Olanzapine and Fluoxetine

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 combines 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 )

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 capsules have not been studied. Make dosage adjustments, 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 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 have 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 in 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 capsules (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. Olanzapine and fluoxetine capsules have 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 Monoamine 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 capsules. Conversely, at least 5 weeks should be allowed after stopping olanzapine and fluoxetine capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)] . 2.5 Use of Olanzapine and Fluoxetine Capsules with Other MAOIs su…

5 WARNINGS AND PRECAUTIONS Neuroleptic Malignant Syndrome : Manage with immediate discontinuation and close monitoring ( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue if DRESS is suspected ( 5.4 ) Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) H y perg lycemia and Diabetes Mellitus : In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death. Monitor for symptoms of hyperglycemia. Perform fasting blood glucose testing before beginning, and periodically during treatment. ( 5.5 ) D ys l ipidemia : Appropriate clinical monitoring is recommended, including fasting blood lipid testing before beginning, and periodically during, treatment ( 5.5 ) W e ight Gain : Consider potential consequences of weight gain. Monitor weight regularly ( 5.5 ) Serotonin Syndrome : Serotonin syndrome has been reported with SSRIs and SNRIs, including olanzapine and fluoxetine capsules, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue olanzapine and fluoxetine capsules and serotonergic agents and initiate supportive treatment. If concomitant use of olanzapine and fluoxetine capsules with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.6). Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.7) Allergic Reactions and Rash : Discontinue upon appearance of rash or allergic phenomena (5.8) Activation of Mania/Hypomania : Screen for Bipolar Disorder and monitor for activation of mania/hypomania (5.9) Tardive Dyskinesia : Discontinue if clinically appropriate (5.10) Orthostatic Hypotension : Can be associated with bradycardia and syncope. Risk is increased during initial dose titration. Use caution in patients with cardiovascular disease or cerebrovascular disease, and those conditions that could affect hemodynamic responses (5.11) Leukopenia, Neutropenia, and Agranulocytosis : Has been reported with antipsychotics, including olanzapine and fluoxetine capsules. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Consider discontinuing olanzapine and fluoxetine capsules at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.13) Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.15) Increased Risk of Bleeding : SSRIs increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.16) Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing olanzapine and fluoxetine capsules if symptomatic hyponatremia occurs (SIADH) (5.17) Potential for Cognitive and Motor Impairment : Has potential to impair judgment, thinking, and motor skills. Caution patients about operating machinery (5.18) QT Prolongation : QT prolongation and ventricular arrhythmia including Torsade de Pointes have been reported with fluoxetine. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.20) Anticholinergic (antimuscarinic) Effects : Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, history of paralytic ileus or related conditions (5.21) Hyperprolactinemia : May…

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) P imozide : Do not use. Risk of QT interval 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 capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules is contraindicated because of an increased risk of serotonin syndrome. The use of olanzapine and fluoxetine capsules 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 capsules 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) and Warnings and Precautions (5.6)] . 4.2 Other Contraindications 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 thioridazine prolong the QT interval. Olanzapine and fluoxetine capsules can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Olanzapine and fluoxetine capsules can also prolong the QT interval.

7 DRUG INTERACTIONS The risks of using olanzapine and fluoxetine capsules 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 capsules. 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 capsules or when olanzapine and fluoxetine capsules have been recently discontinued (5.6, 7.7) CN S Acting Drugs : Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules and other CNS-active drugs is required (7.2) A n t ihypertensive Agent : Enhanced antihypertensive effect (7.7) Le v odopa and Dopa m ine Agonists : May antagonize levodopa/dopamine agonists (7.7) B e n z od iazepines : May potentiate orthostatic hypotension and sedation (7.6, 7.7) C lozapine : May elevate clozapine levels (7.7) Ha loperidol : Elevated haloperidol levels have been observed (7.7) Carba m a z ep ine : Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity (7.7) P hen yt o in : Potential for elevated phenytoin levels and clinical anticonvulsant toxicity (7.7) A lcohol : May potentiate sedation and orthostatic hypotension (7.7) S ero t onerg ic 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 capsules should be considered (7.6) Drugs t hat 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 t hat 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), and Warnings and Precautions (5.6)]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules 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 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with olanzapine and fluoxetine capsules increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of olanzapine and fluoxetine and/or concomitant serotonergic drugs [see Warnings and Precautions (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 …

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 Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.16) and 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). 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. Maternal Adverse Reactions Use of olanzapine and fluoxetine capsules in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.16)]. 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 va…

8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (dopamine D 2 receptor blockade), treatment with olanzapine and fluoxetine capsules 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)].

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.2)] Neuroleptic Malignant syndrome (NMS) [see Warnings and Precautions (5.3)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)] Hyperglycemia [see Warnings and Precautions (5.5)] Dyslipidemia [see Warnings and Precautions (5.5)] Weight Gain [see Warnings and Precautions (5.5)] Serotonin Syndrome [see Warnings and Precautions (5.6)] Angle-Closure Glaucoma [see Warnings and Precautions (5.7)] Allergic Reactions and Rash [see Warnings and Precautions (5.8)] Activation of Mania/Hypomania [see Warnings and Precautions (5.9)] Tardive Dyskinesia [see Warnings and Precautions (5.10)] Orthostatic Hypotension [see Warnings and Precautions (5.11)] Falls [see Warnings and Precautions (5.12)] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.13)] Dysphagia [see Warnings and Precautions (5.14)] Seizures [see Warnings and Precautions (5.15)] Increased Risk of Bleeding [see Warnings and Precautions (5.16)] Hyponatremia [see Warnings and Precautions (5.17)] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.18)] Body Temperature Dysregulation [see Warnings and Precautions (5.19)] QT Prolongation [see Warnings and Precautions (5.20)] Anticholinergic (antimuscarinic) Effects [see Warnings and Precautions (5.21)] Hyperprolactinemia [see Warnings and Precautions (5.22)] Discontinuation Adverse Reactions [see Warnings and Precautions (5.25)] Sexual Dysfunction [see Warnings and Precautions (5.26)] Most common adverse reactions (≥5% and at least twice that for placebo) in adults: sedation, weight increased, appetite increased, dry mouth, fatigue, edema, tremor, disturbance in attention, blurred vision. Children and adolescents: sedation, weight increased, appetite increased, tremor, triglyceride increased, hepatic enzymes increased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo 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 capsules consisting of 2547 patients with treatment resistant depression, depressive episodes associated with Bipolar I Disorder, Major Depressive Disorder with psychosis, or sexual dysfunction with approximately 1085 patient-years of exposure. The conditions and duration of treatment with olanzapine and fluoxetine capsules varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or long-term exposure. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Controlled Studies Including Depressive Episodes Associated with Bipolar I Disorder and Treatment Resistant Depression - Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine capsules group discontinued due to adverse reactions compared with 4.4% of the 477 patients for placebo. Adverse reactions leading to discontinuation associated with the …