FDA label ab9d67ba-3e66-4664-a376-b65a4bfa7331

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 a 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 a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a 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. ZYPREXA (olanzapine) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 , 5.14 ) and Patient Counseling Information ( 17.2 )] . When using ZYPREXA 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 PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis. ( 5.1 , 5.14 , 17.2 ) When using ZYPREXA and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

5 WARNINGS AND PRECAUTIONS When using ZYPREXA and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 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. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.14 ), and Patient Counseling Information ( 17.2 )] . 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 a 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 ( 17.2 )] . 5.2 Suicide The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I 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) A 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 a 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 a 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 ( 17.3 )] . 5.4 Hyperglycemia Physicians 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 ( 17.4 )] . 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 a continuum and olanzapine appears to have a 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 1 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 2 highest serum concentrations was 15.0 mg/dL. In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL. Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a 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 a baseline random glucose level greater than or equal to 200 mg/dL, and/or a baseline fasting glucose level greater than or equal to 126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days). In an analysis of 8 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 2 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 Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Normal to High Olanzapine 543 2.2% 345 12.8% Fasting (less than 100 mg/dL to greater than or equal to 126 mg/dL) Placebo 293 3.4% NA a NA a Glucose Borderline to High Olanzapine 178 17.4% 127 26.0% (greater than or equal to 100 mg/dL and less than 126 mg/dL to greater than or equal to 126 mg/dL) Placebo 96 11.5% NA a NA a a Not Applicable. 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 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a 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 3 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 exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Normal to High (less than 100 mg/dL to greater than or equal to 126 mg/dL) Olanzapine Placebo 124 53 0% 1.9% 108 NA a 0.9% NA a Glucose Borderline to High (greater than or equal to 100 mg/dL and less than 126 mg/dL to greater than or equal to 126 mg/dL) Olanzapine Placebo 14 13 14.3% 0% 13 NA a 23.1% NA a a Not Applicable. Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). ( 5.1 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I 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 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. ( 5.3 ) Hyperglycemia: 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. ( 5.4 ) Hyperlipidemia: 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 ) Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. ( 5.6 ) Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.7 ) Orthostatic 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. ( 5.8 ) Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including ZYPREXA. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. ( 5.11 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. ( 5.12 ) Hyperprolactinemia: May elevate prolactin levels. ( 5.15 ) Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate. ( 5.16 ) Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. ( 5.17 )

<table width="100%" ID="i6172dadf-0312-4d70-84a1-7943f694bfac"> <caption>Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies </caption> <tbody> <tr> <td> </td> <td> </td> <td> </td> <td> <content styleCode="bold">Up to</content> <content styleCode="bold"/> <content styleCode="bold"> </content> </td> <td> <content styleCode="bold">12 weeks exposure </content> </td> <td> <content styleCode="bold">At least</content> </td> <td> <content styleCode="bold">48 weeks exposure </content> </td> </tr> <tr> <td> <content styleCode="bold">Laboratory Analyte</content> </td> <td> <content styleCode="bold"> Category Change (at least once) from Baseline </content> </td> <td> <content styleCode="bold">Treatment Arm</content> </td> <td> <content styleCode="bold">N</content> </td> <td> <content styleCode="bold">Patients</content> </td> <td> <content styleCode="bold">N</content> </td> <td> <content styleCode="bold">Patients</content> </td> </tr> <tr> <td> </td> <td>Normal to High </td> <td>Olanzapine </td> <td>543 </td> <td>2.2% </td> <td>345 </td> <td>12.8% </td> </tr> <tr> <td>Fasting </td> <td>(less than 100 mg/dL to greater than or equal to 126 mg/dL)</td> <td>Placebo </td> <td>293 </td> <td>3.4% </td> <td>NA^a </td> <td>NA^a </td> </tr> <tr> <td>Glucose </td> <td>Borderline to High </td> <td>Olanzapine </td> <td>178 </td> <td>17.4% </td> <td>127 </td> <td>26.0% </td> </tr> <tr> <td> </td> <td>(greater than or equal to 100 mg/dL and less than 126 mg/dL to greater than or equal to 126 mg/dL) </td> <td>Placebo </td> <td>96 </td> <td>11.5% </td> <td>NA^a </td> <td>NA^a </td> </tr> </tbody> </table>

