Quetiapine Fumarate: Package Insert and Label Information (Page 2 of 9)

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Quetiapine extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

5.4 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 quetiapine. Rare cases of NMS have been reported with quetiapine. 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 creatine 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 (CNS) 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.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics 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.
Adults:

Table 3: Fasting Glucose-Proportion of Patients Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled Studies1
1. Includes quetiapine tablets and quetiapine extended-release tablets data.
Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%)
Fasting Glucose Normal to High(<100 mg/dL to ≥ 126 mg/dL) Quetiapine 2907 71 (2.4%)
Placebo 1346 19 (1.4%)
Borderline to High(≥ 100 mg/dL and<126 mg/dL to ≥ 126 mg/dL) Quetiapine 572 67 (11.7%)
Placebo 279 33 (11.8%)

In a 24-week trial (active-controlled, 115 patients treated with quetiapine tablets) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of post-glucose challenge glucose level ≥200 mg/dL was 1.7% and the incidence of a fasting blood glucose level ≥126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.
In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for quetiapine tablets (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5 mg/dL for quetiapine and -0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18 per 100 patient years for quetiapine tablets (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581). Table 4 shows the percentage of patients with shifts in blood glucose to ≥126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.

Table 4: Percentage of Patients with Shifts from Normal Baseline in Blood Glucose to ≥126 mg/dL (assumed fasting) in MDD Adjunct Therapy Trials by Dose
Laboratory Analyte Treatment Arm N Patients n (%)
Blood Glucose ≥126 mg/dL Quetiapine Extended-Release Tablets150 mg 280 19 (7%)
Quetiapine Extended-Release Tablets300 mg 269 32 (12%)
Placebo 277 17 (6%)

Children and Adolescents:

Safety and effectiveness of quetiapine extended-release tablets are supported from studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.2)]. In a placebo-controlled quetiapine extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine extended-release tablets (n=60) compared to placebo (n=62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the quetiapine extended-release tablets or placebo-treated groups with a baseline normal fasting glucose level (<100 mg/dL) that had an increase in blood glucose level >126 mg/dL. There was one patient in the quetiapine extended-release tablets group with a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) who had an increase in blood glucose level of >126 mg/dL compared to zero patients in the placebo group.
In a placebo-controlled quetiapine tablets monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine tablets (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.7 mg/dL. In a placebo-controlled quetiapine tablets monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine tablets (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a blood glucose level of ≥126 mg/dL.

Dyslipidemia

Adults:
Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with quetiapine extended-release tablets.

Table 5: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication
1. 6 weeks duration 2. 8 weeks duration 3. 3 weeks duration
Laboratory Analyte Indication Treatment Arm N Patients n (%)
Total Cholesterol ≥240 mg/dL Schizophrenia 1 Quetiapine Extended-Release Tablets 718 67 (9%)
Placebo 232 21 (9%)
BipolarDepression 2 Quetiapine Extended-Release Tablets 85 6 (7%)
Placebo 106 3 (3%)
Bipolar Mania 3 Quetiapine Extended-Release Tablets 128 9 (7%)
Placebo 134 5 (4%)
Major Depressive Disorder (Adjunct Therapy)1 Quetiapine Extended-Release Tablets 420 67 (16%)
Placebo 213 15 (7%)
Triglycerides≥200 mg/dL Schizophrenia 1 Quetiapine Extended-Release Tablets 659 118 (18%)
Placebo 214 11 (5%)
BipolarDepression 2 Quetiapine Extended-Release Tablets 84 7 (8%)
Placebo 93 7 (8%)
Bipolar Mania 3 Quetiapine Extended-Release Tablets 102 15 (15%)
Placebo 125 8 (6%)
Major Depressive Disorder (Adjunct Therapy)1 Quetiapine Extended-Release Tablets 458 75 (16%)
Placebo 223 18 (8%)
LDL-Cholesterol ≥160 mg/dL Schizophrenia 1 Quetiapine Extended-Release Tablets 691 47 (7%)
Placebo 227 17 (8%)
BipolarDepression 2 Quetiapine Extended-Release Tablets 86 3 (4%)
Placebo 104 2 (2%)
Bipolar Mania 3 Quetiapine Extended-Release Tablets 125 5 (4%)
Placebo 135 2 (2%)
Major Depressive Disorder (Adjunct Therapy)1 Quetiapine Extended-Release Tablets 457 51 (11%)
Placebo 219 21 (10%)
HDL-Cholesterol ≤40 mg/dL Schizophrenia 1 Quetiapine Extended-Release Tablets 600 87 (15%)
Placebo 195 23 (12%)
Bipolar Depression 2 Quetiapine Extended-Release Tablets 78 7 (9%)
Placebo 83 6 (7%)
Bipolar Mania 3 Quetiapine Extended-Release Tablets 100 19 (19%)
Placebo 115 15 (13%)
Major Depressive Disorder (Adjunct Therapy)1 Quetiapine Extended-Release Tablets 470 34 (7%)
Placebo 230 19 (8%)

In quetiapine tablets clinical trials for schizophrenia, the percentage of patients with shifts in cholesterol and triglycerides from baseline to clinically significant levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol parameters were not measured in these studies. In quetiapine tablets clinical trials for bipolar depression, the following percentage of patients had shifts from baseline to clinically significant levels for the four lipid parameters measured: total cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol 6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were not measured in the bipolar mania studies. Table 6 shows the percentage of patients in MDD adjunctive therapy trials with clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by dose.

