Quetiapine Fumarate (quetiapine fumarate 200 mg) Dailymed

6 Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see  Warnings and Precautions (5.1)] • Suicidal thoughts and behaviors in adolescents and young adults [see  Warnings and Precautions (5.2)] • Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.3)] • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)] • Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [see  Warnings and Precautions (5.5)] • Tardive dyskinesia [see  Warnings and Precautions (5.6)] • Hypotension [see  Warnings and Precautions (5.7)] • 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) ]


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 Mallinckrodt LLC at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 tablets consisting of approximately 3400 patients exposed to quetiapine fumarate extended-release tablets 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 uled. 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 tablets 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 tablets 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 tablets discontinued due to an adverse reaction compared to 4% (5/140) on placebo. SomnolenceSomnolence combines adverse reaction terms somnolence and sedation was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% for quetiapine fumarate extended-release tablets 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 tablets discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in quetiapine fumarate extended-release tablets 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 tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablets 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 Tablets 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 tablets (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablets 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

* Somnolence combines adverse reaction terms somnolence and sedation. † Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia dystonia, extrapyramidal disorder, hypertonia, movement disorder, muscle rigidity, parkinsonism, parkinsonian gait, and tardive dyskinesia.
Preferred Term	Quetiapine Fumarate ER Tablets (N=951)	Placebo (N=319)
Somnolence*  Dry Mouth  Dizziness  Extrapyramidal Symptoms† Orthostatic Hypotension  Constipation  Dyspepsia  Heart Rate Increased  Tachycardia  Fatigue  Hypotension  Vision Blurred  Toothache  Increased Appetite  Muscle Spasms  Tremor  Akathisia  Anxiety  Schizophrenia  Restlessness	25%  12%  10%  8%  7%  6%  5%  4%  3%  3%  3%  2%  2%  2%  2%  2%  2%  2%  2%  2%	10%  1%  4%  5%  5%  5%  2%  1%  1%  2%  1%  1%  0%  0%  1%  1%  1%  1%  1%  1%

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 tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablets 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%). 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 tablets (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablets 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

* Somnolence combines adverse reaction terms somnolence and sedation. † Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness and tremor.
Preferred Term	Quetiapine Fumarate ER Tablets (N=151)	Placebo (N=160)
Somnolence* Dry Mouth  Dizziness  Constipation  Dyspepsia  Fatigue  Weight Gain  Extrapyramidal Symptoms† Nasal Congestion  Dysarthria  Increased Appetite  Back Pain  Toothache  Heart Rate Increased  Abnormal Dreams  Orthostatic Hypotension  Tachycardia  Vision Blurred  Sluggishness  Lethargy	50%  34%  10%  10%  7%  7%  7%  7%  5%  5%  4%  3%  3%  3%  3%  3%  2%  2%  2%  2%	12%  7%  4%  3%  4%  4%  1%  4%  1%  0%  2%  2%  1%  0%  0%  0%  1%  1%  1%  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 tablets (incidence of 5% or greater) and observed at a rate on quetiapine fumarate extended-release tablets 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 tablets 300 mg/day where the incidence in patients treated with quetiapine fumarate extended-release tablets 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

* Somnolence combines adverse reaction terms somnolence and sedation. † Extrapyramidal symptoms include the terms: dystonia, extrapyramidal disorder, hypertonia, and tremor.
Preferred Term	Quetiapine Fumarate ER Tablets (N=137)	Placebo (N=140)
Somnolence* Dry Mouth  Dizziness  Increased Appetite  Constipation  Dyspepsia  Weight Gain  Fatigue  Irritability  Viral Gastroenteritis  Arthralgia  Extrapyramidal Symptoms† Paraesthesia  Back Pain  Muscle Spasms  Toothache  Abnormal Dreams  Ear Pain  Seasonal Allergy  Sinusitis  Decreased Appetite  Myalgia  Disturbance in Attention  Migraine  Restless Legs Syndrome  Anxiety  Sinus Headache  Libido Decreased  Pollakiuria  Sinus Congestion  Hyperhidrosis  Orthostatic Hypotension  Urinary Tract Infection  Heart Rate Increased  Neck Pain  Dysarthria  Akathisia  Hypersomnia  Mental Impairment  Confusional State  Disorientation	52%  37%  13%  12%  8%  7%  7%  6%  4%  4%  4%  4%  3%  3%  3%  3%  3%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%	13%  7%  11%  6%  6%  1%  1%  2%  3%  1%  1%  1%  2%  1%  1%  0%  0%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  1%  0%  0%  0%  0%  0%  0%  0%  0%  0%

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 tablets (incidence of 5% or greater and observed at a rate on quetiapine fumarate extended-release tablets 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 tablets (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with quetiapine fumarate extended-release tablets was greater than the incidence in placebo-treated patients.

