FDA label 379c4eae-9c82-2edc-e054-00144ff8d46c

Boxed Warning Section Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen 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 fumarate is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ] . Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of quetiapine fumarate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Quetiapine fumarate is not approved for use in patients under ten years of age [see Warnings and Precautions (5.2) ] .

Warnings And Precautions Section Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Atypical antipsychotic drugs, including quetiapine, are associated with an increased risk of death; causes of death are variable. ( 5.1 ) Suicidality and Antidepressant Drugs: Increased the risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder and other psychiatric disorders. ( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. ( 5.3 ) Hyperglycemia and Diabetes Mellitus (DM): Ketoacidosis, hyperosmolar coma and death have been reported in patients treated with atypical antipsychotics, including quetiapine. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. When starting treatment, patients with diabetes or risk factors for diabetes should undergo blood glucose testing before and during treatment. ( 5.4 ) Hyperlipidemia: Undesirable alterations in lipids have been observed. Increases in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol have been reported in clinical trials. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during treatment. ( 5.5 ) Weight Gain: Patients should receive regular monitoring of weight. ( 5.6 ) Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.7 ) Orthostatic Hypotension: Associated dizziness, tachycardia and syncope may occur especially during the initial dose titration period. ( 5.8 ) Increased Blood Pressure in Children and Adolescents: Blood pressure should be measured at the beginning of, and periodically during treatment in children and adolescents. ( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis have been reported with atypical antipsychotics including quetiapine fumarate. Patients with a pre-existing low white cell count (WBC) or a history of leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months of treatment and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors. ( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment. Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment. ( 5.11 ) QT Prolongation : Postmarketing cases show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines know to cause electrolyte imbalance or increase QT interval. Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval. ( 5.12 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high risk patients should accompany drug therapy. ( 5.21 ) See Full Prescribing Information for additional WARNINGS and PRECAUTIONS . Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Quetiapine fumarate is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] . 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 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 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 nonpsychiatric, 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 fumarate 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, 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. It should be noted that quetiapine fumarate is approved for use in treating adult bipolar depression. 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 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. 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 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 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 quetiapine fumarate (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5 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 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 –1.7 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 treatment-emergent blood glucose level of ≥126 mg/dL. 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 quetiapine fumarate. 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 (%) Total Cholesterol ≥240 mg/dL Schizophrenia a Quetiapine Fumarate 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression b Quetiapine Fumarate 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia a Quetiapine Fumarate 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression b Quetiapine Fumarate 436 59 (14%) Placebo 232 20 (9%) LDL-Cholesterol ≥160 mg/dL Schizophrenia a Quetiapine Fumarate na c na c Placebo na c na c Bipolar Depression b Quetiapine Fumarate 465 29 (6%) Placebo 256 12 (5%) HDL-Cholesterol ≤40 mg/dL Schizophrenia a Quetiapine Fumarate na c na c Placebo na c na c Bipolar Depression b Quetiapine Fumarate 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 quetiapine fumarate. 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 (%) Total Cholesterol ≥200 mg/dL Schizophrenia a Quetiapine Fumarate 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania b Quetiapine Fumarate 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia a Quetiapine Fumarate 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania b Quetiapine Fumarate 149 32 (22%) Placebo 60 8 (13%) LDL-Cholesterol ≥130 mg/dL Schizophrenia a Quetiapine Fumarate 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania b Quetiapine Fumarate 169 13 (8%) Placebo 74 4 (5%) HDL-Cholesterol ≤40 mg/dL Schizophrenia a Quetiapine Fumarate 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania b Quetiapine Fumarate 154 16 (10%) Placebo 61 4 (7%) Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight [see Patient Counseling Information (17) ] . 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: In clinical trials with quetiapine fumarate the following increases in weight have been reported. Table 5: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia a Quetiapine Fumarate 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) b Quetiapine Fumarate 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) c Quetiapine Fumarate 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression d 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 the table below. Table 6: Proportion 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 a Quetiapine Fumarate 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania b Quetiapine Fumarate 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2 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. When treating pediatric patients with quetiapine fumarate for any indication, weight gain should be assessed against that expected for normal growth. 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. There is no known treatment for established cases of tardive dyskinesia, although the syndrome 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 fumarate 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 fumarate, drug discontinuation should be considered. However, some patients may require treatment with quetiapine fumarate despite the presence of the syndrome. Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonist properties. Syncope was reported in 1% (28/3265) of the patients treated with quetiapine fumarate, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs. Orthostatic hypotension, dizziness, and syncope may lead to falls. Quetiapine fumarate 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) [see Adverse Reactions (6.2) ] . The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see Dosage and Administration (2) ] . If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine fumarate 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 fumarate 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. In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate. Agranulocytosis (including fatal cases) has also been reported. 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 fumarate 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 <1000/mm 3 ) should discontinue quetiapine fumarate and have their WBC followed until recovery [see Adverse Reactions (6.2) ] . The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology, Animal Toxicology (13.2) ] . Lens changes have also been observed in adults, children and adolescents during long-term quetiapine fumarate treatment, but a causal relationship to quetiapine fumarate 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. 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 postmarketing 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 [see Drug Interactions (7) ] . 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). During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. As with other antipsychotics, quetiapine fumarate 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. 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. About 0.7% (26/3489) of quetiapine fumarate patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment. In the mania adjunct studies, where quetiapine fumarate was added to lithium or divalproex, 12% (24/196) of quetiapine fumarate treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels. Of the quetiapine fumarate treated patients with elevated TSH levels, 3 had simultaneous low free T 4 levels. In all quetiapine trials, the incidence of potentially clinically significant shifts in thyroid hormones and TSH were*: decrease in free T 4 , 2% (357/17513); decrease in total T 4 , 4% (75/1861); decrease in free T 3 , 0.4% (53/13766); decrease in total T 3 , 2% (26/1312), and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged. Table 7 shows the incidence of these shifts in short-term placebo-controlled clinical trials. Table 7: Incidence of Potentially Clinically Significant Shifts in Thyroid Hormone Levels and TSH in Short Term Placebo-Controlled Clinical Trials* 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 % 0.6% 0.7% 0.1% 0.5% 0% 0.2% 0% 3.2% 2.7% (37/1097) (4/651) (52/7218) (4/3668) (2/369) (0/113) (11/5673) (1/2679) (240/7587) (105/3912) * Based on shifts from normal baseline to potentially clinically important value at anytime 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. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T 3 and TSH was 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% (1/3007) for placebo. Generally, these changes in thyroid hormone levels were of no clinical significance. Children and Adolescents: 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 to potentially clinically important thyroid function values at any time for quetiapine fumarate 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 fumarate treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment. Adults: During clinical trials with quetiapine, 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: 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 clinically significant value (>20 mcg/L males; > 26 mcg/L females at any time) was 13.4% (18/134) for quetiapine fumarate compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine fumarate compared to 0% (0/39) for placebo in females. Like other drugs that antagonize dopamine D 2 receptors, quetiapine fumarate 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) ] . Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate compared to 1% (3/194) for placebo. In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294). These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate. In bipolar depression trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo. Somnolence was a commonly reported adverse event reported in patients treated with quetiapine fumarate especially during the 3 to 5 day period of initial dose-titration. In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine fumarate compared to 11% (22/206) of placebo patients. In acute bipolar mania trials using quetiapine fumarate as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine fumarate compared to 4% of placebo patients. In acute bipolar mania trials using quetiapine fumarate as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine fumarate compared to 9% (19/203) of placebo patients. In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine fumarate compared to 15% (51/347) of placebo patients. Since quetiapine fumarate 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 fumarate therapy does not affect them adversely. Somnolence may lead to falls. One case of priapism in a patient receiving quetiapine fumarate has been reported prior to market introduction. While a causal relationship to use of quetiapine fumarate has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that quetiapine fumarate may share this capacity. Severe priapism may require surgical intervention. Although not reported with quetiapine fumarate, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine fumarate 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. 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 fumarate and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. The possibility of a suicide attempt is inherent in bipolar disorder and schizophrenia; close supervision of high risk patients should accompany drug therapy. Prescriptions for quetiapine fumarate should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. In two 8-week clinical studies in patients with bipolar depression (N=1048), the incidence of treatment emergent suicidal ideation or suicide attempt was low and similar to placebo (quetiapine fumarate 300 mg, 6/350, 1.7%; quetiapine fumarate 600 mg, 9/348, 2.6%; Placebo, 7/347, 2%). Clinical experience with quetiapine fumarate in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3) ] . Quetiapine fumarate has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with quetiapine fumarate, caution should be observed in cardiac patients [see Warnings and Precautions (5.8) ] . Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate. In short-term placebo-controlled, monotherapy clinical trials with quetiapine fumarate 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 fumarate extended-release tablets and 6.7% (71/1065) for placebo. The incidence of the individual adverse events (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 withdrawal is advised.