Table 6: Percentage of Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels in MDD Adjunctive Therapy Trials by Dose
1. 6 weeks duration
Laboratory Analyte Treatment Arm 1 N Patients n (%)
Cholesterol ≥240 mg/dL Quetiapine Extended-Release Tablets150 mg 223 41 (18%)
Quetiapine Extended-Release Tablets300 mg 197 26 (13%)
Placebo 213 15 (7%)
Triglycerides ≥200 mg/dL Quetiapine Extended-Release Tablets150 mg 232 36 (16%)
Quetiapine Extended-Release Tablets300 mg 226 39 (17%)
Placebo 223 18 (8%)
LDL-Cholesterol ≥160 mg/dL Quetiapine Extended-Release Tablets150 mg 242 29 (12%)
Quetiapine Extended-Release Tablets300 mg 215 22 (10%)
Placebo 219 21 (10%)
HDL-Cholesterol ≤40 mg/dL Quetiapine Extended-Release Tablets150 mg 238 14 (6%)
Quetiapine Extended-Release Tablets300 mg 232 20 (9%)
Placebo 230 19 (8%)

Children and Adolescents:

Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].
In a placebo-controlled quetiapine extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥130 mg/dL), and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for quetiapine extended-release tablets vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release tablets vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine extended-release tablets vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine extended-release tablets vs. 15% (11/74) for placebo. Table 7 shows the percentage of children and adolescents with shifts in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline to clinically significant levels by indication in clinical trials with quetiapine tablets in adolescents (13 to 17 years) with schizophrenia and in children and adolescents (10 to 17 years) with bipolar mania.

Table 7: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication
1. 13 to 17 years, 6 weeks duration 2. 10 to 17 years, 3 weeks duration
Laboratory Analyte Indication Treatment Arm N Patients n (%)
Total Cholesterol≥200 mg/dL Schizophrenia 1 Quetiapine Tablets 107 13 (12%)
Placebo 56 1 (2%)
Bipolar Mania 2 Quetiapine Tablets 159 16 (10%)
Placebo 66 2 (3%)
Triglycerides ≥150 mg/dL Schizophrenia 1 Quetiapine Tablets 103 17 (17%)
Placebo 51 4 (8%)
Bipolar Mania 2 Quetiapine Tablets 149 32 (22%)
Placebo 60 8 (13%)
LDL-Cholesterol ≥130 mg/dL Schizophrenia 1 Quetiapine Tablets 112 4 (4%)
Placebo 60 1 (2%)
Bipolar Mania 2 Quetiapine Tablets 169 13 (8%)
Placebo 74 4 (5%)
HDL-Cholesterol ≤40 mg/dL Schizophrenia 1 Quetiapine Tablets 104 16 (15%)
Placebo 54 10 (19%)
Bipolar Mania 2 Quetiapine Tablets 154 16 (10%)
Placebo 61 4 (7%)

Weight Gain

Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.
Adults: Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.

Table 8: Percentage of Patients with Weight Gain ≥7% of Body Weight (Adults) by Indication
1. 6 weeks duration 2. 3 weeks duration 3. 8 weeks duration
Vital sign Indication Treatment Arm N Patients n (%)
Weight Gain ≥7% of Body Weight Schizophrenia 1 Quetiapine Extended-Release Tablets 907 90 (10%)
Placebo 299 16 (5%)
Bipolar Mania 2 Quetiapine Extended-Release Tablets 138 7 (5%)
Placebo 150 0 (0%)
Bipolar Depression 3 Quetiapine Extended-Release Tablets 110 9 (8%)
Placebo 125 1 (1%)
Major Depressive Disorder (Adjunctive Therapy)1 Quetiapine Extended-Release Tablets 616 32 (5%)
Placebo 302 5 (2%)

In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for quetiapine tablets (23%) compared to placebo (6%). Table 9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.

Table 9: Percentage of Patients with Weight Gain ≥7% of Body Weight in MDD Adjunctive Therapy Trials by Dose (Adults)
Vital sign Treatment Arm N Patients n (%)
Weight Gain ≥7% of Body Weight in MDD Adjunctive Therapy Quetiapine Extended-Release Tablets150 mg 309 10 (3%)
Quetiapine Extended-Release Tablets 300 mg 307 22 (7%)
Placebo 302 5 (2%)

Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)]. In a clinical trial for quetiapine extended-release tablets in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for quetiapine extended-release tablets vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the quetiapine extended-release tablets group vs. 0.6 kg in the placebo group.
Weight gain was greater in patients 10 to 12 years of age compared to patients 13 to 17 years of age. The percentage of patients 10 to 12 years of age with weight gain ≥7% at any time was 28% (7/25) for quetiapine extended-release tablets vs. 0% (0/28) for placebo. The percentage of patients 13 to 17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for quetiapine extended-release tablets vs. 13.9% (10/72) for placebo. Table 10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with quetiapine tablets in adolescents (13 to 17 years) with schizophrenia and in children and adolescents (10 to 17 years) with bipolar mania.

Table 10: Percentage of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents)
1. 6 weeks duration 2. 3 weeks duration
Vital sign Indication Treatment Arm N Patients n (%)
Weight Gain ≥7% of Body Weight Schizophrenia 1 Quetiapine Tablets 111 23 (21%)
Placebo 44 3 (7%)
Bipolar Mania 2 Quetiapine Tablets 157 18 (12%)
Placebo 68 0 (0%)

The mean change in body weight in the schizophrenia trial was 2 kg in the quetiapine tablets group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine tablets group and 0.4 kg in the placebo group.
In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine tablets. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on quetiapine tablets met this criterion after 26 weeks of treatment.
When treating pediatric patients with quetiapine tablets for any indication, weight gain should be assessed against that expected for normal growth.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2020. All Rights Reserved.