Quetiapine Fumarate: Package Insert and Label Information (Page 4 of 9)

5.16 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on quetiapine extended-release tablets compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on quetiapine extended-release tablets compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on quetiapine extended-release tablets compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls.
In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on quetiapine extended-release tablets respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively).

5.17 Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine extended-release tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.18 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Quetiapine extended-release tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.19 Discontinuation Syndrome

Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. In short-term placebo-controlled, monotherapy clinical trials with quetiapine extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine extended-release tablets and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1-week post-discontinuation. Gradual dose reduction is advised [see Use in Specific Populations (8.1)].

5.20 Anticholinergic (antimuscarinic) Effects

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine extended-release tablets are used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine extended-release tablets should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Drug Interactions (7.1), Overdosage (10.1), and Clinical Pharmacology (12.1)].

Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction. Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility.

Quetiapine extended-release tablets should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation.

6 ADVERSE REACTIONS

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

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 extended-release tablets consisting of approximately 3400 patients exposed to quetiapine 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 listed.
Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials:

Schizophrenia: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥2% for quetiapine 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 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 extended-release tablets discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in quetiapine 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 extended-release tablets discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence 2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% in quetiapine 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 extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine 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 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 extended-release tablets (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with quetiapine 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
1. Somnolence combines adverse reaction terms somnolence and sedation.2. 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 Extended-Release Tablets (N=951) Placebo (N=319)
Somnolence 1 25% 10%
Dry Mouth 12% 1%
Dizziness 10% 4%
Extrapyramidal Symptoms 2 8% 5%
Orthostatic Hypotension 7% 5%
Constipation 6% 5%
Dyspepsia 5% 2%
Heart Rate Increased 4% 1%
Tachycardia 3% 1%
Fatigue 3% 2%
Hypotension 3% 1%
Vision Blurred 2% 1%
Toothache 2% 0%
Increased Appetite 2% 0%
Muscle Spasms 2% 1%
Tremor 2% 1%
Akathisia 2% 1%
Anxiety 2% 1%
Schizophrenia 2% 1%
Restlessness 2% 1%

In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of quetiapine extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine 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%).
____________________________________
2 Somnolence combines adverse reaction terms somnolence and sedation. Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with quetiapine extended-release tablets (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with quetiapine 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
1. Somnolence combines adverse reaction terms somnolence and sedation.2. Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness, and tremor.
Preferred Term Quetiapine Extended-Release Tablets (N=151) Placebo (N=160)
Somnolence 1 50% 12%
Dry Mouth 34% 7%
Dizziness 10% 4%
Constipation 10% 3%
Dyspepsia 7% 4%
Fatigue 7% 4%
Weight Gain 7% 1%
Extrapyramidal Symptoms 2 7% 4%
Nasal Congestion 5% 1%
Dysarthria 5% 0%
Increased Appetite 4% 2%
Back Pain 3% 2%
Toothache 3% 1%
Heart Rate Increased 3% 0%
Abnormal Dreams 3% 0%
Orthostatic Hypotension 3% 0%
Tachycardia 2% 1%
Vision Blurred 2% 1%
Sluggishness 2% 1%
Lethargy 2% 1%

In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of quetiapine extended-release tablets (incidence of 5% or greater) and observed at a rate on quetiapine 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 extended-release tablets 300 mg/day where the incidence in patients treated with quetiapine 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
1. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: dystonia, extrapyramidal disorder, hypertonia, and tremor.
Preferred Term Quetiapine Extended-Release Tablets (N=137) Placebo (N=140)
Somnolence 1 52% 13%
Dry Mouth 37% 7%
Dizziness 13% 11%
Increased Appetite 12% 6%
Constipation 8% 6%
Dyspepsia 7% 1%
Weight Gain 7% 1%
Fatigue 6% 2%
Irritability 4% 3%
Viral Gastroenteritis 4% 1%
Arthralgia 4% 1%
Extrapyramidal Symptoms 2 4% 1%
Paraesthesia 3% 2%
Back Pain 3% 1%
Muscle Spasms 3% 1%
Toothache 3% 0%
Abnormal Dreams 3% 0%
Ear Pain 2% 1%
Seasonal Allergy 2% 1%
Sinusitis 2% 1%
Decreased Appetite 2% 1%
Myalgia 2% 1%
Disturbance in Attention 2% 1%
Migraine 2% 1%
Restless Legs Syndrome 2% 1%
Anxiety 2% 1%
Sinus Headache 2% 1%
Libido Decreased 2% 1%
Pollakiuria 2% 1%
Sinus Congestion 2% 1%
Hyperhidrosis 2% 1%
Orthostatic Hypotension 2% 1%
Urinary Tract Infection 2% 0%
Heart Rate Increased 2% 0%
Neck Pain 2% 0%
Dysarthria 2% 0%
Akathisia 2% 0%
Hypersomnia 2% 0%
Mental Impairment 2% 0%
Confusional State 2% 0%
Disorientation 2% 0%