<table width="100%" ID="ibcdb48d5-0391-40bd-879e-62add43fb504"> <caption>Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies </caption> <tbody> <tr> <td> </td> <td> </td> <td> </td> <td> <content styleCode="bold">Up to </content> </td> <td> <content styleCode="bold">12 weeks exposure </content> </td> <td> <content styleCode="bold">At least </content> </td> <td> <content styleCode="bold">24 weeks exposure </content> </td> </tr> <tr> <td> <content styleCode="bold">Laboratory Analyte</content> </td> <td> <content styleCode="bold">Category Change (at least once) from Baseline</content> </td> <td> <content styleCode="bold">Treatment Arm</content> </td> <td> <content styleCode="bold">N</content> </td> <td> <content styleCode="bold">Patients</content> </td> <td> <content styleCode="bold">N</content> </td> <td> <content styleCode="bold">Patients</content> </td> </tr> <tr> <td> Fasting </td> <td>Normal to High (less than 100 mg/dL to greater than or equal to 126 mg/dL) </td> <td>Olanzapine Placebo </td> <td>124 53 </td> <td>0% 1.9% </td> <td>108 NA^a </td> <td>0.9% NA^a </td> </tr> <tr> <td>Glucose </td> <td>Borderline to High (greater than or equal to 100 mg/dL and less than 126 mg/dL to greater than or equal to 126 mg/dL) </td> <td>Olanzapine Placebo </td> <td>14 13 </td> <td>14.3% 0% </td> <td>13 NA^a </td> <td>23.1% NA^a </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS When using ZYPREXA and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Clinical Trials in Adults The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 8661 adult patients with approximately 4165 patient-years of exposure to oral olanzapine and 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 Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I 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 Alzheimer's disease representing approximately 29 patient-years of exposure; (4) 5788 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia. In addition, 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 I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure, is included below. 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 I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I 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 a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a 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, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. 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 a 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 physician 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 (1) oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and (2) intramuscular olanzapine for injection in agitated patients with schizophrenia or bipolar I mania. 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 I 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). Agitation — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular olanzapine for injection vs 0% for placebo). Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a 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 1 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 Event Adverse Reaction Olanzapine (N=248) Placebo (N=118) Postural hypotensino 5 2 Constipation 9 3 Weight gain 6 1 Dizziness 11 4 Personality disorder a 8 4 Akathisia 5 1 a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=125) Placebo (N=129) Asthenia 15 6 Dry mouth 22 7 Constipation 11 5 Dyspepsia 11 5 Increased appetite 6 3 Somnolence 35 13 Dizziness 18 6 Tremor 6 3 Olanzapine Intramuscular — There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine for injection-treated patients and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) during the placebo-controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar I mania was 6% for intramuscular olanzapine for injection and 3% for placebo. 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 Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=532) Placebo (N=294) Body as a Whole Accidental injury 12 8 Asthenia 10 9 Fever 6 2 Back pain 5 2 Chest pain 3 1 Cardiovascular System Postural hypotension 3 1 Tachycardia 3 1 Hypertension 2 1 Digestive System Dry mouth 9 5 Constipation 9 4 Dyspepsia 7 5 Vomiting 4 3 Increased appetite 3 2 Hemic and Lymphatic System Ecchymosis 5 3 Metabolic and Nutritional Disorders Weight gain 5 3 Peripheral edema 3 1 Musculoskeletal System Extremity pain (other than joint) 5 3 Joint pain 5 3 Nervous System Somnolence 29 13 Insomnia 12 11 Dizziness 11 4 Abnormal gait 6 1 Tremor 4 3 Akathisia 3 2 Hypertonia 3 2 Articulation impairment 2 1 Respiratory System Rhinitis 7 6 Cough increased 6 3 Pharyngitis 4 3 Special Senses Amblyopia 3 2 Urogenital System Urinary incontinence 2 1 Urinary tract infection 2 1 Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate In the bipolar I 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 12: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials — Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate (N=229) Placebo with lithium or valproate (N=115) Dry mouth 32 9 Weight gain 26 7 Increased appetite 24 8 Dizziness 14 7 Back pain 8 4 Constipation 8 4 Speech disorder 7 1 Increased salivation 6 2 Amnesia 5 2 Paresthesia 5 2 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 13 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 ≥5 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 13: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine as Adjunct to Lithium or Valproate Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate (N=229) Placebo with lithium or valproate (N=115) Body as a Whole Asthenia 18 13 Back pain 8 4 Accidental injury 4 2 Chest pain 3 2 Cardiovascular System Hypertension 2 1 Digestive System Dry mouth 32 9 Increased appetite 24 8 Thirst 10 6 Constipation 8 4 Increased salivation 6 2 Metabolic and Nutritional Disorders Weight gain 26 7 Peripheral edema 6 4 Edema 2 1 Nervous System Somnolence 52 27 Tremor 23 13 Depression 18 17 Dizziness 14 7 Speech disorder 7 1 Amnesia 5 2 Paresthesia 5 2 Apathy 4 3 Confusion 4 1 Euphoria 3 2 Incoordination 2 0 Respiratory System Pharyngitis 4 1 Dyspnea 3 1 Skin and Appendages Sweating 3 1 Acne 2 0 Dry skin 2 0 Special Senses Amblyopia 9 5 Abnormal vision 2 0 Urogenital System Dysmenorrhea a 2 0 Vaginitis a 2 0 a Denominator used was for females only (olanzapine, N=128; placebo, N=51). For 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. Adverse Reactions Occurring at an Incidence of 1% or More among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or bipolar I mania. Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials with Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia or Bipolar I Mania Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=415) Placebo (N=150) Body as a Whole Asthenia 2 1 Cardiovascular System Hypotension 2 0 Postural hypotension 1 0 Nervous System Somnolence 6 3 Dizziness 4 2 Tremor 1 0 Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Oral Olanzapine Monotherapy: Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia ( 6.1 ) Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth ( 6.1 ) Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor ( 6.1 ) Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity ( 6.1 ) Combination of ZYPREXA and Lithium or Valproate: Manic or Mixed Episodes, Bipolar I Disorder (Adults) – dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia ( 6.1 ) ZYPREXA and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for Symbyax. ( 6 ) ZYPREXA IntraMuscular for Injection: Agitation with Schizophrenia and Bipolar I Mania (Adults) – somnolence ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

