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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, constipation, dizziness, increased appetite, dyspepsia, weight gain, fatigue, dysarthria, and nasal congestion ( 6.1 ) Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )] Falls [see WARNINGS AND PRECAUTIONS ( 5.8 )] Increases in blood pressure (children and adolescents) [see WARNINGS AND PRECAUTIONS ( 5.9 )] Leukopenia, neutropenia and agranulocytosis [see WARNINGS AND PRECAUTIONS ( 5.10 )] Cataracts [see WARNINGS AND PRECAUTIONS ( 5.11 )] QT Prolongation [see WARNINGS AND PRECAUTIONS ( 5.12 )] Seizures [see WARNINGS AND PRECAUTIONS ( 5.13 )] Hypothyroidism [see WARNINGS AND PRECAUTIONS ( 5.14 )] Hyperprolactinemia [see WARNINGS AND PRECAUTIONS ( 5.15 )] Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS ( 5.16 )] Body temperature regulation [see WARNINGS AND PRECAUTIONS ( 5.17 )] Dysphagia [see WARNINGS AND PRECAUTIONS ( 5.18 )] Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS ( 5.19 )] Anticholinergic (antimuscarinic) Effects [see WARNINGS AND PRECAUTIONS, ( 5.20 )] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from a clinical trial database for quetiapine fumarate extended-release tablet consisting of approximately 3400 patients exposed to quetiapine fumarate extended-release tablet for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses and ECG results. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for quetiapine fumarate extended-release tablet in schizophrenia trials. Bipolar I Disorder, Manic or Mixed Episodes: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for quetiapine fumarate extended-release tablet in the bipolar mania trial. Bipolar Disorder, Depressive Episode: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on quetiapine fumarate extended-release tablet discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in quetiapine fumarate extended-release tablet in the bipolar depression trial. MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on quetiapine fumarate extended-release tablet discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in quetiapine fumarate extended-release tablet in MDD trials. Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablet (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablet at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%). Adverse Reactions occurring at an Incidence of 2% or more Among quetiapine fumarate extended-release tablet Treated Patients in Short-Term, Placebo-Controlled Trials Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with quetiapine fumarate extended-release tablet (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablet was greater than the incidence in placebo-treated patients. In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablet (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablet at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%). 2 Somnolence combines adverse reaction terms somnolence and sedation. Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with quetiapine fumarate extended-release tablet (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablet was greater than the incidence in placebo-treated patients. Table 12: Adverse Reactions in 6-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia Preferred Term Quetiapine Fumarate Extended-Release Tablet (N=951) Placebo (N=319) Somnolence Somnolence combines adverse reaction terms somnolence and sedation. 25% 10% Dry Mouth 12% 1% Dizziness 10% 4% Extrapyramidal Symptoms Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia dystonia, extrapyramidal disorder, hypertonia, movement disorder, muscle rigidity,parkinsonism, parkinsonian gait, and tardive dyskinesia. 8% 5% Orthostatic Hypotension 7% 5% Constipation 6% 5% Dyspepsia 5% 2% Heart Rate Increased 4% 1% Tachycardia 3% 1% Fatigue 3% 2% Hypotension 3% 1% Vision blurred 2% 1% Toothache 2% 0% Increased Appetite 2% 0% Muscle Spasms 2% 1% Tremor 2% 1% Akathisia 2% 1% Anxiety 2% 1% Schizophrenia 2% 1% Restlessness 2% 1% In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablet (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablet at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%). Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with quetiapine fumarate extended-release tablet 300 mg/day where the incidence in patients treated with quetiapine fumarate extended-release tablet was greater than the incidence in placebo-treated patients. Table 13: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania Preferred Term Quetiapine Fumarate Extended-Release Tablet (N=151) Placebo (N=160) Somnolence Somnolence combines adverse reaction terms somnolence and sedation. 50% 12% Dry Mouth 34% 7% Dizziness 10% 4% Constipation 10% 3% Dyspepsia 7% 4% Fatigue 7% 4% Weight Gain 7% 1% Extrapyramidal Symptoms Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness and tremor. 