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 ]
• Increases in blood pressure (children and adolescents) [see Warnings and Precautions 5.8 ]
• Leukopenia, neutropenia and agranulocytosis [see Warnings and Precautions 5.9 ]
• Cataracts [see Warnings and Precautions 5.10 ]
• QT Prolongation [see Warnings and Precautions 5.11 ]
• Seizures [see Warnings and Precautions 5.12 ]
• Hypothyroidism [see Warnings and Precautions 5.13 ]
• Hyperprolactinemia [see Warnings and Precautions 5.14 ]
• Potential for cognitive and motor impairment [see Warnings and Precautions 5.15 ]
• Body temperature regulation [see Warnings and Precautions 5.16 ]
• Dysphagia [see Warnings and Precautions 5.17 ]
• Discontinuation Syndrome [see Warnings and Precautions 5.18 ]

Most common adverse reactions (incidence ≥ 5% and twice placebo):

Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia ( 6.1 )

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

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE Customer Response Line at 1-855-361-3993 or drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Study Experience

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 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.

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.

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 ( 5.7   and 5.18   )].

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% 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 2% 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 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 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 9: Adverse Reaction Incidence in 3- to 12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)

Preferred Term	Quetiapine Fumarate (n = 719)	Placebo (n = 404)
Headache	21%	14%
Agitation	20%	17%
Somnolence	18%	8%
Dizziness	11%	5%
Dry Mouth	9%	3%
Constipation	8%	3%
Pain	7%	5%
Tachycardia	6%	4%
Vomiting	6%	5%
Asthenia	5%	3%
Dyspepsia	5%	1%
Weight Gain	5%	1%
ALT Increased	5%	1%
Anxiety	4%	3%
Pharyngitis	4%	3%
Rash	4%	2%
Abdominal Pain	4%	1%
Postural Hypotension	4%	1%
Back Pain	3%	1%
AST Increased	3%	1%
Rhinitis	3%	1%
Fever	2%	1%
Gastroenteritis	2%	0%
Amblyopia	2%	1%

 

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

Preferred Term	Quetiapine Fumarate (n = 196)	Placebo (n = 203)
Somnolence	34%	9%
Dry Mouth	19%	3%
Headache	17%	13%
Asthenia	10%	4%
Constipation	10%	5%
Dizziness	9%	6%
Tremor	8%	7%
Abdominal Pain	7%	3%
Postural Hypotension	7%	2%
Agitation	6%	4%
Weight Gain	6%	3%
Pharyngitis	6%	3%
Back Pain	5%	3%
Hypertonia	4%	3%
Rhinitis	4%	2%
Peripheral Edema	4%	2%
Twitching	4%	1%
Dyspepsia	4%	3%
Depression	3%	2%
Amblyopia	3%	2%
Speech Disorder	3%	1%
Hypotension	3%	1%
Hormone Level Altered	3%	0%
Heaviness	2%	1%
Infection	2%	1%
Fever	2%	1%
Hypertension	2%	1%
Tachycardia	2%	1%
Increased Appetite	2%	1%
Hypothyroidism	2%	1%
Incoordination	2%	1%
Thinking Abnormal	2%	0%
Anxiety	2%	0%
Ataxia	2%	0%
Sinusitis	2%	1%
Sweating	2%	1%
Urinary Tract Infection	2%	1%

 

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

Preferred Term	Quetiapine Fumarate (n = 698)	Placebo (n = 347)
SomnolenceSomnolence combines adverse reaction terms somnolence and sedation	57%	15%
Dry Mouth	44%	13%
Dizziness	18%	7%
Constipation	10%	4%
Fatigue	10%	8%
Dyspepsia	7%	4%
Vomiting	5%	4%
Increased Appetite	5%	3%
Lethargy	5%	2%
Nasal Congestion	5%	3%
Orthostatic Hypotension	4%	3%
Akathisia	4%	1%
Palpitations	4%	1%
Vision Blurred	4%	2%
Weight increased	4%	1%
Arthralgia	3%	2%
Paraesthesia	3%	2%
Cough	3%	1%
Extrapyramidal Disorder	3%	1%
Irritability	3%	1%
Dysarthria	3%	0%
Hypersomnia	3%	0%
Sinus Congestion	2%	1%
Abnormal Dreams	2%	1%
Tremor	2%	1%
Gastroesophageal Reflux Disease	2%	1%
Pain in Extremity	2%	1%
Asthenia	2%	1%
Balance Disorder	2%	1%
Hypoaesthesia	2%	1%
Dysphagia	2%	0%
Restless Legs Syndrome	2%	0%

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 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, 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: 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.