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 extended-release tablets (incidence of 5% or greater and observed at a rate on quetiapine 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 extended-release tablets (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with quetiapine 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
1. Somnolence combines the adverse reaction terms somnolence and sedation.2. Extrapyramidal symptoms include the terms: cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor.
Preferred Term Quetiapine Extended-Release Tablets 150 mg (N=315) Quetiapine Extended-Release Tablets 300 mg (N=312) Placebo (N=309)
Somnolence 1 37% 43% 9%
Dry Mouth 27% 40% 8%
Fatigue 14% 11% 4%
Dizziness 11% 12% 7%
Nausea 7% 8% 7%
Constipation 6% 11% 4%
Irritability 4% 2% 3%
Extrapyramidal Symptoms 2 4% 6% 4%
Vomiting 3% 1% 1%
Upper Respiratory Tract Infection 3% 2% 2%
Weight Increased 3% 5% 0%
Increased Appetite 3% 5% 3%
Back Pain 3% 3% 1%
Vertigo 2% 2% 1%
Vision Blurred 2% 1% 1%
Dyspepsia 2% 3% 2%
Influenza 2% 1% 0%
Fall 2% 0% 1%
Muscle Spasms 2% 1% 1%
Lethargy 2% 1% 1%
Akathisia 2% 2% 1%
Abnormal Dreams 2% 2% 1%
Anxiety 2% 2% 1%
Depression 2% 1% 1%

Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label
Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/or syncope), and priapism.
Extrapyramidal Symptoms (EPS):

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat EPS.

Adults: In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo.
In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 8% for quetiapine extended-release tablets and 8% for quetiapine 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 tablets in schizophrenia patients. In Tables 16 to 19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo-Controlled Clinical Trials for Schizophrenia
Preferred Term Quetiapine Extended- Release Tablets 300 mg/day (N=91) Quetiapine Extended- Release Tablets 400 mg/day (N=227) Quetiapine Extended- Release Tablets 600 mg/day (N=310) Quetiapine Extended- Release 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 4 1.3 1 0.3 8 0.8 0 0
Parkinsonism 1 1.1 3 1.3 11 3.6 7 2.2 22 2.3 4 1.3
Akathisia 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 to 800 mg/day of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 6.6% for quetiapine 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% for any adverse reaction.

Table 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Clinical Trial for Bipolar Mania
1. There were no adverse reactions with the preferred term of dyskinetic event.
Preferred Term 1 Quetiapine Extended-Release Tablets (N=151) Placebo (N=160)
n % n %
Dystonic event 1 0.7 0 0
Parkinsonism 4 2.7 3 1.9
Akathisia 2 1.3 1 0.6
Other extrapyramidal event 3 2 2 1.3

In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of quetiapine extended-release tablets, the incidence of any adverse reactions related to EPS was 4.4% for quetiapine 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
1. There were no adverse reactions with the preferred term of dyskinetic event.
Preferred Term 1 Quetiapine Extended-Release Tablets (N=137) Placebo (N=140)
n % n %
Dystonic event 2 1.5 0 0
Parkinsonism 1 0.7 1 0.7
Akathisia 2 1.5 0 0
Other extrapyramidal event 1 0.7 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 extended-release tablets, the incidence of any adverse reactions related to EPS was 5.1% for quetiapine 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 Extended- Release Tablets 150 mg/day (N=315) Quetiapine Extended- Release Tablets 300 mg/day (N=312) All Doses (N=627) Placebo (N=309)
n % n % n % n %
Dystonic event 1 0.3 0 0 1 0.2 0 0
Parkinsonism 3 1 4 1.3 7 1.1 5 1.6
Akathisia 5 1.6 8 2.6 13 2.1 3 1
Dyskinetic event 0 0 1 0.3 1 0.2 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 tablets consisting of over 1000 pediatric patients. This database includes 677 adolescents (13 to 17 years old) exposed to quetiapine tablets for the treatment of schizophrenia and 393 children and adolescents (10 to 17 years old) exposed to quetiapine 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 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 extended-release tablets 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 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 Tablets Treated Patients in Short-Term, Placebo-Controlled Trials

Schizophrenia (Adolescents, 13 to 17 years old)