<table width="100%" ID="i22a95068-c2d8-4628-8c3f-d0f0350824d3"> <caption>Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials &#x2014; SCHIZOPHRENIA </caption> <tbody> <tr> <td> </td> <td> <content styleCode="bold">Percentage of Patients</content> </td> <td> <content styleCode="bold">Reporting Event</content> </td> </tr> <tr> <td> <content styleCode="bold"> Adverse Reaction </content> </td> <td> <content styleCode="bold">Olanzapine (N=248) </content> </td> <td> <content styleCode="bold">Placebo (N=118) </content> </td> </tr> <tr> <td>Postural hypotensino </td> <td>5 </td> <td>2 </td> </tr> <tr> <td>Constipation </td> <td>9 </td> <td>3 </td> </tr> <tr> <td>Weight gain </td> <td>6 </td> <td>1 </td> </tr> <tr> <td>Dizziness </td> <td>11 </td> <td>4 </td> </tr> <tr> <td>Personality disorder^a </td> <td>8 </td> <td>4 </td> </tr> <tr> <td>Akathisia </td> <td>5 </td> <td>1 </td> </tr> </tbody> </table>

<table width="100%" ID="ia2830025-b55a-4406-84be-15e321afc0f8"> <caption>Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials &#x2014; Bipolar I Disorder (Manic or Mixed Episodes) </caption> <col align="left" width="33%"/> <col align="left" width="33%"/> <col align="left" width="33%"/> <tbody> <tr> <td> <content styleCode="bold">Adverse Reaction</content> </td> <td> <content styleCode="bold">Percentage of Patients Reporting Event</content> </td> </tr> <tr> <td> <content styleCode="bold">Olanzapine (N=125)</content> </td> <td> <content styleCode="bold">Placebo (N=129)</content> </td> </tr> <tr> <td>Asthenia </td> <td>15 </td> <td>6 </td> </tr> <tr> <td>Dry mouth </td> <td>22 </td> <td>7 </td> </tr> <tr> <td>Constipation </td> <td>11 </td> <td>5 </td> </tr> <tr> <td>Dyspepsia </td> <td>11 </td> <td>5 </td> </tr> <tr> <td>Increased appetite </td> <td>6 </td> <td>3 </td> </tr> <tr> <td>Somnolence </td> <td>35 </td> <td>13 </td> </tr> <tr> <td>Dizziness </td> <td>18 </td> <td>6 </td> </tr> <tr> <td>Tremor </td> <td>6 </td> <td>3 </td> </tr> </tbody> </table>

