Quetiapine Fumarate Er

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Quetiapine extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING]. 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 4,400 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 1,000 patients treated) are provided in Table 2. Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 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 nonpsychiatric. 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 extended-release 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 extended-release tablets, 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 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 1 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%) 1. Includes quetiapine tablets and quetiapine extended-release tablets data. 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 +5.0 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 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 tablets 150 mg 280 19 (7%) Quetiapine extended-release tablets 300 mg 269 32 (12%) Placebo 277 17 (6%) Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets is 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 –1.70 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 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%) Bipolar Depression 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%) Bipolar Depression 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%) Bipolar Depression 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%) 1. 6 weeks duration 2. 8 weeks duration 3. 3 weeks duration 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 Laboratory Analyte Treatment Arm1 N Patients n (%) Cholesterol ≥ 240 mg/dL Quetiapine extended-release tablets 150 mg 223 41 (18%) Quetiapine extended-release tablets 300 mg 197 26 (13%) Placebo 213 15 (7%) Triglycerides ≥ 200 mg/dL Quetiapine extended-release tablets 150 mg 232 36 (16%) Quetiapine extended-release tablets 300 mg 226 39 (17%) Placebo 223 18 (8%) LDL-Cholesterol ≥ 160 mg/dL Quetiapine extended-release tablets 150 mg 242 29 (12%) Quetiapine extended-release tablets 300 mg 215 22 (10%) Placebo 219 21 (10%) HDL-Cholesterol ≤ 40 mg/dL Quetiapine extended-release tablets 150 mg 238 14 (6%) Quetiapine extended-release tablets 300 mg 232 20 (9%) Placebo 230 19 (8%) 1. 6 weeks duration Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets is 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 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%) 1. 13 to 17 years, 6 weeks duration 2. 10 to 17 years, 3 weeks duration 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 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%) 1. 6 weeks duration 2. 3 weeks duration 3. 8 weeks duration 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 tablets 150 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 is 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) 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%) 1. 6 weeks duration 2. 3 weeks duration The mean change in body weight in the schizophrenia trial was 2.0 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. 5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, quetiapine extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.Given these considerations, quetiapine extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome. 5.7 Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its ά1-adrenergic antagonist properties. Syncope was reported in 0.3% (5/1866) of the patients treated with quetiapine extended-release tablets across all indications, compared with 0.2% (2/928) on placebo. Syncope was reported in 1% (28/3265) of the patients treated with quetiapine tablets, compared with 0.2% (2/954) on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls. Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. 5.8 Falls Atypical antipsychotic drugs, including quetiapine extended-release tablets, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Increases in Blood Pressure (Children and Adolescents) Safety and effectiveness of quetiapine extended-release tablets is 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 clinical trial (8 weeks duration) in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for quetiapine extended-release tablets and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for quetiapine extended-release tablets and 36.0% (36/100) for placebo. In placebo-controlled trials in children and adolescents with schizophrenia (13 to 17 years old, 6-week duration) or bipolar mania (10 to 17 years old, 3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine tablets and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine tablets and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment. 5.10 Leukopenia, Neutropenia, and Agranulocytosis In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine. Agranulocytosis has also been reported. Agranulocytosis has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate. Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine extended-release tablets at the first sign of a decline in WBC in absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1,000/mm 3) should discontinue quetiapine extended-release tablets and have their WBC followed until recovery. 5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see NONCLINICAL TOXICOLOGY (13.2)]. Lens changes have also been observed in adults, children, and adolescents during long-term quetiapine treatment but a causal relationship to quetiapine use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment. 5.12 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE (10.1)] , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy). 5.13 Seizures During short-term clinical trials with quetiapine extended-release tablets, seizures occurred in 0.05% (1/1866) of patients treated with quetiapine extended-release tablets across all indications compared to 0.3% (3/928) on placebo. During clinical trials with quetiapine tablets, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine tablets compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. 5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T 4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T 4, in addition to clinical assessment, should be measured at baseline and at follow-up. In quetiapine extended-release tablets clinical trials across all indications 1.8% (24/1336) of patients on quetiapine extended-release tablets versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on quetiapine extended-release tablets versus 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH). About 0.7% (26/3489) of quetiapine tablets patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment. In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were 1: decrease in free T 4 (<0.8 LLN), 2.0% (357/17513); decrease in total T 4 (<0.8 LLN), 4.0% (75/1861); decrease in free T 3 (<0.8 LLN), 0.4% (53/13766); decrease in total T 3 (<0.8 LLN), 2.0% (26/1312), and increase in TSH (>5 mIU/L), 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged. Table 11 shows the incidence of these shifts in short term placebo-controlled clinical trials. Table 11: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-term Placebo-Controlled Clinical Trials 1,2 Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4% (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) 1. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline. Shifts in total T 4, free T 4, total T 3 and free T 3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time. 2. Includes quetiapine tablets and quetiapine extended-release tablets data. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo. 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 acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for quetiapine tablets treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the quetiapine tablets treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment. 5.15 Hyperprolactinemia Adults: During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo. Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets is 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 acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 mcg/L males; > 26 mcg/L females at any time) was 13.4% (18/134) for quetiapine tablets compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine tablets compared to 0% (0/39) for placebo in females. Like other drugs that antagonize dopamine D 2 receptors, quetiapine extended-release tablets elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary, and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see NONCLINICAL TOXICOLOGY (13.1)]. 5.16 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on quetiapine extended-release tablets compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on quetiapine extended-release tablets compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on quetiapine extended-release tablets compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls. In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on quetiapine extended-release tablets respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively). 5.17 Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine extended-release tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. 5.18 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Quetiapine extended-release tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.19 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. In short-term placebo-controlled, monotherapy clinical trials with quetiapine extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine extended-release tablets and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1-week post-discontinuation. Gradual dose reduction is advised [see USE IN SPECIFIC POPULATIONS (8.1)]. 5.20 Anticholinergic (antimuscarinic) Effects Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine extended-release tablets are used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine extended-release tablets should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine extended-release tablets are used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine extended-release tablets should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see DRUG INTERACTIONS (7.1), OVERDOSAGE (10.1) ,and CLINICAL PHARMACOLOGY (12.1)] . Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction. Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility.