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

5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18 14 additional cases
18 to 24 5 additional cases
Decreases Compared to Placebo
25 to 64 1 fewer case
≥65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for quetiapine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

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 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. 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 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 *

* Includes quetiapine and quetiapine extended-release data

Laboratory Analyte Category Change ( At Least Once ) from Baseline Treatment Arm N Patients n (%)
Normal to High (<100 mg/dL to ≥126 mg/dL) Quetiapine 2907 71 (2.4%)
Placebo 1346 19 (1.4%)
Fasting Glucose 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) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a 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 (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 (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 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 (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL. In a placebo-controlled quetiapine 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 (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 extended-release 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 (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 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 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.

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

Table5:PercentageofChildrenandAdolescentswithShiftsinTotalCholesterol , Triglycerides , LDL-Cholesterol,andHDL-CholesterolfromBaselinetoClinicallySignificantLevels $NoTableFooter
*
13 to 17 years, 6 weeks duration
10 to 17 years, 3 weeks duration
Laboratory Analyte Indication Treatment Arm N Patients n (%)
Schizophrenia * Quetiapine 107 13 (12%)
Placebo 56 1 (2%)
Total Cholesterol ≥200 mg/dL Bipolar Mania Quetiapine 159 16 (10%)
Placebo 66 2 (3%)
Schizophrenia * Quetiapine 103 17 (17%)
Placebo 51 4 (8%)
Triglycerides ≥150 mg/dL Bipolar Mania Quetiapine 149 32 (22%)
Placebo 60 8 (13%)
Schizophrenia * Quetiapine 112 4 (4%)
Placebo 60 1 (2%)
LDL-Cholesterol ≥130 mg/dL Bipolar Mania Quetiapine 169 13 (8%)
Placebo 74 4 (5%)
Schizophrenia * Quetiapine 104 16 (15%)
Placebo 54 10 (19%)
HDL-Cholesterol ≤40 mg/dL Bipolar Mania Quetiapine 154 16 (10%)
Placebo 61 4 (7%)

In a placebo-controlled quetiapine extended-release 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 vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine extended-release vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine extended-release 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 the following increases in weight have been reported.

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

Children and Adolescents:

In two clinical trials with quetiapine, 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)
*
6 weeks duration
3 weeks duration
Vital Sign Indication Treatment Arm N Patients n (%)
Schizophrenia * Quetiapine 111 23 (21%)
Placebo 44 3 (7%)
Weight Gain 7 % of Body Weight Bipolar Mania Quetiapine 157 18 (12%)
Placebo 68 0 (0%)

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

In a clinical trial for quetiapine extended-release 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 vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the quetiapine extended-release group vs. 0.6 kg in the placebo group.

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

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