quetiapine fumarate (quetiapine fumarate 25 mg) Dailymed

6 Adverse Reactions

Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia. (6.1)

Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-667-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Study Experience

Adults

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

The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 4300 patients.  This database includes 698 patients exposed to quetiapine fumarate for the treatment of bipolar depression, 405 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine fumarate for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of quetiapine fumarate for the treatment of schizophrenia.

Of these approximately 4300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with quetiapine fumarate varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure.  Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories.

In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions for schizophrenia and bipolar mania. MedDRA terminology has been used to classify reported adverse reactions for bipolar depression.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type uled. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adults

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials:

Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for quetiapine fumarate vs. 3% for placebo) in a pool of controlled trials.  However, discontinuations due to somnolence (0.8% quetiapine fumarate vs. 0% placebo) and hypotension (0.4% quetiapine fumarate vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.8 and 5.16)].

Bipolar Disorder:

Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine fumarate vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine fumarate vs. 5.9% for placebo in adjunct therapy.

Depression: Overall, discontinuations due to adverse reactions were 12.3% for quetiapine fumarate 300 mg vs. 19.0% for quetiapine fumarate 600 mg and 5.2% for placebo.

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

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

Adverse Reactions Occurring at an Incidence of 1% or More Among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials:

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

Table 8 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 1% or more of patients treated with quetiapine fumarate (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients.

Table 8: Treatment-Emergent Adverse Reaction Incidence in 3 to 12 Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)Reactions for which the quetiapine fumarate incidence was equal to or less than placebo are not uled in the table, but included the following: accidental injury, akathisia, chest pain, cough increased, depression, diarrhea, extrapyramidal syndrome, hostility, hypertension, hypertonia, hypotension, increased appetite, infection, insomnia, leukopenia, malaise, nausea, nervousness, paresthesia, peripheral edema, sweating, tremor, and weight loss.

Body System/ Preferred Term	Quetiapine Fumarate (n=719)	PLACEBO (n=404)
Body as a Whole
Headache	21%	14%
Pain	7%	5%
Asthenia	5%	3%
Abdominal Pain	4%	1%
Back Pain	3%	1%
Fever	2%	1%
Cardiovascular
Tachycardia	6%	4%
Postural Hypotension	4%	1%
Digestive
Dry Mouth	9%	3%
Constipation	8%	3%
Vomiting	6%	5%
Dyspepsia	5%	1%
Gastroenteritis	2%	0%
Gamma Glutamyl Transpeptidase Increased	1%	0%
Metabolic and Nutritional
Weight Gain	5%	1%
ALT Increased	5%	1%
AST Increased	3%	1%
Nervous
Agitation	20%	17%
Somnolence	18%	8%
Dizziness	11%	5%
Anxiety	4%	3%
Respiratory
Pharyngitis	4%	3%
Rhinitis	3%	1%
Skin and Appendages
Rash	4%	2%
Special Senses
Amblyopia	2%	1%

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

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 1% or more of patients treated with quetiapine fumarate (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients.

Table 9: Treatment-Emergent Adverse Reaction Incidence in 3 Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy)Reactions for which the quetiapine fumarate incidence was equal to or less than placebo are not uled in the table, but included the following: akathisia, diarrhea, insomnia, nausea, accidental injury, chest pain, face edema, flu syndrome, electrocardiogram abnormal, vomiting, gastritis, SGPT increased, weight loss, nervousness, paresthesia, extrapyramidal syndrome, confusion, cough increased, rash and urinary incontinence.