7% 4% Nasal Congestion 5% 1% Dysarthria 5% 0% Increased Appetite 4% 2% Back Pain 3% 2% Toothache 3% 1% Heart Rate Increased 3% 0% Abnormal Dreams 3% 0% Orthostatic Hypotension 3% 0% Tachycardia 2% 1% Vision Blurred 2% 1% Sluggishness 2% 1% Lethargy 2% 1% In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablet (incidence of 5% or greater and observed at a rate on quetiapine fumarate extended-release tablet and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation (300 mg only: 11%) and weight increased (300 mg only: 5%). Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with quetiapine fumarate extended-release tablet (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablet was greater than the incidence in placebo-treated patients. Table 14: Adverse Reactions in an 8-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Depression Preferred Term Quetiapine Fumarate Extended-Release Tablet (N=137) Placebo (N=140) Somnolence Somnolence combines adverse reaction terms somnolence and sedation. 52% 13% Dry Mouth 37% 7% Dizziness 13% 11% Increased Appetite 12% 6% Constipation 8% 6% Dyspepsia 7% 1% Weight Gain 7% 1% Fatigue 6% 2% Irritability 4% 3% Viral Gastroenteritis 4% 1% Arthralgia 4% 1% Extrapyramidal Symptoms Extrapyramidal symptoms include the terms: dystonia, extrapyramidal disorder, hypertonia, and tremor. 4% 1% Paraesthesia 3% 2% Back Pain 3% 1% Muscle Spasms 3% 1% Toothache 3% 0% Abnormal Dreams 3% 0% Ear Pain 2% 1% Seasonal Allergy 2% 1% Sinusitis 2% 1% Decreased Appetite 2% 1% Myalgia 2% 1% Disturbance in Attention 2% 1% Migraine 2% 1% Restless Legs Syndrome 2% 1% Anxiety 2% 1% Sinus Headache 2% 1% Libido Decreased 2% 1% Pollakiuria 2% 1% Sinus Congestion 2% 1% Hyperhidrosis 2% 1% Orthostatic Hypotension 2% 1% Urinary Tract Infection 2% 0% Heart Rate Increased 2% 0% Neck Pain 2% 0% Dysarthria 2% 0% Akathisia 2% 0% Hypersomnia 2% 0% Mental Impairment 2% 0% Confusional State 2% 0% Disorientation 2% 0% Adverse Reactions In Clinical Trials With Quetiapine And Not Listed Elsewhere In The Label Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), and priapism. Extrapyramidal Symptoms (EPS) Dystonia: Class Effect Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat EPS. Adults In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo. In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of quetiapine fumarate extended-release tablet, the incidence of any adverse reactions related to EPS was 8% for quetiapine fumarate extended-release tablet and 8% for quetiapine fumarate tablet (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group. At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of quetiapine fumarate tablet in schizophrenia patients. In Tables 16 to 19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder. Table 15: Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose Preferred Term Quetiapine Fumarate Extended-Release Tablet 150 mg (N=315) Quetiapine Fumarate Extended-Release Tablet 300 mg (N=312) Placebo (N=309) Somnolence Somnolence combines the adverse reaction terms somnolence and sedation. 37% 43% 9% Dry Mouth 27% 40% 8% Fatigue 14% 11% 4% Dizziness 11% 12% 7% Nausea 7% 8% 7% Constipation 6% 11% 4% Irritability 4% 2% 3% Extrapyramidal Symptoms Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor 4% 6% 4% Vomiting 3% 1% 1% Upper Respiratory Tract Infection 3% 2% 2% Weight Increased 3% 5% 0% Increased Appetite 3% 5% 3% Back pain 3% 3% 1% Vertigo 2% 2% 1% Vision Blurred 2% 1% 1% Dyspepsia 2% 3% 2% Influenza 2% 1% 0% Fall 2% 0% 1% Muscle Spasms 2% 1% 1% Lethargy 2% 1% 1% Akathisia 2% 2% 1% Abnormal Dreams 2% 2% 1% Anxiety 2% 2% 1% Depression 2% 1% 1% In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400 to 800 mg/day of quetiapine fumarate extended-release tablet, the incidence of any adverse reactions related to EPS was 6.6% for quetiapine fumarate extended-release tablet and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction. Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo-Controlled Clinical Trials for Schizophrenia Preferred Term Quetiapine Fumarate Extended - Release Tablet 300 mg / day ( N = 91 ) Quetiapine Fumarate Extended - Release Tablet 400 mg / day ( N = 227 ) Quetiapine Fumarate Extended - Release Tablet 600 mg / day ( N = 310 ) Quetiapine Fumarate Extended - Release Tablet 800 mg / day ( N = 323 ) All Doses ( N = 951 ) Placebo ( N = 319 ) n % n % n % n % n % n % Dystonic event 3 3.3 0 0.0 4 1.3 1 0.3 8 0.8 0 0.0 Parkinsonism 1 1.1 3 1.3 11 3.6 7 2.2 22 2.3 4 1.3 Akathisia 0 0.0 3 1.3 7 2.3 7 2.2 17 1.8 4 1.3 Dyskinetic event 2 2.2 1 0.4 1 0.3 1 0.3 5 0.5 2 0.6 Other extrapyramidal event 3 3.3 4 1.8 7 2.3 12 3.7 26 2.7 7 2.2 In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of quetiapine fumarate extended-release tablet, the incidence of any adverse reactions related to EPS was 4.4% for quetiapine fumarate extended-release tablet and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction. Table 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Mania Preferred Term There were no adverse reactions with the preferred term of dyskinetic event. Quetiapine Fumarate Extended-Release Tablet (N=151) Placebo (N=160) n % n % Dystonic event 1 0.7 0 0.0 Parkinsonism 4 2.7 3 1.9 Akathisia 2 1.3 1 0.6 Other extrapyramidal event 3 2.0 2 1.3 In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of quetiapine fumarate extended-release tablet, the incidence of any adverse reactions related to EPS was 5.1% for quetiapine fumarate extended-release tablet and 4.2% for the placebo group. Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose: Table 18: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Depression Preferred Term There were no adverse reactions with the preferred term of dyskinetic event. Quetiapine Fumarate Extended-Release Tablet (N=137) Placebo (N=140) n % n % Dystonic event 2 1.5 0 0.0 Parkinsonism 1 0.7 1 0.7 Akathisia 2 1.5 0 0.0 Other extrapyramidal event 1 0.7 0 0.0 Children and Adolescents The information below is derived from a clinical trial database for quetiapine fumarate tablet consisting of over 1000 pediatric patients. This database includes 677 adolescents (13 to 17 years old) exposed to quetiapine fumarate tablet for the treatment of schizophrenia and 393 children and adolescents (10 to 17 years old) exposed to quetiapine fumarate tablet for the treatment of acute bipolar mania. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse reaction leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo). Bipolar I Mania: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on quetiapine fumarate tablet and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0%). Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials In an acute (8-week) quetiapine fumarate extended-release tablet trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablet (incidence of 5% or greater and at least twice that for placebo) were: dizziness (7%), diarrhea (5%), fatigue (5%) and nausea (5%). In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%). In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). Adverse Reactions Occurring at an Incidence of ≥ 2% among Quetiapine Fumarate Tablet Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 to 17 years old): The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day. Table 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with quetiapine fumarate tablet (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate tablet was greater than the incidence in placebo-treated patients. Adverse reactions that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%). Table 19: Adverse Reactions Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration) Preferred Term Quetiapine Fumarate Extended - Release Tablet 150 mg / day ( N = 315 ) Quetiapine Fumarate Extended - Release Tablet 300 mg / day ( N = 312 ) All Doses ( N = 627 ) Placebo ( N = 309 ) n % n % n % n % Dystonic event 1 0.3 0 0.0 1 0.2 0 0.0 Parkinsonism 3 1.0 4 1.3 7 1.1 5 1.6 Akathisia 5 1.6 8 2.6 13 2.1 3 1.0 Dyskinetic event 0 0.0 1 0.3 1 0.2 0 0.0 Other extrapyramidal event 5 1.6 7 2.2 12 1.9 5 1.6 Bipolar I Mania (Children and Adolescents 10 to 17 years old): The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day. Table 21 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine fumarate tablet (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate tablet was greater than the incidence in placebo-treated patients. Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%). Table 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients Preferred Term Quetiapine Fumarate Tablet 400 mg (N=73) Quetiapine Fumarate Tablet 800 mg (N=74) Placebo (N=75) Somnolence Somnolence combines adverse reaction terms somnolence and sedation. 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia. 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnea 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% Extrapyramidal Symptoms Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet in children and adolescent patients 10 to 17 years of age [see CLINICAL STUDIES ( 14.1 and 14.2 )]. In a short-term placebo-controlled quetiapine fumarate extended-release tablet monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar depression (8-week duration), in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% (1/92) for quetiapine fumarate extended-release tablet and 0% (0/100) for placebo. In a short-term placebo-controlled quetiapine fumarate tablet monotherapy trial in adolescent patients (13 to 17 years of age) with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine fumarate tablet and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (e.g., akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled quetiapine fumarate tablet monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for quetiapine fumarate tablet and 1.1% (1/90) for placebo. In Tables 22 and 23, dystonic events included nuchal rigidity, hypertonia, dystonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder. Table 22 below presents a listing of patients with adverse reactions associated with EPS in the short-term placebo-controlled quetiapine tablet monotherapy trial in adolescent patients with schizophrenia (6-week duration). Table 21: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Preferred Term Quetiapine Fumarate Tablet 400 mg (N=95) Quetiapine Fumarate Tablet 600 mg (N=98) Placebo (N=90) Somnolence Somnolence combines adverse reaction terms somnolence and sedation. 