FDA label d592fca4-8cd3-7771-e053-2a95a90aff3c

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS 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 [ see Warnings and Precautions (5.1) ]. Quetiapine is not approved for the treatment of patients with dementia-related psychosis [ see Warnings and Precautions (5.1) ]. Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [ see Warnings and Precautions (5.2) ]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [ see Warnings and Precautions (5.2) ]. Quetiapine is not approved for use in pediatric patients under ten years of age [ see Use in Specific Populations (8.4) ]. W ARNING : INCREASEDMORTALITYINELDERLYPATIENTS WITHDEMENTIA-RELATEDPSYCHOSIS;andSUICIDAL THOUGHTSANDBEHAVIORS S e efullprescribing informationforcompleteboxedwarning . In cr e a s e dMortalityin ElderlyPatientswithDementia-Related Psychosis · El d e r l y patients withdementia-relatedpsychosis treatedwith antipsychoticdrugsareatanincreasedriskofdeath.Quetiapine tablets is not approved forelderlypatients with dementia-relatedpsychosis (5.1) Su ici d al T h o u g ht sandBehaviors · Increasedriskofsuicidalthoughtsandbehaviorin children, adolescentsandyoungadultstakingantidepressants (5.2) · Monitor for worsening and emergence of suicidal thoughts and behaviors (5.2)

5 WARNINGS AND PRECAUTIONS · Ce rebrovascularAdverseReactions: Increasedincidence of cerebrovascularadverseevents(e.g.,stroke,transientischemicattack) has beenseenin elderlypatientswith dementia-relatedpsychoses treatedwithatypical antipsychotic drugs (5.3) · N e u rolepticMalignantSyndrome (NMS): Managewithimmediatediscontinuationandclosemonitoring (5.4) · MetabolicChanges: Atypical antipsychoticshavebeenassociatedwithmetabolicchanges.Thesemetabolicchanges includehyperglycemia, dyslipidemia,andweightgain (5.5) · HyperglycemiaandDiabetes Mellitus:Monitorpatientsforsymptomsof hyperglycemiaincludingpolydipsia,polyuria, polyphagia,andweakness.Monitorglucose regularlyinpatientswithdiabetesoratriskfor diabetes · Dyslipidemia: Undesirablealterationshavebeenobservedin patients treatedwithatypicalantipsychotics.Appropriateclinical monitoring isrecommended,including fastingbloodlipidtesting atthebeginning of,andperiodically,duringtreatment · WeightGain:Gain in bodyweighthas beenobserved;clinical monitoringof weightisrecommended · T a rdiveDyskinesia: Discontinueifclinicallyappropriate 432 (5.6) · H y p ot e n s i o n : Usewith cautionin patientswithknowncardiovascularor cerebrovascular disease (5.7) · I nc reased Blood Pressure in ChildrenandAdolescents: Monitorblood pressureat thebeginning of,andperiodicallyduringtreatment inchildren andadolescents (5.8) · L eu k o p e n i a ,NeutropeniaandAgranulocytosis: Monitor completeblood countfrequentlyduring the first fewmonthsoftreatment in patientswith apre-existinglow whitecellcountorahistoryofleukopenia/neutropenia and discontinue quetiapineatthe firstsignofadeclineinWBCinabsence of othercausative factors (5.9) · C a ta r a c t s: Lens changeshavebeenobservedin patients during long-term quetiapinetreatment.Lensexaminationisrecommendedwhenstarting treatment and at6-month intervalsduring chronictreatment (5.10) 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 is 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 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2. T able 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated A ge Range D rug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases D ecreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. A l l 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. F a milies 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 should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. 5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Quetiapine is not approved for the treatment of patients with dementia- related psychosis [see also Boxed Warning and Warnings and Precautions (5.1 )]. 5.4 Neuroleptic Malignant Syndrome(NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated 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 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. Adults: T able 3: Fasting Glucose – Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤12 weeks) P l acebo - Control l e d Studies 2 L aboratory A nalyte C ategory Change ( A t Least Once) f rom Baseline T rea t me n t Arm N P a tie n t s 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 ≥26 PJ/G/) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) 2 Includes quetiapine tablets and quetiapine extended-release tablets. In a 24-week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a 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/dLwas 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine. In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for quetiapine(646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose lavel (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581). Children and Adolescents: In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was – 0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled quetiapine monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥ 100 mg/dL and <126mg/dL) had a treatment emergent blood glucose level ≥ 126mg/dL. 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. Dyslipidemia Adults: Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL- cholesterol from baseline by indication in clinical trials with Quetiapine. T able 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication L aboratory A nalyte Indication T reatment Arm N P a t ients n (%) Total Cholesterol ≥240 PJ/G/ Schizophrenia 1 Quetiapine 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression 2 Quetiapine 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia 1 Quetiapine 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression 2 Quetiapine 436 59 (14%) Placebo 232 20 (9%) LDL- Cholesterol ≥160 mg/dL Schizophrenia 1 Quetiapine na 3 na 3 Placebo na 3 na 3 Bipolar Depression 2 Quetiapine 465 29 (6%) Placebo 256 12 (5%) HDL- Cholesterol ≤40 PJ/G/ Schizophrenia 1 Quetiapine na 3 na 3 Placebo na 3 na 3 Bipolar Depression 2 Quetiapine 393 56 (14%) Placebo 214 29 (14%) 1. 6 weeks duration 2. 8 weeks duration 3. Parameters not measured in the quetiapine registration studies for schizophrenia. Lipid parameters also were not measured in the bipolar mania registration studies. Children and Adolescents: Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine. T able 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL- Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels L aboratory A nalyte Indication T reatment Arm N P a t ients n (%) Total Cholesterol ≥200 PJ/G/ Schizophrenia 1 Quetiapine 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania 2 Quetiapine 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 PJ/G/ Schizophrenia 1 Quetiapine 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania 2 Quetiapine 149 32 (22%) Placebo 60 8 (13%) LDL- Cholestrol ≥ 130 mg/dL Schizophrenia 1 Quetiapine 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania 2 Quetiapine 169 13 (8%) Placebo 74 4 (5%) HDL- Cholestrol ≤ 40 mg/dL Schizophrenia 1 Quetiapine 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania 2 Quetiapine 154 16 (10%) Placebo 61 4 (7%) 1. 13 to 17 years, 6 weeks duration 2. 