Body System/ Preferred Term	Quetiapine Fumarate (n=196)	PLACEBO (n=203)
Body as a Whole
Headache	17%	13%
Asthenia	10%	4%
Abdominal Pain	7%	3%
Back Pain	5%	3%
Hormone Level Altered	3%	0%
Heaviness	2%	1%
Infection	2%	1%
Fever	2%	1%
Neck Rigidity	1%	0%
Cardiovascular
Postural Hypotension	7%	2%
Hypotension	3%	1%
Hypertension	2%	1%
Tachycardia	2%	1%
Hemorrhage	1%	0%
Digestive
Dry Mouth	19%	3%
Constipation	10%	5%
Dyspepsia	4%	3%
Increased Appetite	2%	1%
Flatulence	1%	0%
Gastrointestinal Disorder	1%	0%
Endocrine
Hypothyroidism	2%	1%
Hemic and Lymphatic
Lymphadenopathy	1%	0%
Metabolic and Nutritional
Weight Gain	6%	3%
Peripheral Edema	4%	2%
Musculoskeletal
Twitching	4%	1%
Joint Disorder	1%	0%
Nervous
Somnolence	34%	9%
Dizziness	9%	6%
Tremor	8%	7%
Agitation	6%	4%
Hypertonia	4%	3%
Depression	3%	2%
Speech Disorder	3%	1%
Incoordination	2%	1%
Thinking Abnormal	2%	0%
Anxiety	2%	0%
Ataxia	2%	0%
Respiratory
Pharyngitis	6%	3%
Rhinitis	4%	2%
Sinusitis	2%	1%
Skin and Appendages
Sweating	2%	1%
Special Senses
Amblyopia	3%	2%
Ear Disorder	1%	0%
Ear Pain	1%	0%
Urogenital
Urinary Tract Infection	2%	1%
Female Lactation	1%	0%
Impotence	1%	0%
Urinary Tract Disorder	1%	0%

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

Table 10 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 1% or more of patients treated with quetiapine fumarate (doses of 300 and 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients.

Table 10: Treatment-Emergent Adverse Reaction Incidence in 8 Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar DepressionReactions for which the quetiapine fumrate incidence was equal to or less than placebo are not uled in the table, but included the following: nausea, upper respiratory tract infection, headache, tinnitus, diarrhea, flatulence, toothache, stomach discomfort, abdominal pain, pyrexia, peripheral edema, nasopharyngitis, influenza, bronchitis, viral gastroenteritis, accidental overdose, decreased appetite, back pain, muscle twitching, myalgia, muscle cramp, headache, insomnia, anxiety, nightmare, libido decreased, suicidal ideation, pollakiuria, dyspnoea, pharyngolaryngeal pain, night sweats and hot flush.

Body System / Preferred Term	Quetiapine Fumarate (n=698)	PLACEBO (n=347)
Cardiac Disorders
Palpitations	4%	1%
Tachycardia	1%	0%
Eye Disorders
Vision Blurred	4%	2%
Gastrointestinal Disorders
Dry Mouth	44%	13%
Constipation	10%	4%
Dyspepsia	7%	4%
Vomiting	5%	4%
Gastroesophageal Reflux Disease	2%	1%
Dysphagia	2%	0%
General Disorders and Administrative Site Conditions
Fatigue	10%	8%
Asthenia	2%	1%
Injury, Poisoning and Procedural Complications
Injury	1%	0%
Investigations
Weight increased	4%	1%
Metabolism and Nutrition Disorders
Increased Appetite	5%	3%
Musculoskeletal and Connective Tissue Disorders
Arthralgia	3%	2%
Pain in Extremity	2%	1%
Nervous System Disorders
SomnolenceSomnolence combines adverse reaction terms somnolence and sedation.	57%	15%
Dizziness	18%	7%
Lethargy	5%	2%
Akathisia	4%	1%
Extrapyramidal Disorder	3%	1%
Paraesthesia	3%	2%
Dysarthria	3%	0%
Hypersomnia	3%	0%
Tremor	2%	1%
Restless Legs Syndrome	2%	0%
Balance Disorder	2%	1%
Hypoaesthesia	2%	1%
Dystonia	1%	0%
Dizziness, postural	1%	0%
Dyskinesia	1%	0%
Dysgeusia	1%	0%
Psychiatric disorders
Irritability	3%	1%
Abnormal Dreams	2%	1%
Confusional State	1%	0%
Respiratory, Thoracic, and Mediastinal Disorders
Nasal Congestion	5%	3%
Cough	3%	1%
Sinus Congestion	2%	1%
Vascular Disorders
Orthostatic Hypotension	4%	3%
Hypertension	1%	0%

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

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

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

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

The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS).

