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions ( 7.7 )] . Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because the metabolism of fluoxetine is not proportional to dose. However, norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine.

20220707

12

3 DOSAGE FORMS AND STRENGTHS Capsules (mg olanzapine/mg equivalent fluoxetine): 3 mg/25 mg 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg Capsules: 3 mg olanzapine/25 mg fluoxetine, 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, and 12 mg/50 mg (mg equivalent olanzapine/mg equivalent fluoxetine) ( 3 )

Olanzapine and Fluoxetine olanzapine and fuoxetine OLANZAPINE OLANZAPINE FLUOXETINE HYDROCHLORIDE FLUOXETINE GELATIN MAGNESIUM STEARATE TITANIUM DIOXIDE METHYL ALCOHOL FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED STARCH, CORN ALCOHOL D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 PROPYLENE GLYCOL SHELLAC white opaque body orange opaque cap 277;par Olanzapine and Fluoxetine olanzapine and fuoxetine OLANZAPINE OLANZAPINE FLUOXETINE HYDROCHLORIDE FLUOXETINE GELATIN MAGNESIUM STEARATE STARCH, CORN TITANIUM DIOXIDE D&C YELLOW NO. 10 FERRIC OXIDE YELLOW ALCOHOL FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 FERROSOFERRIC OXIDE METHYL ALCOHOL PROPYLENE GLYCOL SHELLAC rich yellow opaque 250;par Olanzapine and Fluoxetine olanzapine and fuoxetine OLANZAPINE OLANZAPINE FLUOXETINE HYDROCHLORIDE FLUOXETINE GELATIN MAGNESIUM STEARATE STARCH, CORN TITANIUM DIOXIDE FERRIC OXIDE YELLOW D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 FERROSOFERRIC OXIDE METHYL ALCOHOL ALCOHOL PROPYLENE GLYCOL SHELLAC FD&C RED NO. 3 FD&C YELLOW NO. 6 rich yellow opaque cap light grey opaque body 251;par Olanzapine and Fluoxetine olanzapine and fuoxetine OLANZAPINE OLANZAPINE FLUOXETINE HYDROCHLORIDE FLUOXETINE GELATIN MAGNESIUM STEARATE STARCH, CORN TITANIUM DIOXIDE FERRIC OXIDE YELLOW D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 FERROSOFERRIC OXIDE METHYL ALCOHOL ALCOHOL PROPYLENE GLYCOL SHELLAC D&C RED NO. 28 FERRIC OXIDE RED dark tan opaque body red opaque cap 252;par Olanzapine and Fluoxetine olanzapine and fuoxetine OLANZAPINE OLANZAPINE FLUOXETINE HYDROCHLORIDE FLUOXETINE GELATIN MAGNESIUM STEARATE STARCH, CORN TITANIUM DIOXIDE FERRIC OXIDE YELLOW D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 FERROSOFERRIC OXIDE METHYL ALCOHOL ALCOHOL PROPYLENE GLYCOL SHELLAC D&C RED NO. 28 FD&C RED NO. 3 FD&C YELLOW NO. 6 light grey opaque body red opaque cap 253;par

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity, or fertility studies were conducted with olanzapine and fluoxetine. The following data are based on findings in studies performed with the individual components, and all dose multiples (based on body surface area) reflect the maximum recommended human dose (MRHD) of 12 mg olanzapine, or 50 mg fluoxetine in olanzapine and fluoxetine capsules. Carcinogenesis Olanzapine — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 1 to 12 times the MRHD based on mg/m 2 body surface area] and 0.25, 2, and 8 mg/kg/day (equivalent to up to 3 times the oral MRHD based on mg/m 2 body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5 and 4 mg/kg/day (males) and 0.25, 1, 4 and 8 mg/kg/day (females) (equivalent to up to 3 and 7 times the oral MRHD based on mg/m 2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 3 times the daily oral MRHD based on mg/m 2 body surface area. These tumors were not increased in another mouse study in females dosed at (up to 12 times the daily oral MRHD based on mg/m 2 body surface area); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (1 and 3 times the oral MRHD based on mg/m 2 body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the finding of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.22)] . Fluoxetine — 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 2 and 1 times, respectively, the MRHD of 20 mg given to children based on mg/m 2 body surface area), produced no evidence of carcinogenicity. Mutagenesis Olanzapine — No evidence of genotoxic potential for olanzapine was found in following tests: Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Fluoxetine — No evidence of genotoxic potential for fluoxetine and norfluoxetine was found in the following tests: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility Olanzapine and Fluoxetine — Fertility studies were not conducted with olanzapine and fluoxetine. However, in a repeat-dose rat toxicology study of 3 months duration, ovary weight was decreased in females treated with the low-dose [2 and 4 mg/kg/day (approximately 2 and 1 times the MRHD of 12 mg (olanzapine) and 50 mg (fluoxetine) based on mg/m 2 body surface area), respectively] and high-dose [4 and 8 mg/kg/day (3and 2 times the MRHD based on mg/m 2 body surface area), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high-dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3-month repeat-dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high-dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (14 and 3 times the MRHD based on mg/m 2 body surface area), respectively] and with olanzapine alone (5 mg/kg/day or 14 times the MRHD based on mg/m 2 body surface area). Olanzapine — In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (18 and 2 times the daily oral MRHD of 12 mg given to adults based on mg/m 2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male-mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (4 times the MRHD based on mg/m 2 body surface area). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (1 times the daily oral MRHD based on mg/m 2 body surface area); therefore, olanzapine may produce a delay in ovulation. Fluoxetine —Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 1and 2 times the MRHD of 50 mg given to adolescents based on mg/m 2 body surface area) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity, or fertility studies were conducted with olanzapine and fluoxetine. The following data are based on findings in studies performed with the individual components, and all dose multiples (based on body surface area) reflect the maximum recommended human dose (MRHD) of 12 mg olanzapine, or 50 mg fluoxetine in olanzapine and fluoxetine capsules. Carcinogenesis Olanzapine — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 1 to 12 times the MRHD based on mg/m 2 body surface area] and 0.25, 2, and 8 mg/kg/day (equivalent to up to 3 times the oral MRHD based on mg/m 2 body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5 and 4 mg/kg/day (males) and 0.25, 1, 4 and 8 mg/kg/day (females) (equivalent to up to 3 and 7 times the oral MRHD based on mg/m 2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 3 times the daily oral MRHD based on mg/m 2 body surface area. These tumors were not increased in another mouse study in females dosed at (up to 12 times the daily oral MRHD based on mg/m 2 body surface area); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (1 and 3 times the oral MRHD based on mg/m 2 body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the finding of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.22)] . Fluoxetine — 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 2 and 1 times, respectively, the MRHD of 20 mg given to children based on mg/m 2 body surface area), produced no evidence of carcinogenicity. Mutagenesis Olanzapine — No evidence of genotoxic potential for olanzapine was found in following tests: Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Fluoxetine — No evidence of genotoxic potential for fluoxetine and norfluoxetine was found in the following tests: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility Olanzapine and Fluoxetine — Fertility studies were not conducted with olanzapine and fluoxetine. However, in a repeat-dose rat toxicology study of 3 months duration, ovary weight was decreased in females treated with the low-dose [2 and 4 mg/kg/day (approximately 2 and 1 times the MRHD of 12 mg (olanzapine) and 50 mg (fluoxetine) based on mg/m 2 body surface area), respectively] and high-dose [4 and 8 mg/kg/day (3and 2 times the MRHD based on mg/m 2 body surface area), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high-dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3-month repeat-dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high-dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (14 and 3 times the MRHD based on mg/m 2 body surface area), respectively] and with olanzapine alone (5 mg/kg/day or 14 times the MRHD based on mg/m 2 body surface area). Olanzapine — In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (18 and 2 times the daily oral MRHD of 12 mg given to adults based on mg/m 2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male-mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (4 times the MRHD based on mg/m 2 body surface area). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (1 times the daily oral MRHD based on mg/m 2 body surface area); therefore, olanzapine may produce a delay in ovulation. Fluoxetine —Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 1and 2 times the MRHD of 50 mg given to adolescents based on mg/m 2 body surface area) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)] .

