1 INDICATIONS AND USAGE Olanzapine is an atypical antipsychotic indicated: As oral formulation for the: Treatment of schizophrenia.

(1.1) Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial.

(14.1) Adolescents (ages 13 to 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) Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.

(1.2) Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial.

(14.2) Adolescents (ages 13 to 17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I 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) Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks.

(1.3) Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder.

(1.2) Efficacy was established in two 6-week clinical trials in adults (14.2) .

Maintenance efficacy has not been systematically evaluated.

As Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination for the: Treatment of depressive episodes associated with bipolar I disorder.

(1.5) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.

Treatment of treatment resistant depression.

( 1.6 ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.

1.1 Schizophrenia 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 to 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 I Disorder (Manic or Mixed Episodes) Monotherapy — Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.

Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial.

In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13 to 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 — Olanzapine orally disintegrating tablets are indicated for the treatment of manic or mixed episodes associated with bipolar I 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 I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging.

For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I 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 I disorder be initiated only after a 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 I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

1.5 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder Olanzapine orally disintegrating tablets and fluoxetine in combination are indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies.

When using olanzapine orally disintegrating tablets and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

1.6 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Treatment Resistant Depression Oral Olanzapine orally disintegrating tablets and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients.

When using Olanzapine orally disintegrating tablets and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of treatment resistant depression.

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: 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 Olanzapin e 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 ) 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 Aurobindo Pharma USA, Inc.

at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Clinical Trials in Adults The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine.

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 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.

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 I 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 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 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 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.

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).

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 hypotension 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) Percentage of Patients Reporting Event Adverse Reaction 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 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 Dose Dependency of Adverse Reactions A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of 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 a schizophrenia trial involving fixed dosage ranges of oral olanzapine.

It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 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 a trend.

Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo Percentage of Patients Reporting Event Adverse Reaction Placebo (N=68) Olanzapine 5 ± 2.5 mg/day (N=65) Olanzapine 10 ± 2.5 mg/day (N=64) Olanzapine 15 ± 2.5 mg/day (N=69) Asthenia 15 8 9 20 Dry mouth 4 3 5 13 Nausea 9 0 2 9 Somnolence 16 20 30 39 Tremor 3 0 5 7 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 13: 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 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 ≥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 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of 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.

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 a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Percentage of patients with a Simpson-Angus Scale total score >3.

b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

Percentage of Patients Reporting Event Placebo Olanzapine 5 ± 2.5 mg/day Olanzapine 10 ± 2.5 mg/day Olanzapine 15 ± 2.5 mg/day Parkinsonism a 15 14 12 14 Akathisia b 23 16 19 27 The 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 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.

c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.

d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.

e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

Percentage of Patients Reporting Event Placebo (N=68) Olanzapine 5 ± 2.5 mg/day (N=65) Olanzapine 10 ± 2.5 mg/day (N=64) Olanzapine 15 ± 2.5 mg/day (N=69) Dystonic events a 1 3 2 3 Parkinsonism events b 10 8 14 20 Akathisia events c 1 5 11 10 Dyskinetic events d 4 0 2 1 Residual events e 1 2 5 1 Any extrapyramidal event 16 15 25 32 The 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 I Disorder — Adolescents a Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.

Categories a Percentage of Patients Reporting Event Placebo (N=89) Olanzapine (N=179) Dystonic events 0 1 Parkinsonism events 2 1 Akathisia events 4 6 Dyskinetic events 0 1 Nonspecific events 0 4 Any extrapyramidal event 6 10 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 a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 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 a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt 1 ; Rare: chills and fever, hangover effect, sudden death 1 .

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: amenorrhea 2 , breast pain, decreased menstruation, impotence 2 , increased menstruation 2 , menorrhagia 2 , metrorrhagia 2 , polyuria 2 , urinary frequency, urinary retention, urinary urgency, urination impaired.

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions.

They are included here because of their seriousness.

2 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 to 17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reactions Percentage of Patients Reporting Event 6 Week Trial % Schizophrenia Patients 3 Week Trial % Bipolar Patients Olanzapine (N=72) Placebo (N=35) Olanzapine (N=107) Placebo (N=54) Sedation a 39 9 48 9 Weight increased 31 9 29 4 Headache 17 6 17 17 Increased appetite 17 9 29 4 Dizziness 8 3 7 2 Abdominal pain b 6 3 6 7 Pain in extremity 6 3 5 0 Fatigue 3 3 14 6 Dry mouth 4 0 7 0 a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

b Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper.

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3 to 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 to 17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes]) Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=179) Placebo (N=89) Sedation a 44 9 Weight increased 30 6 Increased appetite 24 6 Headache 17 12 Fatigue 9 4 Dizziness 7 2 Dry mouth 6 0 Pain in extremity 5 1 Constipation 4 0 Nasopharyngitis 4 2 Diarrhea 3 0 Restlessness 3 2 Liver enzymes increased b 8 1 Dyspepsia 3 1 Epistaxis 3 0 Respiratory tract infection c 3 2 Sinusitis 3 0 Arthralgia 2 0 Musculoskeletal stiffness 2 0 a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

b The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes.

c Patients 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.

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 ≥3 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 ≥5 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 Hy’s 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 I 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 (≥3 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 ≥3 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 ≥5 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 Hy’s 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 a 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 olanzapine’s 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 a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine 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, stuttering 1 , venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, somnambulism, and syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

1 Stuttering was only studied in oral and long acting injection (LAI) formulations.