Symbyax (Page 3 of 15)

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue SYMBYAX if DRESS is suspected.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Adults — Healthcare providers should consider the risks and benefits when prescribing SYMBYAX to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking SYMBYAX should be monitored regularly for worsening of glucose control. Patients starting treatment with SYMBYAX 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, SYMBYAX 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 SYMBYAX 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). SYMBYAX-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 SYMBYAX-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 SYMBYAX studies.

Table 2: Changes in Random Glucose Levels from Adult SYMBYAX Studies

a Not Applicable.

Up to 12 weeks exposure At least 48 weeks exposure
Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients
Random Glucose Normal to High(<140 mg/dL to ≥200 mg/dL) SYMBYAX 609 2.3% 382 3.1%
Placebo 346 0.3% NAa NAa
Borderline to High(≥140 mg/dL and <200 mg/dL to ≥200 mg/dL) SYMBYAX 44 34.1% 27 37.0%
Placebo 28 3.6% NAa NAa

In a 47-week SYMBYAX 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)].

Table 3: Changes in Fasting Glucose Levels from a Single Adult SYMBYAX Study

a Not Applicable.

Up to 27 Weeks Exposure(Randomized, Double-Blind Phase) Up to 47 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) SYMBYAX 90 4.4% 130 11.5%
Fluoxetine 96 5.2% NAa NAa
Borderline to High(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) SYMBYAX 98 18.4% 79 32.9%
Fluoxetine 97 7.2% NAa NAa

Controlled fasting glucose data is limited for SYMBYAX; 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 9-12 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 SYMBYAX for treatment of bipolar I depression in patients 10 to 17 years of age, there were no clinically meaningful differences observed between SYMBYAX and placebo for mean change in fasting glucose levels. Table 4 shows categorical changes in fasting blood glucose from the pediatric SYMBYAX study.

Table 4: Changes in Fasting Glucose Levels from a Single Pediatric SYMBYAX Study in Bipolar Depression

a Impaired Glucose Tolerance.

Up to 8 weeks exposure
Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients
Fasting Glucose Normal to High(<100 mg/dL to ≥126 mg/dL) SYMBYAX 125 4.8%
Placebo 65 1.5%
Normal/IGTa to High(<126 mg/dL to ≥126 mg/dL) SYMBYAX 156 5.8%
Placebo 78 1.3%
Normal/IGT (<126 mg/dL) to ≥140 mg/dL) SYMBYAX 156 1.9%
Placebo 78 0.0%

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.

Table 5: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.

Up to 12 weeks exposure At least 24 weeks exposure
Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients
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

Dyslipidemia

Undesirable alterations in lipids have been observed with SYMBYAX use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using SYMBYAX, is recommended.

Adults — Clinically meaningful, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with SYMBYAX use. Clinically meaningful increases in total cholesterol have also been seen with SYMBYAX use.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, SYMBYAX-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
NonfastingTriglycerides Increase by ≥50 mg/dL SYMBYAX 174 67.8%
Olanzapine 172 72.7%
Normal to High(<150 mg/dL to ≥500 mg/dL) SYMBYAX 57 0%
Olanzapine 58 0%
Borderline to High(≥150 mg/dL and <500 mg/dL to ≥500 mg/dL) SYMBYAX 106 15.1%
Olanzapine 103 8.7%
NonfastingTotal Cholesterol Increase by ≥40 mg/dL SYMBYAX 685 35%
Olanzapine 749 22.7%
Placebo 390 9%
Normal to High(<200 mg/dL to ≥240 mg/dL) SYMBYAX 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) SYMBYAX 213 36.2%
Olanzapine 261 27.6%
Placebo 111 9.9%

A 47-week SYMBYAX 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 SYMBYAX Treatment Duration up to 47 Weeks

a Not Applicable.