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>Table 1 </caption> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Age Range </th> <th colspan="1">Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated </th> </tr> <tr> <td/> <td> <content styleCode="bold">Increases Compared to Placebo</content> </td> </tr> <tr> <td>&lt;18 </td> <td>14 additional cases </td> </tr> <tr> <td>18-24 </td> <td>5 additional cases </td> </tr> <tr> <td/> <td> <content styleCode="bold">Decreases Compared to Placebo</content> </td> </tr> <tr> <td>25-64 </td> <td>1 fewer case </td> </tr> <tr> <td>&#x2265;65 </td> <td>6 fewer cases </td> </tr> </tbody> </table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>Table 2: Fasting Glucose&#x2014;Proportion of Patients Shifting to &#x2265; 126 mg/dL in Short-Term (&#x2264; 12 weeks) Placebo-Controlled Studies </caption> <col span="1"/> <col span="1"/> <col span="1"/> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Laboratory Analyte </th> <th colspan="1">Category Change (At Least Once) from Baseline </th> <th colspan="1">Treatment Arm </th> <th colspan="1">N </th> <th colspan="1">Patients n (%) </th> </tr> <tr> <td>Fasting Glucose </td> <td> Normal to High (&lt;100 mg/dL to &#x2265; 126 mg/dL) </td> <td>Quetiapine </td> <td>2907 </td> <td>71 (2.4%) </td> </tr> <tr> <td>Placebo </td> <td>1346 </td> <td>19 (1.4%) </td> </tr> <tr> <td> Borderline to High (&#x2265; 100 mg/dL and &lt;126 mg/dL to &#x2265; 126 mg/dL) </td> <td>Quetiapine </td> <td>572 </td> <td>67 (11.7%) </td> </tr> <tr> <td>Placebo </td> <td>279 </td> <td>33 (11.8%) </td> </tr> </tbody> </table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>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 </caption> <col span="1"/> <col span="1"/> <col span="1"/> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Laboratory Analyte </th> <th colspan="1">Indication</th> <th colspan="1">Treatment Arm</th> <th colspan="1">N</th> <th colspan="1">Patients n (%) </th> </tr> <tr> <td>Total Cholesterol &#x2265;240 mg/dL </td> <td>Schizophrenia ^a </td> <td>Quetiapine Fumarate </td> <td>137 </td> <td>24 (18%) </td> </tr> <tr> <td>Placebo </td> <td>92 </td> <td>6 (7%) </td> </tr> <tr> <td>Bipolar Depression ^b </td> <td>Quetiapine Fumarate </td> <td>463 </td> <td>41 (9%) </td> </tr> <tr> <td>Placebo </td> <td>250 </td> <td>15 (6%) </td> </tr> <tr> <td>Triglycerides &#x2265;200 mg/dL </td> <td>Schizophrenia ^a </td> <td>Quetiapine Fumarate </td> <td>120 </td> <td>26 (22%) </td> </tr> <tr> <td>Placebo </td> <td>70 </td> <td>11 (16%) </td> </tr> <tr> <td>Bipolar Depression ^b </td> <td>Quetiapine Fumarate </td> <td>436 </td> <td>59 (14%) </td> </tr> <tr> <td>Placebo </td> <td>232 </td> <td>20 (9%) </td> </tr> <tr> <td>LDL-Cholesterol &#x2265;160 mg/dL </td> <td>Schizophrenia ^a </td> <td>Quetiapine Fumarate </td> <td>na ^c </td> <td>na ^c </td> </tr> <tr> <td>Placebo </td> <td>na ^c </td> <td>na ^c </td> </tr> <tr> <td>Bipolar Depression ^b </td> <td>Quetiapine Fumarate </td> <td>465 </td> <td>29 (6%) </td> </tr> <tr> <td>Placebo </td> <td>256 </td> <td>12 (5%) </td> </tr> <tr> <td>HDL-Cholesterol &#x2264;40 mg/dL </td> <td>Schizophrenia ^a </td> <td>Quetiapine Fumarate </td> <td>na ^c </td> <td>na ^c </td> </tr> <tr> <td>Placebo </td> <td>na ^c </td> <td>na ^c </td> </tr> <tr> <td>Bipolar Depression ^b </td> <td>Quetiapine Fumarate </td> <td>393 </td> <td>56 (14%) </td> </tr> <tr> <td>Placebo </td> <td>214 </td> <td>29 (14%) </td> </tr> </tbody> </table>

Adverse Reactions Section Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia. ( 6.1 ) Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adults Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 4300 patients. This database includes 698 patients exposed to quetiapine fumarate for the treatment of bipolar depression, 405 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine fumarate for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of quetiapine fumarate for the treatment of schizophrenia. Of these approximately 4300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with quetiapine fumarate varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions for schizophrenia and bipolar mania. MedDRA terminology has been used to classify reported adverse reactions for bipolar depression. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adults Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials: Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for quetiapine fumarate vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence (0.8% quetiapine fumarate vs. 0% placebo) and hypotension (0.4% quetiapine fumarate vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.8 and 5.16) ] . Bipolar Disorder: Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine fumarate vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine fumarate vs. 5.9% for placebo in adjunct therapy. Depression: Overall, discontinuations due to adverse reactions were 12.3% for quetiapine fumarate 300 mg vs. 19% for quetiapine fumarate 600 mg and 5.2% for placebo. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials: In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of quetiapine fumarate monotherapy (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%). Adverse Reactions Occurring at an Incidence of 1% or More Among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials: The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied. Table 8 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 1% or more of patients treated with quetiapine fumarate (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Table 8: Treatment-Emergent Adverse Reaction Incidence in 3- to 12­-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy) 1 Body System/Preferred Term Quetiapine Fumarate (n=719) Placebo (n=404) Body as a Whole Headache 21% 14% Pain 7% 5% Asthenia 5% 3% Abdominal Pain 4% 1% Back Pain 3% 1% Fever 2% 1% Cardiovascular Tachycardia 6% 4% Postural Hypotension 4% 1% Digestive Dry Mouth 9% 3% Constipation 8% 3% Vomiting 6% 5% Dyspepsia 5% 1% Gastroenteritis 2% 0% Gamma Glutamyl Transpeptidase Increased 1% 0% Metabolic and Nutritional Weight Gain 5% 1% ALT Increased 5% 1% AST Increased 3% 1% Nervous Agitation 20% 17% Somnolence 18% 8% Dizziness 11% 5% Anxiety 4% 3% Respiratory Pharyngitis 4% 3% Rhinitis 3% 1% Skin and Appendages Rash 4% 2% Special Senses Amblyopia 2% 1% In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%). Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 1% or more of patients treated with quetiapine fumarate (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Table 9: Treatment-Emergent Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy) 1 Body System/Preferred Term Quetiapine Fumarate (n=196) Placebo (n=203) Body as a Whole Headache 17% 13% Asthenia 10% 4% Abdominal Pain 7% 3% Back Pain 5% 3% Hormone Level Altered 3% 0% Heaviness 2% 1% Infection 2% 1% Fever 2% 1% Neck Rigidity 1% 0% Cardiovascular Postural Hypotension 7% 2% Hypotension 3% 1% Hypertension 2% 1% Tachycardia 2% 1% Hemorrhage 1% 0% Digestive Dry Mouth 19% 3% Constipation 10% 5% Dyspepsia 4% 3% Increased Appetite 2% 1% Flatulence 1% 0% Gastrointestinal Disorder 1% 0% Endocrine Hypothyroidism 2% 1% Hemic and Lymphatic Lymphadenopathy 1% 0% Metabolic and Nutritional Weight Gain 6% 3% Peripheral Edema 4% 2% Musculoskeletal Twitching 4% 1% Joint Disorder 1% 0% Nervous Somnolence 34% 9% Dizziness 9% 6% Tremor 8% 7% Agitation 6% 4% Hypertonia 4% 3% Depression 3% 2% Speech Disorder 3% 1% Incoordination 2% 1% Thinking Abnormal 2% 0% Anxiety 2% 0% Ataxia 2% 0% Respiratory Pharyngitis 6% 3% Rhinitis 4% 2% Sinusitis 2% 1% Skin and Appendages Sweating 2% 1% Special Senses Amblyopia 3% 2% Ear Disorder 1% 0% Ear Pain 1% 0% Urogenital Urinary Tract Infection 2% 1% Female Lactation 1% 0% Impotence 1% 0% Urinary Tract Disorder 1% 0% In bipolar depression studies (up to 8 weeks), the most commonly observed treatment emergent adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%). Table 10 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 1% or more of patients treated with quetiapine fumarate (doses of 300 and 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Table 10: Treatment-Emergent Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression 1 Body System/Preferred Term Quetiapine Fumarate (n=698) Placebo (n=347) Cardiac Disorders Palpitations 4% 1% Tachycardia 1% 0% Eye Disorders Vision Blurred 4% 2% Gastrointestinal Disorders Dry Mouth 44% 13% Constipation 10% 4% Dyspepsia 7% 4% Vomiting 5% 4% Gastroesophageal Reflux Disease 2% 1% Dysphagia 2% 0% General Disorders and Administrative Site Conditions Fatigue 10% 8% Asthenia 2% 1% Injury, Poisoning and Procedural Complications Injury 1% 0% Investigations Weight Increased 4% 1% Metabolism and Nutrition Disorders Increased Appetite 5% 3% Musculoskeletal and Connective Tissue Disorders Arthralgia 3% 2% Pain in Extremity 2% 1% Nervous System Disorders Somnolence 2 57% 15% Dizziness 18% 7% Lethargy 5% 2% Akathisia 4% 1% Extrapyramidal Disorder 3% 1% Paraesthesia 3% 2% Dysarthria 3% 0% Hypersomnia 3% 0% Tremor 2% 1% Restless Legs Syndrome 2% 0% Balance Disorder 2% 1% Hypoaesthesia 2% 1% Dystonia 1% 0% Dizziness, Postural 1% 0% Dyskinesia 1% 0% Dysgeusia 1% 0% Psychiatric Disorders Irritability 3% 1% Abnormal Dreams 2% 1% Confusional State 1% 0% Respiratory, Thoracic, and Mediastinal Disorders Nasal Congestion 5% 3% Cough 3% 1% Sinus Congestion 2% 1% Vascular Disorders Orthostatic Hypotension 4% 3% Hypertension 1% 0% Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors. Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials Dose-related Adverse Reactions: Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of quetiapine fumarate (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain. Adverse Reactions in Clinical Trials with Quetiapine and not listed elsewhere in the Label: The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS). Extrapyramidal Symptoms: Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Adults: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of quetiapine fumarate (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of treatment-emergent extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with quetiapine fumarate treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to treat emergent EPS. Table 11: Adverse Experiences Potentially Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 Weeks Duration) Preferred Term Placebo (N=51) Quetiapine Fumarate 75 mg/day (N=53) Quetiapine Fumarate 150 mg/day (N=48) Quetiapine Fumarate 300 mg/day (N=52) Quetiapine Fumarate 600 mg/day (N=51) Quetiapine Fumarate 750 mg/day (N=54) n % n % n % n % n % n % Dystonic event a 4 7.8 2 3.8 2 4.2 0 0 2 3.9 3 5.6 Parkinsonism b 4 7.8 2 3.8 0 0 1 1.9 1 2 1 1.9 Akathisia c 4 7.8 1 1.9 1 2.1 0 0 0 0 1 1.9 Dyskinetic event d 0 0 2 3.8 0 0 0 0 1 2 0 0 Other extrapyramidal event e 4 7.8 2 3.8 0 0 3 5.8 3 5.9 1 1.9 Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1; -1.2; -1.6; -1.8 and -1.8. The rate of anticholinergic medication use to treat emergent EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12% and 11%. In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of quetiapine fumarate, there were no differences between the quetiapine fumarate and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS. In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of quetiapine fumarate, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups. Children and Adolescents: The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 1000 pediatric patients. This database includes 677 patients exposed to quetiapine fumarate for the treatment of schizophrenia and 393 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania. Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Children and Adolescents Adolescents 13 to 17 Years of Age with Schizophrenia The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions for quetiapine-­treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on quetiapine fumarate and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo). Commonly Observed Adverse Reactions In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%). Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 5% or more of patients treated with quetiapine fumarate (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8.2% vs. 14.9%), dry mouth (4.1% vs. 9.5%), and tachycardia (5.5% vs. 8.1%). Table 12: Treatment-Emergent Adverse Reaction Incidence in a 6­-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients Body System/Preferred Term Quetiapine Fumarate (n=147) Placebo (n=75) Central Nervous System Disorders Somnolence 1 34% 11% Digestive Dry Mouth 7% 1% Cardiovascular Disorders Tachycardia 7% 0% Nervous System Disorders Dizziness 12% 5% Children and Adolescents 10 to 17 years of age with Bipolar Mania The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions for quetiapine-­treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse events leading to discontinuation in 1% or more of patients on quetiapine fumarate and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%), fatigue (2.1% vs. 0), irritability (1.6% vs. 0) and syncope (1% vs. 0). Commonly Observed Adverse Reactions In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 5% or more of patients treated with quetiapine fumarate (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (49% vs. 57%), nausea (6.3% vs. 10.2%) and tachycardia (5.3% vs. 8.2%). Table 13: Treatment-Emergent Adverse Reaction Incidence in a 3-­Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Body System/Preferred Term Quetiapine Fumarate (n=193) Placebo (n=90) Nervous System Disorders Somnolence 1 53% 14% Dizziness 18% 2% Fatigue 11% 4% Metabolism and Nutrition Disorders Increased Appetite 9% 1% Weight Increased 6% 0% Gastrointestinal Disorders Nausea 8% 4% Vomiting 8% 3% Dry Mouth 7% 0% Cardiac Disorders Tachycardia 7% 0% Adverse Reactions in Schizophrenia and Bipolar Mania Clinical Trials Commonly Observed Adverse Reactions In acute therapy for schizophrenia and bipolar mania (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (47%), dizziness (15%), fatigue (9%), increased appetite (8%), dry mouth (7%), tachycardia (7%), and weight increased (5%). Table 14 enumerates the pooled incidence of adverse reactions that occurred during acute therapy of children and adolescents (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania). The table includes only those reactions that occurred in 1% or more of patients treated with quetiapine (doses of 400, 600, or 800 mg/day) and for which the incidence in patients treated with quetiapine was greater than the incidence in patients treated with placebo. Table 14: Adverse Reactions (incidence ≥ 1% and greater than placebo) in Short-Term, Placebo-Controlled Trials of Children and Adolescents (10 to 17 years of age) with Bipolar Mania or Schizophrenia 1 Body System/Preferred Term Quetiapine Fumarate (n=340) Placebo (n=165) Central/Nervous System Disorders Somnolence 2 47% 15% Dizziness 15% 4% Fatigue 9% 4% Irritability 4% 1% Tremor 3% 2% Akathisia 2% 1% Syncope 2% 0% Lethargy 1% 0% Metabolism and Nutrition Disorders Increased Appetite 8% 2% Weight Increased 5% 1% Digestive Dry Mouth 7% 1% Cardiovascular Disorders Tachycardia 8% 0% Musculoskeletal and Connective Tissue Disorders Arthralgia 3% 1% Back Pain 2% 1% Musculoskeletal Stiffness 2% 1% Respiratory, Thoracic and Mediastinal Disorders Nasal Congestion 3% 2% Gastrointestinal Disorders Vomiting 7% 6% Stomach Discomfort 2% 1% Skin and Subcutaneous Tissue Disorders Acne 2% 1% General Disorders and Administration Site Conditions Pyrexia 2% 1% Asthenia 2% 1% Psychiatric Disorders Aggression 2% 1% Restlessness 1% 0% Eye Disorders Vision Blurred 2% 1% Infections and Infestations Tooth Abscess 1% 0% Extrapyramidal Symptoms: In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% for quetiapine fumarate and 5.3% for placebo, though the incidence of the individual adverse events (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% for quetiapine fumarate and 1.1% for placebo. Table 15 below presents a listing of patients with AEs potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration). Table 15: Adverse Experiences Potentially Associated with EPS in the Short-Term Placebo-Controlled Monotherapy Trial in Adolescent Patients with Schizophrenia (6-Week Duration) Preferred Term Placebo (N=75) Quetiapine Fumarate 400 mg/day (N=73) Quetiapine Fumarate 800 mg/day (N=74) All Quetiapine Fumarate (N=147) n % n % n % n % Dystonic event a 0 0 2 2.7 0 0 2 1.4 Parkinsonism b 2 2.7 4 5.5 4 5.4 8 5.4 Akathisia c 3 4 3 4.1 4 5.4 7 4.8 Dyskinetic event d 0 0 2 2.7 0 0 2 1.4 Other Extrapyramidal Event e 0 0 2 2.7 2 2.7 4 2.7 Table 16 below presents a listing of patients with Adverse Experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration). Table 16: Adverse Experiences