WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. When using olanzapine and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. oElderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). (5.1)oSuicide: The possibility of suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax. (5.2)oNeuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected. (5.4)oMetabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. (5.5)oHyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.5) oDyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5) oWeight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.5) oTardive Dyskinesia: Discontinue if clinically appropriate. (5.6)oOrthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses. (5.7)oLeukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine orally disintegrating tablets. Patients with history of 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 and discontinuation of olanzapine orally disintegrating tablets should be considered at the first sign of clinically significant decline in WBC in the absence of other causative factors. (5.9)oSeizures: Use cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold. (5.11)oPotential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. (5.12)oAnticholinergic (Antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. (5.14)oHyperprolactinemia: May elevate prolactin levels. (5.15)oUse in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate. (5.16)oLaboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. (5.17) oElderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). (5.1). oSuicide: The possibility of suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax. (5.2). oNeuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3). oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected. (5.4). oMetabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. (5.5)oHyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.5) oDyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5) oWeight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.5) oHyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.5) oDyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5) oWeight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.5) oTardive Dyskinesia: Discontinue if clinically appropriate. (5.6). oOrthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses. (5.7). oLeukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine orally disintegrating tablets. Patients with history of 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 and discontinuation of olanzapine orally disintegrating tablets should be considered at the first sign of clinically significant decline in WBC in the absence of other causative factors. (5.9). oSeizures: Use cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold. (5.11). oPotential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. (5.12). oAnticholinergic (Antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. (5.14). oHyperprolactinemia: May elevate prolactin levels. (5.15). oUse in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate. (5.16). oLaboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. (5.17) 5.1 Elderly Patients with Dementia-Related Psychosis. Increased Mortality. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine orally disintegrating tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)]. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively). Cerebrovascular Adverse Events (CVAE), Including Stroke. Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was significantly higher incidence of cerebrovascular adverse events 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 and Patient Counseling Information (17)]. 5.2 Suicide. The possibility of suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.3 Neuroleptic Malignant Syndrome (NMS). potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.The diagnostic evaluation of patients with this syndrome is complicated. In arriving at diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17)]. 5.4Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected [see Patient Counseling Information (17)].. 5.5 Metabolic Changes. Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapines specific metabolic profile is presented below.. Hyperglycemia and Diabetes Mellitus. Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17)]. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on continuum and olanzapine appears to have greater association than some other atypical antipsychotics. Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the highest serum concentrations was 15.0 mg/dL. In study of healthy volunteers, subjects who received olanzapine (N 22) for weeks had mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N 19) had mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL. Olanzapine Monotherapy in Adults. In an analysis of placebo-controlled adult olanzapine monotherapy studies with median treatment duration of approximately weeks, olanzapine was associated with greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with baseline random glucose level >= 200 mg/dL, and/or baseline fasting glucose level >= 126 mg/dL). Olanzapine-treated patients had greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days). In an analysis of placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N 855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N 599). Table shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies. Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy StudiesUp to 12 weeks exposureAt least 48 weeks exposureLaboratory AnalyteCategory Change (at least once) from BaselineTreatmentArmNPatientsNPatientsFasting GlucoseNormal to High (< 100 mg/dL to >= 126 mg/dL)Olanzapine5432.2%34512.8%Placebo2933.4%NULLNot Applicable. NULL Borderline to High (>= 100 mg/dL and 126 mg/dL to >= 126 mg/dL)Olanzapine17817.4%12726.0%Placebo9611.5%NULL NULL The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N 487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time. Olanzapine Monotherapy in Adolescents. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N 121). Table shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies. Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies Up to 12 weeks exposureAt least 24 weeks exposureLaboratory AnalyteCategory Change (at least once) from BaselineTreatmentArmNPatientsNPatientsFasting GlucoseNormal to High (< 100 mg/dL to >= 126 mg/dL)Olanzapine124 0% 108 0.9%Placebo53 1.9% NULLNot Applicable. NULL Borderline to High (>= 100 mg/dL and 126 mg/dL to >= 126 mg/dL)Olanzapine14 14.3% 13 23.1%Placebo13 0% NULL NULL Dyslipidemia. Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)]. Clinically significant, and sometimes very high (> 500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use. Olanzapine Monotherapy in Adults. In an analysis of placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL, respectively, compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels. In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months. The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table shows categorical changes in fasting lipids values.Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy StudiesUp to 12 weeks exposureAt least 48 weeks exposureLaboratory AnalyteCategory Change (at least once) from BaselineTreatmentArmNPatientsNPatientsFasting TriglyceridesIncrease by >= 50 mg/dLOlanzapine745 39.6% 487 61.4%Placebo 402 26.1% NULLNot Applicable. NULL Normal to High (< 150 mg/dL to >= 200 mg/dL)Olanzapine457 9.2% 293 32.4%Placebo251 4.4% NULL NULL Borderline to High (>= 150 mg/dL and 200 mg/dL to >= 200 mg/dL)Olanzapine135 39.3% 75 70.7%Placebo65 20.0% NULL NULL Fasting Total CholesterolIncrease by >= 40 mg/dLOlanzapine745 21.6% 489 32.9%Placebo 402 9.5% NULL NULL Normal to High(< 200 mg/dL to >= 240 mg/dL)Olanzapine392 2.8% 283 14.8%Placebo207 2.4% NULL NULL Borderline to High(>= 200 mg/dL and 240 mg/dL to >= 240 mg/dL)Olanzapine222 23.0% 125 55.2%Placebo112 12.5% NULL NULL Fasting LDL CholesterolIncrease by >= 30 mg/dLOlanzapine536 23.7% 483 39.8%Placebo 304 14.1% NULL NULL Normal to High(< 100 mg/dL to >= 160 mg/dL)Olanzapine154 0% 123 7.3%Placebo821.2% NULL NULL Borderline to High(>= 100 mg/dL and 160 mg/dL to >= 160 mg/dL)Olanzapine302 10.6% 284 31.0%Placebo173 8.1% NULL NULL In phase of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase of CATIE, the mean increase in total cholesterol was 9.4 mg/dL. Olanzapine Monotherapy in Adolescents. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents. In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table shows categorical changes in fasting lipids values in adolescents. Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies Up to weeks exposureAt least 24 weeks exposureLaboratory AnalyteCategory Change (at least once) from BaselineTreatmentArmNPatientsNPatientsFasting TriglyceridesIncrease by >= 50 mg/dLOlanzapine138 37.0% 122 45.9%Placebo 66 15.2% NULLNot Applicable. NULL Normal to High (< 90 mg/dL to 130 mg/dL)Olanzapine67 26.9% 66 36.4%Placebo28 10.7% NULL NULL Borderline to High (>= 90 mg/dL and <= 130 mg/dL to 130 mg/dL)Olanzapine37 59.5% 31 64.5%Placebo17 35.3% NULL NULL Fasting Total CholesterolIncrease by >= 40 mg/dLOlanzapine13814.5%12214.8%Placebo 664.5%NULL NULL Normal to High (< 170 mg/dL to >= 200 mg/dL)Olanzapine876.9%787.7%Placebo432.3%NULL NULL Borderline to High (>= 170 mg/dL and 200 mg/dL to >= 200 mg/dL)Olanzapine3638.9%3357.6%Placebo137.7%NULL NULL Fasting LDL CholesterolIncrease by >= 30 mg/dLOlanzapine137 17.5% 121 22.3%Placebo 63 11.1% NULL NULL Normal to High (< 110 mg/dL to >= 130 mg/dL)Olanzapine98 5.1% 92 10.9%Placebo44 4.5% NULL NULL Borderline to High (>= 110 mg/dL and 130 mg/dL to >= 130 mg/dL)Olanzapine29 48.3% 21 47.6%Placebo9 0% NULL NULL Weight Gain. Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information (17)]. Olanzapine Monotherapy in Adults. In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with median exposure of weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with median exposure to event of weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients. In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, = 2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure. Table includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Table 6: Weight Gain with Olanzapine Use in Adults Amount Gained kg (lb)6 Weeks (N 7465)(%)6 Months (N 4162)(%)12 Months(N 1345)(%)24 Months (N 474)(%)36 Months(N 147)(%)<= 026.224.320.823.217.00 to <= (0-11 lb)57.036.026.023.425.2> to <= 10 (11-22 lb)14.924.624.224.118.4> 10 to <= 15 (22-33 lb)1.810.914.911.417.0> 15 to <= 20 (33-44 lb)0.13.18.69.311.6> 20 to <= 25 (44-55 lb)00.93.35.14.1> 25 to <= 30 (55-66 lb)00.21.42.34.8> 30 (> 66 lb)00.10.81.22Dose group differences with respect to weight gain have been observed. In single 8-week randomized, double-blind, fixed-dose study comparing 10 (N 199), 20 (N 200) and 40 (N 200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: kg) was observed with significant differences between 10 vs 40 mg/day.. Olanzapine Monotherapy in Adolescents. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Mean increase in weight in adolescents was greater than in adults. In placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients. Table 7: Weight Gain with Olanzapine Use in Adolescents from Placebo-Controlled TrialsOlanzapine-treated patientsPlacebo-treated patientsMean change in body weight from baseline (median exposure 3 weeks)4.6 kg (10.1 lb)0.3 kg (0.7 lb)Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% 4 weeks)9.8% (median exposure to 7% 8 weeks)Percentage of patients who gained at least 15% of baseline body weight7.1% (median exposure to 15% 19 weeks)2.7% (median exposure to 15% 8 weeks)In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, = 179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N 106), overweight (N 26) and obese (N 17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.Table shows data on adolescent weight gain with olanzapine pooled from clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond months of treatment.Table 8: Weight Gain with Olanzapine Use in Adolescents Amount Gained kg (lb)6 Weeks(N 243)(%)6 Months(N 191)(%)<= 02.92.10 to <= (0-11 lb)47.324.6> to <= 10 (11-22 lb)42.426.7> 10 to <= 15 (22-33 lb)5.822.0> 15 to <= 20 (33-44 lb)0.812.6> 20 to <= 25 (44-55 lb)0.89.4> 25 to <= 30 (55-66 lb)02.1> 30 to <= 35 (66-77 lb)00> 35 to <= 40 (77-88 lb)00> 40 (> 88 lb)00.5 5.6 Tardive Dyskinesia. syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.Given these considerations, olanzapine should be prescribed in manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome. For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products. 5.7 Orthostatic Hypotension. Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its 1-adrenergic antagonistic properties [see Patient Counseling Information (17)]. From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in >= 20% (1277/6030) of patients.For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with mg QD [see Dosage and Administration (2)]. more gradual titration to the target dose should be considered if hypotension occurs. Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies. The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)]. 5.8Falls Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis. Class Effect. In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine orally disintegrating tablets. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with history of clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine orally disintegrating tablets should be considered at the first sign of clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count 1000/mm3) should discontinue olanzapine orally disintegrating tablets and have their WBC followed until recovery. 5.10 Dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is common cause of morbidity and mortality in patients with advanced Alzheimers disease. Olanzapine is not approved for the treatment of patients with Alzheimers disease. 5.11 Seizures. During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimers dementia. Olanzapine is not approved for the treatment of patients with Alzheimers disease. Conditions that lower the seizure threshold may be more prevalent in population of 65 years or older. 5.12 Potential for Cognitive and Motor Impairment. Somnolence was commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database. Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Patient Counseling Information (17)]. 5.13 Body Temperature Regulation. Disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17)]. 5.14 Anticholinergic (Antimuscarinic) Effects. Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology (12.2)]. In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1) ].. 5.15 Hyperprolactinemia. As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, factor of potential importance if the prescription of these drugs is contemplated in patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males). In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to weeks) with schizophrenia or bipolar disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)]. Based on search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.2 Based on search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.3 Based on search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.Dose group differences with respect to prolactin elevation have been observed. In single 8-week randomized, double-blind, fixed-dose study comparing 10 (N 199), 20 (N 200) and 40 (N 200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of 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%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.. 5.16 Use in Combination with Fluoxetine, Lithium, or Valproate. When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax. When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate [see Drug Interactions (7)]. 5.17 Laboratory Tests. Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.5) and Patient Counseling Information (17) ].

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. When using olanzapine and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (>= 5% and at least twice that for placebo) associated with:Oral Olanzapine Monotherapy:oSchizophrenia (Adults) postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia. (6.1)oSchizophrenia (Adolescents) sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth. (6.1)oManic or Mixed Episodes, Bipolar Disorder (Adults) asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor. (6.1)oManic or Mixed Episodes, Bipolar Disorder (Adolescents) sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity. (6.1) Combination of Olanzapine and Lithium or Valproate:oManic or Mixed Episodes, Bipolar Disorder (Adults) dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. (6.1) Olanzapine and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for Symbyax. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oSchizophrenia (Adults) postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia. (6.1). oSchizophrenia (Adolescents) sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth. (6.1). oManic or Mixed Episodes, Bipolar Disorder (Adults) asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor. (6.1). oManic or Mixed Episodes, Bipolar Disorder (Adolescents) sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity. (6.1) oManic or Mixed Episodes, Bipolar Disorder (Adults) dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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. Clinical Trials in Adults. The information below for olanzapine is derived from clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine plus 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimers disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimers disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011; and (6) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar disorder (manic or mixed episodes), or dementia. Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure.The conditions and duration of treatment with olanzapine 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 longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations. Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar disorder (manic or mixed episodes) and agitation. Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, treatment-emergent adverse reaction of the type listed. reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain complete understanding of the safety profile of olanzapine. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied. Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials. The following findings are based on premarketing trials of oral olanzapine for schizophrenia, bipolar disorder (manic or mixed episodes), subsequent trial of patients having various psychiatric symptoms in association with Alzheimers disease, and premarketing combination trials. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials. Schizophrenia: Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo). Bipolar Disorder (Manic or Mixed Episodes) Monotherapy: Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo). Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials. Bipolar Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate: In study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%).. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials. The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were: Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials SCHIZOPHRENIA Percentage of Patients Reporting EventAdverse ReactionOlanzapine(N 248)Placebo(N 118)Postural hypotension52Constipation93Weight gain61Dizziness114Personality disorderPersonality disorder is the COSTART term for designating nonaggressive objectionable behavior. 84Akathisia51Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials Bipolar Disorder (Manic or Mixed Episodes) Percentage of Patients Reporting EventAdverse ReactionOlanzapine(N 125)Placebo(N 129)Asthenia156Dry mouth227Constipation115Dyspepsia115Increased appetite63Somnolence3513Dizziness186Tremor63. Adverse Reactions Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses >= 2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials. Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine Percentage of Patients Reporting EventBody System/Adverse ReactionOlanzapine(N 532)Placebo(N 294)Body as WholeAccidental injury 128Asthenia109Fever62Back pain52Chest pain31Cardiovascular SystemPostural hypotension31Tachycardia31Hypertension21Digestive SystemDry mouth95Constipation94Dyspepsia75Vomiting43Increased appetite32Hemic and Lymphatic SystemEcchymosis53Metabolic and Nutritional DisordersWeight gain53Peripheral edema31Musculoskeletal SystemExtremity pain (other than joint)53Joint pain53Nervous SystemSomnolence2913Insomnia1211Dizziness114Abnormal gait61Tremor43Akathisia32Hypertonia32Articulation impairment21Respiratory SystemRhinitis 76Cough increased63Pharyngitis43Special SensesAmblyopia32Urogenital SystemUrinary incontinence21Urinary tract infection21. Dose Dependency of Adverse Reactions. dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In single 8-week randomized, double-blind, fixed-dose study comparing 10 (N 199), 20 (N 200) and 40 (N 200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions (5.5, 5.15)].The following table addresses dose relatedness for other adverse reactions using data from schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was trend. Table 12: Percentage of Patients from Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the Dose Range Groups and PlaceboAdverse ReactionPercentage of Patients Reporting EventPlacebo(N 68)Olanzapine5 +- 2.5 mg/day(N 65)Olanzapine10 +- 2.5 mg/day(N 64)Olanzapine15 +- 2.5 mg/day(N 69)Asthenia 158920Dry mouth 43513Nausea9029Somnolence16203039Tremor3057. Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate. In the bipolar disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of >= 5% and at least twice placebo) were:Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials Bipolar Disorder (Manic or Mixed Episodes) Percentage of Patients Reporting EventAdverse ReactionOlanzapine with lithium or valproate(N 229)Placebo with lithium or valproate(N 115)Dry mouth 329Weight gain267Increased appetite248Dizziness 147Back pain84Constipation84Speech disorder71Increased salivation62Amnesia52Paresthesia52. Adverse Reactions Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine as Adjunct to Lithium or Valproate. Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses >= mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials. Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate Percentage of Patients Reporting EventBody System/Adverse ReactionOlanzapine with lithium or valproate(N 229)Placebo with lithium or valproate(N 115)Body as Whole Asthenia 1813Back pain 84Accidental injury 42Chest pain 32Cardiovascular System Hypertension 21Digestive System Dry mouth 329Increased appetite 248Thirst 106Constipation 84Increased salivation 62Metabolic and Nutritional Disorders Weight gain 267Peripheral edema 64Edema 21Nervous System Somnolence 5227Tremor 2313Depression 1817Dizziness 147Speech disorder 71Amnesia 52Paresthesia 52Apathy 43Confusion 41Euphoria 32Incoordination 20Respiratory System Pharyngitis 41Dyspnea 31Skin and Appendages Sweating 31Acne 20Dry skin 20Special Senses Amblyopia 95Abnormal vision 20Urogenital System DysmenorrheaDenominator used was for females only (olanzapine, = 128; placebo, = 51). 20Vaginitis 20For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products. Extrapyramidal Symptoms. The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in controlled clinical trial comparing oral olanzapine at fixed doses with placebo in the treatment of schizophrenia in 6-week trial.Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia Acute PhasePercentage of Patients Reporting EventPlaceboOlanzapine +- 2.5 mg/dayOlanzapine 10 +- 2.5 mg/dayOlanzapine 15 +- 2.5 mg/dayParkinsonismPercentage of patients with Simpson-Angus Scale total score 3. 15141214AkathisiaPercentage of patients with Barnes Akathisia Scale global score >= 2. 23161927The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at fixed doses with placebo in the treatment of schizophrenia in 6-week trial. Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia Acute PhasePercentage of Patients Reporting EventPlacebo(N 68)Olanzapine +- 2.5 mg/day(N 65)Olanzapine 10 +- 2.5 mg/day(N 64)Olanzapine 15 +- 2.5 mg/day(N 69)Dystonic eventsPatients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. 1323Parkinsonism eventsPatients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. 1081420Akathisia eventsPatients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. 151110Dyskinetic eventsPatients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. 4021Residual eventsPatients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching. 1251Any extrapyramidal event16152532The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day). Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar Disorder AdolescentsCategoriesCategories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.Percentage of Patients Reporting EventPlacebo(N 89)Olanzapine(N 179)Dystonic events01Parkinsonism events21Akathisia events46Dyskinetic events01Nonspecific events04Any extrapyramidal event 610. Dystonia, Class Effect. 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 olanzapine use. Other Adverse Reactions. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine. Following is list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses >= mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which 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 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; rare reactions are those occurring in fewer than 1/1000 patients. Body as Whole: Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1 Cardiovascular System: Infrequent: cerebrovascular accident, vasodilatation.Digestive System: Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.Hemic and Lymphatic System: Infrequent: thrombocytopenia.Metabolic and Nutritional Disorders: Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.Musculoskeletal System: Rare: osteoporosis.Nervous System: Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.Respiratory System: Infrequent: epistaxis; Rare: lung edema. Skin and Appendages: Infrequent: alopecia. Special Senses: Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis. Urogenital System: Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired. These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. Adjusted for gender. Clinical Trials in Adolescent Patients (Age 13 to 17 Years). Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses >= 2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21. Table 21: Treatment-Emergent Adverse Reactions of >= 5% Incidence Among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar Disorder (Manic or Mixed Episodes)Adverse ReactionPercentage of Patients Reporting Event6 Week Trial Schizophrenia Patients3 Week Trial Bipolar PatientsOlanzapine(N 72)Placebo (N 35)Olanzapine(N 107)Placebo(N 54)SedationPatients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. 399489Weight increased319294Headache1761717Increased appetite179294Dizziness8372Abdominal painPatients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper. 6367Pain in extremity6350Fatigue33146Dry mouth 4070 Adverse Reactions Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term (3-6 Weeks), Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses >= 2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22. Table 22: Treatment-Emergent Adverse Reactions of >= 2% Incidence Among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar Disorder [Manic or Mixed Episodes])Adverse ReactionPercentage of Patients Reporting EventOlanzapine(N 179)Placebo(N 89)SedationPatients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. 449Weight increased 306Increased appetite 246Headache1712Fatigue 94Dizziness 72Dry mouth 60Pain in extremity 51Constipation 40Nasopharyngitis 42Diarrhea 30Restlessness 32Liver enzymes increasedThe terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes. 81Dyspepsia 31Epistaxis 30Respiratory tract infectionPatients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection. 32Sinusitis 30Arthralgia 20Musculoskeletal stiffness 20. Vital Signs and Laboratory Studies. Vital Sign Changes. Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials [see Warnings and Precautions (5)]. Laboratory Changes. Olanzapine Monotherapy in Adults. An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT <= 90 IU/L, the incidence of ALT elevations to 200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued. In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from 3 times the upper limit of normal [ULN] at baseline to >= times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations >= times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hys Rule.From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in >= 1% (88/5245) of patients.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. Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions (5.15)], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK. From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in >= 3% (171/4641) of patients.. Olanzapine Monotherapy in Adolescents. In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (>= times ULN in patients with ALT at baseline 3 times ULN), (12% vs 2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT (10% vs 1%); and elevated prolactin (47% vs 7%). In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from 3 times ULN at baseline to >= times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations >= times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hys Rule.. ECG Changes. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapines potential for inducing orthostatic changes [see Warnings and Precautions (5.7)]. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily from population of uncertain size, it is difficult to reliably estimate their frequency or evaluate causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering1, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of >= 240 mg/dL and random triglyceride levels of >= 1000 mg/dL have been reported. Stuttering was only studied in oral and long acting injection (LAI) formulations.