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)

Preferred Term	QuetiapineFumarate 75 mg/day (N = 53)		QuetiapineFumarate 150 mg/day (N = 48)		QuetiapineFumarate 300 mg/day (N = 52)		QuetiapineFumarate 600 mg/day (N = 51)		QuetiapineFumarate 750 mg/day (N = 54)		Placebo (N = 51)
	n	%	n	%	n	%	n	%	n	%	n	%
Dystonic event	2	3.8	2	4.2	0	0	2	3.9	3	5.6	4	7.8
Parkinsonism	2	3.8	0	0	1	1.9	1	2	1	1.9	4	7.8
Akathisia	1	1.9	1	2.1	0	0	0	0	1	1.9	4	7.8
Dyskinetic event	2	3.8	0	0	0	0	1	2	0	0	0	0
Other extrapyramidal event	2	3.8	0	0	3	5.8	3	5.9	1	1.9	4	7.8

 

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, -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 children and adolescents (10 to 17 years old) exposed to quetiapine fumarate 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 fumarate 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 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) quetiapine fumarate extended-release trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release (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 Fumarate 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 treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% 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% 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

Preferred Term	Quetiapine Fumarate400 mg (n = 73)	Quetiapine Fumarate800 mg (n = 74)	Placebo (n = 75)
SomnolenceSomnolence combines adverse reaction terms somnolence and sedation.	33%	35%	11%
Dizziness	8%	15%	5%
Dry Mouth	4%	10%	1%
TachycardiaTachycardia combines adverse reaction terms tachycardia and sinus tachycardia.	6%	11%	0%
Irritability	3%	5%	0%
Arthralgia	1%	3%	0%
Asthenia	1%	3%	1%
Back Pain	1%	3%	0%
Dyspnoea	0%	3%	0%
Abdominal Pain	3%	1%	0%
Anorexia	3%	1%	0%
Tooth Abscess	3%	1%	0%
Dyskinesia	3%	0%	0%
Epistaxis	3%	0%	1%
Muscle Rigidity	3%	0%	0%

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 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 (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than 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 (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

Preferred Term	Quetiapine Fumarate400 mg (n = 95)	Quetiapine Fumarate600 mg (n = 98)	Placebo (n = 90)
SomnolenceSomnolence combines adverse reactions terms somnolence and sedation	50%	57%	14%
Dizziness	19%	17%	2%
Nausea	6%	10%	4%
Fatigue	14%	9%	4%
Increased Appetite	10%	9%	1%
TachycardiaTachycardia combines adverse reaction terms tachycardia and sinus tachycardia.	6%	9%	1%
Dry Mouth	7%	7%	0%
Vomiting	8%	7%	3%
Nasal Congestion	3%	6%	2%
Weight Increased	6%	6%	0%
Irritability	3%	5%	1%
Pyrexia	1%	4%	1%
Aggression	1%	3%	0%
Musculoskeletal Stiffness	1%	3%	1%
Accidental Overdose	0%	2%	0%
Acne	3%	2%	0%
Arthralgia	4%	2%	1%
Lethargy	2%	2%	0%
Pallor	1%	2%	0%
Stomach Discomfort	4%	2%	1%
Syncope	2%	2%	0%
Vision Blurred	3%	2%	0%
Constipation	4%	2%	0%
Ear Pain	2%	0%	0%
Paraesthesia	2%	0%	0%
Sinus Congestion	3%	0%	0%
Thirst	2%	0%	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% (19/147) for quetiapine fumarate and 5.3% (4/75) 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% (7/193) for quetiapine fumarate and 1.1% (1/90) for placebo.