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia. 6% 9% 0% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% Irritability 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% Paresthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% Table 23 below presents a listing of patients with adverse reactions associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration). Table 22: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-controlled Trial in Adolescent Patients with Schizophrenia (6-week duration). Preferred Term Quetiapine Fumarate Tablet 400 mg / day ( N = 73 ) Quetiapine Fumarate Tablet 800 mg / day ( N = 74 ) All Quetiapine Fumarate Tablet ( 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 Laboratory, ECG and Vital Sign Changes Observed in Clinical Studies Laboratory Changes: Neutrophil Counts Adults: In three-arm quetiapine fumarate extended-release tablet placebo-controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥ 1.5 x 10 9 /L, the incidence of at least one occurrence of neutrophil count <1.5 x 10 9 /L was 1.5% in patients treated with quetiapine fumarate extended-release tablet and 1.5% for quetiapine fumarate tablet, compared to 0.8% in placebo-treated patients. In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 10 9 /L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine, compared to 0.1% (2/1349) in patients treated with placebo [see WARNINGS AND PRECAUTIONS ( 5.10 )]. Transaminase Elevations: Adults: Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. The proportions of adult patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials ranged between 1% and 2% for quetiapine fumarate extended-release tablet compared to 2% for placebo. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate tablet compared to 1% (3/194) for placebo. These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine. Decreased Hemoglobin: Adults In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2%(219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients. Interference with Urine Drug Screens There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g. chromatographic methods) should be considered. ECG Changes: Adults 2.5% of quetiapine fumarate extended-release tablet patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine fumarate extended-release tablet was associated with a mean increase in heart rate, assessed by ECG, of 6.3 beats per minute compared to a mean increase of 0.4 beats per minute for placebo. This is consistent with the rates for quetiapine fumarate tablet. The incidence of adverse reactions of tachycardia was 1.9% for quetiapine fumarate extended-release tablet compared to 0.5% for placebo. Quetiapine fumarate tablet use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. The slight tendency for tachycardia may be related to quetiapine's potential for inducing orthostatic changes [see WARNINGS AND PRECAUTIONS ( 5.7 )]. Children and Adolescents Safety and effectiveness of quetiapine fumarate extended-release tablet is supported by studies of quetiapine fumarate tablet in children and adolescent patients 10 to 17 years of age [(see CLINICAL STUDIES ( 14.1 and 14.2 )]. In an acute (8-week) quetiapine fumarate extended-release tablet trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (> 110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine fumarate extended-release tablet and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine fumarate extended-release tablet, compared to 0.3 bpm in the placebo group [see WARNINGS AND PRECAUTIONS ( 5.7 )]. In the acute (6-week) quetiapine fumarate tablet schizophrenia trial in adolescents (13 to 17 years of age), increases in heart rate (> 110 bpm) occurred in 5.2% of patients receiving quetiapine fumarate tablet 400 mg and 8.5% of patients receiving quetiapine fumarate tablet 800 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine fumarate tablet 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see WARNINGS AND PRECAUTIONS ( 5.7 )]. In the acute (3-week) quetiapine fumarate tablet bipolar mania trial in children and adolescents (10 to 17 years of age), increases in heart rate (> 110 bpm) occurred in 1.1% of patients receiving quetiapine fumarate tablet 400 mg and 4.7% of patients receiving quetiapine fumarate tablet 600 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine fumarate tablet 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [see WARNINGS AND PRECAUTIONS ( 5.7 )]. Table 23: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration) Preferred Term There were no adverse reactions with the preferred term of dystonic or dyskinetic events. Quetiapine Fumarate Tablet 400 mg / day ( N = 95 ) Quetiapine Fumarate Tablet 600 mg / day ( N = 98 ) All Quetiapine Fumarate Tablet ( 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 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of quetiapine fumarate tablet. 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, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) , decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, urinary retention and acute generalized exanthematous pustulosis (AGEP).