LACTATION SECTION.


8.2 Lactation. Risk Summary. Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mothers underlying condition.. Clinical Considerations. Infants exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.


13.2 Animal Toxicology and/or Pharmacology. In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m2 body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to times the daily oral MRHD based on mg/m2 body surface area) in studies of months duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m2 body surface area) for months or 16 mg/kg (8 times the daily oral MRHD based on mg/m2 body surface area) for or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

BOXED WARNING SECTION.


WARNING: 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. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Olanzapine orally disintegrating tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1), Use in Specific Populations (8.5), and Patient Counseling Information (17)]. When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSISSee full prescribing information for complete boxed warningoElderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine orally disintegrating tablets are not approved for the treatment of patients with dementia-related psychosis. (5.1, 8.5, 17) When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax(R).. oElderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine orally disintegrating tablets are not approved for the treatment of patients with dementia-related psychosis. (5.1, 8.5, 17) When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax(R).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m2 body surface area) and 0.25, 2, mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m2 body surface area). Rats were dosed for years at doses of 0.25, 1, 2.5, mg/kg/day (males) and 0.25, 1, 4, mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in mouse study in female mice at times the daily oral MRHD based on mg/m2 body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m2 body surface area; in this study, there was high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at >= mg/kg/day and in female rats dosed at >= mg/kg/day (0.5 and times the daily oral MRHD based on mg/m2 body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.15)]. Mutagenesis. No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNULL synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Impairment of Fertility. In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at dose of 22.4 mg/kg/day and female fertility was decreased at dose of mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at mg/kg/day (2.5 times the daily oral MRHD based on mg/m2 body surface area). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m2 body surface area); therefore olanzapine may produce delay in ovulation.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through combination of dopamine and serotonin type (5HT2) antagonism. 12.2 Pharmacodynamics. Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki 4, 11, and nM, respectively), dopamine D1-4 (Ki 11-31 nM), histamine H1 (Ki 7 nM), and adrenergic receptors (Ki 19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki 57 nM) and muscarinic M1-5 (Ki 73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD, and -adrenergic receptors (Ki 10 uM). 12.3 Pharmacokinetics. Oral Administration, Monotherapy. Olanzapine is well absorbed and reaches peak concentrations in approximately hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that olanzapine tablet and olanzapine orally disintegrating tablet dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady state concentrations in about week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age. Olanzapine is extensively distributed throughout the body, with volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of to 1100 ng/mL, binding primarily to albumin and 1-acid glycoprotein. Metabolism and Elimination. Following single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. Specific Populations. Renal Impairment. Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied. Hepatic Impairment. Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, study of the effect of impaired liver function in subjects (n 6) with clinically significant (Childs Pugh Classification and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine. Geriatric. In study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (>= 65 years) than in nonelderly subjects (< 65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2)]. Gender. Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. Smoking Status. Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended. Race. In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended. Combined Effects. The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit combination of factors that may result in slower metabolism of olanzapine [see Dosage and Administration (2)]. Adolescents (Ages 13 to 17 Years). In clinical studies, most adolescents were nonsmokers and this population had lower average body weight, which resulted in higher average olanzapine exposure compared to adults.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 14.1 Schizophrenia. Adults. The efficacy of oral olanzapine in the treatment of schizophrenia was established in short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. single haloperidol arm was included as comparative treatment in of the trials, but this trial did not compare these drugs on the full range of clinically relevant doses for both. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), multi-text inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered particularly useful subset for assessing actively psychotic schizophrenic patients. second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, more recently developed scales were employed; these included the 30-text Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 texts of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow: (1)In 6-week, placebo-controlled trial (n 149) involving fixed olanzapine doses of and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity. (2)In 6-week, placebo-controlled trial (n 253) involving fixed-dose ranges of olanzapine (5 +- 2.5 mg/day, 10 +- 2.5 mg/day, and 15 +- 2.5 mg/day) on once daily schedule, the highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group. (3)In longer-term trial, adult outpatients (n 326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately weeks and followed for an observation period of up to months. Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings. (1)In 6-week, placebo-controlled trial (n 149) involving fixed olanzapine doses of and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity. (2)In 6-week, placebo-controlled trial (n 253) involving fixed-dose ranges of olanzapine (5 +- 2.5 mg/day, 10 +- 2.5 mg/day, and 15 +- 2.5 mg/day) on once daily schedule, the highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group. (3)In longer-term trial, adult outpatients (n 326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately weeks and followed for an observation period of up to months. Adolescents. The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n 107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group.While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.. 14.2 Bipolar Disorder (Manic or Mixed Episodes). Adults. Monotherapy. The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without rapid-cycling course. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-text clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in range from (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow: (1)In one 3-week placebo-controlled trial (n 67) which involved dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome. (2)In 4-week placebo-controlled trial (n 115) which involved dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. (3)In another trial, 361 patients meeting DSM-IV criteria for manic or mixed episode of bipolar disorder who had responded during an initial open-label treatment phase for about weeks, on average, to olanzapine 5-20 mg/day were randomized to either continuation of olanzapine at their same dose (n 225) or to placebo (n 136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having decrease of the Y-MRS total score to <= 12 and HAM-D 21 to <= 8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to >= 15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced significantly longer time to relapse. (1)In one 3-week placebo-controlled trial (n 67) which involved dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome. (2)In 4-week placebo-controlled trial (n 115) which involved dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. (3)In another trial, 361 patients meeting DSM-IV criteria for manic or mixed episode of bipolar disorder who had responded during an initial open-label treatment phase for about weeks, on average, to olanzapine 5-20 mg/day were randomized to either continuation of olanzapine at their same dose (n 225) or to placebo (n 136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having decrease of the Y-MRS total score to <= 12 and HAM-D 21 to <= 8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to >= 15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced significantly longer time to relapse. Adjunct to Lithium or Valproate. The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in controlled trials in patients who met the DSM-IV criteria for bipolar disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without rapid-cycling course. The results of the trials follow: (1)In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >= 16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.(2)In second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >= 16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score. (1)In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >= 16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.. (2)In second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >= 16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score. Adolescents. Acute Monotherapy. The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar disorder (with or without psychotic features) according to the DSM-IV-TR (n 161). Diagnosis was confirmed by the K-SADS-PL.The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. oNone with olanzapine monotherapy.oWhen using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.oFor specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.. oNone with olanzapine monotherapy.. oWhen using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.. oFor specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.. oNone with olanzapine monotherapy.oWhen using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax(R). (4)oWhen using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. (4). oNone with olanzapine monotherapy.. oWhen using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax(R). (4). oWhen using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. (4).

DEPENDENCE SECTION.


9.3 Dependence. In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to times the daily oral MRHD based on mg/m2 body surface area. Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through combination of dopamine and serotonin type (5HT2) antagonism.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m2 body surface area) and 0.25, 2, mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m2 body surface area). Rats were dosed for years at doses of 0.25, 1, 2.5, mg/kg/day (males) and 0.25, 1, 4, mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m2 body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in mouse study in female mice at times the daily oral MRHD based on mg/m2 body surface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m2 body surface area; in this study, there was high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at >= mg/kg/day and in female rats dosed at >= mg/kg/day (0.5 and times the daily oral MRHD based on mg/m2 body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.15)]. Mutagenesis. No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNULL synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Impairment of Fertility. In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at dose of 22.4 mg/kg/day and female fertility was decreased at dose of mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at mg/kg/day (2.5 times the daily oral MRHD based on mg/m2 body surface area). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m2 body surface area); therefore olanzapine may produce delay in ovulation.. 13.2 Animal Toxicology and/or Pharmacology. In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m2 body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to times the daily oral MRHD based on mg/m2 body surface area) in studies of months duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the daily oral MRHD based on mg/m2 body surface area) for months or 16 mg/kg (8 times the daily oral MRHD based on mg/m2 body surface area) for or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

DESCRIPTION SECTION.