Table 15 presents a uling 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 to 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)

Preferred Term	QuetiapineFumarate400 mg/day(N = 73)		QuetiapineFumarate800 mg/day(N = 74)		All QuetiapineFumarate(N = 147)		Placebo(N = 75)
	n	%	n	%	n	%	n	%
Dystonic event	2	2.7	0	0	2	1.4	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
Dyskinetic event	2	2.7	0	0	2	1.4	0	0
Other Extrapyramidal Event	2	2.7	2	2.7	4	2.7	0	0

 

Table 16 presents a uling 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)

Preferred TermThere were no adverse experiences with the preferred term of dystonic or dyskinetic events.	QuetiapineFumarate 400 mg/day (N = 95)		QuetiapineFumarate 600 mg/day (N = 98)		AllQuetiapineFumarate (N = 193)		Placebo (N = 90)
	n	%	n	%	n	%	n	%
Parkinsonism	2	2.1	1	1	3	1.6	1	1.1
Akathisia	1	1	1	1	2	1	0	0
Other Extrapyramidal Event	1	1.1	1	1	2	1	0	0

Other Adverse Reactions Observed During the Premarketing 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.

^* Adjusted for gender

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 fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count < 1 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 [see Warnings and Precautions ( 5.9   )].

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 fumarate 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 fumarate (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 fumarate. 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 fumarate 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 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: 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, QT_c, 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 ( 5.7 )]. 

Children and Adolescents: In the acute (6 week) schizophrenia trial in adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine fumarate 400 mg and 8.5% (5/74) of patients receiving quetiapine fumarate 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 fumarate 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, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 1.1% (1/89) of patients receiving quetiapine fumarate 400 mg and 4.7% (4/85) of patients receiving quetiapine fumarate 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 fumarate 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) quetiapine fumarate extended-release trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (> 110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine fumarate extended-release and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine fumarate extended-release, compared to 0.3 bpm in the placebo group [see Warnings and Precautions (5.7)].

6.2 Postmarketing Experience

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

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

• Pregnancy: Limited human data. Based on animal data, may cause fetal harm. Quetiapine should be used only if the potential benefit justifies the potential risk ( 8.1 )
• Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother’s health (8.3)

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies of quetiapine fumarate use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data

There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including quetiapine fumarate), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Animal Data

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect at doses up to 2.4 times the maximum recommended human dose (MRHD) for schizophrenia of 800 mg/day based on mg/m² body surface area. However, there was evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring at approximately 1 and 2 times the MRHD of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1 to 2 times the MRHD (all doses tested) in rabbits.

In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.12, and 0.24 times the MRHD of 800 mg/day based on mg/m² body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.

8.2 Labor and Delivery

The effect of quetiapine fumarate on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Quetiapine fumarate was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from quetiapine fumarate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health.

In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 mcg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N = 8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).

8.4 Pediatric Use

In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ].

Schizophrenia

The efficacy and safety of quetiapine fumarate in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [see Indications and Usage (1.1), Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.1)].

Safety and effectiveness of quetiapine fumarate in pediatric patients less than 13 years of age with schizophrenia have not been established.

Maintenance

The safety and effectiveness of quetiapine fumarate in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. The safety and effectiveness of quetiapine fumarate in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.

Bipolar Mania

The efficacy and safety of quetiapine fumarate in the treatment of mania in children and adolescents ages 10 to 17 years with Bipolar I disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [see Indications and Usage (1.2), Dosage and Administration (2.3 ), Adverse Reactions (6.1), and Clinical Studies (14.2) ].

Safety and effectiveness of quetiapine fumarate in pediatric patients less than 10 years of age with bipolar mania have not been established.

Bipolar Depression

Safety and effectiveness of quetiapine fumarate in pediatric patients less than 18 years of age with bipolar depression have not been established. A clinical trial with quetiapine fumarate extended-release was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established.

Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and C_max of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see Clinical Pharmacology (12.3) ].

8.5 Geriatric Use

Of the approximately 3700 patients in clinical studies with quetiapine fumarate, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of quetiapine fumarate in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine fumarate, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine fumarate was reduced by 30% to 50% in elderly patients when compared to younger patients [see Clinical Pharmacology (12.3  ) and Dosage and Administration ( 2.3 )].

8.6 Renal Impairment

Clinical experience with quetiapine fumarate in patients with renal impairment is limited [see Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day to 50 mg/day [see Dosage and Administration (2.3 ) and Clinical Pharmacology (12.3)].