Olanzapine: Package Insert and Label Information (Page 2 of 8)
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, non-fasting 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 2 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.
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.
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| 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 * | 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.
Olanzapine Monotherapy in Adolescents
The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N = 121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.
Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies
| Up to 12 weeks exposure | At least 24 weeks exposure | |||||
| Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | Patients | N | Patients |
| Fasting Glucose | Normal to High (< 100 mg/dL to ≥ 126 mg/dL) | Olanzapine | 124 | 0% | 108 | 0.9% |
| Placebo | 53 | 1.9% | NAa | NAa | ||
| Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) | Olanzapine | 14 | 14.3% | 13 | 23.1% | |
| Placebo | 13 | 0% | NAa | NAa | ||
a) Not Applicable.
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.
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 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.
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| 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 * | NA * | ||
Normal to High | Olanzapine | 457 | 9.2% | 293 | 32.4% | |
| Placebo | 251 | 4.4% | NA * | NA * | ||
Borderline to High | 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 | Olanzapine | 392 | 2.8% | 283 | 14.8% | |
| Placebo | 207 | 2.4% | NA * | NA * | ||
Borderline to High | 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 | Olanzapine | 154 | 0% | 123 | 7.3% | |
| Placebo | 82 | 1.2% | NA * | NA * | ||
Borderline to High | 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.
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
| 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 | 37.0% | 122 | 45.9% |
| Placebo | 66 | 15.2% | NAa | NAa | ||
| Normal to High (< 90 mg/dL to > 130 mg/dL) | Olanzapine | 67 | 26.9% | 66 | 36.4% | |
| Placebo | 28 | 10.7% | NAa | NAa | ||
| 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% | NAa | NAa | ||
| Fasting Total Cholesterol | Increase by ≥ 40 mg/dL | Olanzapine | 138 | 14.5% | 122 | 14.8% |
| Placebo | 66 | 4.5% | NAa | NAa | ||
| Normal to High (< 170 mg/dL to ≥ 200 mg/dL) | Olanzapine | 87 | 6.9% | 78 | 7.7% | |
| Placebo | 43 | 2.3% | NAa | NAa | ||
| 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% | NAa | NAa | ||
| Fasting LDL Cholesterol | Increase by ≥ 30 mg/dL | Olanzapine | 137 | 17.5% | 121 | 22.3% |
| Placebo | 63 | 11.1% | NAa | NAa | ||
| Normal to High (< 110 mg/dL to ≥ 130 mg/dL) | Olanzapine | 98 | 5.1% | 92 | 10.9% | |
| Placebo | 44 | 4.5% | NAa | NAa | ||
| Borderline to High (≥ 110 mg/dL and < 130 mg/dL to ≥ 130 mg/dL) | Olanzapine | 29 | 48.3% | 21 | 47.6% | |
| Placebo | 9 | 0% | NAa | NAa | ||
a) Not Applicable.
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