Data from FDA - Curated by EPG Health - Last updated 01 April 2018

Indication(s)

1 INDICATIONS AND USAGE Olanzapine and Fluoxetine is 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)

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Advisory information

contraindications
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.
Adverse reactions
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)] Hyperprolactinemia [see Warnings and Precautions (5.22)] Discontinuation Adverse Reactions [see Warnings and Precautions (5.25)] 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, physicians 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: death1. 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, pruritis; Rare: exfoliative dermatitis. Special Senses — Frequent: taste perversion; Infrequent: abnormality of accommodation, dry eyes. Urogenital System — Frequent: breast pain, menorrhagia2, urinary frequency, urinary incontinence; Infrequent: amenorrhea2, female lactation2, hypomenorrhea2, metrorrhagia2, urinary retention, urinary urgency, urination impaired; Rare: breast engorgement2. 1This term represents a serious adverse event but does not meet the definition for adverse drug reactions. It is included here because of its seriousness. 2Adjusted for gender. Other Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy The following adverse reactions were not observed in olanzapine and fluoxetine HCl -treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: aplastic anemia, bruxism, cholestatic jaundice, diabetic coma, dyskinesia, eosinophilic pneumonia 3, erythema multiforme, espohgeal ulcer, gynecological bleeding, headache, hypotension, jaundice, neutropenia, restless legs syndrome, sudden unexpected death3, sweating, and violent behaviors3. Random triglyceride levels of ≥1000 mg/dL have been reported. 3These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 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 aIncludes somnolence, sedation, and hypersomnia. No lethargy was reported. bIncludes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, gamma-glutamyltransferase increased, and transaminases increased. 6.2 Vital Signs and Laboratory Studies Adults: Vital Signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in olanzapine and fluoxetine HCl -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 QTCF≥450 msec for males and QTcF≥470 msec for females has been reported frequently (≥1%). The incidence of QTCF>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 QTC 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 dymenorrhoea, galactorrhoea, and ovulation disorder. QT Interval Prolongation – Olanzapine and Fluoxetine was associated with a statistically significant greater mean increase in QTcF interval (8.2 msec [95% CI 6.2, 10.2]) compared with placebo. No patients developed QTc increases ≥60 msec or QTc ≥480 msec [see Warnings and Precautions ( 5.20) ]. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of olanzapine and fluoxetine HCl. 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 HCl therapy include the following: rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis).