ANDA077742

Olanzapine and Fluoxetine

olanzapine and fuoxetine

49884-252

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL – 3mg/25mg - 30 CAPSULES 3mg/25mg label 3mg/25mg label

RECENT MAJOR CHANGES Warnings and Precautions, Sexual Dysfunction ( 5.26 ) 9/2021

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking olanzapine and fluoxetine capsules. Information on Medication Guide Healthcare providers should inform patients, their families, and their caregivers about the potential benefits and potential risks associated with treatment with olanzapine and fluoxetine capsules and should counsel them in its appropriate use. A patient Medication Guide is available for olanzapine and fluoxetine capsules. The healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's healthcare provider, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo. Olanzapine and Fluoxetine capsules are not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Neuroleptic Malignant Syndrome (NMS) Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine, a component of olanzapine and fluoxetine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions ( 5.3 )] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.4 )] . Hyperglycemia and Diabetes Mellitus Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients and caregivers should be counseled that metabolic changes have occurred during treatment with olanzapine and fluoxetine. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking olanzapine and fluoxetine capsules [see Warnings and Precautions ( 5.5 )] . Dyslipidemia Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine and fluoxetine. Patients should have their lipid profile monitored regularly [see Warnings and Precautions ( 5.5 )] . Weight Gain Patients should be counseled that weight gain has occurred during treatment with olanzapine and fluoxetine. Patients should have their weight monitored regularly [see Warnings and Precautions ( 5.5 )] . Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of olanzapine and fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort [see Contraindications ( 4.1 ) Warnings and Precautions ( 5.6 ) and Drug Interactions (7.3) ]. Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms. Angle-Closure Glaucoma Patients should be advised that taking olanzapine and fluoxetine capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions ( 5.7 )] . Allergic Reactions and Rash Patients should be advised to notify their healthcare provider if they develop a rash or hives [see Warnings and Precautions ( 5.8 )] . Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.6 , 7.7 )] . Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting. Abnormal Bleeding Patients should be cautioned about the concomitant use of olanzapine and fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions ( 5.16 )] . Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking olanzapine and fluoxetine capsules. Hyponatremia Patients should be advised that hyponatremia has been reported during treatment with SNRIs and SSRIs, including olanzapine and fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions ( 5.17 )] . Potential for Cognitive and Motor Impairment Olanzapine and Fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine and fluoxetine therapy does not affect them adversely [see Warnings and Precautions ( 5.18 )] . Body Temperature Dysregulation Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions ( 5.19 )] . Concomitant Medication Patients should be advised to inform their healthcare provider if they are taking Prozac, Sarafem, fluoxetine, Zyprexa, or Zyprexa Zydis, or Zyprexa Relprevv. Patients should be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions. Patients should also be advised to inform their healthcare providers if they plan to discontinue any medications they are taking while taking olanzapine and fluoxetine capsules, as stopping a medication may also impact the overall blood level of olanzapine and fluoxetine [see Warnings and Precautions ( 5.23 )] . Discontinuation of Treatment with Olanzapine and Fluoxetine Patients should be advised to take olanzapine and fluoxetine capsules exactly as prescribed, and to continue taking olanzapine and fluoxetine capsules as prescribed even after their mood symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking olanzapine and fluoxetine capsules, without consulting their healthcare provider [see Warnings and Precautions ( 5.25 )] . Alcohol Patients should be advised to avoid alcohol while taking olanzapine and fluoxetine capsules [see Drug Interactions ( 7.6 , 7.7 )] . Use in Specific Populations Pregnancy - Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine and fluoxetine capsules. Advise patients that olanzapine and fluoxetine capsules use later in pregnancy may lead to extrapyramidal symptoms (tremors, abnormal muscle movements), an increased risk for neonatal complications requiring prolonged hospitalization, respiratory distress, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine and fluoxetine capsules during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation ― Advise breastfeeding women using olanzapine and fluoxetine capsules to monitor infants for agitation, irritability, poor weight gain, poor feeding, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs. [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that olanzapine and fluoxetine capsules may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Pediatric Use ― Safety and efficacy of olanzapine and fluoxetine in patients 10 to 17 years of age have been established for the acute treatment of Depressive Episodes Associated with Bipolar I Disorder. The types of adverse reactions observed with olanzapine and fluoxetine in children and adolescents were generally similar to those observed in adults. However, the magnitude and frequency of some changes were greater in children and adolescents than adults. These included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the QT interval. Educate patients, families, and caregivers about these risks [see Warnings and Precautions ( 5.5 , 5.18 , 5.20 ), Adverse Reactions ( 6.1 ), and Use in Specific Populations ( 8.4 )]. The frequency of weight gain ≥7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with olanzapine and fluoxetine were similar to those observed in adolescents treated with olanzapine monotherapy [see Warnings and Precautions ( 5.5 , 5.20 ), Adverse Reactions ( 6.1 ), and Use in Specific Populations ( 8.4 )] . The safety and effectiveness of olanzapine and fluoxetine for the treatment of bipolar I depression in patients under 10 years of age have not been established. The safety and effectiveness of olanzapine and fluoxetine for treatment resistant depression in patients under 18 years of age have not been established. QT Prolongation Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions ( 5.20 )] .