11 DESCRIPTION. Olanzapine orally disintegrating tablets, USP are an atypical antipsychotic that belong to the thienobenzodiazepine class. The chemical designation is 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine. The molecular formula is C17H20N4S, which corresponds to molecular weight of 312.44. The chemical structure is: Olanzapine, USP is yellow crystalline solid, which is practically insoluble in water. Olanzapine orally disintegrating tablets are intended for oral administration only. Each orally disintegrating tablet contains olanzapine equivalent to mg (16 umol), 10 mg (32 umol), 15 mg (48 umol) or 20 mg (64 umol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. Olanzapine orally disintegrating tablets also contain the following inactive ingredients: aspartame, colloidal silicon dioxide, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose and sodium lauryl sulfate. Meets USP Disintegration Test 2.. Olanzapine Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Schizophrenia in adults (2.1)Oral: Start at 5-10 mg once daily; Target: 10 mg/day within several daysSchizophrenia in adolescents (2.1)Oral: Start at 2.5-5 mg once daily; Target: 10 mg/dayBipolar Disorder (manic or mixed episodes) in adults (2.2)Oral: Start at 10 or 15 mg once dailyBipolar Disorder (manic or mixed episodes) in adolescents (2.2)Oral: Start at 2.5-5 mg once daily; Target: 10 mg/dayBipolar Disorder (manic or mixed episodes) with lithium or valproate in adults (2.2)Oral: Start at 10 mg once dailyDepressive Episodes associated with Bipolar Disorder in adults (2.5)Oral in combination with fluoxetine: Start at mg of oral olanzapine and 20 mg of fluoxetine once dailyDepressive Episodes associated with Bipolar Disorder in children and adolescents (2.5)Oral in combination with fluoxetine: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once dailyTreatment Resistant Depression in adults (2.6)Oral in combination with fluoxetine: Start at mg of oral olanzapine and 20 mg of fluoxetine once dailyoLower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. (2.1)oOlanzapine may be given without regard to meals. (2.1) Olanzapine and Fluoxetine in Combination:oDosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (2.5, 2.6)oOlanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar disorder or treatment resistant depression. (2.5, 2.6)oSafety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. (2.5, 2.6)oSafety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17. (2.5). oLower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. (2.1). oOlanzapine may be given without regard to meals. (2.1) oDosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (2.5, 2.6). oOlanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar disorder or treatment resistant depression. (2.5, 2.6). oSafety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. (2.5, 2.6). oSafety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17. (2.5). 2.1 Schizophrenia. Adults. Dose Selection. Oral olanzapine should be administered on once-a-day schedule without regard to meals, generally beginning with to 10 mg initially, with target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than week, since steady state for olanzapine would not be achieved for approximately week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of mg QD are recommended. Efficacy in schizophrenia was demonstrated in dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to dose greater than the target dose of 10 mg/day (i.e., to dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day. Dosing in Special Populations. The recommended starting dose is mg in patients who are debilitated, who have predisposition to hypotensive reactions, who otherwise exhibit combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients >= 65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7) and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients. Maintenance Treatment. The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine orally disintegrating tablets for approximately weeks and were then followed for relapse has been demonstrated in placebo-controlled trial [see Clinical Studies (14.1)]. The healthcare provider who elects to use olanzapine orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.. Adolescents. Dose Selection. Oral olanzapine should be administered on once-a-day schedule without regard to meals with recommended starting dose of 2.5 or mg, with target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on flexible dose range of 2.5 to 20 mg/day in clinical trials, with mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or mg are recommended. The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.1)].. Maintenance Treatment. The efficacy of olanzapine orally disintegrating tablets for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.. 2.2 Bipolar Disorder (Manic or Mixed Episodes). Adults. Dose Selection for Monotherapy. Oral olanzapine should be administered on once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of mg QD are recommended. Short-term (3-4 weeks) antimanic efficacy was demonstrated in dose range of mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)]. Maintenance Monotherapy. The benefit of maintaining bipolar patients on monotherapy with oral olanzapine at dose of to 20 mg/day, after achieving responder status for an average duration of weeks, was demonstrated in controlled trial [see Clinical Studies (14.2)]. The healthcare provider who elects to use olanzapine orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Dose Selection for Adjunctive Treatment. When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals. Antimanic efficacy was demonstrated in dose range of mg to 20 mg/day in clinical trials [see Clinical Studies (14.2)]. The safety of doses above 20 mg/day has not been evaluated in clinical trials.. Adolescents. Dose Selection. Oral olanzapine should be administered on once-a-day schedule without regard to meals with recommended starting dose of 2.5 or mg, with target dose of 10 mg/day. Efficacy in adolescents with bipolar disorder (manic or mixed episodes) was demonstrated based on flexible dose range of 2.5 to 20 mg/day in clinical trials, with mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or mg are recommended.The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.2)].. Maintenance Treatment. The efficacy of olanzapine orally disintegrating tablets for the maintenance treatment of bipolar disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.. 2.3 Administration of Olanzapine Orally Disintegrating Tablets. Immediately upon opening the bottle, using dry hands, remove tablet and place entire olanzapine orally disintegrating tablet in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.. 2.5Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar Disorder When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults. Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with dose range of olanzapine to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.. Children and Adolescents (10-17 Years of Age). Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.Table 1: Approximate Dose Correspondence Between SymbyaxSymbyax (olanzapine/fluoxetine HCl) is fixed-dose combination of olanzapine and fluoxetine. and the Combination of Olanzapine and FluoxetineForSymbyax(mg/day)Use in CombinationOlanzapine(mg/day)Fluoxetine(mg/day)3 mg olanzapine/25 mg fluoxetine2.5206 mg olanzapine/25 mg fluoxetine52012 mg olanzapine/25 mg fluoxetine10 2.5206 mg olanzapine/50 mg fluoxetine540 1012 mg olanzapine/50 mg fluoxetine10 2.540 10While there is no body of evidence to answer the question of how long patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar disorder, including the depressive episodes associated with bipolar disorder, is chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar disorder.. 2.6Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with dose range of olanzapine to 18 mg and fluoxetine 25 to 50 mg.Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.While there is no body of evidence to answer the question of how long patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to separate trials of different antidepressants of adequate dose and duration in the current episode) is chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.Olanzapine monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to antidepressants of adequate dose and duration in the current episode). 2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations. The starting dose of oral olanzapine 2.5-5 mg with fluoxetine 20 mg should be used for patients with predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under 10 years of age [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Olanzapine Orally Disintegrating Tablets, USP are available containing mg, 10 mg, 15 mg or 20 mg of olanzapine, USP.oThe mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE1 on the other side.oThe 10 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE2 on the other side. oThe 15 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE3 on the other side. oThe 20 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE4 on the other side.. oThe mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE1 on the other side.. oThe 10 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE2 on the other side. oThe 15 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE3 on the other side. oThe 20 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE4 on the other side.. oOrally Disintegrating Tablets (not scored): 5, 10, 15, 20 mg. (3). oOrally Disintegrating Tablets (not scored): 5, 10, 15, 20 mg. (3).

DRUG ABUSE AND DEPENDENCE SECTION.


9 DRUG ABUSE AND DEPENDENCE. 9.3 Dependence. In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to times the daily oral MRHD based on mg/m2 body surface area. Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies. oDiazepam: May potentiate orthostatic hypotension. (7.1, 7.2)oAlcohol: May potentiate orthostatic hypotension. (7.1)oCarbamazepine: Increased clearance of olanzapine. (7.1)oFluvoxamine: May increase olanzapine levels. (7.1)oOlanzapine and Fluoxetine in Combination: Also refer to the Drug Interactions section of the package insert for Symbyax. (7.1)oCNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol. (7.2)oAntihypertensive Agents: Enhanced antihypertensive effect. (7.2)oLevodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. (7.2)oOther Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products. (7.2). oDiazepam: May potentiate orthostatic hypotension. (7.1, 7.2). oAlcohol: May potentiate orthostatic hypotension. (7.1). oCarbamazepine: Increased clearance of olanzapine. (7.1). oFluvoxamine: May increase olanzapine levels. (7.1). oOlanzapine and Fluoxetine in Combination: Also refer to the Drug Interactions section of the package insert for Symbyax. (7.1). oCNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol. (7.2). oAntihypertensive Agents: Enhanced antihypertensive effect. (7.2). oLevodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. (7.2). oOther Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products. (7.2). 7.1 Potential for Other Drugs to Affect Olanzapine. Diazepam. The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)]. Cimetidine and Antacids. Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine. Inducers of CYP1A2. Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. Alcohol. Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)]. Inhibitors of CYP1A2. Fluvoxamine: Fluvoxamine, CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine. Inhibitors of CYP2D6. Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for days) causes small (mean 16%) increase in the maximum concentration of olanzapine and small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax. Warfarin. Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2)]. Inducers of CYP1A2 or Glucuronyl Transferase. Omeprazole and rifampin may cause an increase in olanzapine clearance. Charcoal. The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about hours after dosing, charcoal may be useful treatment for olanzapine overdose.. Anticholinergic Drugs. Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.14)]. 7.2 Potential for Olanzapine to Affect Other Drugs. CNS Acting Drugs. Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol. Antihypertensive Agents. Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents. Levodopa and Dopamine Agonists. Olanzapine may antagonize the effects of levodopa and dopamine agonists. Lithium. Multiple doses of olanzapine (10 mg for days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium [see Warnings and Precautions (5.16)]. Valproate. Olanzapine (10 mg daily for weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate [see Warnings and Precautions (5.16)]. Effect of Olanzapine on Drug Metabolizing Enzymes. In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. Imipramine. Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. Warfarin. Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)]. Diazepam. Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions (7.1)]. Alcohol. Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)]. Biperiden. Multiple doses of olanzapine did not influence the kinetics of biperiden. Theophylline. Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential. Infertility. Females Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.15)].

GERIATRIC USE SECTION.