Extrapyramidal Symptoms:

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

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

Table 11: Adverse experiences potentially associated with EPS in a short-term, placebo-controlled multiple fixed-dose Phase III schizophrenia trial (6 weeks duration)

Preferred Term	Placebo (N=51)		Quetiapine Fumarate 75 mg/day (N=53)		Quetiapine Fumarate 150 mg/day (N=48)		Quetiapine Fumarate 300 mg/day (N=52)		Quetiapine Fumarate 600 mg/day (N=51)		Quetiapine Fumarate 750 mg/day (N=54)
	n	%	n	%	n	%	n	%	n	%	n	%
Dystonic eventPatients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle ridgidity	4	7.8	2	3.8	2	4.2	0	0.0	2	3.9	3	5.6
ParkinsonismPatients with the following terms were counted in this category: cogwheel rigidity, tremor	4	7.8	2	3.8	0	0.0	1	1.9	1	2.0	1	1.9
AkathisiaPatients with the following terms were counted in this category: akathisia	4	7.8	1	1.9	1	2.1	0	0.0	0	0.0	1	1.9
Dyskinetic eventPatients with the following terms were counted in this category: tardive dyskinesia,dyskinesia, choreoathetosis	0	0.0	2	3.8	0	0.0	0	0.0	1	2.0	0	0.0
Other extraphyrmidal eventPatients with the following terms were counted in this category: restlessness, extrapyramidal disorder	4	7.8	2	3.8	0	0.0	3	5.8	3	5.9	1	1.9

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

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

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

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

Children and Adolescents:

The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 1000 pediatric patients.  This database includes 677 patients exposed to quetiapine fumarate for the treatment of schizophrenia and 393 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania.

Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Children and Adolescents

Adolescents 13 to 17 years of age with Schizophrenia

The following findings were based on a 6 week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).

Commonly Observed Adverse Reactions

In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia ( 7%).

Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent  adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 5% or more of patients treated with quetiapine fumarate (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients.

Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8.2% vs. 14.9%), dry mouth (4.1% vs. 9.5%), and tachycardia (5.5% vs. 8.1%).

Table 12: Treatment-Emergent Adverse Reaction Incidence in a 6 Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

Body System/Preferred Term	Quetiapine Fumarate (n=147)	PLACEBO (n=75)
Central Nervous System Disorders
SomnolenceSomnolence combines adverse event terms somnolence and sedation	34%	11%
Digestive
Dry Mouth	7%	1%
Cardiovascular Disorders
Tachycardia	7%	0%
Nervous System Disorder
Dizziness	12%	5%

Children and Adolescents 10 to 17 years of age with Bipolar Mania

The following findings were based on a 3 week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse events leading to discontinuation in 1% or more of patients on quetiapine and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%), fatigue (2.1% vs. 0), irritability (1.6% vs. 0) and syncope (1% vs. 0).

Commonly Observed Adverse Reactions

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

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent  adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 5% or more of patients treated with quetiapine fumarate (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients.

Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (49% vs. 57%), nausea (6.3% vs. 10.2%) and tachycardia (5.3% vs. 8.2%).

Table 13: Treatment-Emergent Adverse Reaction Incidence in a 3 Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients

Body System/Preferred Term	Quetiapine Fumarate (n=193)	PLACEBO (n=90)
Nervous System Disorders
SomnolenceSomnolence combines adverse event terms somnolence and sedation	53%	14%
Dizziness	18%	2%
Fatigue	11%	4%
Metabolism and Nutrition Disorders
Increased Appetite	9%	1%
Weight Increased	6%	0%
Gastrointestinal Disorders
Nausea	8%	4%
Vomiting	8%	3%
Dry Mouth	7%	0%
Cardiac Disorders
Tachycardia	7%	0%

Adverse Reactions in Schizophrenia and Bipolar Mania Clinical Trials

Commonly Observed Adverse Reactions

In acute therapy for schizophrenia and bipolar mania (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (47%), dizziness (15%), fatigue (9%), increased appetite (8%), dry mouth (7%), tachycardia (7%), and weight increased (5%).