10 to 17 years, 3 weeks duration In Placebo-controlled quetiapine extended-release tablets monotherapy study (8 week 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. Weight Gain Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight. Adults : In clinical trials with quetiapinethe following increases in weight have been reported. Table 6: Proportion of Patients with Weight Gain ≥ 7% of Body Weight (Adults) V it al Sign Indication T reatment Arm N P a tie n ts n (%) Weight Gain ≥ 7 % RI B ody Weight Schizophrenia 1 Quetiapine 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) 2 Quetiapine 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) 3 Quetiapine 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression 4 Quetiapine 554 47 (8%) Placebo 295 7 (2%) 1. up to 6 weeks duration 2. up to 12 weeks duration 3. up to 3 weeks duration 4. up to 8 weeks duration Children and Adolescents: In two clinical trials with quetiapine, one in bipolar mania and one in schizophrenia, reported increases in weight are included in table 7. T able 7 : Proportion of Patients with Weight Gain ≥ 7% of Body Weight (Children and Adolescents) V it al Sign Indication T reatment Arm N P a tie n ts n (%) Weight G ain ≥ 7 % RI B ody Schizophrenia 1 Quetiapine 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania 2 Quetiapine 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 group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine group and 0.4 kg in the placebo group. In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on quetiapine met this criterion after 26 weeks of treatment. In clinical trials 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 placeo group. When treating pediatric patients with quetiapine 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. 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 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, 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 α 1 -adrenergic antagonist properties. Syncope was reported in 1% (28/3265) of the patients treated with quetiapine, 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 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). The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see Dosage and Administration (2.2) ] . If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. 5.8 Increases in Blood Pressure(Children and Adolescents) 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 (≥200 mm Hg) was 15.2% (51/335) for quetiapine and 5.5% (9./163) for placebo; the incidence of increases at time in diastolic blood pressure (≥100 mm HG) was 40.6% (136/335) for quetiapine 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 the placebo controlled quetiapine extended-release tablets clinical trials (8 weeks duration) in children and adolescents (10 to 17years 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. 5.9 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine. 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 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/mm3) should discontinue quetiapine and have their WBC followed until recovery. 5.10 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. 5.11 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 [see Drug Interactions (7.1)]. 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). 5.12 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. 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. 5.13 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T4) 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 T4, 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 T4, in addition to clinical assessment, should be measured at baseline and at follow-up. In the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels. Of the quetiapine treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels (free T4 <0.8 LLN). About 0.7% (26/3489) of quetiapine patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment. In all quetiapine trials, the incidence of significant shifts in thyroid hormones and TSH were1: decrease in free T4 (free T4 <0.8 LLN), 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged. Table 8 shows the incidence of these shifts in short term placebo-controlled clinical trials. T able 8: Incidence of shifts in thyroid hormone levels and TSH in short-term placebo-controlled clinical trials 1 Total T4 F r ee T4 Total T3 F r ee T3 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 anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mlU/L at any time. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo. 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 for thyroid function values at any time for Quetiapine 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 treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment. 5.14 Hyperprolactinemia 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 value (>20 μg/L males; > 26 μg/L females at any time) was 13.4% (18/134) for quetiapine compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females. Like other drugs that antagonize dopamine D2 receptors, quetiapine 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)]. 5.15 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with quetiapine especially during the 3-5 day period of initial dose-titration. In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine compared to 11% (22/206) of placebo patients. In acute bipolar mania trials using quetiapine as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine compared to 4% of placebo patients. In acute bipolar mania trials using quetiapine as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine compared to 9% (19/203) of placebo patients. In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine compared to 15% (51/347) 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. 5.16 Body Temperature Regulation Although not reported with quetiapine, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine 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. 5.17 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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.18 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. 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 cellspacing="0" cellpadding="0" border="0" width="border-collapse: collapse"><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">A</content><content styleCode="bold">ge Range</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">D</content><content styleCode="bold">rug-Placebo Difference in</content> <content styleCode="bold">Number of Cases of Suicidality per 1000 Patients Treated</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">Increases Compared to Placebo</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">&lt;18 </td><td align="justify" styleCode="Rrule" valign="top">14 additional cases </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">18 to 24 </td><td align="justify" styleCode="Rrule" valign="top">5 additional cases </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">D</content><content styleCode="bold">ecreases Compared to Placebo</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">25 to 64 </td><td align="justify" styleCode="Rrule" valign="top">1 fewer case </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">&#x2265;65 </td><td align="justify" styleCode="Rrule" valign="top">6 fewer cases </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="727"><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">L</content><content