QUETIAPINE FUMARATE (Page 3 of 13)

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 is not approved for the treatment of patients with dementia-related psychosis [see also 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 fumarate. Rare cases of NMS have been reported with quetiapine fumarate. 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 creatinine 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 ¹

1. Includes quetiapine 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	2,907	71 (2.4%)
		Placebo	1,346	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) 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 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 (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine fumarate 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 (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 quetiapine fumarate 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 fumarate (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL. In a placebo-controlled quetiapine fumarate 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 fumarate (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.

In a placebo-controlled quetiapine fumarate 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 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.

Dyslipidemia

Adults:

Table 4 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 quetiapine fumarate.

Table 4: 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. Parameters not measured in the quetiapine fumarate registration studies for schizophrenia.
Laboratory Analyte	Indication	Treatment Arm	N	Patients n (%)
Total Cholesterol ≥240 mg/dL	Schizophrenia 1	Quetiapine Fumarate	137	24 (18 %)
		Placebo	92	6 (7 %)
	Bipolar Depression 2	Quetiapine Fumarate	463	41 (9 %)
		Placebo	250	15 (6 %)
Triglycerides ≥200 mg/dL	Schizophrenia 1	Quetiapine Fumarate	120	26 (22 %)
		Placebo	70	11 (16 %)
	Bipolar Depression 2	Quetiapine Fumarate	436	59 (14 %)
		Placebo	232	20 (9 %)
LDL-Cholesterol ≥160 mg/dL	Schizophrenia 1	Quetiapine Fumarate	na 3	na 3
		Placebo	na 3	na 3
	Bipolar Depression 2	Quetiapine Fumarate	465	29 (6 %)
		Placebo	256	12 (5 %)
HDL-Cholesterol ≤ 40 mg/dL	Schizophrenia 1	Quetiapine Fumarate	na 3	na 3
		Placebo	na 3	na 3
	Bipolar Depression 2	Quetiapine Fumarate	393	56 (14 %)
		Placebo	214	29 (14 %)

Children and Adolescents:

Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine fumarate.

Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels

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 Fumarate	107	13 (12 %)
		Placebo	56	1 (2 %)
	Bipolar Mania 2	Quetiapine Fumarate	159	16 (10 %)
		Placebo	66	2 (3 %)
Triglycerides ≥150 mg/dL	Schizophrenia 1	Quetiapine Fumarate	103	17 (17 %)
		Placebo	51	4 (8 %)
	Bipolar Mania 2	Quetiapine Fumarate	149	32 (22 %)
		Placebo	60	8 (13 %)
LDL-Cholesterol ≥130 mg/dL	Schizophrenia 1	Quetiapine Fumarate	112	4 (4 %)
		Placebo	60	1 (2 %)
	Bipolar Mania 2	Quetiapine Fumarate	169	13 (8 %)
		Placebo	74	4 (5 %)
HDL-Cholesterol ≤ 40 mg/dL	Schizophrenia 1	Quetiapine Fumarate	104	16 (15 %)
		Placebo	54	10 (19 %)
	Bipolar Mania 2	Quetiapine Fumarate	154	16 (10 %)
		Placebo	61	4 (7 %)

In a placebo-controlled quetiapine fumarate 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 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.

Weight Gain

Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.

Adults:

In clinical trials with quetiapine fumarate the following increases in weight have been reported.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults)

1. up to 6 weeks duration
2. up to 12 weeks duration
3. up to 3 weeks duration
4. up to 8 weeks duration
Vital Sign	Indication	Treatment Arm	N	Patients n (%)
Weight Gain ≥7 % of Body Weight	Schizophrenia 1	Quetiapine Fumarate	391	89 (23 %)
		Placebo	206	11 (6 %)
	Bipolar Mania (monotherapy) 2	Quetiapine Fumarate	209	44 (21 %)
		Placebo	198	13 (7 %)
	Bipolar Mania (adjunct therapy) 3	Quetiapine Fumarate	196	25 (13 %)
		Placebo	203	8 (4 %)
	Bipolar Depression 4	Quetiapine Fumarate	554	47 (8 %)
		Placebo	295	7 (2 %)

Children and Adolescents:

In two clinical trials with quetiapine fumarate, one in bipolar mania and one in schizophrenia, reported increases in weight are included in table 7.

Table 7: Proportion 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 Fumarate	111	23 (21 %)
		Placebo	44	3 (7 %)
	Bipolar Mania 2	Quetiapine Fumarate	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. 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 met this criterion after 26 weeks of treatment.

In a clinical trial for quetiapine fumarate 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 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.

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