Table 14 enumerates the pooled incidence of adverse reactions that occurred during acute therapy of children and adolescents (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania). The table includes only those reactions that occurred in 1% or more of patients treated with quetiapine (doses of 400, 600, or 800 mg/day) and for which the incidence in patients treated with quetiapine was greater than the incidence in patients treated with placebo.

Table 14: Adverse Reactions (incidence ≥ 1% and greater than placebo) in Short-Term, Placebo-Controlled Trials of Children and Adolescents (10 to 17 years of age) with Bipolar Mania or SchizophreniaThreshold criteria were applied before rounding to the nearest integer

Body System/Preferred Term	Quetiapine Fumarate (n=340)	PLACEBO (n=165)
Central/Nervous System Disorder
SomnolenceSomnolence combines adverse event terms somnolence and sedation	47%	15%
Dizziness	15%	4%
Fatigue	9%	4%
Irritability	4%	1%
Tremor	3%	2%
Akathisia	2%	1%
Syncope	2%	0%
Lethargy	1%	0%
Metabolism and Nutrition Disorders
Increased Appetite	8%	2%
Weight Increased	5%	1%
Digestive
Dry Mouth	7%	1%
Cardiovascular Disorders
Tachycardia	8%	0%
Musculoskeletal and Connective Tissue Disorders
Arthralgia	3%	1%
Back Pain	2%	1%
Musculoskeletal Stiffness	2%	1%
Respiratory, Thoracic and Mediastinal Disorder
Nasal Congestion	3%	2%
Gastrointestinal Disorder
Vomiting	7%	6%
Stomach Discomfort	2%	1%
Skin and Subcutaneous Tissue Disorders
Acne	2%	1%
General Disorders and Administration Site Conditions
Pyrexia	2%	1%
Asthenia	2%	1%
Psychiatric Disorders
Aggression	2%	1%
Restlessness	1%	0%
Eye Disorders
Vision Blurred	2%	1%
Infections and Infestations
Tooth Abscess	1%	0%

Extrapyramidal Symptoms:

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

Table 15 below presents a uling of patients with AEs potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6 week duration).

Table 15: Adverse experiences potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6 week duration)

Preferred Term	Placebo (N=75)		Quetiapine Fumarate 400 mg/day (N=73)		Quetiapine Fumarate 800 mg/day (N=74)		All Quetiapine Fumarate (N=147)
	n	%	n	%	n	%	n	%
Dystonic eventPatients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity	0	0.0	2	2.7	0	0.0	2	1.4
ParkinsonismPatients with the following terms were counted in this category: cogwheel rigidity, tremor	2	2.7	4	5.5	4	5.4	8	5.4
AkathisiaPatients with tthe following terms were counted in this category: akathisia	3	4.0	3	4.1	4	5.4	7	4.8
Dyskinetic eventPatients with the following terms were counted in tis category: tardive dyskinesia, dyskinesia, choreoathetosis	0	0.0	2	2.7	0	0.0	2	1.4
Other Extrapyramidal EventsPatients with the following terms were counted in this category: restlessness, extrapyramidal disorder	0	0.0	2	2.7	2	2.7	4	2.7

Table 16 below presents a uling of patients with Adverse Experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3 week duration).

Table 16: Adverse experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3 week duration)

Preferred Term There were no adverse experiences with the preferred term of dystonic or dyskinetic events.	Placebo (N=90)		Quetiapine Fumarate 400 mg/day (N=95)		Quetiapine Fumarate 600 mg/day (N=98)		All Quetiapine Fumarate (N=193)
	n	%	n	%	n	%	n	%
ParkinsonismPatients with the following terms were counted in this category: cogwheel rigidity, tremor	1	1.1	2	2.1	1	1.0	3	1.6
AkathisiaPatients with the following terms were countedin this category: akathisia	0	0.0	1	1.0	1	1.0	2	1.0
Other Extrapyramidal EventsPatients with the following terms were counted in this category: restlessness, extrapyramidal disorder	0	0.0	1	1.1	1	1.0	2	1.0