8.5 Geriatric Use. Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be different tolerability profile in this population compared to 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 higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n 1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)]. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of lower starting dose for any geriatric patient [see Boxed Warning, Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients >= 65 years of age to determine whether they respond differently from younger patients.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Olanzapine Orally Disintegrating Tablets, USP are available containing mg, 10 mg, 15 mg or 20 mg of olanzapine, USP.The mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE1 on the other side. They are available as follows:NDC 0378-5510-93bottles of 30 tabletsThe 10 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE2 on the other side. They are available as follows:NDC 0378-5511-93bottles of 30 tabletsThe 15 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE3 on the other side. They are available as follows:NDC 0378-5512-93bottles of 30 tabletsThe 20 mg tablets are yellow, round, unscored tablets debossed with on one side of the tablet and OE4 on the other side. They are available as follows:NDC 0378-5513-93bottles of 30 tablets. 16.2 Storage and Handling. Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect olanzapine orally disintegrating tablets from light and moisture.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Olanzapine orally disintegrating tablets are an atypical antipsychotic indicated: As oral formulation for the: oTreatment of schizophrenia. (1.1)oAdults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. (14.1) oAdolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia (14.1). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.1)oAcute treatment of manic or mixed episodes associated with bipolar disorder and maintenance treatment of bipolar disorder. (1.2)oAdults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar disorder: two 3- to 4-week trials and one maintenance trial. (14.2)oAdolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar disorder (14.2). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.2) oMedication therapy for pediatric patients with schizophrenia or bipolar disorder should be undertaken only after thorough diagnostic evaluation and with careful consideration of the potential risks. (1.3) oAdjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar disorder. (1.2) oEfficacy was established in two 6-week clinical trials in adults (14.2). Maintenance efficacy has not been systematically evaluated. As Olanzapine and Fluoxetine in Combination for the:oTreatment of depressive episodes associated with bipolar disorder. (1.5)oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.oTreatment of treatment resistant depression. (1.6)oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.. oTreatment of schizophrenia. (1.1)oAdults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. (14.1) oAdolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia (14.1). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.1). oAdults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. (14.1) oAdolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia (14.1). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.1). oAcute treatment of manic or mixed episodes associated with bipolar disorder and maintenance treatment of bipolar disorder. (1.2)oAdults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar disorder: two 3- to 4-week trials and one maintenance trial. (14.2)oAdolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar disorder (14.2). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.2) oAdults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar disorder: two 3- to 4-week trials and one maintenance trial. (14.2). oAdolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar disorder (14.2). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.2) oMedication therapy for pediatric patients with schizophrenia or bipolar disorder should be undertaken only after thorough diagnostic evaluation and with careful consideration of the potential risks. (1.3) oAdjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar disorder. (1.2) oEfficacy was established in two 6-week clinical trials in adults (14.2). Maintenance efficacy has not been systematically evaluated. oEfficacy was established in two 6-week clinical trials in adults (14.2). Maintenance efficacy has not been systematically evaluated. oTreatment of depressive episodes associated with bipolar disorder. (1.5)oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.. oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.. oTreatment of treatment resistant depression. (1.6)oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.. oEfficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.. 1.1 Schizophrenia. Oral olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial [see Clinical Studies (14.1)]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5)]. 1.2 Bipolar Disorder (Manic or Mixed Episodes). Monotherapy. Oral olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar disorder and maintenance treatment of bipolar disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar disorder (ages 13-17), efficacy was established in one 3-week trial [see Clinical Studies (14.2)]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5)]. Adjunctive Therapy to Lithium or Valproate. Oral olanzapine orally disintegrating tablets are indicated for the treatment of manic or mixed episodes associated with bipolar disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies (14.2)]. 1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar Disorder Pediatric schizophrenia and bipolar disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar disorder be initiated only after thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar disorder should be part of total treatment program that often includes psychological, educational and social interventions.. 1.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar Disorder. Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar disorder, based on clinical studies. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar disorder. 1.6Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression Oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.Olanzapine monotherapy is not indicated for the treatment of treatment resistant depression.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulation. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking olanzapine orally disintegrating tablets as monotherapy or in combination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking olanzapine orally disintegrating tablets, call your doctor. When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke: Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine orally disintegrating tablets had significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo. Olanzapine orally disintegrating tablets are not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]. Neuroleptic Malignant Syndrome (NMS): Patients and caregivers should be counseled that potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine orally disintegrating tablets. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Patients should be advised to report to their healthcare provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)].Hyperglycemia and Diabetes Mellitus: Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctors instructions about how often to check their blood sugar while taking olanzapine orally disintegrating tablets [see Warnings and Precautions (5.5)]. Dyslipidemia: Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine orally disintegrating tablets. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)]. Weight Gain: Patients should be counseled that weight gain has occurred during treatment with olanzapine orally disintegrating tablets. Patients should have their weight monitored regularly [see Warnings and Precautions (5.5)]. Orthostatic Hypotension: Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting. Potential for Cognitive and Motor Impairment: Because olanzapine orally disintegrating tablets have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Warnings and Precautions (5.12)]. Body Temperature Regulation: Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see Warnings and Precautions (5.13)]. Concomitant Medication: Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax. Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is potential for interactions [see Drug Interactions (7)]. Alcohol: Patients should be advised to avoid alcohol while taking olanzapine orally disintegrating tablets [see Drug Interactions (7)]. Phenylketonurics: Olanzapine orally disintegrating tablets contain phenylalanine (1.12, 2.23, 3.35, or 4.46 mg per 5, 10, 15, or 20 mg tablet, respectively) [see Description (11)]. Use in Specific Populations: Pregnancy: Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with olanzapine orally disintegrating tablets. Advise patients that olanzapine orally disintegrating tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in neonate. Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to olanzapine orally disintegrating tablets during pregnancy [see Use in Specific Populations (8.1)].Lactation: Advise breastfeeding women using olanzapine orally disintegrating tablets to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].Infertility: Advise females of reproductive potential that olanzapine orally disintegrating tablets may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].Pediatric Use: Olanzapine orally disintegrating tablets are indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with olanzapine orally disintegrating tablets and advised that these risks may lead them to consider other drugs first [see Indications and Usage (1.1, 1.2)]. Safety and effectiveness of olanzapine in patients under 13 years of age have not been established. Safety and efficacy of olanzapine and fluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar disorder. Safety and effectiveness of olanzapine and fluoxetine in combination in patients 10 years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)]. Need for Comprehensive Treatment Program in Pediatric Patients: Olanzapine orally disintegrating tablets are indicated as an integral part of total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine orally disintegrating tablets have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare providers assessment of the chronicity and severity of the patients symptoms [see Indications and Usage (1.3)].

OVERDOSAGE SECTION.


10 OVERDOSAGE. 10.1 Human Experience. In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses. In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with >= 10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, patient was reported to survive an acute olanzapine ingestion of approximately g of oral olanzapine. 10.2 Management of Overdose. There is no specific antidote to an overdose of olanzapine. The possibility of multiple drug involvement should be considered. Establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.Contact Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax prescribing information.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 5 mg. NDC 0378-5510-93Olanzapine Orally Disintegrating Tablets, USP mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Phenylketonurics: Contains phenylalanine (a component of aspartame) 1.12 mg per tablet.Rx only 30 TabletsEach tablet contains:Olanzapine, USP mgUsual Dosage: See accompanyingprescribing information.Keep this and all medication out of thereach of children.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light and moisture.DO NOT OPEN BOTTLE UNTIL IMMEDIATELY PRIOR TO USE.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX5510H2Meets USP Disintegration Test 2.Dispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Code No.: MH/DRUGS/25/NKD/89. Olanzapine Orally Disintegrating Tablets mg Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar disorder were established in short-term studies in adolescents (ages 13 to 17 years). Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in range of 2.5 to 20 mg/day [see Clinical Studies (14.1, 14.2)]. Recommended starting dose for adolescents is lower than that for adults [see Dosage and Administration (2.1, 2.2)]. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see Warnings and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.1) ]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Indications and Usage (1.1, 1.2)].Safety and effectiveness of olanzapine in children 13 years of age have not been established [see Patient Counseling Information (17) ]. Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar disorder.Safety and effectiveness of olanzapine and fluoxetine in combination in children 10 years of age have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki 4, 11, and nM, respectively), dopamine D1-4 (Ki 11-31 nM), histamine H1 (Ki 7 nM), and adrenergic receptors (Ki 19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki 57 nM) and muscarinic M1-5 (Ki 73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD, and -adrenergic receptors (Ki 10 uM).

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Oral Administration, Monotherapy. Olanzapine is well absorbed and reaches peak concentrations in approximately hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that olanzapine tablet and olanzapine orally disintegrating tablet dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady state concentrations in about week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age. Olanzapine is extensively distributed throughout the body, with volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of to 1100 ng/mL, binding primarily to albumin and 1-acid glycoprotein. Metabolism and Elimination. Following single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. Specific Populations. Renal Impairment. Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied. Hepatic Impairment. Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, study of the effect of impaired liver function in subjects (n 6) with clinically significant (Childs Pugh Classification and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine. Geriatric. In study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (>= 65 years) than in nonelderly subjects (< 65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2)]. Gender. Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. Smoking Status. Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended. Race. In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended. Combined Effects. The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit combination of factors that may result in slower metabolism of olanzapine [see Dosage and Administration (2)]. Adolescents (Ages 13 to 17 Years). In clinical studies, most adolescents were nonsmokers and this population had lower average body weight, which resulted in higher average olanzapine exposure compared to adults.

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk Summary. Neonates exposed to antipsychotic drugs, including olanzapine, 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 of pregnant women exposed to olanzapine have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m2 body surface area; some fetal toxicities were observed at these doses (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defects, loss, or other 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 Embryo/Fetal Risk There is risk to the mother from untreated schizophrenia or bipolar disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is direct result of the illness or other comorbid factors.. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.. Data. Human Data Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. retrospective cohort study from Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.. Animal Data In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m2 body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m2 body surface area).