The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.
Table 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with quetiapine tablets (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine 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
1. Somnolence combines adverse reaction terms somnolence and sedation.2. Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
Preferred Term Quetiapine Tablets 400 mg (N=73) Quetiapine Tablets 800 mg (N=74) Placebo (N=75)
Somnolence 1 33% 35% 11%
Dizziness 8% 15% 5%
Dry Mouth 4% 10% 1%
Tachycardia 2 6% 11% 0%
Irritability 3% 5% 0%
Arthralgia 1% 3% 0%
Asthenia 1% 3% 1%
Back Pain 1% 3% 0%
Dyspnea 0% 3% 0%
Abdominal Pain 3% 1% 0%
Anorexia 3% 1% 0%
Tooth Abscess 3% 1% 0%
Dyskinesia 3% 0% 0%
Epistaxis 3% 0% 1%
Muscle Rigidity 3% 0% 0%

Bipolar I Mania (Children and Adolescents 10 to 17 years old)

The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.
Table 21 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine tablets (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine 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
1. Somnolence combines adverse reaction terms somnolence and sedation.2. Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.
Preferred Term Quetiapine Tablets 400 mg (N=95) Quetiapine Tablets 600 mg (N=98) Placebo (N=90)
Somnolence 1 50% 57% 14%
Dizziness 19% 17% 2%
Nausea 6% 10% 4%
Fatigue 14% 9% 4%
Increased Appetite 10% 9% 1%
Tachycardia 2 6% 9% 0%
Dry Mouth 7% 7% 0%
Vomiting 8% 7% 3%
Nasal Congestion 3% 6% 2%
Weight Increased 6% 6% 0%
Irritability 3% 5% 1%
Pyrexia 1% 4% 1%
Aggression 1% 3% 0%
Musculoskeletal Stiffness 1% 3% 1%
Accidental Overdose 0% 2% 0%
Acne 3% 2% 0%
Arthralgia 4% 2% 1%
Lethargy 2% 2% 0%
Pallor 1% 2% 0%
Stomach Discomfort 4% 2% 1%
Syncope 2% 2% 0%
Vision Blurred 3% 2% 0%
Constipation 4% 2% 0%
Ear Pain 2% 0% 0%
Paresthesia 2% 0% 0%
Sinus Congestion 3% 0% 0%
Thirst 2% 0% 0%

Extrapyramidal Symptoms:

Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].
In a short-term placebo-controlled quetiapine extended-release tablets monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar depression (8-week duration), in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% (1/92) for quetiapine extended-release tablets and 0% (0/100) for placebo.
In a short-term placebo-controlled quetiapine tablets monotherapy trial in adolescent patients (13 to 17 years of age) with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine 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 tablets monotherapy trial in children and adolescent patients (10 to 17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for quetiapine 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 listing of patients with adverse reactions associated with EPS in the short-term placebo-controlled quetiapine 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 Tablets 400 mg/day (N=73) Quetiapine Tablets 800 mg/day (N=74) All Quetiapine Tablets (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 23 below presents a listing of patients with adverse reactions associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 23: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo- Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)
1. There were no adverse reactions with the preferred term of dystonic or dyskinetic events.
Preferred Term 1 Quetiapine Tablets 400 mg/day (N=95) Quetiapine Tablets 600 mg/day (N=98) All Quetiapine Tablets (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

Laboratory, ECG and vital sign changes observed in clinical studies

Laboratory Changes:
Neutrophil Counts
Adults: In three-arm quetiapine 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 extended-release tablets and 1.5% for quetiapine tablets, compared to 0.8% in placebo-treated patients.
In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1 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 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 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, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.
Interference with Urine Drug Screens
There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered.
ECG Changes:
Adults:2.5% of quetiapine extended-release tablets patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine extended-release tablets were 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 tablets. The incidence of adverse reactions of tachycardia was 1.9% for quetiapine extended-release tablets compared to 0.5% for placebo. Quetiapine 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 extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].
In an acute (8-week) quetiapine extended-release tablets 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 extended-release tablets and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine extended-release tablets, compared to 0.3 bpm in the placebo group [see Warnings and Precautions (5.7)].
In the acute (6-week) quetiapine tablets schizophrenia trial in adolescents (13 to 17 years of age), increases in heart rate (>110 bpm) occurred in 5.2% of patients receiving quetiapine tablets 400 mg and 8.5% of patients receiving quetiapine 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 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 tablets bipolar mania trial in children and adolescents (10 to 17 years of age), increases in heart rate (>110 bpm) occurred in 1.1% of patients receiving quetiapine tablets 400 mg and 4.7% of patients receiving quetiapine 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 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)].

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