RECENT MAJOR CHANGES SECTION

Highlight: Warnings and Precautions (5.15) 1/2025

RECENT MAJOR CHANGES

Warnings and Precautions (5.15) 1/2025

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DESCRIPTION SECTION

11 DESCRIPTION

Olanzapine is an atypical antipsychotic that belongs 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 C 17H 20N 4S, which corresponds to a molecular weight of 312.44. The chemical structure is:

Olanzapine, USP is a yellow crystalline solid, which is practically insoluble in water.

Olanzapine tablets, USP are intended for oral administration only.

Each tablet contains olanzapine equivalent to 2.5 mg (8 μmol), 5 mg (16 μmol), 7.5 mg (24 μmol), 10 mg (32 μmol), 15 mg (48 μmol), or 20 mg (64 μmol). Inactive ingredients are crospovidone, magnesium stearate, mannitol and microcrystalline cellulose.

For olanzapine tablets, USP: Meets USP Dissolution Test 2.

Olanzapine orally disintegrating tablets, USP are intended for oral administration only.

Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 μmol), 10 mg (32 μmol), 15 mg (48 μmol) or 20 mg (64 μmol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. Olanzapine orally disintegrating tablets, USP also contain the following inactive ingredients: aspartame, crospovidone, magnesium stearate, mannitol and microcrystalline cellulose.

For olanzapine orally disintegrating tablets, USP: Meets USP Disintegration Test 2.

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DOSAGE & ADMINISTRATION SECTION

Highlight:

Schizophrenia in adults ( 2.1)	Oral: Start at 5 to10 mg once daily; Target: 10 mg/day within several days
Schizophrenia in adolescents ( 2.1)	Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day
Bipolar I Disorder (manic or mixed episodes) in adults ( 2.2)	Oral: Start at 10 or 15 mg once daily
Bipolar I Disorder (manic or mixed episodes) in adolescents ( 2.2)	Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day
Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults ( 2.2)	Oral: Start at 10 mg once daily
Depressive Episodes associated with Bipolar I Disorder in adults ( 2.5)	Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily
Depressive Episodes associated with Bipolar I 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 daily
Treatment Resistant Depression in adults ( 2.6)	Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily

• Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. ( 2.1)

• Olanzapine may be given without regard to meals. ( 2.1)

Olanzapine and Fluoxetine in Combination:

• Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. ( 2.5, 2.6)

• Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. ( 2.5, 2.6)

• Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. ( 2.5, 2.6).

• Safety 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 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Adults

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a 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 a dose greater than the target dose of 10 mg/day (i.e., to a 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 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a 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 for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies ( 14.1)]. The healthcare provider who elects to use olanzapine 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 a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a 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 5 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 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 I Disorder (Manic or Mixed Episodes)

Adults

Dose Selection for Monotherapy — Oral olanzapine should be administered on a 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 5 mg QD are recommended.

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 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 I patients on monotherapy with oral olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies ( 14.2)]. The healthcare provider who elects to use olanzapine 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 a dose range of 5 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 a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a 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 5 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 for the maintenance treatment of bipolar I 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.

2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes

Associated with Bipolar I 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 5 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 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 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 to 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 3 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 Symbyaxa and the Combination of Olanzapine and Fluoxetine

a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine
** For**	** Use in Combination**
** Symbyax** ** (mg/day)**	** Olanzapine** ** (mg/day)**	** Fluoxetine** ** (mg/day)**
3 mg olanzapine/25 mg fluoxetine	2.5	20
6 mg olanzapine/25 mg fluoxetine	5	20
12 mg olanzapine/25 mg fluoxetine	10+2.5	20
6 mg olanzapine/50 mg fluoxetine	5	40+10
12 mg olanzapine/50 mg fluoxetine	10+2.5	40+10

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a 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 I disorder.

2.6 Olanzapine 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 5 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 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 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 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 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 a 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 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a 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 2 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 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine 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 a 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)] .

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CONTRAINDICATIONS SECTION

Highlight: * None with olanzapine monotherapy.(4)

• When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax®.( 4)
• When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. ( 4)

4 CONTRAINDICATIONS

• None with olanzapine monotherapy.
• When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.
• For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.

BOXED WARNING SECTION

• None with olanzapine monotherapy.(4)
• When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax®.( 4)
• When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. ( 4)

WARNINGS AND PRECAUTIONS SECTION

Highlight: * 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)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected. ( 5.4)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. ( 5.5)
• Hyperglycemia 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)
• Dyslipidemia: 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. ( 5.5)
• Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.6)
• 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. ( 5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine. 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 olanzapine 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)
• Anticholinergic (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)
• 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)

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.

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 is 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 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)].

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)].