MEDICATION GUIDE Olanzapine and Fluoxetine Capsules USP (oh-LAN-zah-peen and floo-OX-eh-teen) Read the Medication Guide that comes with olanzapine and fluoxetine capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about olanzapine and fluoxetine capsules. What is the most important information I should know about Olanzapine and Fluoxetine Capsules? Olanzapine and Fluoxetine Capsules may cause serious side effects, including: Suicidal thoughts or actions. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). High blood sugar (hyperglycemia). High fat levels in your blood (increased cholesterol and triglycerides), especially in children and adolescents age 10 to 17. Weight gain, especially in children and adolescents age 10 to 17. These serious side effects are described below. Suicidal thoughts or actions. Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions : 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. 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) or 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 list 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. 2. Increased risk of death in elderly people who are confused, have memeory loss and have lost touch with reality (dementia-related psychosis). Olanzapine and fluoxetine capsules are not approved for treating psychosis in elderly people with dementia. 3. High blood sugar (hyperglycemia): High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to: build up of acid in the blood due to ketones (ketoacidosis) coma death Your doctor should do tests to check your blood sugar before you start taking olanzapine and fluoxetine capsules and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine and fluoxetine capsules are stopped. People with diabetes and some people who did not have diabetes before taking olanzapine and fluoxetine hydrochloride need to take medicine for high blood sugar even after they stop taking olanzapine and fluoxetine capsules. If you have diabetes, follow your doctor's instructions about how often to check your blood sugar while taking olanzapine and fluoxetine capsules. Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking olanzapine and fluoxetine capsules: feel very thirsty need to urinate more than usual feel very hungry feel weak or tired feel sick to your stomach feel confused, or your breath smells fruity. 4. High fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with olanzapine and fluoxetine capsules, especially in children and adolescents (10 to 17 years old) You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking olanzapine and fluoxetine capsules and during treatment. 5. Increase in weight (weight gain): Weight gain is common in people who take olanzapine and fluoxetine capsules. Children and adolescents (10 to 17 years old) who received olanzapine, one of the drugs in olanzapine and fluoxetine capsules, are more likely to gain weight and to gain more weight than adults. Olanzapine and fluoxetine capsules are not approved for use in people less than 18 years. Some people may gain a lot of weight while taking olanzapine and fluoxetine capsules, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising. What are Olanzapine and Fluoxetine Capsules? Olanzapine and fluoxetine capsules are a prescription medicine used for: short-term treatment of episodes of depression that happen with Bipolar I Disorder. treatment of episodes of depression that do not respond to 2 other medicines, also called treatment resistant depression, in adults. Olanzapine and fluoxetine capsules contain two medicines, olanzapine and fluoxetine hydrochloride. It is not known if olanzapine and fluoxetine capsules are safe and effective in children under the age of 10. The symptoms of Bipolar I Disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep. With treatment, some of your symptoms of Bipolar I Disorder may improve. The symptoms of Bipolar I Disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep. With treatment, some of your symptoms of Bipolar I Disorder may improve. The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior. With treatment, some of your symptoms of treatment resistant depression may improve. If you do not think you are getting better, call your doctor. Who should not take Olanzapine and Fluoxetine Capsules? Do not take olanzapine and fluoxetine capsules if you take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 5 weeks of stopping olanzapine and fluoxetine capsules unless directed to do so by your physician. Do not start olanzapine and fluoxetine if you stopped taking and MAOI in the last 2 weeks unless directed to do so by your physician. People who take olanzapine and fluoxetine close in time to an MAOI can have serious and life-threatening side effects, with symptoms including: high fever continued muscle spasms that you cannot control rigid muscles changes in heart rate and blood pressure that happen fast confusion unconsciousness. Do not take olanzapine and fluoxetine capsules if you take Mellaril ® (thioridazine). Do not take Mellaril ® within 5 weeks of stopping olanzapine and fluoxetine capsules. Mellaril ® can cause serious heart rhythm problems and you could die suddenly. Do not take olanzapine and fluoxetine capsules if you take the antipsychotic medicine pimozide (Orap ® ). Do not take pimozide (Orap ® ) within 5 weeks of stopping olanzapine and fluoxetine capsules. What should I tell my doctor before taking Olanzapine and Fluoxetine Capsules? Olanzapine and fluoxetine capsules may not be right for you. Before starting olanzapine and fluoxetine capsules, tell your doctor about all your medical conditions, including if you have or had any of the following: heart problems seizures (convulsions) diabetes or high blood sugar levels (hyperglycemia) high cholesterol or triglyceride levels in your blood liver problems low or high blood pressure strokes or “mini-strokes” also called transient ischemic attacks (TIAs) bleeding problems Alzheimer's disease Angle-closure glaucoma enlarged prostate in men bowel obstruction breast cancer are pregnant or plan to become pregnant. It is not known if olanzapine and fluoxetine capsules will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. If you become pregnant while taking olanzapine and fluoxetine capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications at 1-866-961-­2388 or visit https://womensmentalhealth.org/clinical-and-research­-programs/pregnancyregistry. are breast-feeding or plan to breast-feed. Olanzapine and Fluoxetine can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take olanzapine and fluoxetine capsules. Before starting olanzapine and fluoxetine capsules, tell your doctor about all the medicines that you take, including : Prescription and non-prescription medicines Vitamins, and herbal supplements Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs, or antipsychotics Tramadol and fentanyl Amphetamines Over-the-counter supplements such as tryptophan or St. John’s Wort Electroconvulsive therapy (ECT) Olanzapine and fluoxetine and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take olanzapine and fluoxetine capsules with your other medicines. Do not start or stop any medicine while taking olanzapine and fluoxetine capsules without talking to your doctor first. If you take olanzapine and fluoxetine capsules, you should not take any other medicines that contain: olanzapine (the active ingredient in Zyprexa ® and Zyprexa Zydis ® ) or fluoxetine hydrochloride (the active ingredient