Quetiapine Fumarate Extended Release (Page 3 of 12)

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 fumarate 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 Studies *
*
Includes quetiapine fumarate tablets and quetiapine fumarate 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 fumarate 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 fumarate tablets (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 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 18.0 per 100 patient years for quetiapine fumarate 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 fumarate extended-release tablets

150 mg

280

19 (7%)

Quetiapine fumarate extended-release tablets 300 mg

269

32 (12%)

Placebo

277

17 (6%)

Children and Adolescents:

Safety and effectiveness of quetiapine fumarate extended-release tablets is supported from studies of quetiapine fumarate tablets in children and adolescent patients 10 to 17 years of age [ see Clinical Studies (14.2) ]. In a placebo-controlled quetiapine fumarate extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 – 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine fumarate 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 fumarate 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 fumarate 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 fumarate tablets monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine fumarate tablets (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled quetiapine fumarate tablets monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine fumarate 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 fumarate 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
*
6 weeks duration
8 weeks duration
3 weeks duration

Laboratory

Analyte

Indication

Treatment Arm

N

Patients

n (%)

Total Cholesterol ≥240 mg/dL

Schizophrenia *

Quetiapine fumarate extended-release tablets

718

67 (9%)

Placebo

232

21 (9%)

Bipolar Depression

Quetiapine fumarate extended-release tablets

85

6 (7%)

Placebo

106

3 (3%)

Bipolar Mania

Quetiapine fumarate extended-release tablets

128

9 (7%)

Placebo

134

5 (4%)

Major Depressive Disorder (Adjunct Therapy) *

Quetiapine fumarate extended-release tablets

420

67 (16%)

Placebo

213

15 (7%)

Triglycerides ≥200 mg/dL

Schizophrenia *

Quetiapine fumarate extended-release tablets

659

118 (18%)

Placebo

214

11 (5%)

Bipolar Depression

Quetiapine fumarate extended-release tablets

84

7 (8%)

Placebo

93

7 (8%)

Bipolar Mania

Quetiapine fumarate extended-release tablets

102

15 (15%)

Placebo

125

8 (6%)

Major Depressive Disorder (Adjunct Therapy) *

Quetiapine fumarate extended-release tablets

458

75 (16%)

Placebo

223

18 (8%)

LDL-Cholesterol ≥ 160 mg/dL

Schizophrenia *

Quetiapine fumarate extended-release tablets

691

47 (7%)

Placebo

227

17 (8%)

Bipolar Depression

Quetiapine fumarate extended-release tablets

86

3 (4%)

Placebo

104

2 (2%)

Bipolar Mania

Quetiapine fumarate extended-release tablets

125

5 (4%)

Placebo

135

2 (2%)

Major Depressive Disorder (Adjunct Therapy) *

Quetiapine fumarate extended-release tablets

457

51 (11%)

Placebo

219

21 (10%)

HDL-Cholesterol ≤ 40 mg/dL

Schizophrenia *

Quetiapine fumarate extended-release tablets

600

87 (15%)

Placebo

195

23 (12%)

Bipolar Depression

Quetiapine fumarate extended-release tablets

78

7 (9%)

Placebo

83

6 (7%)

Bipolar Mania

Quetiapine fumarate extended-release tablets

100

19 (19%)

Placebo

115

15 (13%)

Major Depressive Disorder (Adjunct Therapy) *

Quetiapine fumarate extended-release tablets

470

34 (7%)

Placebo

230

19 (8%)

In quetiapine fumarate 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 fumarate 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
*
6 weeks duration

Laboratory

Analyte

Treatment Arm *

N

Patients

n (%)

Cholesterol ≥ 240 mg/dL

Quetiapine fumarate extended-release tablets

150 mg

223

41 (18%)

Quetiapine fumarate extended-release tablets

300 mg

197

26 (13%)

Placebo

213

15 (7%)

Triglycerides ≥ 200 mg/dL

Quetiapine fumarate extended-release tablets

150 mg

232

36 (16%)

Quetiapine fumarate extended-release tablets

300 mg

226

39 (17%)

Placebo

223

18 (8%)

LDL-Cholesterol ≥ 160 mg/dL

Quetiapine fumarate extended-release tablets

150 mg

242

29 (12%)

Quetiapine fumarate extended-release tablets

300 mg

215

22 (10%)