Potentially Associated with EPS in a Short-Term Placebo-Controlled Monotherapy Trial in Children and Adolescent Patients with Bipolar Mania (3-Week Duration) Preferred Term* Placebo (N=90) Quetiapine Fumarate 400 mg/day (N=95) Quetiapine Fumarate 600 mg/day (N=98) All Quetiapine Fumarate (N=193) n % n % n % n % Parkinsonism a 1 1.1 2 2.1 1 1 3 1.6 Akathisia b 0 0 1 1 1 1 2 1 Other Extrapyramidal Event c 0 0 1 1.1 1 1 2 1 Adverse Reactions in Long-Term Open-Label Trial The adverse reactions reported in a 26-week, open-label trial with quetiapine fumarate in 5% or greater of the children and adolescent patients with schizophrenia or bipolar mania were somnolence (30%), headache (19%), vomiting (11%), increased weight (13%), insomnia (8%), nausea (10%), fatigue (8%), dizziness (9%), increased appetite (7%), upper respiratory tract infection (7%), agitation (5%), tachycardia (5%), and irritability (5%). Other Adverse Reactions Observed During the Premarketing Evaluation of Quetiapine Fumarate Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with quetiapine fumarate at multiple doses ≥ 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already listed in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with quetiapine fumarate, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Nervous System: Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased*, urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased*, neuralgia, stuttering, subdural hematoma. Body as a Whole: Frequent: flu syndrome; Infrequent: neck pain, pelvic pain*, suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis; Rare: abdomen enlarged. Digestive System: Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis. Cardiovascular System: Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration. Respiratory System: Frequent: cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation. Metabolic and Nutritional System: Infrequent: weight loss, alkaline phosphatase increased, hyperlipemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication. Skin and Appendages System: Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration. Urogenital System: Infrequent: dysmenorrhea*, vaginitis* , urinary incontinence, metrorrhagia*, impotence*, dysuria, vaginal moniliasis*, abnormal ejaculation*, cystitis, urinary frequency, amenorrhea*, female lactation*, leukorrhea*, vaginal hemorrhage*, vulvovaginitis*, orchitis*; Rare: gynecomastia*, nocturia, polyuria, acute kidney failure. Special Senses: Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma. Musculoskeletal System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain. Hemic and Lymphatic System: Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia. Endocrine System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism. *adjusted for gender Hyperglycemia, hyperlipidemia, weight gain, orthostatic hypotension and changes in thyroid hormone levels have been reported with quetiapine. Increases in blood pressure have also been reported with quetiapine in children and adolescents [see Warnings and Precautions (5.4 , 5.5 , 5.6 , 5.8 , 5.9 and 5.14 )] . Neutrophil Counts In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1 x 10 9 /L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine fumarate, compared to 0.1% (2/1349) in patients treated with placebo. 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 fumarate at the first sign of a decline in WBC in absence of other causative factors [see Warnings and Precautions (5.10) ] . Decreased Hemoglobin In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients. ECG Changes Adults: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine fumarate/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine fumarate compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine fumarate compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine fumarate compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to > 120 beats per minute. Quetiapine fumarate use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine fumarate’s potential for inducing orthostatic changes [see Warnings and Precautions (5.8) ] . Children and Adolescents: In the acute (6 week) schizophrenia trial in adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine fumarate 400 mg and 8.5% (5/74) of patients receiving quetiapine fumarate 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine fumarate 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see Warnings and Precautions (5.8) ] . In the acute (3 week) bipolar mania trial in children and adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 1.1% (1/95) of patients receiving quetiapine fumarate 400 mg and 2.4% (2/98) of patients receiving quetiapine fumarate 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine fumarate 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [see Warnings and Precautions (5.8) ] . The following adverse reactions were identified during post approval of quetiapine fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction which were temporally related to quetiapine fumarate therapy include: anaphylactic reaction and galactorrhea. Other adverse reactions reported since market introduction, which were temporally related to quetiapine fumarate therapy, but not necessarily causally related, include the following: agranulocytosis, cardiomyopathy, hyponatremia, myocarditis, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and decreased platelets. In postmarketing clinical trials, elevations in total cholesterol (predominantly LDL cholesterol), somnambulism (and other related events) and hypothermia have been reported.

