Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults:

The information below is derived from a clinical trial database for quetiapine consisting of over 4,300 patients. This database includes 698 patients exposed to quetiapine for the treatment of bipolar depression, 405 patients exposed to quetiapine for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of quetiapine for the treatment of schizophrenia.

Of these approximately 4,300 subjects, approximately 4,000 (2,300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2,400 patient-years. The conditions and duration of treatment with quetiapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

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: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for quetiapine vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence (0.8% quetiapine vs. 0% placebo) and hypotension (0.4% quetiapine vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.7 and 5.19)].

Bipolar Disorder:

Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine vs. 5.9% for placebo in adjunct therapy. Depression: Overall, discontinuations due to adverse reactions were 12.3% for quetiapine 300 mg vs. 19.0% for quetiapine 600 mg and 5.2% for placebo.

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials:

In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of quetiapine monotherapy (incidence of 5% or greater) and observed at a rate on quetiapine at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%).

Adverse Reactions Occurring at an Incidence of 2% or More Among quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials:

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence in the population studied.

Table 9 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2% or more of patients treated with quetiapine (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 9: Adverse Reaction Incidence in 3-to12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)

In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of quetiapine (incidence of 5% or greater) and observed at a rate on quetiapine at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%).

Table 10 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2% or more of patients treated with quetiapine (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 10: Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy)

In bipolar depression studies (up to 8 weeks), the most commonly observed adverse reactions associated with the use of quetiapine (incidence of 5% or greater) and observed at a rate on quetiapine at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%).

Table 11 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2% or more of patients treated with quetiapine (doses of 300 and 600 mg/day) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression

1. Somnolence combines adverse reaction terms somnolence and sedation

Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors.

Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials

Dose-related Adverse Reactions: Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of quetiapine (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain.

Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label:

The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity, and elevations in serum creatine phosphokinase (not associated with NMS), galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope) decreased platelets, somnambulism (and other related events), elevations in gamma-GT levels,hypothermia, dyspnea, eosinophilia, urinary retention, intestinal obstruction and priapism.

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: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of quetiapine (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with quetiapine treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to EPS.

In Table 12, 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 12: Adverse Reactions Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration)

Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1.0, -1.2; -1.6; -1.8 and -1.8. The rate of anticholinergic medication use to treat EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12% and 11%.

In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of quetiapine, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS.

In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of quetiapine, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity, and muscle rigidity) were generally low and did not exceed 4% in any treatment group.

The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups.

Children and Adolescents

The information below is derived from a clinical trial database for quetiapine consisting of over 1000 pediatric patients. This database includes 677 patients exposed to quetiapine for the treatment of schizophrenia and 393 children and adolescents (10 to 17 years old) exposed to quetiapine 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 event leading to discontinuation in 1% 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 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 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%).

In an acute (8-week) SEROQUEL XR trial in children and adolescents (10 to17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater and at least twice that for placebo) were dizziness 7%, diarrhea 5%, fatigue 5% and nausea 5%.

Adverse Reactions Occurring at an Incidence of ≥ 2% among Quetiapine 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 13 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 (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine was at least twice 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 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

1. Somnolence combines adverse reaction terms somnolence and sedation.

2. Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.

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.

Commonly Observed Adverse Reactions

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

Table 14 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 (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine 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 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients

1. Somnolence combines adverse reactions terms somnolence and sedation.

2. Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.

Extrapyramidal Symptoms:

In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or quetiapine and 1.1% (1/90) for placebo.

Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

In Tables 15 - 16 dystonic event included nuchal rigidity, hypertonia, 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 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-Controlled Trial in Adolescent Patients with Schizophrenia (6-week duration)

Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)

1. There were no adverse reactions with the preferred term of dystonic or dyskinetic events.

Laboratory, ECG, and vital sign changes observed in clinical studies

Laboratory Changes:

Neutrophil Counts Adults: In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 109/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. 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 compared to 1% (3/194) for placebo. In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1% for both quetiapine (3/560) and placebo (3/294). These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine. In bipolar depression trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for quetiapine and 2% (6/347) for placebo.

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 haemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on atleast 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: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine /placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to > 120 beats per minute. Quetiapine use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine's potential for inducing orthostatic changes [see Warnings and Precautions (5.7)].

Children and Adolescents: In the acute (6-week) schizophrenia trial in adolescents, increases in heart rate (> 110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine 400 mg and 8.5% (5/74) of patients receiving quetiapine 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine 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) bipolar mania trial in children and adolescents, increases in heart rate (> 110 bpm) occurred in 1.1% (1/89) of patients receiving quetiapine 400 mg and 4.7% (4/85) of patients receiving quetiapine 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine 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)].

In an acute (8-week) SEROQUEL XR trial in children and adolescents (10 to17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10 to12 years and 13 to 17 years) occurred in 0% of patients receiving SEROQUEL XR and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine extended-release, compared to 0.3 bpm in the placebo group [see Warnings and Precautions (5.7)].