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) SYMBYAX 47 2.1% 83 19.3%
Fluoxetine 59 3.4% NAa NAa
Borderline to High (≥200 and <240 mg/dL to ≥240 mg/dL) SYMBYAX 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) SYMBYAX 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) SYMBYAX 115 17.4% 128 46.9%
Fluoxetine 134 10.4% NAa NAa
Fasting HDLCholesterol Normal to Low(≥40 mg/dL to <40 mg/dL) SYMBYAX 199 39.2% 193 45.1%
Fluoxetine 208 25.5% NAa NAa
Fasting Triglycerides Normal to High(<150 mg/dL to ≥200 mg/dL) SYMBYAX 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) SYMBYAX 47 51.1% 40 72.5%
Fluoxetine 41 26.8% NAa NAa

Fasting lipid data is limited for SYMBYAX; 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 4-6 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.

Up to 12 weeks exposure At least 48 weeks exposure
Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients
Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4%
Placebo 402 26.1% NAa NAa
Fasting Normal to High Olanzapine 457 9.2% 293 32.4%
Triglycerides (<150 mg/dL to ≥200 mg/dL) Placebo 251 4.4% NAa NAa
Borderline to High Olanzapine 135 39.3% 75 70.7%
(≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) Placebo 65 20.0% NAa NAa
Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9%
Placebo 402 9.5% NAa NAa
Fasting Normal to High Olanzapine 392 2.8% 283 14.8%
Total Cholesterol (<200 mg/dL to ≥240 mg/dL) Placebo 207 2.4% NAa NAa
Borderline to High Olanzapine 222 23.0% 125 55.2%
(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) Placebo 112 12.5% NAa NAa
Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8%
Placebo 304 14.1% NAa NAa
Fasting Normal to High Olanzapine 154 0% 123 7.3%
LDL Cholesterol (<100 mg/dL to ≥160 mg/dL) Placebo 82 1.2% NAa NAa
Borderline to High Olanzapine 302 10.6% 284 31.0%
(≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) Placebo 173 8.1% NAa NAa

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 SYMBYAX for treatment of bipolar I depression in patients 10 to 17 years of age, there were clinically meaningful and statistically significant differences observed between SYMBYAX 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 SYMBYAX study.

Table 9: Changes in Fasting Lipids Values from a Single Pediatric SYMBYAX Study in Bipolar Depression
Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 8 weeks exposure
N Patients
FastingTriglycerides Increase by ≥50 mg/dL SYMBYAX 158 70.3%
Placebo 81 38.3%
Normal to High(<90 mg/dL to ≥130 mg/dL) SYMBYAX 71 39.4%
Placebo 31 19.4%
Borderline to High(≥90 mg/dL and <130 mg/dL to ≥130 mg/dL) SYMBYAX 13 84.6%
Placebo 12 33.3%
Normal/borderline to High(<130 mg/dL to ≥130 mg/dL) SYMBYAX 106 52.8%
Placebo 56 25.0%
Normal to borderline/high(<90 mg/dL to ≥90 mg/dL) SYMBYAX 71 73.2%
Placebo 31 41.9%
Normal/borderline/high to very high(<500 mg/dL to ≥500 mg/dL) SYMBYAX 158 2.5%
Placebo 81 1.2%
FastingTotal Cholesterol Increase by ≥40 mg/dL SYMBYAX 158 52.5%
Placebo 81 8.6%
Normal to High(<170 mg/dL to ≥200 mg/dL) SYMBYAX 81 12.3%
Placebo 44 4.5%
Borderline to High(≥170 mg/dL and <200 mg/dL to ≥200 mg/dL) SYMBYAX 22 72.7%
Placebo 11 24.3%
Normal/borderline to High(<200 mg/dL to ≥200 mg/dL) SYMBYAX 126 32.5%
Placebo 67 10.4%
Normal to borderline/high(<170 mg/dL to ≥170 mg/dL) SYMBYAX 81 58.0%
Placebo 44 31.8%
FastingLDL Cholesterol Increase by ≥30 mg/dL SYMBYAX 158 53.8%
Placebo 81 23.5%
Normal to High(<110 mg/dL to ≥130 mg/dL) SYMBYAX 112 13.4%
Placebo 62 6.5%
Borderline to High(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL) SYMBYAX 12 75.0%
Placebo 3 0.0%
Normal/borderline to High(<130 mg/dL to ≥130 mg/dL) SYMBYAX 138 21.7%
Placebo 77 7.8%
Normal to borderline/high(<110 mg/dL to ≥110 mg/dL) SYMBYAX 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

a Not Applicable.