Table 15: Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose

* Somnolence combines the adverse reaction terms somnolence and sedation. † Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor.
Preferred Term	Quetiapine Fumarate ER Tablets 150 mg (N=315)	Quetiapine Fumarate ER Tablets 300 mg (N=312)	Placebo (N=309)
Somnolence*  Dry Mouth  Fatigue  Dizziness  Nausea  Constipation  Irritability  Extrapyramidal Symptoms†  Vomiting  Upper Respiratory Tract Infection  Weight Increased  Increased Appetite  Back Pain  Vertigo  Vision Blurred  Dyspepsia  Influenza  Fall  Muscle Spasms  Lethargy  Akathisia  Abnormal Dreams  Anxiety  Depression	37%  27%  14%  11%  7%  6%  4%  4%  3%  3%  3%  3%  3%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%  2%	43%  40%  11%  12%  8%  11%  2%  6%  1%  2%  5%  5%  3%  2%  1%  3%  1%  0%  1%  1%  2%  2%  2%  1%	9%  8%  4%  7%  7%  4%  3%  4%  1%  2%  0%  3%  1%  1%  1%  2%  0%  1%  1%  1%  1%  1%  1%  1%

Adverse Reactions in clinical trials with quetiapine and not uled 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 emergent 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 tablets, the incidence of any adverse reactions related to EPS was 8% for quetiapine fumarate extended-release tablets and 8% for quetiapine fumarate tablets (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 tablets in schizophrenia patients.

In Tables 16 –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 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo-Controlled Clinical Trials for Schizophrenia

Preferred Term	Quetiapine Fumarate ER Tablets 300 mg/day (N=91)		Quetiapine Fumarate ER Tablets 400 mg/day (N=227)		Quetiapine Fumarate ER  Tablets 600 mg/day (N=310)		Quetiapine Fumarate ER Tablets 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 mania, utilizing the dose range of 400-800 mg/day of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 6.6% for quetiapine fumarate extended-release tablets 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 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Mania

* There were no adverse reactions with the preferred term of dyskinetic event.
Preferred Term*	Quetiapine Fumarate ER Tablets (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 a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of quetiapine fumarate extended-release tablets, the incidence of any adverse reactions related to EPS was 4.4% for quetiapine fumarate extended-release tablets 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 18: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Depression

* There were no adverse reactions with the preferred term of dyskinetic event.
Preferred Term*	Quetiapine Fumarate ER Tablets (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

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 tablets, the incidence of any adverse reactions related to EPS was 5.1% for quetiapine fumarate extended-release tablets 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 19: Adverse Reactions Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration)

Preferred Term	Quetiapine Fumarate ER Tablets 150 mg/day (N=315)		Quetiapine Fumarate ER Tablets 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

Children and Adolescents

The information below is derived from a clinical trial database for quetiapine fumarate tablets consisting of over 1000 pediatric patients. This database includes 677 adolescents (13-17 years old) exposed to quetiapine fumarate tablets for the treatment of schizophrenia and 393 children and adolescents (10-17 years old) exposed to quetiapine fumarate tablets 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 tablets 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 tablets trial in children and adolescents (10-17 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 tablets (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 Treated Patients in Short-Term, Placebo-Controlled Trials

Schizophrenia (Adolescents, 13 – 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 tablets (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate tablets 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 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

* Somnolence combines adverse reaction terms somnolence and sedation. † Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
Preferred Term	Quetiapine Fumarate Tablets 400 mg (N=73)	Quetiapine Fumarate Tablets 800 mg (N=74)	Placebo (N=75)
Somnolence* Dizziness  Dry Mouth  Tachycardia† Irritability  Arthralgia  Asthenia  Back Pain  Dyspnea  Abdominal Pain  Anorexia  Tooth Abscess  Dyskinesia  Epistaxis  Muscle Rigidity	33% 8% 4%6% 3% 1% 1% 1% 0% 3% 3%  3%  3%  3%  3%	35%  15% 10% 11% 5% 3% 3% 3%  3%  1%  1%  1%  0%  0%  0%	11%  5% 1% 0% 0% 0% 1%  0%  0%  0%  0%  0%  0%  1%  0%

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 treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine fumarate tablets (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate tablets 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 21: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients

* Somnolence combines adverse reaction terms somnolence and sedation. † Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
Preferred Term	Quetiapine Fumarate Tablets 400 mg (N=95)	Quetiapine Fumarate Tablets 600 mg (N=98)	Placebo (N=90)
Somnolence* Dizziness  Nausea  Fatigue  Increased Appetite  Tachycardia† Dry Mouth  Vomiting  Nasal Congestion  Weight Increased  Irritability  Pyrexia  Aggression  Musculoskeletal Stiffness  Accidental Overdose  Acne  Arthralgia  Lethargy  Pallor  Stomach Discomfort  Syncope  Vision Blurred  Constipation  Ear Pain  Paresthesia  Sinus Congestion  Thirst	50%  19% 6% 14% 10% 6% 7% 8%  3% 6% 3% 1% 1% 1% 0% 3% 4% 2% 1% 4% 2% 3% 4% 2% 2% 3% 2%	57%  17%  10% 9%  9% 9% 7%  7% 6% 6% 5% 4% 3% 3% 2% 2%  2%  2%  2%  2%  2%  2%  2%  0%  0%  0%  0%	14%  2%  4%  4%  1%  0%  0%  3%  2%  0%  1%  1%  0%  1%  0%  0%  1%  0%  0%  1%  0%  0%  0%  0%  0%  0%  0%

Extrapyramidal Symptoms:

Safety and effectiveness of Quetiapine Fumarate Extended-release Tablets is supported by studies of quetiapine fumarate tablets in children and adolescent patients 10-17 years of age [see Clinical Studies(14.1 and 14.2)]. In a short-term placebo-controlled quetiapine fumarate extended-release tablets monotherapy trial in children and adolescent patients (10-17 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 tablets and 0% (0/100) for placebo. In a short-term placebo-controlled quetiapine fumarate tablets monotherapy trial in adolescent patients (13-17 years of age) with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine fumarate tablets 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 tablets monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for quetiapine fumarate tablets 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 uling of patients with adverse reactions associated with EPS in the short-term placebo- controlled quetiapine fumarate tablets monotherapy trial in adolescent patients with schizophrenia (6-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 Tablets 400 mg/day (N=73)		Quetiapine Fumarate Tablets 800 mg/day (N=74)		All Quetiapine FumarateTablets (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

Table 23 below presents a uling 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 23: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)

* There were no adverse reactions with the preferred term of dystonic or dyskinetic events.
Preferred Term*	Quetiapine Fumarate Tablets 400 mg/day (N=95)		Quetiapine Fumarate Tablets 600 mg/day (N=98)		All Quetiapine Fumarate Tablets (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

Laboratory, ECG and vital sign changes observed in clinical studies

Laboratory Changes: Neutrophil Counts

Adults: In three-arm quetiapine fumarate extended-release tablets placebo-controlled monotherapy clinical trials, among patients with a baseline  neutrophil count ≥1.5 x 10⁹/L, the incidence of at least one occurrence of neutrophil count <1.5 x 10⁹/L was 1.5% in patients treated with quetiapine fumarate extended-release tablets and 1.5% for quetiapine fumarate tablets, 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 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. 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 tablets 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 tablets 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, decrease 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 tablets patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine fumarate extended-release tablets 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 tablets. The incidence of adverse reactions of tachycardia was 1.9% for quetiapine fumarate extended-release tablets compared to 0.5% for placebo.  Quetiapine fumarate tablets 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 Tablets is supported by studies of quetiapine fumarate tablets in children and adolescent patients 10-17 years of age [(see Clinical Studies (14.1 and 14.2)].

In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10-12 years and 13-17 years) occurred in 0% of patients receiving quetiapine fumarate extended-release tablets and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine fumarate extended-release tablets, compared to 0.3 bpm in the placebo group [see Warnings and Precautions (5.7)].

In the acute (6-week) quetiapine fumarate tablets schizophrenia trial in adolescents (13-17 years of age), increases in heart rate (>110 bpm) occurred in 5.2% of patients receiving quetiapine fumarate tablets 400 mg and 8.5% of patients receiving quetiapine fumarate tablets 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 tablets 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 tablets bipolar mania trial in children and adolescents (10-17 years of age), increases in heart rate (>110 bpm) occurred in 1.1% of patients receiving quetiapine fumarate tablets 400 mg and 4.7% of patients receiving quetiapine fumarate tablets 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 tablets 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)] .

6.2 Postmarketing Experience

The following adverse reactions were identified during post approval use 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 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, and urinary retention.