5.4 Drug 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 a 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. Olanzapine's 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 to 126 mg/dL, nonfasting 140 to 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 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 ≥200 mg/dL, and/or a baseline fasting glucose level ≥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 to 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

a Not Applicable.
	** Up to 12 weeks exposure**	** At least 48 weeks exposure**
** LaboratoryAnalyte**	** Category Change** ** (at least once) from Baseline**	** Treatment** ** Arm**	** N**	** Patients**	** N**	** Patients**
	Normal to High	Olanzapine	543	2.2%	345	12.8%
Fasting	(<100 mg/dL to ≥126 mg/dL)	Placebo	293	3.4%	NA a	NA a
Glucose	Borderline to High (≥100 mg/dL and <126 mg/dL	Olanzapine	178	17.4%	127	26.0%
	to ≥126 mg/dL)	Placebo	96	11.5%	NA a	NA a

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 to 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

a Not Applicable.
	** 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**
	Normal to High	Olanzapine	124	0%	108	0.9%
Fasting	(<100 mg/dL to ≥126 mg/dL)	Placebo	53	1.9%	NA a	NA a
Glucose	Borderline to High (≥100 mg/dL and <126	Olanzapine	14	14.3%	13	23.1%
	mg/dL to ≥126 mg/dL)	Placebo	13	0%	NA a	NA a

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 5 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 a 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 to 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 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

a Not Applicable
			** 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**
	Increase by ≥50	Olanzapine	745	39.6%	487	61.4%
	mg/dL	Placebo	402	26.1%	NA a	NA a
	Normal to High (<150	Olanzapine	457	9.2%	293	32.4%
Fasting	mg/dL to ≥200 mg/dL)	Placebo	251	4.4%	NA a	NA a
Triglycerides	Borderline to High	Olanzapine	135	39.3%	75	70.7%
	(≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	Placebo	65	20.0%	NA a	NA a
	Increase by	Olanzapine	745	21.6%	489	32.9%
	≥40 mg/dL	Placebo	402	9.5%	NA a	NA a
	Normal to High	Olanzapine	392	2.8%	283	14.8%
Fasting	(<200 mg/dL to ≥240 mg/dL)	Placebo	207	2.4%	NA a	NA a
Total	Borderline to High	Olanzapine	222	23.0%	125	55.2%
Cholesterol	(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	Placebo	112	12.5%	NA a	NA a
	Increase by	Olanzapine	536	23.7%	483	39.8%
	≥30 mg/dL	Placebo	304	14.1%	NA a	NA a
	Normal to High	Olanzapine	154	0%	123	7.3%
Fasting LDL Cholesterol	(<100 mg/dL to ≥160 mg/dL)	Placebo	82	1.2%	NA a	NA a
	Borderline to High	Olanzapine	302	10.6%	284	31.0%
	(≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	Placebo	173	8.1%	NA a	NA a

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 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 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I 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 a 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 a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.
			** Up to 6 weeks exposure**	** At least 24 weeks exposure**
** Laboratory Analyte**	** Category Change (at least once) from Baseline**	** Treatment Arm**	** N**	** Patients**	** N**	** Patients**
	Increase by ≥50 mg/dL	Olanzapine	138	37.0%	122	45.9%
		Placebo	66	15.2%	NA a	NA a
	Normal to High	Olanzapine	67	26.9%	66	36.4%
Fasting	(<90 mg/dL to 130 mg/dL)	Placebo	28	10.7%	NA a	NA a
Triglycerides	Borderline to High (≥90 mg/dL and	Olanzapine	37	59.5%	31	64.5%
	≤130 mg/dL to 130 mg/dL)	Placebo	17	35.3%	NA a	NA a
	Increase by ≥40 mg/dL	Olanzapine	138	14.5%	122	14.8%
		Placebo	66	4.5%	NA a	NA a
	Normal to High (<170mg/dL to	Olanzapine	87	6.9%	78	7.7%
Fasting	≥200 mg/dL)	Placebo	43	2.3%	NA a	NA a
Total Cholesterol	Borderline to High	Olanzapine	36	38.9%	33	57.6%
	(≥170mg/dL and <200 mg/dL to ≥200 mg/dL)	Placebo	13	7.7%	NA a	NA a
	Increase by ≥30 mg/dL	Olanzapine	137	17.5%	121	22.3%
		Placebo	63	11.1%	NA a	NA a
Fasting	Normal to High	Olanzapine	98	5.1%	92	10.9%
LDL Cholesterol	(<110 mg/dL to ≥130 mg/dL)	Placebo	44	4.5%	NA a	NA a
	Borderline to High	Olanzapine	29	48.3%	21	47.6%
	(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	Placebo	9	0%	NA a	NA a

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 a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a 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, N=2,021). 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 6 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=7,465)** ** (%)**	** 6 Months** ** (N=4,162)** ** (%)**	** 12 Months** ** (N=1,345)** ** (%)**	** 24 Months** ** (N=474)** ** (%)**	** 36 Months** ** (N=147)** ** (%)**
≤0	26.2	24.3	20.8	23.2	17.0
0 to ≤5 (0 to11 lb)	57.0	36.0	26.0	23.4	25.2
5 to ≤10 (11 to 22 lb)	14.9	24.6	24.2	24.1	18.4
10 to ≤15 (22 to 33 lb)	1.8	10.9	14.9	11.4	17.0
15 to ≤20 (33 to 44 lb)	0.1	3.1	8.6	9.3	11.6
20 to ≤25 (44 to 55 lb)	0	0.9	3.3	5.1	4.1
25 to ≤30 (55 to 66 lb)	0	0.2	1.4	2.3	4.8
30 (>66 lb)	0	0.1	0.8	1.2	2