RECENT MAJOR CHANGES SECTION.


Warnings and Precautions, Tardive Dyskinesia (5.6) 10/2019Warnings and Precautions, Use in Patients with Concomitant Illness (5.14) Removed 4/2020Warnings and Precautions, Anticholinergic (Antimuscarinic) Effects (5.14) 4/2020.

RISKS.


Risk Summary. Neonates exposed to antipsychotic drugs, including olanzapine, 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 of pregnant women exposed to olanzapine have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m2 body surface area; some fetal toxicities were observed at these doses (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defects, loss, or other 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.

SPL MEDGUIDE SECTION.


Medication Guide. Olanzapine Orally Disintegrating Tablets, USP(oh lan za peen)Read the Medication Guide that comes with olanzapine orally disintegrating tablets before you start taking them and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about olanzapine orally disintegrating tablets.What is the most important information should know about olanzapine orally disintegrating tabletsOlanzapine orally disintegrating tablets may cause serious side effects, including:1.Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).2.High blood sugar (hyperglycemia).3.High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.4.Weight gain, especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.These serious side effects are described below.1.Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Olanzapine orally disintegrating tablets are not approved for treating psychosis in elderly people with dementia.2.High blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:oa build up of acid in your blood due to ketones (ketoacidosis)ocomaodeathYour doctor should do tests to check your blood sugar before you start taking olanzapine orally disintegrating tablets and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine orally disintegrating tablets are stopped. People with diabetes and some people who did not have diabetes before taking olanzapine orally disintegrating tablets need to take medicine for high blood sugar even after they stop taking olanzapine orally disintegrating tablets.If you have diabetes, follow your doctors instructions about how often to check your blood sugar while taking olanzapine orally disintegrating tablets.Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking olanzapine orally disintegrating tablets:ofeel very thirstyoneed to urinate more than usualofeel very hungryofeel weak or tiredofeel sick to your stomachofeel confused or your breath smells fruity.3.High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with olanzapine orally disintegrating tablets, especially in teenagers (13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking olanzapine orally disintegrating tablets and during treatment. 4.Weight gain. Weight gain is very common in people who take olanzapine orally disintegrating tablets. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when olanzapine is used in combination with fluoxetine. Some people may gain lot of weight while taking olanzapine orally disintegrating tablets, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating healthy, balanced diet, and exercising.What are olanzapine orally disintegrating tablets Olanzapine orally disintegrating tablets are prescription medicine used to treat:oschizophrenia in people age 13 or older.obipolar disorder, including: omanic or mixed episodes that happen with bipolar disorder in people age 13 or older.omanic or mixed episodes that happen with bipolar disorder, when used with the medicine lithium or valproate, in adults.olong-term treatment of bipolar disorder in adults.oepisodes of depression that happen with bipolar disorder, when used with the medicine fluoxetine (Prozac(R)) in people age 10 or older.oepisodes of depression that do not get better after other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults.Olanzapine orally disintegrating tablets have not been approved for use in children under 13 years of age. Olanzapine in combination with fluoxetine has not been approved for use in children under 10 years of age.The symptoms of schizophrenia include hearing voices, seeing things that are not there, having beliefs that are not true, and being suspicious or withdrawn.The symptoms of bipolar disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and decreased need for sleep.The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior.Some of your symptoms may improve with treatment. If you do not think you are getting better, call your doctor.What should tell my doctor before taking olanzapine orally disintegrating tabletsOlanzapine orally disintegrating tablets may not be right for you. Before starting olanzapine orally disintegrating tablets, tell your doctor if you have or had:oheart problemsoseizuresodiabetes or high blood sugar levels (hyperglycemia)ohigh cholesterol or triglyceride levels in your bloodoliver problemsolow or high blood pressureostrokes or mini-strokes also called transient ischemic attacks (TIAs)oAlzheimers diseaseonarrow-angle glaucomaoenlarged prostate in menobowel obstructionophenylketonuria, because olanzapine orally disintegrating tablets contain phenylalanineobreast cancerothoughts of suicide or hurting yourselfoany other medical conditionoare pregnant or plan to become pregnant. It is not known if olanzapine will harm your unborn baby.oIf you become pregnant while receiving olanzapine orally disintegrating tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/.oare breast-feeding or plan to breast-feed. Olanzapine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take olanzapine orally disintegrating tablets. Tell your doctor if you exercise lot or are in hot places often.The symptoms of bipolar disorder, treatment resistant depression, or schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away. Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Olanzapine orally disintegrating tablets and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take olanzapine orally disintegrating tablets with your other medicines. Do not start or stop any medicine while taking olanzapine orally disintegrating tablets without talking to your doctor first. How should take olanzapine orally disintegrating tabletsoTake olanzapine orally disintegrating tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine orally disintegrating tablets until it is right for you.oIf you miss dose of olanzapine orally disintegrating tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine orally disintegrating tablets at the same time.oTo prevent serious side effects, do not stop taking olanzapine orally disintegrating tablets suddenly. If you need to stop taking olanzapine orally disintegrating tablets, your doctor can tell you how to safely stop taking them.oIf you take too many olanzapine orally disintegrating tablets, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.oOlanzapine orally disintegrating tablets can be taken with or without food.oOlanzapine orally disintegrating tablets are usually taken one time each day.oTake olanzapine orally disintegrating tablets as follows:oBe sure that your hands are dry.oOpen the bottle.oAs soon as you open the bottle, remove the tablet and put it into your mouth.oThe tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid.oCall your doctor if you do not think you are getting better or have any concerns about your condition while taking olanzapine orally disintegrating tablets. What should avoid while taking olanzapine orally disintegrating tabletsoOlanzapine orally disintegrating tablets can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine orally disintegrating tablets affect you.oAvoid drinking alcohol while taking olanzapine orally disintegrating tablets. Drinking alcohol while you take olanzapine orally disintegrating tablets may make you sleepier than if you take olanzapine orally disintegrating tablets alone. What are the possible side effects of olanzapine orally disintegrating tablets Serious side effects may happen when you take olanzapine orally disintegrating tablets, including:oSee What is the most important information should know about olanzapine orally disintegrating tablets, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.oIncreased incidence of stroke or mini-strokes called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). Olanzapine orally disintegrating tablets are not approved for these patients.oNeuroleptic Malignant Syndrome (NMS): NMS is rare but very serious condition that can happen in people who take antipsychotic medicines, including olanzapine orally disintegrating tablets. NMS can cause death and must be treated in hospital. Call your doctor right away if you become severely ill and have any of these symptoms:ohigh feveroexcessive sweatingorigid musclesoconfusionochanges in your breathing, heartbeat, and blood pressure. oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with olanzapine orally disintegrating tablets. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.oTardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking olanzapine orally disintegrating tablets. It may also start after you stop taking olanzapine orally disintegrating tablets. Tell your doctor if you get any body movements that you can not control.oDecreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.oDifficulty swallowing, that can cause food or liquid to get into your lungs.oSeizures: Tell your doctor if you have seizure during treatment with olanzapine orally disintegrating tablets.oProblems with control of body temperature: You could become very hot, for instance when you exercise lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:osweating too much or not at allodry mouthofeeling very hotofeeling thirstyonot able to produce urine. Common side effects of olanzapine orally disintegrating tablets include: lack of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having hard or infrequent stools, dizziness, changes in behavior, or restlessness.Other common side effects in teenagers (13-17 years old) include: headache, stomach-area (abdominal) pain, pain in your arms or legs, or tiredness. Teenagers experienced greater increases in prolactin, liver enzymes, and sleepiness, as compared with adults.Tell your doctor about any side effect that bothers you or that does not go away.These are not all the possible side effects with olanzapine orally disintegrating tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store olanzapine orally disintegrating tabletsoStore olanzapine orally disintegrating tablets at room temperature, between 20 to 25C (68 to 77F).oKeep olanzapine orally disintegrating tablets away from light.oKeep olanzapine orally disintegrating tablets dry and away from moisture. Keep olanzapine orally disintegrating tablets and all medicines out of the reach of children. General information about olanzapine orally disintegrating tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use olanzapine orally disintegrating tablets for condition for which they were not prescribed. Do not give olanzapine orally disintegrating tablets to other people, even if they have the same condition. They may harm them.This Medication Guide summarizes the most important information about olanzapine orally disintegrating tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about olanzapine orally disintegrating tablets that was written for healthcare professionals. For more information about olanzapine orally disintegrating tablets call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).What are the ingredients in olanzapine orally disintegrating tabletsActive ingredient: olanzapineInactive ingredients: aspartame, colloidal silicon dioxide, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose and sodium lauryl sulfate.This Medication Guide has been approved by the U.S. Food and Drug Administration.The brands listed are trademarks of their respective owners.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India 75074455Revised: 8/2020MX:OLANOD:R11. 1.Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).. 2.High blood sugar (hyperglycemia).. 3.High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.. 4.Weight gain, especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.. 1.Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Olanzapine orally disintegrating tablets are not approved for treating psychosis in elderly people with dementia.. 2.High blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:oa build up of acid in your blood due to ketones (ketoacidosis)ocomaodeath. oa build up of acid in your blood due to ketones (ketoacidosis). ocoma. odeath. ofeel very thirsty. oneed to urinate more than usual. ofeel very hungry. ofeel weak or tired. ofeel sick to your stomach. ofeel confused or your breath smells fruity.. 3.High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with olanzapine orally disintegrating tablets, especially in teenagers (13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking olanzapine orally disintegrating tablets and during treatment. 4.Weight gain. Weight gain is very common in people who take olanzapine orally disintegrating tablets. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when olanzapine is used in combination with fluoxetine. Some people may gain lot of weight while taking olanzapine orally disintegrating tablets, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating healthy, balanced diet, and exercising.. oschizophrenia in people age 13 or older.. obipolar disorder, including: omanic or mixed episodes that happen with bipolar disorder in people age 13 or older.omanic or mixed episodes that happen with bipolar disorder, when used with the medicine lithium or valproate, in adults.olong-term treatment of bipolar disorder in adults.. omanic or mixed episodes that happen with bipolar disorder in people age 13 or older.. omanic or mixed episodes that happen with bipolar disorder, when used with the medicine lithium or valproate, in adults.. olong-term treatment of bipolar disorder in adults.. oepisodes of depression that happen with bipolar disorder, when used with the medicine fluoxetine (Prozac(R)) in people age 10 or older.. oepisodes of depression that do not get better after other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults.. oheart problems. oseizures. odiabetes or high blood sugar levels (hyperglycemia). ohigh cholesterol or triglyceride levels in your blood. oliver problems. olow or high blood pressure. ostrokes or mini-strokes also called transient ischemic attacks (TIAs). oAlzheimers disease. onarrow-angle glaucoma. oenlarged prostate in men. obowel obstruction. ophenylketonuria, because olanzapine orally disintegrating tablets contain phenylalanine. obreast cancer. othoughts of suicide or hurting yourself. oany other medical condition. oare pregnant or plan to become pregnant. It is not known if olanzapine will harm your unborn baby.oIf you become pregnant while receiving olanzapine orally disintegrating tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/.. oIf you become pregnant while receiving olanzapine orally disintegrating tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/.. oare breast-feeding or plan to breast-feed. Olanzapine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take olanzapine orally disintegrating tablets. oTake olanzapine orally disintegrating tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine orally disintegrating tablets until it is right for you.. oIf you miss dose of olanzapine orally disintegrating tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine orally disintegrating tablets at the same time.. oTo prevent serious side effects, do not stop taking olanzapine orally disintegrating tablets suddenly. If you need to stop taking olanzapine orally disintegrating tablets, your doctor can tell you how to safely stop taking them.. oIf you take too many olanzapine orally disintegrating tablets, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.. oOlanzapine orally disintegrating tablets can be taken with or without food.. oOlanzapine orally disintegrating tablets are usually taken one time each day.. oTake olanzapine orally disintegrating tablets as follows:oBe sure that your hands are dry.oOpen the bottle.oAs soon as you open the bottle, remove the tablet and put it into your mouth.oThe tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid.. oBe sure that your hands are dry.. oOpen the bottle.. oAs soon as you open the bottle, remove the tablet and put it into your mouth.. oThe tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid.. oCall your doctor if you do not think you are getting better or have any concerns about your condition while taking olanzapine orally disintegrating tablets. oOlanzapine orally disintegrating tablets can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine orally disintegrating tablets affect you.. oAvoid drinking alcohol while taking olanzapine orally disintegrating tablets. Drinking alcohol while you take olanzapine orally disintegrating tablets may make you sleepier than if you take olanzapine orally disintegrating tablets alone. oSee What is the most important information should know about olanzapine orally disintegrating tablets, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.. oIncreased incidence of stroke or mini-strokes called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). Olanzapine orally disintegrating tablets are not approved for these patients.. oNeuroleptic Malignant Syndrome (NMS): NMS is rare but very serious condition that can happen in people who take antipsychotic medicines, including olanzapine orally disintegrating tablets. NMS can cause death and must be treated in hospital. Call your doctor right away if you become severely ill and have any of these symptoms:ohigh feveroexcessive sweatingorigid musclesoconfusionochanges in your breathing, heartbeat, and blood pressure. ohigh fever. oexcessive sweating. origid muscles. oconfusion. ochanges in your breathing, heartbeat, and blood pressure.. oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with olanzapine orally disintegrating tablets. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.. oTardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking olanzapine orally disintegrating tablets. It may also start after you stop taking olanzapine orally disintegrating tablets. Tell your doctor if you get any body movements that you can not control.. oDecreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.. oDifficulty swallowing, that can cause food or liquid to get into your lungs.. oSeizures: Tell your doctor if you have seizure during treatment with olanzapine orally disintegrating tablets.. oProblems with control of body temperature: You could become very hot, for instance when you exercise lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:osweating too much or not at allodry mouthofeeling very hotofeeling thirstyonot able to produce urine. osweating too much or not at all. odry mouth. ofeeling very hot. ofeeling thirsty. onot able to produce urine. oStore olanzapine orally disintegrating tablets at room temperature, between 20 to 25C (68 to 77F).. oKeep olanzapine orally disintegrating tablets away from light.. oKeep olanzapine orally disintegrating tablets dry and away from moisture.