styleCode="bold">aboratory</content> <content styleCode="bold">A</content><content styleCode="bold">nalyte</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">C</content><content styleCode="bold">ategory Change</content> <content styleCode="bold">(</content><content styleCode="bold">A</content><content styleCode="bold">t Least Once)</content> <content styleCode="bold">f</content><content styleCode="bold">rom Baseline</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">T</content><content styleCode="bold">rea</content><content styleCode="bold">t</content><content styleCode="bold">me</content><content styleCode="bold">n</content><content styleCode="bold">t Arm</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">N</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">P</content><content styleCode="bold">a</content><content styleCode="bold">tie</content><content styleCode="bold">n</content><content styleCode="bold">t</content><content styleCode="bold">s</content> <content styleCode="bold">n (%)</content> </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top">Fasting Glucose </td><td rowspan="2" align="justify" styleCode="Rrule" valign="top">Normal to High (&lt;100 mg/dL to &#x2265;126 mg/dL/) </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">2907 </td><td align="justify" styleCode="Rrule" valign="top">71 (2.4%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">1346 </td><td align="justify" styleCode="Rrule" valign="top">19 (1.4%) </td></tr><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top">Borderline to High (&#x2265;100 mg/dL) and &lt;126 mg/dL to &#x2265;26 PJ/G/) </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">572 </td><td align="justify" styleCode="Rrule" valign="top">67 (11.7%) </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"> Placebo </td><td align="justify" styleCode="Rrule" valign="top">279 </td><td align="justify" styleCode="Rrule" valign="top">33 (11.8%) </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="border-collapse: collapse"><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">L</content><content styleCode="bold">aboratory</content> <content styleCode="bold">A</content><content styleCode="bold">nalyte</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">Indication</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">T</content><content styleCode="bold">reatment Arm</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">N</content> </td><td align="justify" styleCode="Rrule" valign="top"><content styleCode="bold">P</content><content styleCode="bold">a</content><content styleCode="bold">t</content><content styleCode="bold">ients n (%)</content> </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top">Total Cholesterol &#x2265;240 PJ/G/ </td><td rowspan="2" align="justify" styleCode="Rrule" valign="top"> Schizophrenia <content styleCode="italics">1</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">137 </td><td align="justify" styleCode="Rrule" valign="top">24 (18%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">92 </td><td align="justify" styleCode="Rrule" valign="top">6 (7%) </td></tr><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top">Bipolar Depression <content styleCode="italics">2</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">463 </td><td align="justify" styleCode="Rrule" valign="top">41 (9%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">250 </td><td align="justify" styleCode="Rrule" valign="top">15 (6%) </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top">Triglycerides &#x2265;200 mg/dL </td><td rowspan="2" align="justify" styleCode="Rrule" valign="top">Schizophrenia <content styleCode="italics">1</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">120 </td><td align="justify" styleCode="Rrule" valign="top">26 (22%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">70 </td><td align="justify" styleCode="Rrule" valign="top">11 (16%) </td></tr><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top">Bipolar Depression <content styleCode="italics">2</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">436 </td><td align="justify" styleCode="Rrule" valign="top">59 (14%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">232 </td><td align="justify" styleCode="Rrule" valign="top">20 (9%) </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top">LDL- Cholesterol &#x2265;160 mg/dL </td><td rowspan="2" align="justify" styleCode="Rrule" valign="top">Schizophrenia <content styleCode="italics">1</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td></tr><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top">Bipolar Depression <content styleCode="italics">2</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">465 </td><td align="justify" styleCode="Rrule" valign="top">29 (6%) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">256 </td><td align="justify" styleCode="Rrule" valign="top">12 (5%) </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top">HDL- Cholesterol &#x2264;40 PJ/G/ </td><td rowspan="2" align="justify" styleCode="Rrule" valign="top">Schizophrenia <content styleCode="italics">1</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td><td align="justify" styleCode="Rrule" valign="top">na <content styleCode="italics">3</content> </td></tr><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top">Bipolar Depression <content styleCode="italics">2</content> </td><td align="justify" styleCode="Rrule" valign="top">Quetiapine </td><td align="justify" styleCode="Rrule" valign="top">393 </td><td align="justify" styleCode="Rrule" valign="top">56 (14%) </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">Placebo </td><td align="justify" styleCode="Rrule" valign="top">214 </td><td align="justify" styleCode="Rrule" valign="top">29 (14%) </td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.1) Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions (5.2) ] Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warnings and Precautions 5.3 ] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions 5.4 ] Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see Warnings and Precautions 5.5 ] Tardive dyskinesia [see Warnings and Precautions 5.6 ] Hypotension [see Warnings and Precautions 5.7 ] Increases in blood pressure (children and adolescents) [see Warnings and Precautions 5.8 ] Leukopenia, neutropenia and agranulocytosis [see Warnings and Precautions 5.9 ] Cataracts [see Warnings and Precautions 5.10 ] QT Prolongation [see Warnings and Precautions 5.11 ] Seizures [see Warnings and Precautions 5.12 ] Hypothyroidism [see Warnings and Precautions 5.13 ] Hyperprolactinemia [ see Warnings and Precautions 5.14 ] Potential for cognitive and motor impairment [see Warnings and Precautions 5.15 ] Body temperature regulation [see Warnings and Precautions 5.16 ] Dysphagia [see Warnings and Precautions 5.17 ] Discontinuation Syndrome [see Warnings and Precautions 5.18 ] 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) Childrenand Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea,vomiting, dry mouth, tachycardia, weight increased (6.1) To report SUSPECTED ADVERSE REACTIONS, contactAscend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Study Experience Becauseclinicalstudiesareconductedunderwidely varyingconditions,adversereactionratesobservedintheclinical studiesof adrugcannotbedirectlycompared toratesin theclinicalstudies ofanotherdrugand