Olanzapine (olanzapine 20 mg) Dailymed

Schizophrenia in adults (2.1)	Oral: Start at 5 mg to 10 mg once daily; Target: 10 mg/day within several days
Schizophrenia in adolescents (2.1)	Oral: Start at 2.5 mg to 5 mg once daily; Target: 10 mg/day
Bipolar I Disorder (manic or mixed episodes) in adults (2.2)	Oral: Start at 10 mg or 15 mg once daily
Bipolar I Disorder (manic or mixed episodes) in adolescents (2.2)	Oral: Start at 2.5 mg 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)

• •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)
• •Olanzapine monotherapy in not indicated for the treatment of depressive episodes associated with bipolar I disorder. (2.5)
• •Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. (2.5)

2.1 Schizophrenia

Dose Selection

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 mg 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 one week, since steady-state for olanzapine would not be achieved for approximately one 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 tablets for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to use olanzapine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

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 mg 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 mg 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 tablets for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

2.2 Bipolar I Disorder (Manic or Mixed Episodes)

Dose Selection for Monotherapy

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 mg 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 physician who elects to use olanzapine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dose Selection for Adjunctive Treatment

When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in 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.

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 mg 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 mg 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 tablets 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.

2.5 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^**.

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 mg to 12.5 mg and fluoxetine 20 mg to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Dosage and Administration information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s olanzapine tablets. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 Symbyax Symbyax^** (olanzapine/fluoxetine HCl) is a fixed dose combination of olanzapine and fluoxetine.** and the Combination of Olanzapine and Fluoxetine

For Symbyax** (mg/day)	Use in Combination
	Olanzapine(mg/day)	Fluoxetine (mg/day)
3 mg olanzapine/25 mg fluoxetine 6 mg olanzapine/25 mg fluoxetine 12 mg olanzapine/25 mg fluoxetine 6 mg olanzapine/50 mg fluoxetine 12 mg olanzapine/50 mg fluoxetine	2.5 5 10 + 2.5 5 10 + 2.5	20 20 20 40+10 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 physician should periodically reexamine the need for continued pharmacotherapy.

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

2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral olanzapine 2.5 mg 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 < 10 years of age [see Warnings and Precautions (5.14) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].

3 Dosage Forms And Strengths

Olanzapine tablets 2.5 mg are peach, round film-coated tablets debossed with M on one side of the tablet and 157 on the other side.

Olanzapine tablets 5 mg are white, round film-coated tablets debossed with M on one side of the tablet and 212 on the other side.

Olanzapine tablets 7.5 mg are white, round film-coated tablets debossed with M on one side of the tablet and 335 on the other side.

Olanzapine tablets 10 mg are white, round film-coated tablets debossed with M on one side of the tablet and 454 on the other side.

Olanzapine tablets 15 mg are white, round film-coated tablets debossed with M over 522 on one side of the tablet and blank on the other side.

Olanzapine tablets 20 mg are white, round film-coated tablets debossed with M over 713 on one side of the tablet and blank on the other side.

• •Tablets (not scored): 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg (3)

4 Contraindications

• •None with olanzapine tablets 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.

• •None with olanzapine monotherapy.
• •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)

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^**.

• • Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). (5.1)
• • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax^**. (5.2)
• • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
• • Hyperglycemia: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.4)
• • Hyperlipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5)
• • Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.6)
• • Tardive Dyskinesia: Discontinue if clinically appropriate. (5.7)
• • Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease and those conditions that could affect hemodynamic responses. (5.8)
• • Leukopenia, Neutropenia and Agranulocytosis: Has been reported with antipsychotics, including 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)
• • 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)

5.1 Elderly Patients with Dementia-Related Psychosis

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, Warnings and Precautions (5.14) and Patient Counseling Information (17.2)].

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs. 1.5%, respectively).

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17.2)].

5.2 Suicide

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17.3)].

5.4 Hyperglycemia

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus or having borderline increased blood glucose level (fasting 100 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 (17.4)].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the two highest serum concentrations was 15 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.

In an analysis of five 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 eight 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

			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
Fasting Glucose	Normal to High (< 100 mg/dL to ≥ 126 mg/dL)	Olanzapine	543	2.2%	345	12.8%
		Placebo	293	3.4%	NA Not Applicable.	NA
	Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)	Olanzapine	178	17.4%	127	26%
		Placebo	96	11.5%	NA	NA

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.

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of three placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (n = 121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3. Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

			Up to 12 weeks exposure		At least 24 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	n	Patients	n	Patients
Fasting Glucose	Normal to High (< 100 mg/dL to ≥ 126 mg/dL)	Olanzapine	124	0%	108	0.9%
		Placebo	53	1.9%	NA Not Applicable.	NA
	Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)	Olanzapine	14	14.3%	13	23.1%
		Placebo	13	0%	NA	NA

5.5 Hyperlipidemia

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 (17.5)].