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 6 weeks exposure At least 24 weeks exposure
N Patients N Patients
FastingTriglycerides 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
FastingTotal 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
FastingLDL 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

Weight Gain

Potential consequences of weight gain should be considered prior to starting SYMBYAX. Patients receiving SYMBYAX 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 SYMBYAX-treated patients was greater than placebo-treated patients [4 kg (8.8 lb) vs -0.3 kg (-0.7 lb)]. Twenty-two percent of SYMBYAX-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 SYMBYAX-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 SYMBYAX-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 SYMBYAX [see Clinical Studies (14.2)].

Table 11: Weight Gain with SYMBYAX Use in a Single Relapse Prevention Study in Adults
Amount Gained kg (lb) Up to 8 Weeks (N=881) (%) Up to 20 Weeks (N=651) (%) Up to 47 Weeks (N=220) (%)
≤0 19.8 14.9 19.1
0 to ≤5 (0-11 lb) 64.1 47.2 37.7
>5 to ≤10 (11-22 lb) 15.1 30.3 27.7
>10 to ≤15 (22-33 lb) 0.9 5.8 10.0
>15 to ≤20 (33-44 lb) 0.1 1.2 3.2
>20 to ≤25 (44-55 lb) 0.0 0.6 1.4
>25 to ≤30 (55-66 lb) 0.0 0.0 0.5
>30 (>66 lb) 0.0 0.0 0.5

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
Amount Gainedkg (lb) 6 Weeks(N=7465)(%) 6 Months(N=4162)(%) 12 Months(N=1345)(%) 24 Months(N=474)(%) 36 Months(N=147)(%)
≤0 26.2 24.3 20.8 23.2 17.0
0 to ≤5 (0-11 lb) 57.0 36.0 26.0 23.4 25.2
>5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4
>10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17.0
>15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6
>20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1
>25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8
>30 (>66 lb) 0 0.1 0.8 1.2 2

Dose group differences with respect to weight gain have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Children and Adolescents — In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, SYMBYAX 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 SYMBYAX-treated patients and 0% of placebo-treated patients. Table 13 depicts weight gain observed in the pediatric SYMBYAX study.

Table 13: Weight Gain with SYMBYAX Use Seen in a Single Pediatric Study in Bipolar Depression
Amount Gainedkg (lb) Up to 8 Weeks(N=170)(%)
≤0 7.1
0 to ≤5 (0-11 lb) 54.7
>5 to ≤10 (11-22 lb) 31.2
>10 to ≤15 (22-33 lb) 7.1
>15 to ≤20 (33-44 lb) 0
>20 to ≤25 (44-55 lb) 0
>25 to ≤30 (55-66 lb) 0
>30 (>66 lb) 0

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
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 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.

Table 15: Weight Gain with Olanzapine Use in Adolescents
Amount Gainedkg (lb) 6 Weeks(N=243)(%) 6 Months(N=191)(%)
≤0 2.9 2.1
0 to ≤5 (0-11 lb) 47.3 24.6
>5 to ≤10 (11-22 lb) 42.4 26.7
>10 to ≤15 (22-33 lb) 5.8 22.0
>15 to ≤20 (33-44 lb) 0.8 12.6
>20 to ≤25 (44-55 lb) 0.8 9.4
>25 to ≤30 (55-66 lb) 0 2.1
>30 to ≤35 (66-77 lb) 0 0
>35 to ≤40 (77-88 lb) 0 0
>40 (>88 lb) 0 0.5

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