maynotreflecttheratesobservedin practice. Adu lt s : Theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover4300 patients.This databaseincludes 698patientsexposedtoquetiapine forthetreatmentofbipolardepression,405patientsexposedto quetiapinefor the treatmentofacutebipolarmania (monotherapyand adjunct therapy),646 patientsexposedto quetiapinefor the maintenancetreatmentofbipolarIdisorderasadjunct therapy, and approximately2600patientsand/ornormalsubjectsexposedto1 ormoredosesofquetiapine for the treatmentofschizophrenia. Of theseapproximately4300subjects,approximately 4000(2300 inschizophrenia,405 inacutebipolarmania,698 inbipolardepression,and 646forthe maintenancetreatmentofbipolarIdisorder)werepatientswhoparticipated inmultipledose effectivenesstrials,andtheirexperiencecorresponded toapproximately2400 patient-years.Theconditionsand durationoftreatmentwith quetiapinevaried greatlyandincluded(inoverlappingcategories)open-labelanddouble-blindphases ofstudies,inpatientsandoutpatients,fixed-dose and dose-titrationstudies,andshort-termorlonger-termexposure. Adversereactions wereassessedbycollectingadverse events,results ofphysicalexaminations,vitalsigns,weights,laboratoryanalyses,ECGs, andresultsofophthalmologic examinations. Thestated frequenciesofadverse reactions represent theproportion ofindividualswho experienced, atleastonce,a treatment-emergent adversereactionofthe typelisted. AdverseReactions Associated with Discontinuation ofTreatment inShort-Term, Placebo-ControlledTrials Schizophrenia: Overall,therewaslittledifferencein the incidenceofdiscontinuationdueto adversereactions(4%forquetiapine vs. 3% for placebo)ina poolofcontrolledtrials. However,discontinuationsdueto somnolence(0.8%quetiapinevs. 0%placebo) andhypotension(0.4%quetiapinevs.0%placebo)wereconsideredtobedrugrelated [see Warningsand Precautions (5.7 and 5.18 )]. BipolarDisorder: Mania: Overall,discontinuations dueto adverse reactions were5.7%for quetiapinevs. 5.1% for placeboin monotherapyand 3.6%forquetiapinevs. 5.9% forplacebo in adjuncttherapy. D epression: Overall, discontinuationsduetoadverse reactionswere12.3%forquetiapine300 mg vs. 19.0% forquetiapine 600 mgand5.2% for placebo. CommonlyObserved AdverseReactionsin Short-Term,Placebo-Controlled Trials: Inthe acutetherapyofschizophrenia(upto 6weeks)and bipolarmania (upto12weeks) trials,the mostcommonlyobserved adversereactionsassociated withtheuseofquetiapinemonotherapy(incidenceof5%orgreater)andobserved atarateon quetiapine at least twicethatofplacebo were somnolence (18%),dizziness(11%),drymouth (9%),constipation(8%), ALT increased(5%),weightgain (5%),and dyspepsia (5%). AdverseReactionsOccurringatanIncidenceof2%orMoreAmong quetiapineTreated Patientsin Short-Term, Placebo-ControlledTrials: Theprescriber shouldbe awarethat the figuresinthetablesand tabulationscannotbe usedtopredict the incidence ofsideeffectsinthe courseofusualmedical practicewherepatientcharacteristicsandotherfactors differfromthose thatprevailedin theclinical trials. Similarly,thecitedfrequenciescannotbecompared withfiguresobtainedfromotherclinicalinvestigationsinvolvingdifferenttreatments,uses, and investigators.Thecited figures,however, doprovide the prescribingphysicianwithsomebasisforestimatingtherelative contributionofdrugandnondrugfactorstothe side effectincidenceinthepopulationstudied. Table9enumeratestheincidence,roundedtothenearestpercent,ofadversereactionsthatoccurred duringacutetherapyofschizophrenia(upto6 weeks)andbipolarmania(upto12 weeks) in2%ormoreofpatientstreated withquetiapine(dosesrangingfrom75to 800mg/day)wheretheincidencein patientstreatedwith quetiapinewasgreaterthanthe incidenceinplacebo-treatedpatients. Table9:AdverseReactionIncidencein3-to12-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofSchizophreniaandBipolarMania(Monotherapy) Preferred Term Quetiapine (n=719) PLACEBO (n=404) Headache 21% 14% Agitation 20% 17% Somnolence 18% 8% Dizziness 11% 5% Dry Mouth 9% 3% Constipation 8% 3% Pain 7% 5% Tachycardia 6% 4% Vomiting 6% 5% Asthenia 5% 3% Dyspepsia 5% 1% Weight Gain 5% 1% ALT Increased 5% 1% Anxiety 4% 3% Pharyngitis 4% 3% Rash 4% 2% Abdominal Pain 4% 1% Postural Hypotension 4% 1% Back Pain 3% 1% AST Increased 3% 1% Rhinitis 3% 1% Fever 2% 1% Gastroenteritis 2% 0% Amblyopia 2% 1% Intheacuteadjuncttherapyofbipolarmania(upto3weeks)studies,themostcommonlyobservedadversereactionsassociated withtheuseof quetiapine(incidenceof 5%or greater)andobserved atarateonquetiapineatleasttwice thatofplacebo weresomnolence(34%),drymouth (19%),asthenia(10%), constipation (10%), abdominalpain (7%),posturalhypotension (7%),pharyngitis (6%),andweightgain (6%). Table10enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 3 weeks)ofacutemaniain 2%ormoreofpatientstreated with quetiapine(dosesrangingfrom100 to 800 mg/day)usedasadjuncttherapytolithiumanddivalproexwheretheincidencein patientstreated with quetiapinewasgreater thantheincidenceinplacebo-treatedpatients. Table10:AdverseReactionIncidencein3-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofBipolarMania(AdjunctTherapy) Preferred Term Quetiapine (n=196) PLACEBO (n=203) Somnolence 34% 9% Dry Mouth 19% 3% Headache 17% 13% Asthenia 10% 4% Constipation 10% 5% Dizziness 9% 6% Tremor 8% 7% Abdominal Pain 7% 3% Postural Hypotension 7% 2% Agitation 6% 4% Weight Gain 6% 3% Pharyngitis 6% 3% Back Pain 5% 3% Hypertonia 4% 3% Rhinitis 4% 2% Peripheral Edema 4% 2% Twitching 4% 1% Dyspepsia 4% 3% Depression 3% 2% Amblyopia 3% 2% Speech Disorder 3% 1% Hypotension 3% 1% Hormone Level Altered 3% 0% Heaviness 2% 1% Infection 2% 1% Fever 2% 1% Hypertension 2% 1% Tachycardia 2% 1% Increased Appetite 2% 1% Hypothyroidism 2% 1% Incoordination 2% 1% Thinking Abnormal 2% 0% Anxiety 2% 0% Ataxia 2% 0% Sinusitis 2% 1% Sweating 2% 1% Urinary Tract Infection 2% 1% Inbipolardepression studies(upto8 weeks), themostcommonlyobserved treatmentemergentadversereactions associatedwiththeuseofquetiapine(incidenceof5%orgreater)and observedatarateonquetiapine atleasttwice thatofplacebo weresomnolence(57%),drymouth (44%),dizziness(18%),constipation(10%),and lethargy (5%). Table11 enumeratestheincidence,rounded tothenearestpercent, ofadversereactionsthatoccurredduringtherapy(upto 8 weeks)ofbipolardepressionin 2% ormoreofpatientstreatedwith quetiapine(doses of300and600mg/day) wheretheincidenceinpatientstreatedwithquetiapinewasgreaterthantheincidencein placebo-treatedpatients. Table11: AdverseReactionIncidencein8-WeekPlacebo-ControlledClinicalTrialsfortheTreatmentofBipolarDepression Preferred Term Quetiapine (n=698) PLACEBO (n=347) Somnolence 3 57% 15% Dry Mouth 44% 13% Dizziness 18% 7% Constipation 10% 4% Fatigue 10% 8% Dyspepsia 7% 4% Vomiting 5% 4% Increased Appetite 5% 3% Lethargy 5% 2% Nasal Congestion 5% 3% Orthostatic Hypotension 4% 3% Akathisia 4% 1% Palpitations 4% 1% Vision Blurred 4% 2% Weight increased 4% 1% Arthralgia 3% 2% Paraesthesia 3% 2% Cough 3% 1% Extrapyramidal Disorder 3% 1% Irritability 3% 1% Dysarthria 3% 0% Hypersomnia 3% 0% Sinus Congestion 2% 1% Abnormal Dreams 2% 1% Tremor 2% 1% Gastroesophageal Reflux Disease 2% 1% Pain in Extremity 2% 1% Asthenia 2% 1% Balance Disorder 2% 1% Hypoaesthesia 2% 1% Dysphagia 2% 0% Restless Legs Syndrome 2% 0% 3. Somnolencecombinesadversereactiontermssomnolenceand sedation Explorationsfor interactionsonthe basis of gender, age,andracedid notrevealanyclinicallymeaningfuldifferencesin theadversereactionoccurrenceon