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.

In an analysis of five 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 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

			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
Fasting Triglycerides	Increase by ≥ 50 mg/dL	Olanzapine	745	39.6%	487	61.4%
		Placebo	402	26.1%	NA Not Applicable.	NA
	Normal to High (< 150 mg/dL to ≥ 200 mg/dL)	Olanzapine	457	9.2%	293	32.4%
		Placebo	251	4.4%	NA	NA
	Borderline to High (≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL)	Olanzapine	135	39.3%	75	70.7%
		Placebo	65	20%	NA	NA
Fasting Total Cholesterol	Increase by ≥ 40 mg/dL	Olanzapine	745	21.6%	489	32.9%
		Placebo	402	9.5%	NA	NA
	Normal to High (< 200 mg/dL to ≥ 240 mg/dL)	Olanzapine	392	2.8%	283	14.8%
		Placebo	207	2.4%	NA	NA
	Borderline to High (≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL)	Olanzapine	222	23%	125	55.2%
		Placebo	112	12.5%	NA	NA
Fasting LDL Cholesterol	Increase by ≥ 30 mg/dL	Olanzapine	536	23.7%	483	39.8%
		Placebo	304	14.1%	NA	NA
	Normal to High (< 100 mg/dL to ≥ 160 mg/dL)	Olanzapine	154	0%	123	7.3%
		Placebo	82	1.2%	NA	NA
	Borderline to High (≥ 100 mg/dL and < 160 mg/dL to ≥ 160 mg/dL)	Olanzapine	302	10.6%	284	31%
		Placebo	173	8.1%	NA	NA

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.

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of three 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 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

			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
Fasting Triglycerides	Increase by ≥ 50 mg/dL	Olanzapine	138	37%	122	45.9%
		Placebo	66	15.2%	NA Not Applicable.	NA
	Normal to High (< 90 mg/dL to > 130 mg/dL)	Olanzapine	67	26.9%	66	36.4%
		Placebo	28	10.7%	NA	NA
	Borderline to High (≥ 90 mg/dL and ≤ 130 mg/dL to > 130 mg/dL)	Olanzapine	37	59.5%	31	64.5%
		Placebo	17	35.3%	NA	NA
Fasting Total Cholesterol	Increase by ≥ 40 mg/dL	Olanzapine	138	14.5%	122	14.8%
		Placebo	66	4.5%	NA	NA
	Normal to High (< 170 mg/dL to ≥ 200 mg/dL)	Olanzapine	87	6.9%	78	7.7%
		Placebo	43	2.3%	NA	NA
	Borderline to High (≥ 170 mg/dL and < 200 mg/dL to ≥ 200 mg/dL)	Olanzapine	36	38.9%	33	57.6%
		Placebo	13	7.7%	NA	NA
Fasting LDL Cholesterol	Increase by ≥ 30 mg/dL	Olanzapine	137	17.5%	121	22.3%
		Placebo	63	11.1%	NA	NA
	Normal to High (< 110 mg/dL to ≥ 130 mg/dL)	Olanzapine	98	5.1%	92	10.9%
		Placebo	44	4.5%	NA	NA
	Borderline to High (≥ 110 mg/dL and < 130 mg/dL to ≥ 130 mg/dL)	Olanzapine	29	48.3%	21	47.6%
		Placebo	9	0%	NA	NA

5.6 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 (17.6)].

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 to ≤ 5 (0 to 11 lb)	57	36	26	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
> 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

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 four 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 Four 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 six 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
> 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

5.7 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 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.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome 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.

5.8 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 α₁-adrenergic antagonistic properties [see Patient Counseling Information (17.7)].

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)].

5.9 Leukopenia, Neutropenia and Agranulocytosis

In clinical trial and/or post-marketing 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 preexisting 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 < 1000/mm³) 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 (17.8)].

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 (17.9)].

5.14 Use in Patients with Concomitant Illness

Clinical experience with olanzapine in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3)].

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with olanzapine, 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 from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma or a history of paralytic ileus or related conditions.

In five placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n = 1,184), the following treatment-emergent 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 (17.2)].

Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients [see Warnings and Precautions (5.8)].

5.15 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia and impotence have been reported in patients receiving prolactin-elevating compounds. Longstanding 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) ]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8,136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3,240] of females), sexual function-related events2 (2% [150/8,136] of females and males) and breast-related events3 (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 events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males) and breast-related events3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)].

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.

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 (5.4, 5.5) and Patient Counseling Information (17.4, 17.5)].