Usage information

Dosing and administration
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 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 Warnings and Precautions (5.21), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3, 12.4)]. Treatment of Pregnant Women — When treating pregnant women with fluoxetine, a component of olanzapine and fluoxetine, during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalizations, respiratory support, and tube feeding. The physician may consider tapering the dose of fluoxetine in the third trimester [see Use in Specific Populations (8.1)]. 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 1mg/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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Olanzapine and fluoxetine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1) Nursing Mothers: Breast feeding is not recommended (8.3) 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 Category C Risk Summary There are no adequate and well-controlled clinical studies with olanzapine and fluoxetine or its components (olanzapine and fluoxetine) in pregnant women. A number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine, and other SSRIs and SNRIs late in the third trimester have developed complications arising immediately upon delivery (respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying) requiring prolonged hospitalization, respiratory support, and tube feeding. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture is consistent with serotonin syndrome. Neonates exposed to olanzapine, a component of olanzapine and fluoxetine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). Olanzapine and Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, taking into account the risk of untreated Bipolar I Depression or Treatment Resistant Depression. Human Data There are no adequate and well-controlled clinical studies with olanzapine and fluoxetine, olanzapine or fluoxetine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine capsules, and other SSRIs or serotonin and norepinephrine reuptake inhibitors (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 features 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 Dosage and Administration (2.3) and Warnings and Precautions (5.6)]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 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. Neonates exposed to antipsychotic drugs (including olanzapine, a component of olanzapine and fluoxetine) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with olanzapine and fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [see Dosage and Administration (2.3)]. Olanzapine and Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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) [1 and 0.5 times the maximum recommended human dose (MRHD) for olanzapine (20 mg) and fluoxetine (80 mg), respectively on a mg/m2 body surface area], and 4 and 8 mg/kg/day (high-dose) [2 and 1 times the MRHD on a mg/m2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [4 and 1 times the MRHD on a mg/m2 basis, respectively], and 8 and 8 mg/kg/day (high-dose) [9 and 2 times the MRHD on a mg/m2 basis, 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 (1 and 0.5 times the MRHD on a mg/m2 body surface area. An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced bodyweight (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 (0.25 and 0.13 times the MRHD on a mg/m2 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 embryo-fetal studies in rats and rabbits, there was no evidence of teratogenicity following administration of olanzapine at doses up to 18 and 30 mg/kg/day, respectively (9 and 30 times the MRHD on a mg/m2 basis, respectively). In a rat teratology study, early resorptions and increased numbers of dead fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m2 basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m2 basis). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Placental transfer of olanzapine occurs in rat pups. Fluoxetine — In oral embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg/day on a mg/m2 basis) 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 (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) 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 (0.6 times the MRHD on a mg/m2 basis). 8.2 Labor and Delivery Olanzapine and Fluoxetine HCl — The effect of olanzapine and fluoxetine HCl on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine and fluoxetine HCl. Olanzapine and fluoxetine HCl should be used during labor and delivery only if the potential benefit justifies the potential risk. Olanzapine — The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine. Fluoxetine — The effect of fluoxetine on labor and delivery in humans is unknown. Fluoxetine crosses the placenta; therefore, there is a possibility that fluoxetine may be associated with adverse effects on the newborn. 8.3 Nursing Mothers Olanzapine and Fluoxetine HCl — Studies evaluating the individual components of olanzapine and fluoxetine HCl in nursing mothers are described below. Because of the potential for serious adverse reactions in nursing infants from olanzapine and fluoxetine HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women not breast-feed when receiving olanzapine and fluoxetine HCl. Olanzapine — In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed. Fluoxetine — Fluoxetine is excreted in human breast milk. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208/mL of norfluoxetine on the 2nd day of feeding. 8.4 Pediatric Use 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 (6.2)]. 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 under 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. Animal 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 20mg/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/m2 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 HCl 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 patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with Schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. 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. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Dosage and Administration (2.3), 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 HCl, 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)].
Pregnancy and lactation
8.3 Nursing Mothers Olanzapine and Fluoxetine HCl — Studies evaluating the individual components of olanzapine and fluoxetine HCl in nursing mothers are described below. Because of the potential for serious adverse reactions in nursing infants from olanzapine and fluoxetine HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women not breast-feed when receiving olanzapine and fluoxetine HCl. Olanzapine — In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed. Fluoxetine — Fluoxetine is excreted in human breast milk. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208/mL of norfluoxetine on the 2nd day of feeding.

Interactions

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 has 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 Cmax 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 QTc prolongation. While a specific study with pimozide and olanzapine and fluoxetine have not been conducted, the potential for drug interactions or QTc 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 QTc 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)].

More information

Category Value
Authorisation number ANDA077742
Agency product number I9W7N6B1KJ
Orphan designation No
Product NDC 49884-277,49884-250,49884-251,49884-252,49884-253
Date Last Revised 28-03-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 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. * Zyprexa®, Zyprexa® Zydis®, Prozac®, Prozac® Weekly™, and Sarafem® are registered trademarks of Eli Lilly and Company. .
Marketing authorisation holder Par Pharmaceutical, Inc.
Warnings WARNING WARNINGS: 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 prescriber. 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), and Patient Counseling Information (17.2)]. 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)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants.Olanzapine and Fluoxetine Hydrochloride are not approved for use in children less than 10 years of age. (5.1, 8.4, 17.2). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1, 17.2). Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine and Fluoxetine Hydrochloride is not approved for the treatment of patients with dementia-related psychosis (5.2, 5.21, 17.3).