SPL UNCLASSIFIED SECTION.


1.1 Schizophrenia. Oral olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial [see Clinical Studies (14.1)]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5)].

STORAGE AND HANDLING SECTION.


16.2 Storage and Handling. Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect olanzapine orally disintegrating tablets from light and moisture.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. oPregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)oPediatric Use: Safety and effectiveness of olanzapine in children 13 years of age have not been established. Safety and effectiveness of olanzapine and fluoxetine in combination in children 10 years of age have not been established. (8.4). oPregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1). oPediatric Use: Safety and effectiveness of olanzapine in children 13 years of age have not been established. Safety and effectiveness of olanzapine and fluoxetine in combination in children 10 years of age have not been established. (8.4). 8.1 Pregnancy. Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk Summary. Neonates exposed to antipsychotic drugs, including olanzapine, 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 of pregnant women exposed to olanzapine have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m2 body surface area; some fetal toxicities were observed at these doses (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defects, loss, or other 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 Embryo/Fetal Risk There is risk to the mother from untreated schizophrenia or bipolar disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is direct result of the illness or other comorbid factors.. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.. Data. Human Data Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. retrospective cohort study from Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.. Animal Data In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based on mg/m2 body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m2 body surface area).. 8.2 Lactation. Risk Summary. Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk (see Clinical Considerations). There is no information on the effects of olanzapine on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mothers underlying condition.. Clinical Considerations. Infants exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential. Infertility. Females Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.15)].. 8.4 Pediatric Use. The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar disorder were established in short-term studies in adolescents (ages 13 to 17 years). Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in range of 2.5 to 20 mg/day [see Clinical Studies (14.1, 14.2)]. Recommended starting dose for adolescents is lower than that for adults [see Dosage and Administration (2.1, 2.2)]. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see Warnings and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.1) ]. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Indications and Usage (1.1, 1.2)].Safety and effectiveness of olanzapine in children 13 years of age have not been established [see Patient Counseling Information (17) ]. Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar disorder.Safety and effectiveness of olanzapine and fluoxetine in combination in children 10 years of age have not been established. 8.5 Geriatric Use. Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be different tolerability profile in this population compared to 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 higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n 1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)]. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of lower starting dose for any geriatric patient [see Boxed Warning, Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients >= 65 years of age to determine whether they respond differently from younger patients.