SEROQUEL (Page 3 of 12)

5.3 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 SEROQUEL. Rare cases of NMS have been reported with SEROQUEL. 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.

5.4 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 treatment-emergent 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.

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 parameters should be managed as clinically appropriate.

Adults:

Table 2: Fasting Glucose — Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies
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 SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent 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 maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for SEROQUEL 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 SEROQUEL (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents: In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13 –17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled SEROQUEL 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 SEROQUEL (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 treatment-emergent blood glucose level of ≥126 mg/dL.

5.5 Hyperlipidemia

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

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 parameters should be managed as clinically appropriate.

Adults:

Table 3 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with SEROQUEL.

Table 3: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication
Laboratory Analyte Indication Treatment Arm N Patients n (%)
*
6 weeks duration
8 weeks duration
Parameters not measured in the SEROQUEL registration studies for schizophrenia. Lipid parameters also were not measured in the bipolar mania registration studies.

Total Cholesterol

≥ 240 mg/dL

Schizophrenia *

SEROQUEL

137

24 (18%)

Placebo

92

6 (7%)

Bipolar Depression

SEROQUEL

463

41 (9%)

Placebo

250 15 (6%)

Triglycerides

≥200 mg/dL

Schizophrenia *

SEROQUEL

120

26 (22%)

Placebo 70 11 (16%)

Bipolar Depression

SEROQUEL

436

59 (14%)
Placebo 232 20 (9%)

LDL-Cholesterol

≥ 160 mg/dL

Schizophrenia *

SEROQUEL

na

na

Placebo

na

na

Bipolar Depression

SEROQUEL

465

29 (6%)

Placebo

256 12 (5%)

HDL-Cholesterol

≤ 40 mg/dL

Schizophrenia *

SEROQUEL

na

na

Placebo

na

na

Bipolar Depression

SEROQUEL

393

56 (14%)

Placebo

214 29 (14%)

Children and Adolescents: Table 4 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with SEROQUEL.

Table 4: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels
Laboratory Analyte Indication Treatment Arm N Patients n (%)
*
13-17 years, 6 weeks duration
10-17 years, 3 weeks duration

Total Cholesterol

≥ 200 mg/dL

Schizophrenia *

SEROQUEL

107

13 (12%)

Placebo

56

1 (2%)

Bipolar Mania

SEROQUEL

159

16 (10%)

Placebo

66 2 (3%)

Triglycerides

≥150 mg/dL

Schizophrenia *

SEROQUEL

103

17 (17%)

Placebo 51 4 (8%)

Bipolar Mania

SEROQUEL

149

32 (22%)
Placebo 60 8 (13%)

LDL-Cholesterol

≥ 130 mg/dL

Schizophrenia *

SEROQUEL

112

4 (4%)

Placebo

60

1 (2%)

Bipolar Mania

SEROQUEL

169

13 (8%)

Placebo

74 4 (5%)

HDL-Cholesterol

≤ 40 mg/dL

Schizophrenia *

SEROQUEL

104

16 (15%)

Placebo

54

10 (19%)

Bipolar Mania

SEROQUEL

154

16 (10%)

Placebo

61 4 (7%)

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