Placebo

219

21 (10%)

HDL-Cholesterol ≤ 40 mg/dL

Quetiapine fumarate extended-release tablets

150 mg

238

14 (6%)

Quetiapine fumarate extended-release tablets

300 mg

232

20 (9%)

Placebo

230

19 (8%)

Children and Adolescents:

Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate 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 fumarate extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10-17 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 fumarate extended-release tablets vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine fumarate extended-release tablets vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine fumarate extended-release tablets vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine fumarate 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 fumarate tablets in adolescents (13–17 years) with schizophrenia and in children and adolescents (10–17 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
*
13-17 years, 6 weeks duration
10-17 years, 3 weeks duration

Laboratory Analyte

Indication

Treatment Arm

N

Patients

n (%)

Total Cholesterol ≥200 mg/dL

Schizophrenia *

Quetiapine fumarate tablets

107

13 (12%)

Placebo

56

1 (2%)

Bipolar Mania

Quetiapine fumarate tablets

159

16 (10%)

Placebo

66

2 (3%)

Triglycerides ≥150 mg/dL

Schizophrena *

Quetiapine fumarate tablets

103

17 (17%)

Placebo

51

4 (8%)

Bipolar Mania

Quetiapine fumarate tablets

149

32 (22%)

Placebo

60

8 (13%)

LDL-Cholesterol ≥ 130 mg/dL

Schizophrenia *

Quetiapine fumarate tablets

112

4 (4%)

Placebo

60

1 (2%)

Bipolar Mania

Quetiapine fumarate tablets

169

13 (8%)

Placebo

74

4 (5%)

HDL-Cholesterol ≤ 40 mg/dL

Schizophrenia *

Quetiapine fumarate tablets

104

16 (15%)

Placebo

54

10 (19%)

Bipolar Mania

Quetiapine fumarate 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
*
6 weeks duration
3 weeks duration
8 weeks duration

Vital sign

Indication

Treatment Arm

N

Patients

n (%)

Weight Gain ≥7% of Body Weight

Schizophrenia *

Quetiapine fumarate extended-release tablets

907

90 (10%)

Placebo

299

16 (5%)

Bipolar Mania

Quetiapine fumarate extended-release tablets

138

7 (5%)

Placebo

150

0 (0%)

Bipolar Depression

Quetiapine fumarate extended-release tablets

110

9 (8%)

Placebo

125

1 (1%)

Major Depressive Disorder (Adjunctive Therapy) *

Quetiapine fumarate 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 fumarate 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

  1. Treatment Arm

N

Patients

n (%)

Weight Gain ≥7% of Body Weight in MDD Adjunctive Therapy

Quetiapine fumarate extended-release tablets

  1. 150 mg

309

10 (3%)

Quetiapine fumarate extended-release tablets

  1. 300 mg

307

22 (7%)

  1. Placebo

302

5 (2%)

Children and Adolescents: Safety and effectiveness of quetiapine fumarate extended-release tablets is supported by studies of quetiapine fumarate 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 fumarate extended-release tablets in children and adolescents (10-17 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 fumarate extended-release tablets vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the quetiapine fumarate extended-release tablets group vs. 0.6 kg in the placebo group.

Weight gain was greater in patients 10-12 years of age compared to patients 13-17 years of age. The percentage of patients 10-12 years of age with weight gain ≥7% at any time was 28% (7/25) for quetiapine fumarate extended-release tablets vs. 0% (0/28) for placebo. The percentage of patients 13 — 17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for quetiapine fumarate 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 fumarate tablets in adolescents (13 – 17 years) with schizophrenia and in children and adolescents (10 – 17 years) with bipolar mania.

Table 10: Percentage of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents)
*
6 weeks duration
3 weeks duration

Vital sign

Indication

Treatment Arm

N

Patients

n (%)

Weight Gain ≥7% of Body Weight

Schizophrenia *

Quetiapine fumarate tablets

111

23 (21%)

Placebo

44

3 (7%)

Bipolar Mania

Quetiapine fumarate tablets

157

18 (12%)

Placebo

68

0 (0%)

The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine fumarate group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine fumarate 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 fumarate 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 fumarate tablets met this criterion after 26 weeks of treatment.

When treating pediatric patients with quetiapine fumarate tablets for any indication, weight gain should be assessed against that expected for normal growth.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.