Adverse Reactions in Long-Term Open-Label Trial

The adverse reactions reported in a 26 week, open-label trial with quetiapine fumarate in 5% or greater of the children and adolescent patients with schizophrenia or bipolar mania were somnolence (30%), headache (19%), vomiting (11%), increased weight (13%), insomnia (8%), nausea (10%), fatigue (8%), dizziness (9%), increased appetite (7%), upper respiratory tract infection (7%), agitation (5%), tachycardia (5%), and irritability (5%).

Other Adverse Reactions Observed During the Pre-Marketing Evaluation of Quetiapine Fumarate

Following is a ul of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with quetiapine fumarate at multiple doses > 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already uled in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with quetiapine fumarate, they were not necessarily caused by it.

Reactions are further categorized by body system and uled in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already uled in the tabulated results from placebo-controlled trials appear in this uling); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Nervous System: Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased, urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased*, neuralgia, stuttering, subdural hematoma.

Body as a Whole: Frequent: flu syndrome; Infrequent: neck pain, pelvic pain, suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis; Rare: abdomen enlarged.

Digestive System: Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis.

Cardiovascular System: Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration.

Respiratory System: Frequent: cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation.

Metabolic and Nutritional System: Infrequent: weight loss, alkaline phosphatase increased, hyperlipemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication.

Skin and Appendages System: Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration.

Urogenital System: Infrequent: dysmenorrhea, vaginitis, urinary incontinence, metrorrhagia, impotence, dysuria, vaginal moniliasis, abnormal ejaculation, cystitis, urinary frequency, amenorrhea, female lactation, leukorrhea, vaginal hemorrhage, vulvovaginitis orchitis; Rare: gynecomastia, nocturia, polyuria, acute kidney failure.

Special Senses: Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma.

Musculoskeletal System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain.

Hemic and Lymphatic System: Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia.

Endocrine System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism.

6.2 Vital Signs and Laboratory Values

Hyperglycemia, hyperlipidemia, weight gain, orthostatic hypotension and changes in thyroid hormone levels have been reported with quetiapine. Increases in blood pressure have also been reported with quetiapine in children and adolescents [see Warnings and Precautions (5.4, 5.5, 5.6, 5.8, 5.9 and 5.13)].

Neutrophil Counts

In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 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 fumarate, compared to 0.1% (2/1349) in patients treated with placebo. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumrate tablets at the first sign of a decline in WBC in absence of other causative factors [see Warnings and Precautions (5.10)].

Decreased Hemoglobin

In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.

ECG Changes

Adults: Between group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine fumarate/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals.  However, the proportions of patients meeting the criteria for tachycardia were compared in four 3 to 6 week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine fumarate compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine fumarate compared to 0% (0/178) incidence for placebo.  In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine fumarate compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to > 120 beats per minute. Quetiapine fumarate use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine fumarate's potential for inducing orthostatic changes [see Warnings and Precautions (5.8)].

Children and Adolescents: In the acute (3 week) bipolar mania trial in children and adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 1.1% (1/95) of patients receiving quetiapine 400 mg and 2.4% (2/98) 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 (5.8)].

In the acute (3 week) bipolar mania trial in children and adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 1.1% (1/95) of patients receiving quetiapine 400 mg and 2.4% (2/98) 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 (5.8)].

6.3 Post Marketing Experience

The following adverse reactions were identified during post approval of quetiapine fumarate tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction which were temporally related to quetiapine fumarate therapy include: anaphylactic reaction and galactorrhea.

Other adverse reactions reported since market introduction, which were temporally related to quetiapine fumarate therapy, but not necessarily causally related, include the following: agranulocytosis, cardiomyopathy, hyponatremia, myocarditis, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and decreased platelets.

In post-marketing clinical trials, elevations in total cholesterol (predominantly LDL cholesterol), somnambulism (and other related events) and hypothermia have been reported.