Dose group differences with respect to weight gain have been observed. 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, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

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 4 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 4 Placebo-Controlled Trials

	** Olanzapine-treated patients**	** Placebo-treated patients**
Mean 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 weight	7.1% (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, N=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 8 shows data on adolescent weight gain with olanzapine pooled from 6 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 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents

** Amount Gained** ** kg (lb)**	** 6 Weeks** ** (N=243)** ** (%)**	** 6 Months** ** (N=191)** ** (%)**
≤0	2.9	2.1
0 to ≤5 (0 to 11 lb)	47.3	24.6
5 to ≤10 (11 to 22 lb)	42.4	26.7
10 to ≤15 (22 to 33 lb)	5.8	22.0
15 to ≤20 (33 to 44 lb)	0.8	12.6
20 to ≤25 (44 to 55 lb)	0.8	9.4
25 to ≤30 (55 to 66 lb)	0	2.1
30 to ≤35 (66 to 77 lb)	0	0
35 to ≤40 (77 to 88 lb)	0	0
40 (>88 lb)	0	0.5

5.6 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be the 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 a 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 a 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 a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a 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 α 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% (1,277/6,030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see Dosage and Administration ( 2)]. A more gradual titration to the target dose should be considered if hypotension occurs.

Syncope was reported in 0.6% (15/2,500) of olanzapine**-**treated patients in phase 2 to 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)].

5.8 Falls

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. 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 a history of a 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 should be considered at the first sign of a 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 <1,000/mm 3) should discontinue olanzapine and have their WBC followed until recovery.

5.10 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

5.11 Seizures

During premarketing testing, seizures occurred in 0.9% (22/2,500) 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 a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was a 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% (9/2,500) 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 body's 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 a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a 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 D 2 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, a factor of potential importance if the prescription of these drugs is contemplated in a 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)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer

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 a pooled analysis from clinical studies including 8,136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual- related events 1 (2% [49/3,240] of females), sexual function-related events 2 (2% [150/8,136] of females and males), and breast-related events 3 (0.7% [23/3,240] of females, 0.2% [9/4,896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I 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 a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (1% [2/168] of females), sexual function-related events 2 (0.7% [3/454] of females and males), and breast-related events 3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations ( 8.4)].

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a 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 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 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)].

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1)

• Pediatric 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 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.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a 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 a 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 I 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/m 2 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 a 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 a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a 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. A retrospective cohort study from a Medicaid database of 9,258 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/m 2 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 a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m 2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2 body surface area). In an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m 2 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 mother's clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother's 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 (D 2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.15)] .

8.4 Pediatric Use

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I 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 a 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 I 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 2,500 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 a 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 a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1,184), 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)] . Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [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.

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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 8 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 a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a 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).

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ADVERSE REACTIONS SECTION

Highlight: 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 Olanzapine 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 Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6 ADVERSE REACTIONS

When using olanzapine 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 10,504 adult patients with approximately 4,765 patient-years of exposure to olanzapine. This database includes: (1) 2,500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1,122 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) 5,788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; (5) 1,843 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 theUse of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA

a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior.
** 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

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

	** Percentage of Patients Reporting Event**
** Body System/Adverse Reaction**	** 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)

** Percentage of Patients Reporting Event**
** Adverse Reaction**	** 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

a Denominator used was for females only (olanzapine, N=128; placebo, N=51).
** Percentage of Patients Reporting Event**
** Body System/Adverse Reaction**	** 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

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.
	** Percentage of Patients Reporting Event**
** Categories****a**	** 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 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.

1These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2Adjusted 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)

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.
	** Percentage of Patients Reporting Event**
	** 6 Week Trial** ** % Schizophrenia Patients**	** 3 Week Trial** ** % Bipolar Patients**
** Adverse Reactions**	** 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

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])

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.
** Percentage of Patients Reporting Event**
** Adverse Reaction**	** 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

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 2,400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2,381). 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% (77/1,426) of patients exposed to olanzapine compared to 1% (10/1,187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1,438) of olanzapine-treated patients, compared to 0.3% (4/1,196) 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% (88/5,245) 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% (171/4,641) 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 (≥3X ULN in patients with ALT at baseline <3X 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, stuttering1, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), fecal incontinence, and somnambulism. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1,000 mg/dL have been reported.

1Stuttering was only studied in oral formulations.

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OVERDOSAGE SECTION

10 OVERDOSAGE

10.1 Human Experience

In premarketing trials involving more than 3,100 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 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Reports have been received of fatalities in association with overdose of olanzapine alone. In 1 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, a patient was reported to survive an acute olanzapine ingestion of approximately 2 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 a 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.

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