in Prozac ® , and Sarafem ® ). You could take too much medicine (overdose). How should I take Olanzapine and Fluoxetine Capsules? Take olanzapine and fluoxetine capsules exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine and fluoxetine capsules until it is right for you. If you miss a dose of olanzapine and fluoxetine capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine and fluoxetine capsules at the same time. To prevent serious side effects, do not stop taking Olanzapine and Fluoxetine Capsules suddenly. If you need to stop taking Olanzapine and Fluoxetine Capsules, your doctor can tell you how to safely stop taking it. If you take too much Olanzapine and Fluoxetine Capsules, call your doctor or poison control center right away, or get emergency treatment. Olanzapine and fluoxetine capsules can be taken with or without food. Olanzapine and fluoxetine capsules are usually taken one time each day, in the evening. If you do not think you are getting better or have any concerns about your condition while taking olanzapine and fluoxetine capsules, call your doctor. What should I avoid while taking Olanzapine and Fluoxetine Capsules? Olanzapine and fluoxetine capsules can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine and fluoxetine capsules affect you. Avoid drinking alcohol while taking olanzapine and fluoxetine capsules. Drinking alcohol while you take olanzapine and fluoxetine capsules may make you sleepier than if you take olanzapine and fluoxetine capsules alone. What are the possible side effects of Olanzapine and Fluoxetine Capsules? Other possible serious risks: Increased risk of death and increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with psychosis related to dementia (a brain disorder that lessens the ability to remember, think, and reason). Olanzapine and fluoxetine capsules are not approved for these patients. Severe allergic reactions: Tell your doctor right away if you get red itchy welts (hives) or, a rash alone or with fever and joint pain, while taking olanzapine and fluoxetine capsules. Call your doctor right away if you become severely ill and have some or all of these symptoms: swelling of your face, eyes, or mouth trouble breathing Neuroleptic malignant syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including olanzapine and fluoxetine capsules. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have some or all of these symptoms: high fever excessive sweating rigid muscles confusion changes in your breathing, heartbeat, and blood pressure Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs. Tardive Dyskinesia: This condition causes body movements that keep happening and that you cannot control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking olanzapine and fluoxetine capsules. It may also start after you stop taking olanzapine and fluoxetine capsules. Tell your doctor if you get any body movements that you cannot control. Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right away if you become severely ill and have some or all of these symptoms: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) sweating or fever nausea, vomiting, and diarrhea muscle rigidity flushing tremor seizures Visual problems: eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Abnormal bleeding: Tell your doctor if you notice any increased or unusual bruising or bleeding while taking olanzapine and fluoxetine capsules, especially if you take one of these medicines: the blood thinner warfarin (Coumadin, Jantoven) a non-steroidal anti-inflammatory drug (NSAID) aspirin Low salt (sodium) levels in the blood (hyponatremia): Call your doctor right away if you become severely ill and have some or all of these symptoms: headache feel weak confusion problems concentrating memory problems feel unsteady Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsade de Pointes). This condition can be life threatening. The symptoms may include: fast, slow, or irregular heartbeat shortness of breath dizziness or fainting Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heart beat, or fainting Difficulty swallowing Seizures Problems with control of body temperature: You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all dry mouth feeling very hot feeling thirsty not able to produce urine Sexual problems (dysfunction): Taking selective serotonin reuptake (SSRIs), including fluoxetine, a component of olanzapine and fluoxetine capsules, may cause sexual problems. Symptoms in males may include: Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include: Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with olanzapine and fluoxetine capsules. There may be treatments your healthcare provider can suggest. Common possible side effects of Olanzapine and Fluoxetine Capsules include: dry mouth, tiredness, sleeping for long period of time, increased appetite, swelling of your hands and feet, drowsiness, tremors (shakes), or blurred vision. Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with olanzapine and fluoxetine capsules. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Olanzapine and Fluoxetine Capsules? Store olanzapine and fluoxetine capsules at room temperature, between 68°F to 77°F (20°C to 25°C) with excursions permitted between 59° to 86°F (15°C to 30°C). Keep olanzapine and fluoxetine capsules away from light. Keep olanzapine and fluoxetine capsules dry and away from moisture. Keep the bottle closed tightly. Keep Olanzapine and Fluoxetine Capsules and all medicines out of the reach of children. General information about Olanzapine and Fluoxetine Capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use olanzapine and fluoxetine capsules for a condition for which it was not prescribed. Do not give olanzapine and fluoxetine capsules to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about olanzapine and fluoxetine capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about olanzapine and fluoxetine capsules that was written for healthcare professionals. For more information about olanzapine and fluoxetine capsules call Par Pharmaceutical at 1-800-828-9393. What are the ingredients in Olanzapine and Fluoxetine Capsules ? Active ingredients: olanzapine and fluoxetine hydrochloride Inactive ingredients: gelatin, magnesium stearate, partially pregelatinized starch, titanium dioxide, and yellow iron oxide. In addition, the 3 mg/25 mg capsule also contains red iron oxide; the 6 mg/50 mg capsule also contains FD&C blue No. 2, FD&C red No. 3, and FD&C yellow No. 6; the 12 mg/25 mg capsule also contains D&C red No. 28, FD&C blue No. 1, FD&C red No. 40, and red iron oxide; and the 12 mg/50 mg capsule also contains D&C red No. 28, FD&C blue No. 1 FD&C blue No. 2, FD&C red No. 3, FD&C red No. 40, and FD&C yellow No. 6. The capsules also have printing in edible black ink which contains the following ingredients: D&C yellow No. 10, ethanol, FD&C blue No. 1, FD&C blue No. 2, FD&C red No. 40, iron oxide black, methanol, n-Butyl alcohol, propylene glycol, and shellac glaze in alcohol. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Par Pharmaceutical. For Medication Guide, please visit www.parpharm.com . This Medication Guide has been approved by the U.S. Food and Drug Administration. Dist. by: Par Pharmaceutical Cranbury, NJ 08512 U.S.A. Mfg. by: Par Formulations Private Limited, M82 and M83, Industrial Area, SEZ, Phase II, Pithampur, Dhar, MP - 454775, District- DHAR Made in India Mfg. Lic. No.: 25/82/2020 OS277-01-74-01 Issued: 12/2021

14 CLINICAL STUDIES Efficacy for olanzapine and fluoxetine capsules was established for the: Acute treatment of depressive episodes in Bipolar I Disorder in adults in 2 short-term, placebo-controlled trials (Studies 1, 2, 3) [see Clinical Studies 14.1 ). Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials (Studies 4, 5, 6) and 1 randomized withdrawal study with an active control (Study 7) [see Clinical Studies 14.2 ] . 14.1 Depressive Episodes Associated with Bipolar I Disorder Adults - The efficacy of olanzapine and fluoxetine HCl for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in 2 identically designed, 8-week, randomized, double-blind, controlled studies of patients who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for Bipolar I Disorder, Depressed utilizing flexible dosing of olanzapine and fluoxetine (6/25 mg, 6/50 mg, or 12/50 mg/day), olanzapine (5 to 20 mg/day), and placebo. These studies included patients (≥18 years of age [n=788]) with or without psychotic symptoms and with or without a rapid cycling course. The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 to 60. The primary outcome measure of these studies was the change from baseline to endpoint in the MADRS total score. In both studies, olanzapine and fluoxetine was statistically significantly superior to both olanzapine monotherapy and placebo in reduction of the MADRS total score. Refer to Table 18 (Studies 1 and 2). Children and Adolescents (ages 10 to 17 years) — The efficacy of olanzapine and fluoxetine for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in a single 8-week, randomized, double-blind, placebo-controlled study of patients, 10 to 17 years of age [N=255], who met Diagnostic and Statistical Manual 4th edition-Text Revision (DSM-IV-TR) criteria for Bipolar I Disorder, Depressed. Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of olanzapine and fluoxetine in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average daily dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day. Flexible dosing is recommended, rather than the forced titration used in the study [see Dosage and Administration ( 2.1 )]. This study included patients with or without psychotic symptoms. The primary rating instrument used to assess depressive symptoms in these studies was the Children’s Depressive Rating Scale-Revised (CDRS-R), a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary outcome measure of this study was the change from baseline to Week 8 in the CDRS-R total score. In this study, olanzapine and fluoxetine was statistically significantly superior to placebo in reduction of the CDRS-R total score. Refer to Table 18 (Study 3). Table 18. Summary of the Primary Efficacy Result for Studies in Bipolar Depression a Study Number (Primary Efficacy Measure) Treatment group Mean baseline score (SD) LS Mean change from baseline (SE) Difference b from Olanzapine and Fluoxetine (95% CI) Study 1 (MADRS) Olanzapine and Fluoxetine Olanzapine Placebo 29.9 (5.0) 32.4 (6.3) 31.2 (5.7) -18.7 (1.8) -14.4 (1.0) -13.3 (1.0) -4.4 (NA) -5.5 (NA) Study 2 (MADRS) Olanzapine and Fluoxetine Olanzapine Placebo 31.7 (6.8) 32.8 (6.1) 31.4 (6.6) -18.44 (1.7) -15.81 (1.0) -10.68 (1.0) -2.6 (NA) -7.8 (NA) Study 3 (CDRS-R) Olanzapine and Fluoxetine Placebo 54.6 (10.0) 53.7 (8.2) -28.43 (1.1) -23.40 (1.5) -5.0 (-8.3, -1.8) a SD – standard deviation; SE – standard error; LS mean – least-squares mean estimate; CI – unadjusted confidence interval; NA – not available. b Difference (olanzapine and fluoxetine minus active comparator or placebo) in least squares estimates. 14.2 Treatment Resistant Depression The efficacy of olanzapine and fluoxetine in acute treatment resistant depression was demonstrated with data from 3 clinical studies (n=579) in adults (18 to 85 years). Doses evaluated in these studies ranged from 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine. An 8-week randomized, double-blind controlled study was conducted to evaluate the efficacy of olanzapine and fluoxetine in patients (n=300) who met DSM-IV criteria for Major Depressive Disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode. Patients who were not responding to an antidepressant in their current episode entered an 8-week open-label fluoxetine lead-in; non-responders were randomized (1:1:1) to receive olanzapine and fluoxetine, olanzapine, or fluoxetine, and were treated for 8 weeks. Olanzapine and fluoxetine was flexibly dosed between 6/50 mg, 12/50 mg, and 18/50 mg. Results from this study yielded statistically significant greater reduction in mean total MADRS scores from baseline to endpoint for olanzapine and fluoxetine versus fluoxetine and olanzapine. See Table 19 (Study 4). A second study with the same treatment-resistant patient population (n=28), when analyzed with change in MADRS as the outcome measure, demonstrated statistically significantly greater reduction in MADRS scores for olanzapine and fluoxetine versus fluoxetine and olanzapine. See Table 19 (Study 5). A third study demonstrated statistically significantly greater reduction in total MADRS scores for olanzapine and fluoxetine versus fluoxetine or olanzapine alone, when analyzed in a subpopulation of depressed patients (n=251) who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dose and duration in the current episode). See Table 19 (Study 6). Table 19: Summary of the Primary Efficacy Result for Studies in Treatment-Resistant Depression a Study Number (Primary Efficacy Measure) Treatment group Mean baseline score (SD) LS Mean change from baseline (SE) Difference b from Olanzapine and Fluoxetine (95% CI) Study 4 (MADRS) Olanzapine and Fluoxetine Olanzapine Fluoxetine 30.6 (6.1) 30.1 (6.3) 30.1 (5.9) -14.1 (1.0) -7.1 (1.0) -8.3 (1.1) -6.9 (NA) -5.8 (NA) Study 5 (HAMD-21) Olanzapine and Fluoxetine Olanzapine Fluoxetine 26.4 (7.5) 24.5 (5.2) 23.5 (6.0) -11.7 (3.3) -5.9 (1.9) -3.8 (3.0) -6.1 (-13.7, 1.5) -6.7 (-14.0, 0.5) Study 6 (MADRS) Olanzapine and Fluoxetine Olanzapine Fluoxetine 30.1 (6.6) 31.5 (6.8) 31.1 (5.6) -13.3 (0.8) -8.8 (1.7) -10.0 (1.4) NA NA a SD – standard deviation; SE – standard error; LS mean – least-squares mean estimate; CI – unadjusted confidence interval; NA – not available. b Difference (olanzapine and fluoxetine minus active comparator or placebo) in least squares estimates. The efficacy of olanzapine and fluoxetine in the maintenance therapy of treatment-resistant depression was demonstrated in a 47-week study (Study 7) in adults (18 to 65 years). Olanzapine and fluoxetine was dosed between 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg, and 18/50 mg. Patients (N=892) met DSM-IV criteria for Major Depressive Disorder and for treatment-resistant depression (a lack of response to 2 antidepressants after at least 6 weeks at or above the minimally effective labeled dose in their current episode of major depressive disorder). Patients were initially treated with open-label olanzapine and fluoxetine; those who responded to and were stabilized on treatment over approximately 20 weeks were randomized to continue receiving treatment with olanzapine and fluoxetine (n=221) or to receive treatment with fluoxetine (n=223) for another 27 weeks. Relapse was assessed using 3 criteria: a 50% increase in Montgomery-Åsberg Depression Rating Scale score from randomization with concomitant Clinical Global Impressions–Severity of Depression score increase to 4 or more; hospitalization due to depression or suicidality; or discontinuation due to lack of efficacy/worsening of depression/suicidality. A total of 15.8% of patients on olanzapine and fluoxetine and 31.8% of patients on fluoxetine relapsed; this difference was statistically significant. Patients receiving continued olanzapine and fluoxetine experienced statistically significantly longer time to relapse over the 27 weeks compared with those receiving fluoxetine ( Figure 1 ). Figure 1