<table width="100%" ID="ic57124c7-df1c-459f-89ef-b6e7ab8a70ca"> <caption>Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine </caption> <col align="left" width="33%"/> <col align="left" width="33%"/> <col align="left" width="33%"/> <tbody> <tr> <td> <content styleCode="bold">Body System/Adverse Reaction</content> </td> <td> <content styleCode="bold">Percentage of Patients Reporting Event</content> </td> </tr> <tr> <td> <content styleCode="bold">Olanzapine (N=532)</content> </td> <td> <content styleCode="bold">Placebo (N=294)</content> </td> </tr> <tr> <td> <content styleCode="bold">Body as a Whole</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Accidental injury </td> <td>12 </td> <td>8 </td> </tr> <tr> <td>Asthenia </td> <td>10 </td> <td>9 </td> </tr> <tr> <td>Fever </td> <td>6 </td> <td>2 </td> </tr> <tr> <td>Back pain </td> <td>5 </td> <td>2 </td> </tr> <tr> <td>Chest pain </td> <td>3 </td> <td>1 </td> </tr> <tr> <td> <content styleCode="bold">Cardiovascular System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Postural hypotension </td> <td>3 </td> <td>1 </td> </tr> <tr> <td>Tachycardia </td> <td>3 </td> <td>1 </td> </tr> <tr> <td>Hypertension </td> <td>2 </td> <td>1 </td> </tr> <tr> <td> <content styleCode="bold">Digestive System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Dry mouth </td> <td>9 </td> <td>5 </td> </tr> <tr> <td>Constipation </td> <td>9 </td> <td>4 </td> </tr> <tr> <td>Dyspepsia </td> <td>7 </td> <td>5 </td> </tr> <tr> <td>Vomiting </td> <td>4 </td> <td>3 </td> </tr> <tr> <td>Increased appetite </td> <td>3 </td> <td>2 </td> </tr> <tr> <td> <content styleCode="bold">Hemic and Lymphatic System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Ecchymosis </td> <td>5 </td> <td>3 </td> </tr> <tr> <td> <content styleCode="bold">Metabolic and Nutritional Disorders</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Weight gain </td> <td>5 </td> <td>3 </td> </tr> <tr> <td>Peripheral edema </td> <td>3 </td> <td>1 </td> </tr> <tr> <td> <content styleCode="bold">Musculoskeletal System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Extremity pain (other than joint) </td> <td>5 </td> <td>3 </td> </tr> <tr> <td>Joint pain </td> <td>5 </td> <td>3 </td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Somnolence </td> <td>29 </td> <td>13 </td> </tr> <tr> <td>Insomnia </td> <td>12 </td> <td>11 </td> </tr> <tr> <td>Dizziness </td> <td>11 </td> <td>4 </td> </tr> <tr> <td>Abnormal gait </td> <td>6 </td> <td>1 </td> </tr> <tr> <td>Tremor </td> <td>4 </td> <td>3 </td> </tr> <tr> <td>Akathisia </td> <td>3 </td> <td>2 </td> </tr> <tr> <td>Hypertonia </td> <td>3 </td> <td>2 </td> </tr> <tr> <td>Articulation impairment </td> <td>2 </td> <td>1 </td> </tr> <tr> <td> <content styleCode="bold">Respiratory System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Rhinitis </td> <td>7 </td> <td>6 </td> </tr> <tr> <td>Cough increased </td> <td>6 </td> <td>3 </td> </tr> <tr> <td>Pharyngitis </td> <td>4 </td> <td>3 </td> </tr> <tr> <td> <content styleCode="bold">Special Senses</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Amblyopia </td> <td>3 </td> <td>2 </td> </tr> <tr> <td> <content styleCode="bold">Urogenital System</content> </td> <td> </td> <td> </td> </tr> <tr> <td>Urinary incontinence </td> <td>2 </td> <td>1 </td> </tr> <tr> <td>Urinary tract infection </td> <td>2 </td> <td>1 </td> </tr> </tbody> </table>