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>Table 8: Treatment-Emergent Adverse Reaction Incidence in 3- to 12&#xAD;-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy) ¹ </caption> <col span="1"/> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Body System/Preferred Term</th> <th colspan="1">Quetiapine Fumarate (n=719) </th> <th colspan="1">Placebo (n=404) </th> </tr> <tr> <td> <content styleCode="bold"> Body as a Whole</content> </td> </tr> <tr> <td> Headache </td> <td>21% </td> <td>14% </td> </tr> <tr> <td> Pain </td> <td>7% </td> <td>5% </td> </tr> <tr> <td> Asthenia </td> <td>5% </td> <td>3% </td> </tr> <tr> <td> Abdominal Pain </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> Back Pain </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Fever </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Cardiovascular</content> </td> </tr> <tr> <td> Tachycardia </td> <td>6% </td> <td>4% </td> </tr> <tr> <td> Postural Hypotension </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Digestive</content> </td> </tr> <tr> <td> Dry Mouth </td> <td>9% </td> <td>3% </td> </tr> <tr> <td> Constipation </td> <td>8% </td> <td>3% </td> </tr> <tr> <td> Vomiting </td> <td>6% </td> <td>5% </td> </tr> <tr> <td> Dyspepsia </td> <td>5% </td> <td>1% </td> </tr> <tr> <td> Gastroenteritis </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> Gamma Glutamyl Transpeptidase Increased </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Metabolic and Nutritional</content> </td> </tr> <tr> <td> Weight Gain </td> <td>5% </td> <td>1% </td> </tr> <tr> <td> ALT Increased </td> <td>5% </td> <td>1% </td> </tr> <tr> <td> AST Increased </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Nervous</content> </td> </tr> <tr> <td> Agitation </td> <td>20% </td> <td>17% </td> </tr> <tr> <td> Somnolence </td> <td>18% </td> <td>8% </td> </tr> <tr> <td> Dizziness </td> <td>11% </td> <td>5% </td> </tr> <tr> <td> Anxiety </td> <td>4% </td> <td>3% </td> </tr> <tr> <td> <content styleCode="bold"> Respiratory</content> </td> </tr> <tr> <td> Pharyngitis </td> <td>4% </td> <td>3% </td> </tr> <tr> <td> Rhinitis </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Skin and Appendages</content> </td> </tr> <tr> <td> Rash </td> <td>4% </td> <td>2% </td> </tr> <tr> <td> <content styleCode="bold"> Special Senses</content> </td> </tr> <tr> <td> Amblyopia </td> <td>2% </td> <td>1% </td> </tr> </tbody> </table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>Table 9: Treatment-Emergent Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy) ¹ </caption> <col span="1"/> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Body System/Preferred Term </th> <th colspan="1">Quetiapine Fumarate (n=196) </th> <th colspan="1">Placebo (n=203) </th> </tr> <tr> <td> <content styleCode="bold"> Body as a Whole </content> </td> </tr> <tr> <td> Headache </td> <td>17% </td> <td>13% </td> </tr> <tr> <td> Asthenia </td> <td>10% </td> <td>4% </td> </tr> <tr> <td> Abdominal Pain </td> <td>7% </td> <td>3% </td> </tr> <tr> <td> Back Pain </td> <td>5% </td> <td>3% </td> </tr> <tr> <td> Hormone Level Altered </td> <td>3% </td> <td>0% </td> </tr> <tr> <td> Heaviness </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Infection </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Fever </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Neck Rigidity </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Cardiovascular </content> </td> </tr> <tr> <td> Postural Hypotension </td> <td>7% </td> <td>2% </td> </tr> <tr> <td> Hypotension </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Hypertension </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Tachycardia </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Hemorrhage </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Digestive </content> </td> </tr> <tr> <td> Dry Mouth </td> <td>19% </td> <td>3% </td> </tr> <tr> <td> Constipation </td> <td>10% </td> <td>5% </td> </tr> <tr> <td> Dyspepsia </td> <td>4% </td> <td>3% </td> </tr> <tr> <td> Increased Appetite </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Flatulence </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Gastrointestinal Disorder </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Endocrine </content> </td> </tr> <tr> <td> Hypothyroidism </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Hemic and Lymphatic</content> </td> </tr> <tr> <td> Lymphadenopathy </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Metabolic and Nutritional</content> </td> </tr> <tr> <td> Weight Gain </td> <td>6% </td> <td>3% </td> </tr> <tr> <td> Peripheral Edema </td> <td>4% </td> <td>2% </td> </tr> <tr> <td> <content styleCode="bold"> Musculoskeletal </content> </td> </tr> <tr> <td> Twitching </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> Joint Disorder </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Nervous </content> </td> </tr> <tr> <td> Somnolence </td> <td>34% </td> <td>9% </td> </tr> <tr> <td> Dizziness </td> <td>9% </td> <td>6% </td> </tr> <tr> <td> Tremor </td> <td>8% </td> <td>7% </td> </tr> <tr> <td> Agitation </td> <td>6% </td> <td>4% </td> </tr> <tr> <td> Hypertonia </td> <td>4% </td> <td>3% </td> </tr> <tr> <td> Depression </td> <td>3% </td> <td>2% </td> </tr> <tr> <td> Speech Disorder </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Incoordination </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Thinking Abnormal </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> Anxiety </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> Ataxia </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Respiratory </content> </td> </tr> <tr> <td> Pharyngitis </td> <td>6% </td> <td>3% </td> </tr> <tr> <td> Rhinitis </td> <td>4% </td> <td>2% </td> </tr> <tr> <td> Sinusitis </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Skin and Appendages</content> </td> </tr> <tr> <td> Sweating </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Special Senses </content> </td> </tr> <tr> <td> Amblyopia </td> <td>3% </td> <td>2% </td> </tr> <tr> <td> Ear Disorder </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Ear Pain </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Urogenital </content> </td> </tr> <tr> <td> Urinary Tract Infection </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Female Lactation </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Impotence </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Urinary Tract Disorder </td> <td>1% </td> <td>0% </td> </tr> </tbody> </table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption>Table 10: Treatment-Emergent Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression ¹ </caption> <col span="1"/> <col span="1"/> <col span="1"/> <tbody> <tr> <th colspan="1">Body System/Preferred Term</th> <th colspan="1">Quetiapine Fumarate (n=698) </th> <th colspan="1">Placebo (n=347) </th> </tr> <tr> <td> <content styleCode="bold"> Cardiac Disorders</content> </td> </tr> <tr> <td> Palpitations </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> Tachycardia </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Eye Disorders</content> </td> </tr> <tr> <td> Vision Blurred </td> <td>4% </td> <td>2% </td> </tr> <tr> <td> <content styleCode="bold"> Gastrointestinal Disorders</content> </td> </tr> <tr> <td> Dry Mouth </td> <td>44% </td> <td>13% </td> </tr> <tr> <td> Constipation </td> <td>10% </td> <td>4% </td> </tr> <tr> <td> Dyspepsia </td> <td>7% </td> <td>4% </td> </tr> <tr> <td> Vomiting </td> <td>5% </td> <td>4% </td> </tr> <tr> <td> Gastroesophageal Reflux Disease </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Dysphagia </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> General Disorders and Administrative Site Conditions</content> </td> </tr> <tr> <td> Fatigue </td> <td>10% </td> <td>8% </td> </tr> <tr> <td> Asthenia </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Injury, Poisoning and Procedural Complications</content> </td> </tr> <tr> <td> Injury </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Investigations</content> </td> <td/> <td/> </tr> <tr> <td> Weight Increased </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Metabolism and Nutrition Disorders</content> </td> </tr> <tr> <td> Increased Appetite </td> <td>5% </td> <td>3% </td> </tr> <tr> <td> <content styleCode="bold"> Musculoskeletal and Connective Tissue Disorders</content> </td> </tr> <tr> <td> Arthralgia </td> <td>3% </td> <td>2% </td> </tr> <tr> <td> Pain in Extremity </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Nervous System Disorders</content> </td> </tr> <tr> <td> Somnolence ² </td> <td>57% </td> <td>15% </td> </tr> <tr> <td> Dizziness </td> <td>18% </td> <td>7% </td> </tr> <tr> <td> Lethargy </td> <td>5% </td> <td>2% </td> </tr> <tr> <td> Akathisia </td> <td>4% </td> <td>1% </td> </tr> <tr> <td> Extrapyramidal Disorder </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Paraesthesia </td> <td>3% </td> <td>2% </td> </tr> <tr> <td> Dysarthria </td> <td>3% </td> <td>0% </td> </tr> <tr> <td> Hypersomnia </td> <td>3% </td> <td>0% </td> </tr> <tr> <td> Tremor </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Restless Legs Syndrome </td> <td>2% </td> <td>0% </td> </tr> <tr> <td> Balance Disorder </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Hypoaesthesia </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Dystonia </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Dizziness, Postural </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Dyskinesia </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> Dysgeusia </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Psychiatric Disorders</content> </td> </tr> <tr> <td> Irritability </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Abnormal Dreams </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> Confusional State </td> <td>1% </td> <td>0% </td> </tr> <tr> <td> <content styleCode="bold"> Respiratory, Thoracic, and Mediastinal Disorders</content> </td> </tr> <tr> <td> Nasal Congestion </td> <td>5% </td> <td>3% </td> </tr> <tr> <td> Cough </td> <td>3% </td> <td>1% </td> </tr> <tr> <td> Sinus Congestion </td> <td>2% </td> <td>1% </td> </tr> <tr> <td> <content styleCode="bold"> Vascular Disorders</content> </td> </tr> <tr> <td> Orthostatic Hypotension </td> <td>4% </td> <td>3% </td> </tr> <tr> <td> Hypertension </td> <td>1% </td> <td>0% </td> </tr> </tbody> </table>