8.5 Geriatric Use Olanzapine and Fluoxetine — Clinical studies of olanzapine and fluoxetine did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration ( 2.3 )] . Olanzapine — Of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥65 years of age. In patients with Schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with Schizophrenia. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient. Fluoxetine — U.S. fluoxetine clinical studies included 687 patients ≥65 years of age and 93 patients ≥75 years of age. 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. SNRIs and SSRIs, including olanzapine and fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.17 )] .

8.2 Lactation Risk Summary Data from published literature report the presence of olanzapine, fluoxetine, and norfluoxetine in human milk (see Data). There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk and reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to fluoxetine through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine or fluoxetine and their metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and fluoxetine capsules and any potential adverse effects on the breastfed child from olanzapine and fluoxetine capsules or the underlying maternal condition. Clinical Considerations Infants exposed to olanzapine and fluoxetine capsules should be monitored for agitation, irritability, poor feeding, poor weight gain, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements). Data A study of nineteen nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL), whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL).

8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (dopamine D 2 receptor blockade), treatment with SYMBYAX may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.22 )].

8.4 Pediatric Use Olanzapine and Fluoxetine -The safety and efficacy of olanzapine and fluoxetine in patients 10 to 17 years of age has been established for the acute treatment of Depressive Episodes Associated with Bipolar I Disorder in a single 8-week randomized, placebo-controlled clinical trial (N = 255) [see Clinical Studies ( 14.1 )] . Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of olanzapine and fluoxetine in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day (lower than that for adults). Flexible dosing is recommended, rather than the forced titration used in the study [see Dosage and Administration ( 2.1 )] . The types of adverse events observed with olanzapine and fluoxetine in children and adolescents were generally similar to those observed in adults. However, the magnitude and frequency of some changes were greater in children and adolescents than adults. These included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the QT interval [see Warnings and Precautions ( 5.5 , 5.20 , 5.22 ), and Vital Signs and Laboratory Studies ( 6.1 )] . The frequency of weight gain ≥7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with olanzapine and fluoxetine were similar to those observed in adolescents treated with olanzapine monotherapy. The safety and efficacy of olanzapine and fluoxetine in combination for the treatment of bipolar I depression in patients under the age of 10 years have not been established. The safety and effectiveness of olanzapine and fluoxetine in combination for treatment resistant depression in patients less than 18 years of age have not been established. Anyone considering the use of olanzapine and fluoxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Olanzapine — Safety and effectiveness of olanzapine in children <13 years of age have not been established. Compared to patients from adult clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels. Juvenile Animal Toxicity Data Fluoxetine — Juvenile animal toxicity studies were performed for fluoxetine alone. Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m 2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including olanzapine and fluoxetine capsules, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies and postmarketing reports of pregnant women exposed to olanzapine or fluoxetine have not established a drug-associated increased risk of major birth defects or miscarriage (see Data). Some studies in pregnant women exposed to fluoxetine have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). In animal studies, administration of the combination of olanzapine and fluoxetine during the period of organogenesis resulted in adverse effects on development (decreased fetal body weights in rats and rabbits and retarded skeletal ossification in rabbits) at maternally toxic doses greater than those used clinically. When administered to rats throughout pregnancy and lactation, an increase in early postnatal mortality was observed at doses similar to those used clinically ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, miscarriage, or another adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Neonates exposed to fluoxetine, and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs and SNRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.6)] . Infants exposed to SSRIs, particularly later in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association. Data Human Data It has been shown that olanzapine and fluoxetine can cross the placenta. Placental passage of olanzapine has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown. Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for persistent pulmonary hypertension (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Olanzapine and Fluoxetine — Embryo-fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [approximately 2 and 1 times the maximum recommended human dose (MRHD) for olanzapine and fluoxetine: for olanzapine (12 mg) and fluoxetine (50 mg), respectively based on mg/m 2 body surface area], and 4 and 8 mg/kg/day (high-dose) [approximately 3 and 2 times the MRHD based on mg/m 2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-­dose) [approximately 6 and 2 times the MRHD based on mg/m 2 body surface area, respectively], and 8 and 8 mg/kg/day (high-dose) [approximately 13 and 3 times the MRHD based on mg/m 2 body surface area, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination. In a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (2 and 1 times the MRHD based on mg/m 2 body surface area, respectively). An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced body weight (approximately 8% in female) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (fluoxetine) mg/kg/day (less than the MRHD based on mg/m 2 body surface area). Among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose. Olanzapine — In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (15 and 49 times the daily oral MRHD of 12 mg based on mg/m 2 body surface area, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (15 times the daily oral MRHD based on mg/m 2 body surface area). Gestation was prolonged at 10 mg/kg/day (8 times the daily oral MRHD based on mg/m 2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (49 times the daily oral MRHD based on mg/m 2 body surface area). Fluoxetine — In embryo-fetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (2 and 6 times, respectively, the MRHD of 50 mg based on mg/m² body surface area) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (approximately 2 times the MRHD based on mg/m² body surface area) during gestation or 7.5 mg/kg/day (approximately 1 times the MRHD based on mg/m² body surface area) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (approximately equal to the MRHD based on mg/m² body surface area).

