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 and fluoxetine capsules if DRESS is suspected.
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
Adults - Healthcare providers should consider the risks and benefits when prescribing olanzapine and fluoxetine capsules 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 and fluoxetine capsules should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine and fluoxetine 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.
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 alone, as well as olanzapine taken concomitantly with fluoxetine. 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.
In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, olanzapine and fluoxetine was associated with a greater mean change in random glucose compared to placebo (+8.65 mg/dL vs. -3.86 mg/dL). The difference in mean changes between olanzapine and fluoxetine and placebo was greater in patients with evidence of glucose dysregulation at baseline (including those 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, or a baseline fasting glucose level ≥126 mg/dL). Olanzapine and Fluoxetine-treated patients had a greater mean HbA1c increase from baseline of 0.15% (median exposure 63 days), compared to a mean HbA1c decrease of 0.04% in fluoxetine-treated subjects (median exposure 57 days) and a mean HbA1c increase of 0.12% in olanzapine-treated patients (median exposure 56 days).
In an analysis of 6 controlled clinical studies, a larger proportion of olanzapine and fluoxetine-treated subjects had glycosuria (4.4%) compared to placebo-treated subjects (1.4%).
The mean change in nonfasting glucose in patients exposed at least 48 weeks was +5.9 mg/dL (N=425).
Table 2 shows short-term and long-term changes in random glucose levels from adult olanzapine and fluoxetine studies.
a Not Applicable.
In a 47-week olanzapine and fluoxetine study, the mean change from baseline to endpoint in fasting glucose was +4.81 mg/dL (n=130). Table 3 shows the categorical changes in fasting glucose [see Clinical Studies (14.2)].
a Not Applicable.
Controlled fasting glucose data is limited for olanzapine and fluoxetine; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (+2.76 mg/dL vs. +0.17 mg/dL).
The mean change in fasting glucose for olanzapine-treated 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.
Children and Adolescents -- In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for treatment of bipolar I depression in patients 10 to 17 years of age, there were no clinically meaningful differences observed between olanzapine and fluoxetine and placebo for mean change in fasting glucose levels. Table 4 shows categorical changes in fasting blood glucose from the pediatric olanzapine and fluoxetine study.
a Impaired Glucose Tolerance.
Olanzapine Monotherapy in Adolescents - 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 vs -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 5 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.
Undesirable alterations in lipids have been observed with olanzapine and fluoxetine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine and fluoxetine, is recommended.
Adults - Clinically meaningful, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine and fluoxetine use. Clinically meaningful increases in total cholesterol have also been seen with olanzapine and fluoxetine use.
In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, olanzapine and fluoxetine-treated patients had an increase from baseline in mean random total cholesterol of 12.1 mg/dL compared to an increase from baseline in mean random total cholesterol of 4.8 mg/dL for olanzapine-treated patients and a decrease in mean random total cholesterol of 5.5 mg/dL for placebo-treated patients. Table 6 shows categorical changes in nonfasting lipid values.
In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), changes (at least once) in nonfasting total cholesterol from normal at baseline to high occurred in 12% (N=150) and changes from borderline to high occurred in 56.6% (N=143) of patients. The mean change in nonfasting total cholesterol was 11.3 mg/dL (N=426).
Table 6: Changes in Nonfasting Lipids Values from Controlled Clinical Studies with Treatment Duration up to 12 Weeks
A 47-week olanzapine and fluoxetine study demonstrated mean changes from baseline to endpoint in fasting total cholesterol (+1.24 mg/dL), LDL cholesterol (+0.29 mg/dL), direct HDL cholesterol (-2.13 mg/dL), and triglycerides (+11.33 mg/dL). Table 7 shows the categorical changes in fasting lipids [see Clinical Studies (14.2)].
Table 7: Changes in Fasting Lipids Values from a Controlled Study with Olanzapine and Fluoxetine Treatment Duration up to 47 Weeks
a Not Applicable.
Fasting lipid data is limited for olanzapine and fluoxetine; however, 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, patients with high baseline lipid levels.
In long-term olanzapine 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 olanzapine-treated 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 8 shows categorical changes in fasting lipids values.
Table 8: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies
a Not Applicable.
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 median increase in total cholesterol was 9.4 mg/dL.
Children and Adolescents - In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for treatment of bipolar I depression in patients 10 to 17 years of age, there were clinically meaningful and statistically significant differences observed between olanzapine and fluoxetine and placebo for mean change in fasting total cholesterol (+16.3 mg/dL vs. -4.3 mg/dL, respectively), LDL cholesterol (+9.7 mg/dL vs -3.5 mg/dL, respectively), and triglycerides (+35.4 mg/dL vs. -3.5 mg/dL, respectively).
The magnitude and frequency of changes in lipids were greater in children and adolescents than previously observed in adults. Table 9 shows categorical changes in fasting lipids values from the pediatric olanzapine and fluoxetine study.
Table 9: Changes in Fasting Lipids Values from a Single Pediatric Olanzapine and Fluoxetine Study in Bipolar Depression
Olanzapine Monotherapy in Adolescents -- 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 olanzapine 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 10 shows categorical changes in fasting lipids values in adolescents.
Table 10: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies
Potential consequences of weight gain should be considered prior to starting olanzapine and fluoxetine capsules. Patients receiving olanzapine and fluoxetine should receive regular monitoring of weight.
Adults - In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for olanzapine and fluoxetine-treated patients was greater than placebo-treated patients [4 kg (8.8 lb) vs -0.3 kg (-0.7 lb)]. Twenty-two percent of olanzapine and fluoxetine-treated patients gained at least 7% of their baseline weight, with a median exposure to event of 6 weeks. This was greater than in placebo-treated patients (1.8%). Approximately 3% of olanzapine and fluoxetine-treated patients gained at least 15% of their baseline weight, with a median exposure to event of 8 weeks. This was greater than in placebo-treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of olanzapine and fluoxetine-treated patients and 0% of placebo-treated patients.
In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), the mean weight gain was 6.7 kg (14.7 lb) (median exposure of 448 days, N=431). The percentages of patients who gained at least 7%, 15% or 25% of their baseline body weight with long-term exposure were 66%, 33%, and 10%, respectively. Discontinuation due to weight gain occurred in 1.2% of patients treated with olanzapine and fluoxetine in combination following at least 48 weeks of exposure.
Table 11 presents the distribution of weight gain in a single long-term relapse prevention study of patients treated for up to 47 weeks with olanzapine and fluoxetine [see Clinical Studies (14.2)].
Table 11: Weight Gain with Olanzapine and Fluoxetine Use in a Single Relapse Prevention Study in Adults
In long-term olanzapine studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). 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 12 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 12: Weight Gain with Olanzapine Use in Adults
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.
Children and Adolescents - In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, olanzapine and fluoxetine was associated with greater mean change in weight compared to placebo (+4.4 kg vs +0.5 kg, respectively). The percentages of children and adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with 8-week exposure were 52%, 14%, and 1%, respectively. The proportion of patients who had clinically significant weight gain was greater in children and adolescent patients compared to short-term data in adults. Discontinuation due to weight gain occurred in 2.9% of olanzapine and fluoxetine-treated patients and 0% of placebo-treated patients. Table 13 depicts weight gain observed in the pediatric olanzapine and fluoxetine study.
Table 13: Weight Gain with Olanzapine and Fluoxetine Use Seen in a Single Pediatric Study in Bipolar Depression
Olanzapine Monotherapy in Adolescents -- 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 14: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials
In long-term olanzapine 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 15 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.