thebasisofthesedemographicfactors. DoseDependencyofAdverseReactionsinShort-Term,Placebo-ControlledTrials D ose-relatedAdverseReactions: Spontaneouslyelicited adversereactiondatafroma studyof schizophreniacomparing fivefixeddosesof quetiapine (75 mg,150mg, 300 mg, 600mg,and 750 mg/day)to placebo wereexploredfordose- relatednessofadversereactions. Logisticregression analysesrevealed apositivedoseresponse(p<0.05)forthefollowingadversereactions:dyspepsia, abdominalpain,and weightgain. AdverseReactionsinclinicaltrialswith quetiapineandnotlistedelsewherein thelabel: Thefollowingadversereactionshavealso beenreportedwithquetiapine:nightmares, hypersensitivityandelevationsinserumcreatine phosphokinase (notassociatedwithNMS), galactorrhea,bradycardia(whichmayoccur atornearinitiationof treatmentandbeassociated withhypotensionand/orsyncope) decreasedplatelets,somnambulism(and otherrelated events),elevationsingamma-GTlevels,hypothermia, and priapism. ExtrapyramidalSymptoms (EPS): D ystonia C l assEffect: Symptomsofdystonia,prolonged abnormalcontractionsofmuscle groups,mayoccur insusceptible individuals duringthefirstfewdaysoftreatment. Dystonicsymptoms include:spasmoftheneckmuscles,sometimesprogressingtotightness ofthethroat,swallowingdifficulty,difficultybreathing, and/orprotrusionofthe tongue. Whilethesesymptomscanoccuratlowdoses, theyoccurmore frequentlyand with greaterseveritywith highpotencyand at higher dosesoffirstgeneration antipsychoticdrugs.Anelevated riskof acutedystoniaisobserved inmales and younger agegroups. FourmethodswereusedtomeasureEPS:(1)Simpson-Angus totalscore(meanchangefrombaseline)whichevaluatesParkinsonismand akathisia,(2) BarnesAkathisiaRatingScale (BARS) GlobalAssessmentScore,(3)incidence ofspontaneouscomplaintsofEPS (akathisia,akinesia, cogwheelrigidity,extrapyramidalsyndrome, hypertonia, hypokinesia, neckrigidity, and tremor),and (4) use ofanticholinergicmedicationstotreatemergentEPS. Adults: Datafromone6-weekclinicaltrialofschizophreniacomparingfive fixeddosesofquetiapine(75,150, 300, 600,750 mg/day) providedevidenceforthelackof treatment-emergentextrapyramidalsymptoms(EPS)anddose- relatednessforEPS associated with quetiapine treatment. ThreemethodswereusedtomeasureEPS:(1)Simpson- Angustotalscore(meanchangefrombaseline)whichevaluatesParkinsonismandakathisia,(2) incidenceofspontaneouscomplaintsofEPS (akathisia,akinesia,cogwheelrigidity,extrapyramidalsyndrome,hypertonia,hypokinesia,neck rigidity, and tremor),and (3)useof anticholinergicmedicationstotreatemergentEPS. InTable 12,dystoniceventincludednuchalrigidity, hypertonia,dystonia,musclerigidity,oculogyration;parkinsonism includedcogwheelrigidity,tremor,drooling, hypokinesia;akathisiaincludedakathisia, psychomotoragitation;dyskinetic event includedtardive dyskinesia, dyskinesia,choreoathetosis;andotherextrapyramidaleventincludedrestlessness,extrapyramidaldisorder,movementdisorder. Table12: AdversereactionsassociatedwithEPS inashort-term,placebo-controlledmultiplefixed-dosePhaseIIIschizophreniatrial (6weeksduration) Preferred Term Quetiapine75 mg/day (N=53) Quetiapine 150 mg/day (N=48) Quetiapine 300 mg/day (N=52) Quetiapine 600 mg/day (N=51) Quetiapine 750 mg/day (N=54) Placebo (N=51) n % n % n % n % n % n % Dystonic event 2 3.8 2 4.2 0 0.0 2 3.9 3 5.6 4 7.8 Parkinsonism 2 3.8 0 0.0 1 1.9 1 2.0 1 1.9 4 7.8 Akathisia 1 1.9 1 2.1 0 0.0 0 0.0 1 1.9 4 7.8 Dyskinetic event 2 3.8 0 0.0 0 0.0 1 2.0 0 0.0 0 0.0 Other extrapyramidal event 2 3.8 0 0.0 3 5.8 3 5.9 1 1.9 4 7.8 Parkinsonismincidenceratesas measured bythe Simpson-Angus totalscoreforplaceboandthefivefixeddoses(75,150, 300,600,750mg/day)were:-0.6;-1.0,-1.2;-1.6;-1.8and-1.8.Therateofanticholinergicmedicationusetotreat emergentEPS forplacebo and thefivefixeddoses was:14%;11%;10%;8%;12%and 11%. Insix additionalplacebo-controlled clinicaltrials(3inacutemaniaand3 inschizophrenia)using variabledosesof quetiapine, therewerenodifferences between the quetiapineand placebotreatmentgroupsintheincidence ofEPS,as assessed bySimpson-Angustotalscores, spontaneouscomplaintsof EPSand the useof concomitantanticholinergicmedicationsto treatEPS. Intwoplacebo-controlled clinicaltrialsforthetreatmentofbipolardepressionusing300 mgand 600 mgofquetiapine, theincidenceofadverse reactions potentiallyrelatedtoEPS was 12% inbothdose groups and 6%inthe placebo group. Inthese studies, theincidenceoftheindividual adversereactions(akathisia,extrapyramidaldisorder,tremor,dyskinesia, dystonia,restlessness, musclecontractionsinvoluntary, psychomotor hyperactivityand musclerigidity)were generallylowand did notexceed 4%inanytreatmentgroup. The3 treatmentgroups weresimilarin meanchange inSAS totalscoreandBARS GlobalAssessmentscore at the endoftreatment.Theuseofconcomitant anticholinergicmedicationswasinfrequentandsimilaracrossthethreetreatment groups. Childrenand Adolescents Theinformationbelow isderivedfroma clinicaltrialdatabaseforquetiapineconsistingofover1000 pediatricpatients. Thisdatabase includes 677patientsexposedto quetiapinefor the treatmentofschizophrenia and393childrenand adolescents(10to 17 yearsold) exposedto quetiapineforthetreatmentofacutebipolarmania. AdverseReactions Associated with Discontinuation ofTreatment inShort-Term,Placebo-ControlledTrialsSchizophrenia:Theincidence ofdiscontinuationduetoadversereactionsfor quetiapine-treated andplacebo-treated patients was8.2%and2.7%, respectively.Theadverse eventleadingtodiscontinuationin 1%or moreofpatientson quetiapineand ata greaterincidence than placebowas somnolence (2.7%and 0%forplacebo). BipolarIMania:The incidenceofdiscontinuation dueto adversereactionsforquetiapine-treated andplacebo-treatedpatientswas11.4% and4.4%, respectively.Theadverse reactionsleadingto discontinuationin 2%ormoreofpatientson quetiapineand ata greaterincidence than placebowere somnolence(4.1% vs.1.1%)andfatigue (2.1%vs.0). CommonlyObservedAdverseReactions inShort-Term,Placebo-ControlledTrials Intherapyforschizophrenia(upto6weeks),themostcommonlyobservedadversereactionsassociatedwiththeuseof quetiapinein adolescents(incidenceof 5%orgreaterand quetiapine incidenceatleasttwicethatfor placebo) weresomnolence(34%), dizziness(12%),drymouth (7%),tachycardia(7%). Inbipolarmaniatherapy(up to3 weeks) the mostcommonlyobservedadversereactionsassociatedwiththeuse of quetiapineinchildrenand adolescents(incidenceof5%or greater andquetiapineincidenceatleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth (7%),and weight increased (6%). Adverse Reactions Occurring at an Incidenceof ≥ 2% Among quetiapine Treated Patients in Short-Term, Placebo-ControlledTrials Schizophrenia (Adolescents,13 to 17 yearsold) Thefollowingfindingswerebasedona6-weekplacebo-controlledtrialinwhichquetiapinewasadministered ineither dosesof 400 or800 mg/day. Table13 enumeratestheincidence,roundedto the nearestpercent,oftreatment-emergent adverse reactionsthatoccurred duringtherapy(up to 6 weeks)ofschizophreniain2%ormoreofpatientstreatedwithquetiapine (doses of400 or800 mg/day)where the incidence inpatientstreatedwithquetiapine was atleast twice the incidence inplacebo-treated patients. Adverse eventsthatwere potentiallydose-relatedwithhigher frequencyinthe800mg group comparedtothe400 mg group includeddizziness(8%vs. 15%), drymouth(4% vs. 10%), and tachycardia(6% vs.11%). Table13: AdverseReactionIncidenceina6-WeekPlacebo-ControlledClinicalTrial fortheTreatment ofSchizophreniainAdolescentPatients Preferred Term Quetiapine 400 mg (n=73) Quetiapine 800 mg (n=74) Placebo (n=75) Somnolence 1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia 2 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnoea 0% 3% 0% Abdominal Pain 3% 1% 0% Anorexia 3% 1% 0% Tooth Abscess 3% 1% 0% Dyskinesia 3% 0% 0% Epistaxis 3% 0% 1% Muscle Rigidity 3% 0% 0% 1. Somnolencecombinesadversereactiontermssomnolenceand sedation. 2. Tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. B i p olarIMania(Childrenand Adolescents 10to17 years old) Thefollowingfindingswerebased on a3-weekplacebo-controlledtrialinwhichquetiapinewasadministeredin eitherdosesof 400 or600 mg/day. CommonlyObservedAdverseReactions Inbipolarmaniatherapy(upto3weeks) themostcommonlyobservedadversereactionsassociatedwiththeuseofquetiapinein children andadolescents(incidenceof5%or greater andquetiapineincidence atleast twicethatfor placebo)weresomnolence(53%),dizziness(18%),fatigue(11%),increasedappetite(9%),nausea(8%), vomiting(8%), tachycardia(7%),drymouth(7%), andweight increased(6%). Table14 enumeratestheincidence,rounded tothenearestpercent, oftreatment-emergent adverse reactionsthatoccurredduringtherapy(up to3 weeks) of bipolar maniain2%ormore of patientstreatedwithquetiapine (doses of400 or600 mg/day)where the incidence inpatientstreatedwithquetiapinewasgreaterthan theincidenceinplacebo-treated patients. Adverseeventsthatwerepotentiallydose-relatedwithhigher frequencyinthe600mg group comparedtothe400 mg group includedsomnolence(50%vs.57%), nausea(6% vs.10%) and tachycardia(6% vs.9%). Table14:AdverseReactionsina3-WeekPlacebo-ControlledClinicalTrial fortheTreatment ofBipolar Maniain ChildrenandAdolescentPatients Preferred Term Quetiapine 400 mg (n=95) Quetiapine 600 mg (n=98) Placebo (n=90) Somnolence 1 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia 2 6% 9% 1% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% iritability 3% 5% 1% Pyrexia 1% 4% 1% Aggression 1% 3% 0% Musculoskeletal Stiffness 1% 3% 1% Accidental Overdose 0% 2% 0% Acne 3% 2% 0% Arthralgia 4% 2% 1% Lethargy 2% 2% 0% Pallor 1% 2% 0% Stomach Discomfort 4% 2% 1% Syncope 2% 2% 0% Vision Blurred 3% 2% 0% Constipation 4% 2% 0% Ear Pain 2% 0% 0% Paraesthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% 1. Somolencecombinesadversereactionstermssomnolenceand sedation. 2. Tachycardiacombinesadversereactiontermstachycardiaand sinustachycardia. ExtrapyramidalSymptoms: Inashort-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration),theaggregatedincidenceofextrapyramidalsymptomswas 12.9%(19/147) for quetiapineand 5.3%(4/75)forplacebo, though theincidenceoftheindividualadverseevents (akathisia,tremor,extrapyramidaldisorder,hypokinesia, restlessness,psychomotorhyperactivity, musclerigidity,dyskinesia)didnotexceed 4.1%in anytreatmentgroup. Ina short-termplacebo-controlledmonotherapytrialinchildrenand adolescentpatientswithbipolarmania(3-weekduration),the aggregatedincidence ofextrapyramidalsymptomswas3.6% (7/193) orquetiapine and 1.1%(1/90)forplacebo. Table15 presentsalistingofpatientswith adversereactionspotentiallyassociated withextrapyramidalsymptoms in the short-termplacebo-controlledmonotherapytrialinadolescentpatientswithschizophrenia(6-weekduration). InTables15– 16dystonicevent includednuchalrigidity,hypertonia,andmusclerigidity;parkinsonismincluded cogwheelrigidityandtremor;akathisiaincludedakathisiaonly; dyskinetic event includedtardive dyskinesia,dyskinesia,andchoreoathetosis;andotherextrapyramidaleventincludedrestlessnessandextrapyramidaldisorder. T able15: AdverseReactionsAssociatedwith ExtrapyramidalSymptomsinthePlacebo-controlled TrialinAdolescentPatientswithSchizophrenia (6-weekduration) Preferred Term Quetiapine 400 mg/day (N=73) Quetiapine 800 mg/day (N=74) All Quetiapine (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2.7 0 0.0 2 1.4 0 0.0 Parkinsonism 4 5.5 4 5.4 8 5.4 2 2.7 Akathisia 3 4.1 4 5.4 7 4.8 3 4.0 Dyskinetic event 2 2.7 0 0.0 2 1.4 0 0.0 Other Extrapyramidal Event 2 2.7 2 2.7 4 2.7 0 0.0 Table16 presentsa listingofpatientswith adversereactions associatedwithextrapyramidalsymptoms in a short-termplacebo-controlled monotherapytrialin childrenand adolescentpatientswith bipolarmania (3-weekduration). Table16: AdverseReactionsAssociatedwithExtrapyramidalSymptomsinaPlacebo-ControlledTrialinChildrenandAdolescentPatientswithBipolarI Mania(3-weekduration) Preferred Term1 Quetiapine 400 mg/day (N=95) Quetiapine 600 mg/day (N=98) All Quetiapine (N=193) Placebo (N=90) n % n % N % N % Parkinsonism 2 2.1 1 1.0 3 1.6 1 1.1 Akathisia 1 1.0 1 1.0 2 1.0 0 0.0 Other Extrapyramidal Event 1 1.1 1 1.0 2 1.0 0 0.0 1. Therewerenoadverseexperienceswith thepreferredtermofdystonicor dyskineticevents. O t herAdverseReactionsObservedDuringthePre-MarketingEvaluationofquetiapine FollowingisalistofCOSTARTterms thatreflecttreatment-emergentadversereactionsasdefinedin the introductiontothe ADVERSE REACTIONS sectionreportedbypatientstreatedwithquetiapine atmultipledoses >75mg/dayduring anyphaseofatrialwithinthe premarketingdatabase ofapproximately2200 patientstreatedfor schizophrenia. Allreported reactionsareincludedexceptthosealreadylistedinthetablesorelsewhereinlabeling,thosereactionsforwhich a drugcause wasremote,and those reaction termswhich weresogeneralastobeuninformative. It is importantto emphasize that, although the reactionsreported occurredduringtreatmentwithquetiapine, theywerenotnecessarilycaused byit. Reactionsarefurthercategorizedbybodysystemandlistedinorderofdecreasingfrequencyaccordingtothefollowingdefinitions:frequentadverse reactionsare those occurringin at least1/100 patients(onlythosenotalreadylistedin thetabulatedresultsfromplacebo-controlledtrialsappearin thislisting); infrequentadverse reactionsarethose occurringin 1/100to 1/1000patients;rare reactions arethoseoccurringinfewerthan1/1000patients. NervousSystem: Infrequent: abnormaldreams,dyskinesia, thinkingabnormal, tardive dyskinesia,vertigo, involuntary movements,confusion,amnesia, psychosis,hallucinations,hyperkinesia,libido increased2,urinaryretention, incoordination,paranoidreaction, abnormalgait, myoclonus,delusions, manicreaction, apathy,ataxia, depersonalization, stupor,bruxism,catatonicreaction,hemiplegia; Rare: aphasia, buccoglossalsyndrome, choreoathetosis, delirium,emotionallability,euphoria, libido decreased2,neuralgia, stuttering,subduralhematoma. Bodyas aWhole: Frequent: flusyndrome; Infrequent: neckpain, pelvicpain2suicideattempt,malaise,photosensitivity reaction, chills,face edema,moniliasis; Rare: abdomen enlarged. D i gestiveSystem: Frequent: anorexia; Infrequent: increasedsalivation,increasedappetite, gammaglutamyltranspeptidase increased, gingivitis, dysphagia, flatulence,gastroenteritis,gastritis,hemorrhoids,stomatitis,thirst,toothcaries,fecalincontinence,gastroesophagealreflux,gumhemorrhage, mouthulceration,rectalhemorrhage, tongueedema; Rare: glossitis, hematemesis,intestinalobstruction, melena,pancreatitis. CardiovascularSystem: Infrequent: vasodilatation,QTintervalprolonged,migraine, bradycardia,cerebralischemia, irregularpulse,Twaveabnormality,bundlebranchblock,cerebrovascularaccident,deep thrombophlebitis,Twaveinversion; Rare: anginapectoris, atrialfibrillation,AV blockfirstdegree,congestiveheartfailure, STelevated,thrombophlebitis,Twaveflattening, STabnormality,increased QRS duration. RespiratorySystem: Frequent: cough increased,dyspnea; Infrequent: pneumonia, epistaxis,asthma; Rare: hiccup, hyperventilation. MetabolicandNutritionalSystem: Infrequent: weightloss, alkalinephosphataseincreased,hyperlipemia,alcohol intolerance, dehydration, hyperglycemia, creatinineincreased,hypoglycemia; Rare: glycosuria,gout, handedema, hypokalemia, waterintoxication. Skin andAppendages System: Infrequent: pruritus,acne,eczema,contactdermatitis,maculopapularrash,seborrhea,skin ulcer; Rare: exfoliativedermatitis,psoriasis,skindiscoloration. U rogenitalSystem: Infrequent: dysmenorrhea2,vaginitis2,urinaryincontinence,metrorrhagia2,impotence2,dysuria,vaginalmoniliasis2,abnormalejaculation2,cystitis,urinary frequency, amenorrhea2,femalelactation2,leukorrhea2, vaginalhemorrhage2,vulvovaginitis2,orchitis2; Rare: gynecomastia2,nocturia,polyuria,acutekidneyfailure. SpecialSenses: Infrequent: conjunctivitis, abnormalvision, dryeyes, tinnitus,taste perversion, blepharitis, eyepain; Rare: abnormalityof accommodation,deafness, glaucoma. M usculoskeletalSystem: Infrequent: pathologicalfracture,myasthenia, twitching, arthralgia,arthritis,leg cramps,bone pain. H emic and LymphaticSystem: Infrequent: leukocytosis, anemia, ecchymosis,eosinophilia, hypochromicanemia;lymphadenopathy, cyanosis; Rare: hemolysis,thrombocytopenia. EndocrineSystem: Infrequent: hypothyroidism, diabetesmellitus; Rare: hyperthyroidism. 2Adjustedfor gender. Laboratory, ECGand vitalsignchanges observed in clinicalstudies LaboratoryChanges: NeutrophilCounts Adults :Inplacebo-controlledmonotherapyclinicaltrials involving3368patientsonquetiapinefumarateand 1515 on placebo,theincidenceofatleastone occurrence ofneutrophilcount<1.0x 109/Lamongpatientswith a normalbaselineneutrophilcountandatleastoneavailablefollowuplaboratorymeasurementwas0.3%(10/2967)inpatientstreatedwithquetiapinefumarate,comparedto 0.1% (2/1349)inpatientstreatedwithplacebo. [seeWarningsand Precautions (5.9)]. TransaminaseElevations Adults :Asymptomatic, transientandreversibleelevationsinserumtransaminases(primarilyALT)havebeenreported. Inschizophreniatrials inadults, theproportions ofpatientswithtransaminase elevationsof> 3times the upper limitsofthe normalreferencerangein apoolof3-to6-weekplacebo-controlledtrialswere approximately6%(29/483)for quetiapine compared to1% (3/194)for placebo.In acutebipolarmaniatrialsinadults,theproportionsof patientswithtransaminaseelevations of> 3 times theupper limitsof thenormalreferencerangein apoolof 3-to12-weekplacebo- controlledtrialswere approximately1%forboth quetiapine (3/560) andplacebo(3/294).These hepatic enzyme elevationsusuallyoccurredwithin thefirst3weeksofdrugtreatmentand promptlyreturned topre-studylevelswithongoingtreatmentwith quetiapine. In bipolardepression trials,theproportionsof patientswithtransaminaseelevations of>3timestheupperlimitsofthenormalreferencerangeintwo8-weekplacebo-controlledtrialswas1%(5/698)for quetiapine and 2% (6/347) forplacebo. DecreasedHemoglobin Adults :Inshort-termplacebo-controlled trials, decreases inhaemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasionoccurred 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 anduncontrolled clinical trials, decreases in haemoglobin to ≤ 13 g/dL males, ≤ 12g/dL females on atleast one occasion occurred in 11% (2277/20729) of quetiapinetreated patients. InterferencewithUrineDrugScreens Therehavebeenliteraturereportssuggestingfalse positive resultsinurine enzyme immunoassaysformethadoneand tricyclic antidepressants inpatientswhohave takenquetiapine. Cautionshouldbeexercisedinthe interpretation of positive urinedrugscreen resultsforthesedrugs, andconfirmation byalternativeanalyticaltechnique(e.g., chromatographic methods)shouldbe considered. ECGChanges Adults: Between-group comparisonsforpooled placebo-controlledtrialsrevealed no statisticallysignificant quetiapine/placebo differencesintheproportionsofpatientsexperiencingpotentiallyimportantchangesinECGparameters,includingQT,QTc,andPR intervals.However,the proportions ofpatientsmeetingthe criteriafor tachycardia werecomparedinfour 3-to 6-weekplacebo-controlled clinicaltrials for the treatmentofschizophrenia revealinga 1%(4/399) incidenceforquetiapine compared to0.6%(1/156)incidence forplacebo. Inacute (monotherapy) bipolar maniatrials the proportions ofpatientsmeetingthe criteriafortachycardia was0.5%(1/192)for quetiapine compared to0% (0/178)incidence forplacebo. In acutebipolarmania(adjunct)trialstheproportionsof patientsmeetingthesamecriteriawas 0.6%(1/166)for quetiapine compared to0%(0/171)incidenceforplacebo. Inbipolardepressiontrials, nopatientshadheart rateincreases to> 120beatsperminute.Quetiapine use wasassociatedwitha meanincrease inheartrate, assessedbyECG,of 7 beats per minutecompared toa mean increaseof1beatper minute amongplacebopatients.Thisslighttendencytotachycardiainadultsmay be relatedtoquetiapine'spotential forinducingorthostaticchanges [see Warnings andPrecautions( 5.7 )] . Childrenand Adolescents: Intheacute(6 week)schizophreniatrialinadolescents, increases inheartrate(>110 bpm)occurredin 5.2%(3/73)ofpatientsreceivingquetiapine400 mgand 8.5%(5/74)ofpatientsreceivingquetiapine 800 mgcomparedto0%(0/75)of patientsreceivingplacebo. Mean increasesinheartratewere3.8bpmand 11.2bpmfor quetiapine 400 mgand800 mg groups, respectively,compared toa decreaseof3.3 bpmin theplacebogroup [seeWarningsand Precautions ( 5.7 )] . In theacute(3 week)bipolarmania trialinchildrenand adolescents,increasesinheartrate (>110bpm) occurredin 1.1%(1/89)ofpatientsreceivingquetiapine400 mgand 4.7% (4/85)ofpatientsreceivingquetiapine600 mg compared to 0%(0/98)ofpatients receivingplacebo.Meanincreases inheartratewere12.8bpmand 13.4 bpmforquetiapine400 mgand 600 mg groups,respectively,compared to a decrease of1.7 bpminthe placebogroup [seeWarningsandPrecautions ( 5.7 )] . 6.2 Post Marketing Experience The following adverse reactions were identified during post approval of quetiapine. 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 therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

<table cellspacing="0" cellpadding="0" border="0" width="border-collapse: collapse"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Preferred Term </td><td styleCode="Rrule" valign="top">Quetiapine (n=719) </td><td styleCode="Rrule" valign="top">PLACEBO (n=404) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Headache </td><td styleCode="Rrule" valign="top">21% </td><td styleCode="Rrule" valign="top">14% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Agitation </td><td styleCode="Rrule" valign="top">20% </td><td styleCode="Rrule" valign="top">17% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Somnolence </td><td styleCode="Rrule" valign="top">18% </td><td styleCode="Rrule" valign="top">8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dizziness </td><td styleCode="Rrule" valign="top">11% </td><td styleCode="Rrule" valign="top">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dry Mouth </td><td styleCode="Rrule" valign="top">9% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Constipation </td><td styleCode="Rrule" valign="top">8% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Pain </td><td styleCode="Rrule" valign="top">7% </td><td styleCode="Rrule" valign="top">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Tachycardia </td><td styleCode="Rrule" valign="top">6% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Vomiting </td><td styleCode="Rrule" valign="top">6% </td><td styleCode="Rrule" valign="top">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Asthenia </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dyspepsia </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Weight Gain </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">ALT Increased </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Anxiety </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Pharyngitis </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Rash </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Abdominal Pain </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Postural Hypotension </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Back Pain </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">AST Increased </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Rhinitis </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Fever </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Gastroenteritis </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Amblyopia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="664"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Preferred Term </td><td styleCode="Rrule" valign="top">Quetiapine (n=196) </td><td styleCode="Rrule" valign="top">PLACEBO (n=203) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Somnolence </td><td styleCode="Rrule" valign="top">34% </td><td styleCode="Rrule" valign="top">9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dry Mouth </td><td styleCode="Rrule" valign="top">19% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Headache </td><td styleCode="Rrule" valign="top">17% </td><td styleCode="Rrule" valign="top">13% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Asthenia </td><td styleCode="Rrule" valign="top">10% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Constipation </td><td styleCode="Rrule" valign="top">10% </td><td styleCode="Rrule" valign="top">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dizziness </td><td styleCode="Rrule" valign="top">9% </td><td styleCode="Rrule" valign="top">6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Tremor </td><td styleCode="Rrule" valign="top">8% </td><td styleCode="Rrule" valign="top">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Abdominal Pain </td><td styleCode="Rrule" valign="top">7% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Postural Hypotension </td><td styleCode="Rrule" valign="top">7% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Agitation </td><td styleCode="Rrule" valign="top">6% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Weight Gain </td><td styleCode="Rrule" valign="top">6% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Pharyngitis </td><td styleCode="Rrule" valign="top">6% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Back Pain </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypertonia </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Rhinitis </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Peripheral Edema </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Twitching </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dyspepsia </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Depression </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Amblyopia </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Speech Disorder </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypotension </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hormone Level Altered </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Heaviness </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Infection </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Fever </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypertension </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Tachycardia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Increased Appetite </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypothyroidism </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Incoordination </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Thinking Abnormal </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Anxiety </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Ataxia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Sinusitis </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Sweating </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Urinary Tract Infection </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="541"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Preferred Term </td><td styleCode="Rrule" valign="top">Quetiapine (n=698) </td><td styleCode="Rrule" valign="top">PLACEBO (n=347) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Somnolence ³ </td><td styleCode="Rrule" valign="top">57% </td><td styleCode="Rrule" valign="top">15% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dry Mouth </td><td styleCode="Rrule" valign="top">44% </td><td styleCode="Rrule" valign="top">13% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dizziness </td><td styleCode="Rrule" valign="top">18% </td><td styleCode="Rrule" valign="top">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Constipation </td><td styleCode="Rrule" valign="top">10% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Fatigue </td><td styleCode="Rrule" valign="top">10% </td><td styleCode="Rrule" valign="top">8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dyspepsia </td><td styleCode="Rrule" valign="top">7% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Vomiting </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Increased Appetite </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Lethargy </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Nasal Congestion </td><td styleCode="Rrule" valign="top">5% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Orthostatic Hypotension </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Akathisia </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Palpitations </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Vision Blurred </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Weight increased </td><td styleCode="Rrule" valign="top">4% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Arthralgia </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Paraesthesia </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Cough </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Extrapyramidal Disorder </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Irritability </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dysarthria </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypersomnia </td><td styleCode="Rrule" valign="top">3% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Sinus Congestion </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Abnormal Dreams </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Tremor </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Gastroesophageal Reflux Disease </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Pain in Extremity </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Asthenia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Balance Disorder </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Hypoaesthesia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Dysphagia </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Restless Legs Syndrome </td><td styleCode="Rrule" valign="top">2% </td><td styleCode="Rrule" valign="top">0% </td></tr></tbody></table>