8 USE IN SPECIFIC POPULATIONS Pregnancy : SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability, tremor) in the neonate. Olanzapine may cause extrapyramidal symptoms and/or withdrawal symptoms in neonates with third trimester exposure (8.1) Pediatric Use : Safety and efficacy of olanzapine and fluoxetine capsules for the treatment of bipolar I depression in patients under 10 years of age have not been established. Safety and efficacy of olanzapine and fluoxetine capsules for treatment resistant depression in patients under 18 years of age have not been established ( 8.4 ) Hepatic Impairment : Use a lower or less frequent dose in patients with cirrhosis ( 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including olanzapine and fluoxetine capsules, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies and postmarketing reports of pregnant women exposed to olanzapine or fluoxetine have not established a drug-associated increased risk of major birth defects or miscarriage (see Data). Some studies in pregnant women exposed to fluoxetine have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). In animal studies, administration of the combination of olanzapine and fluoxetine during the period of organogenesis resulted in adverse effects on development (decreased fetal body weights in rats and rabbits and retarded skeletal ossification in rabbits) at maternally toxic doses greater than those used clinically. When administered to rats throughout pregnancy and lactation, an increase in early postnatal mortality was observed at doses similar to those used clinically ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, miscarriage, or another adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Neonates exposed to fluoxetine, and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs and SNRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.6)] . Infants exposed to SSRIs, particularly later in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association. Data Human Data It has been shown that olanzapine and fluoxetine can cross the placenta. Placental passage of olanzapine has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown. Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for persistent pulmonary hypertension (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Olanzapine and Fluoxetine — Embryo-fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [approximately 2 and 1 times the maximum recommended human dose (MRHD) for olanzapine and fluoxetine: for olanzapine (12 mg) and fluoxetine (50 mg), respectively based on mg/m 2 body surface area], and 4 and 8 mg/kg/day (high-dose) [approximately 3 and 2 times the MRHD based on mg/m 2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-­dose) [approximately 6 and 2 times the MRHD based on mg/m 2 body surface area, respectively], and 8 and 8 mg/kg/day (high-dose) [approximately 13 and 3 times the MRHD based on mg/m 2 body surface area, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination. In a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (2 and 1 times the MRHD based on mg/m 2 body surface area, respectively). An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced body weight (approximately 8% in female) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (fluoxetine) mg/kg/day (less than the MRHD based on mg/m 2 body surface area). Among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose. Olanzapine — In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (15 and 49 times the daily oral MRHD of 12 mg based on mg/m 2 body surface area, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (15 times the daily oral MRHD based on mg/m 2 body surface area). Gestation was prolonged at 10 mg/kg/day (8 times the daily oral MRHD based on mg/m 2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (49 times the daily oral MRHD based on mg/m 2 body surface area). Fluoxetine — In embryo-fetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (2 and 6 times, respectively, the MRHD of 50 mg based on mg/m² body surface area) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (approximately 2 times the MRHD based on mg/m² body surface area) during gestation or 7.5 mg/kg/day (approximately 1 times the MRHD based on mg/m² body surface area) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (approximately equal to the MRHD based on mg/m² body surface area). 8.2 Lactation Risk Summary Data from published literature report the presence of olanzapine, fluoxetine, and norfluoxetine in human milk (see Data). There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk and reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to fluoxetine through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine or fluoxetine and their metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and fluoxetine capsules and any potential adverse effects on the breastfed child from olanzapine and fluoxetine capsules or the underlying maternal condition. Clinical Considerations Infants exposed to olanzapine and fluoxetine capsules should be monitored for agitation, irritability, poor feeding, poor weight gain, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements). Data A study of nineteen nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL), whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (dopamine D 2 receptor blockade), treatment with SYMBYAX may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.22 )]. 8.4 Pediatric Use Olanzapine and Fluoxetine -The safety and efficacy of olanzapine and fluoxetine in patients 10 to 17 years of age has been established for the acute treatment of Depressive Episodes Associated with Bipolar I Disorder in a single 8-week randomized, placebo-controlled clinical trial (N = 255) [see Clinical Studies ( 14.1 )] . Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of olanzapine and fluoxetine in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day (lower than that for adults). Flexible dosing is recommended, rather than the forced titration used in the study [see Dosage and Administration ( 2.1 )] . The types of adverse events observed with olanzapine and fluoxetine in children and adolescents were generally similar to those observed in adults. However, the magnitude and frequency of some changes were greater in children and adolescents than adults. These included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the QT interval [see Warnings and Precautions ( 5.5 , 5.20 , 5.22 ), and Vital Signs and Laboratory Studies ( 6.1 )] . The frequency of weight gain ≥7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with olanzapine and fluoxetine were similar to those observed in adolescents treated with olanzapine monotherapy. The safety and efficacy of olanzapine and fluoxetine in combination for the treatment of bipolar I depression in patients under the age of 10 years have not been established. The safety and effectiveness of olanzapine and fluoxetine in combination for treatment resistant depression in patients less than 18 years of age have not been established. Anyone considering the use of olanzapine and fluoxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Olanzapine — Safety and effectiveness of olanzapine in children <13 years of age have not been established. Compared to patients from adult clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels. Juvenile Animal Toxicity Data Fluoxetine — Juvenile animal toxicity studies were performed for fluoxetine alone. Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m 2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. 8.5 Geriatric Use Olanzapine and Fluoxetine — Clinical studies of olanzapine and fluoxetine did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration ( 2.3 )] . Olanzapine — Of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥65 years of age. In patients with Schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with Schizophrenia. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient. Fluoxetine — U.S. fluoxetine clinical studies included 687 patients ≥65 years of age and 93 patients ≥75 years of age. 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. SNRIs and SSRIs, including olanzapine and fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.17 )] . 8.6 Hepatic Impairment In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of the fluoxetine-component of olanzapine and fluoxetine HCl should be used in patients with cirrhosis. Caution is advised when using olanzapine and fluoxetine HCl in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.4 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Olanzapine and fluoxetine capsules, USP are supplied in 3/25 mg, 6/25 mg, 6/50 mg, 12/25 mg, and 12/50 mg (mg equivalent olanzapine/mg equivalent fluoxetine a ) strengths. Olanzapine and Fluoxetine Capsules CAPSULE STRENGTH 3 mg/25 mg 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg Color white opaque body & orange opaque cap rich yellow opaque body and cap light grey opaque body & rich yellow opaque cap dark tan opaque body & red opaque cap light grey opaque body & red opaque cap Imprintings ‘277’ on body and ‘par’ on cap in black ink ‘par’ on body and ‘250’ on cap in black ink ‘251’ on body and ‘par’ on cap in black ink ‘252’ on body and ‘par’ on cap in black ink ‘253’ on body and ‘par’ on cap in black ink NDC Codes Bottle of 30 49884-277-11 49884-250-11 49884-251-11 49884-252-11 49884-253-11 a Fluoxetine base equivalent 16.2 Storage and Handling Store olanzapine and fluoxetine capsules at room temperature, between 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep container tightly closed and protect from moisture.

16.2 Storage and Handling Store olanzapine and fluoxetine capsules at room temperature, between 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep container tightly closed and protect from moisture.

WARNING WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Suicidal Thoughts and Behaviors — Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the healthcare provider. Olanzapine and Fluoxetine Capsules are not approved for use in children less than 10 years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine and Fluoxetine Capsules are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.2)] . W A RN I N G: SUICIDAL THOUGHTS AND BEHAVIORS and I NCR E A SE D MORTALITY IN ELDERLY PATIENTS WITH D E M E N T I A - R E L A T E D PSYCHOSIS S e e full prescribing information for complete boxed warning. • I ncreased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Olanzapine and Fluoxetine Capsules are not approved for use in children less than 10 years of age. Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1, 8.4). • El derly patients with dementia-related psychosis treated with a ntipsychotic drugs are at an increased risk of death. Olanzapine and Fluoxetine Capsules are not approved for the treatment of patients with dementia-related psychosis (5.2).