Olanzapine and Fluoxetine: Package Insert and Label Information (Page 3 of 13)
Dyslipidemia
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
| Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | Patients |
| Nonfasting Triglycerides | Increase by ≥50 mg/dL | OFC | 174 | 67.8% |
| Olanzapine | 172 | 72.7% | ||
| Normal to High (<150 mg/dL to ≥500 mg/dL) | OFC | 57 | 0% | |
| Olanzapine | 58 | 0% | ||
| Borderline to High (≥150 mg/dL and <500 mg/dL to ≥500 mg/dL) | OFC | 106 | 15.1% | |
| Olanzapine | 103 | 8.7% | ||
| Nonfasting Total Cholesterol | Increase by ≥40 mg/dL | OFC | 685 | 35% |
| Olanzapine | 749 | 22.7% | ||
| Placebo | 390 | 9% | ||
| Normal to High (<200 mg/dL to ≥240 mg/dL) | OFC | 256 | 8.2% | |
| Olanzapine | 279 | 2.9% | ||
| Placebo | 175 | 1.7% | ||
| Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) | OFC | 213 | 36.2% | |
| Olanzapine | 261 | 27.6% | ||
| Placebo | 111 | 9.9% |
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
| Up to 27 Weeks Treatment (Randomized, Double-Blind Phase) | Up to 47 Weeks Treatment | |||||
| Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | Patients | N | Patients |
| Fasting Total Cholesterol | Normal to High (<200 mg/dL to ≥240 mg/dL) | OFC | 47 | 2.1% | 83 | 19.3% |
| Fluoxetine | 59 | 3.4% | NAa | NAa | ||
| Borderline to High (≥200 and <240 mg/dL to ≥240 mg/dL) | OFC | 75 | 28.0% | 73 | 69.9% | |
| Fluoxetine | 83 | 20.5% | NAa | NAa | ||
| Fasting LDL Cholesterol | Normal to High (<100 mg/dL to ≥160 mg/dL) | OFC | 22 | 4.5% | 46 | 8.7% |
| Fluoxetine | 26 | 0% | NAa | NAa | ||
| Borderline to High ( ≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) | OFC | 115 | 17.4% | 128 | 46.9% | |
| Fluoxetine | 134 | 10.4% | NAa | NAa | ||
| Fasting HDL Cholesterol | Normal to Low (≥40 mg/dL to <40 mg/dL) | OFC | 199 | 39.2% | 193 | 45.1% |
| Fluoxetine | 208 | 25.5% | NAa | NAa | ||
| Fasting Triglycerides | Normal to High (<150 mg/dL to ≥200 mg/dL) | OFC | 68 | 16.2% | 115 | 46.1% |
| Fluoxetine | 74 | 5.4% | NAa | NAa | ||
| Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) | OFC | 47 | 51.1% | 40 | 72.5% | |
| Fluoxetine | 41 | 26.8% | NAa | NAa | ||
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
| 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% | NAa | NAa | ||
| Normal to High (<150 mg/dL to ≥200 mg/dL) | Olanzapine | 457 | 9.2% | 293 | 32.4% | |
| Placebo | 251 | 4.4% | NAa | NAa | ||
| Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) | Olanzapine | 135 | 39.3% | 75 | 70.7% | |
| Placebo | 65 | 20.0% | NAa | NAa | ||
| Fasting Total Cholesterol | Increase by ≥40 mg/dL | Olanzapine | 745 | 21.6% | 489 | 32.9% |
| Placebo | 402 | 9.5% | NAa | NAa | ||
| Normal to High (<200 mg/dL to ≥240 mg/dL) | Olanzapine | 392 | 2.8% | 283 | 14.8% | |
| Placebo | 207 | 2.4% | NAa | NAa | ||
| Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) | Olanzapine | 222 | 23.0% | 125 | 55.2% | |
| Placebo | 112 | 12.5% | NAa | NAa | ||
| Fasting LDL Cholesterol | Increase by ≥30 mg/dL | Olanzapine | 536 | 23.7% | 483 | 39.8% |
| Placebo | 304 | 14.1% | NAa | NAa | ||
| Normal to High (<100 mg/dL to ≥160 mg/dL) | Olanzapine | 154 | 0% | 123 | 7.3% | |
| Placebo | 82 | 1.2% | NAa | NAa | ||
| Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) | Olanzapine | 302 | 10.6% | 284 | 31.0% | |
| Placebo | 173 | 8.1% | NAa | NAa | ||
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
| Up to 8 weeks exposure | ||||
| Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | Patients |
| Fasting Triglycerides | Increase by ≥50 mg/dL | OFC | 158 | 70.3% |
| Placebo | 81 | 38.3% | ||
| Normal to High (<90 mg/dL to ≥130 mg/dL) | OFC | 71 | 39.4% | |
| Placebo | 31 | 19.4% | ||
| Borderline to High (≥90 mg/dL and <130 mg/dL to ≥130mg/dL) | OFC | 13 | 84.6% | |
| Placebo | 12 | 33.3% | ||
| Normal/Borderline to High (<130 mg/dL to ≥130 mg/dL) | OFC | 106 | 52.8% | |
| Placebo | 56 | 25.0% | ||
| Normal to Borderline/High ( <90 mg/dL to ≥90 mg/dL) | OFC | 71 | 73.2% | |
| Placebo | 31 | 41.9% | ||
| Normal/Borderline/High to very high (<500 mg/dL to ≥500 mg/dL) | OFC | 158 | 2.5% | |
| Placebo | 81 | 1.2% | ||
| Fasting Total Cholesterol | Increase by ≥40 mg/dL | OFC | 158 | 52.5% |
| Placebo | 81 | 8.6% | ||
| Normal to High (<170 mg/dL to ≥200 mg/dL) | OFC | 81 | 12.3% | |
| Placebo | 44 | 4.5% | ||
| Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL) | OFC | 22 | 72.7% | |
| Placebo | 11 | 24.3% | ||
| Normal/Borderline to High (<200 mg/dL to ≥200 mg/dL) | OFC | 126 | 32.5% | |
| Placebo | 67 | 10.4% | ||
| Normal to Borderline/High ( <170 mg/dL to ≥170 mg/dL) | OFC | 81 | 58.0% | |
| Placebo | 44 | 31.8% | ||
| Fasting LDL Cholesterol | Increase by ≥30 mg/dL | OFC | 158 | 53.8% |
| Placebo | 81 | 23.5% | ||
| Normal to High (<110 mg/dL to ≥130 mg/dL) | OFC | 112 | 13.4% | |
| Placebo | 62 | 6.5% | ||
| Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL) | OFC | 12 | 75.0% | |
| Placebo | 3 | 0.0% | ||
| Normal/Borderline to High (<130 mg/dL to ≥130 mg/dL) | OFC | 138 | 21.7% | |
| Placebo | 77 | 7.8% | ||
| Normal to Borderline/High ( <110 mg/dL to ≥110 mg/dL) | OFC | 112 | 30.4% | |
| Placebo | 62 | 14.5% | ||
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
| 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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