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Seroquel XR

SIDE EFFECTS

Clinical Studies 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.

The information below is derived from a clinical trial database for SEROQUEL XR consisting of approximately 3400 patients exposed to SEROQUEL XR 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.

Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and tabulations that follow, standard MedDRA terminology has been used to classify reported adverse reactions.

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

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

Schizophrenia: There was no difference in the incidence and type of adverse reactions associated with discontinuation (6.4% (61/951) for SEROQUEL XR vs. 7.5% (24/319) for placebo) in a pool of controlled Schizophrenia trials. There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in Schizophrenia trials.

Bipolar Disorder: Mania: In a single clinical trial in patients with bipolar mania, 4.6% (7/151) of patients on SEROQUEL XR discontinued due to an adverse reaction compared to 8.1% (13/160) on placebo. There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in the Bipolar Mania trial.

Depression: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on SEROQUEL XR discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence *was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in SEROQUEL XR in the Bipolar Depression trial.

MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on SEROQUEL XR 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 SEROQUEL XR 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

SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%).

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

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 1% or more in patients treated with SEROQUEL XR (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 11: Treatment-Emergent Adverse Reaction Incidence in 6­Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia1

Body System/ Preferred Term Placebo
(n=319)
SEROQUEL XR
(n=951)
Cardiac Disorders
Tachycardia 1% 3%
Eye Disorders
Vision blurred 1% 2%
Gastrointestinal Disorders
Dry Mouth 1% 12%
Constipation 5% 6%
Dyspepsia 2% 5%
Toothache 0% 2%
General Disorders and Administration Site Conditions
Fatigue 2% 3%
Irritability 0% 1%
Pyrexia 0% 1%
Investigations
Heart Rate Increased 1% 4%
Metabolism and Nutrition Disorders
Increased Appetite 0% 2%
Musculoskeletal and Connective Tissue Disorders
Muscle Spasms 1% 2%
Nervous System Disorders
Somnolence2 10% 25%
Dizziness 4% 10%
Tremor 1% 2%
Akathisia 1% 2%
Extrapyramidal Symptoms3 5% 8%
Psychiatric Disorders
Anxiety 1% 2%
Schizophrenia 1% 2%
Restlessness 1% 2%
Vascular Disorders
Orthostatic 5% 7%
Hypotension
Hypotension 1% 3%
1Reactions for which the SEROQUEL XR incidence was 1% or more and equal to or less than placebo are not listed in the table, but included the following: headache, insomnia, nausea, vomiting, diarrhea, stomach discomfort, weight increased, diastolic blood pressure decreased, systolic blood pressure decreased, arthralgia, back pain, pain in extremity, extrapyramidal disorder, agitation, psychotic disorder, sleep disorder, nasal congestion, hypertension.
2Somnolence combines adverse reaction terms somnolence and sedation.
3Extrapyramidal symptoms that were reported for SEROQUEL XR or placebo include the terms: akathisia, cogwheel rigidity, drooling, dyskinesia dystonia, extrapyramidal disorder, hypertonia, movement disorder, muscle rigidity, oculogyration, parkinsonism, parkinsonian gait, psychomotor hyperactivity, tardive dyskinesia, restlessness and tremor.

In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR 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 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 1% or more of patients treated with SEROQUEL XR (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 12: Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania1

Body System/ Preferred Term Placebo
(n=160)
SEROQUEL XR
(n=151)
Cardiac Disorders
Tachycardia 1% 2%
Eye Disorders    
Vision blurred 1% 2%
Gastrointestinal Disorders
Dry Mouth 7% 34%
Constipation 3% 10%
Dyspepsia 4% 7%
Toothache 1% 3%
General Disorders and Administration Site Conditions
Fatigue 4% 7%
Sluggishness 1% 2%
Pain 0% 1%
Investigations
Weight Gain 1% 7%
Heart Rate Increased 0% 3%
Injury, Poisoning And Procedural Complications
Contusion 0% 1%
Metabolism And Nutrition Disorders
Increased Appetite 2% 4%
Nervous System Disorders
Extrapyramidal Symptoms3 4% 7%
Somnolence2 12% 50%
Dizziness 4% 10%
Dysarthria 0% 5%
Lethargy 1% 2%
Postural Dizziness 0% 1%
Musculoskeletal And Connective Tissue Disorders
Back Pain 2% 3%
Arthralgia 0% 1%
Psychiatric Disorders
Abnormal Dreams 0% 3%
Bipolar I Disorder 0% 1%
Respiratory, Thoracic and Mediastinal Disorders
Nasal Congestion 1% 5%
Dry Throat 0% 1%
Vascular Disorders
Orthostatic Hypotension 0% 3%
1Reactions for which the SEROQUEL XR incidence was 1% or more and equal to or less than placebo are not listed in the table, but included the following: headache, peripheral edema, diarrhea, nausea, vomiting, decreased appetite, muscle spasms, musculoskeletal stiffness, myalgia, tremor, akathisia, insomnia, agitation, nightmare, restlessness, erectile dysfunction, pharyngolaryngeal pain, cough, and hypotension.
2Somnolence combines adverse reaction terms somnolence and sedation.
3Extrapyramidal symptoms that were reported for SEROQUEL XR or placebo include the terms: akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness and tremor.

In the 8-week placebo-controlled bipolar depression study, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%).

Table 13: enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 1% or more of patients treated with SEROQUEL XR 300 mg/day where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 13: Treatment-Emergent Adverse Reactions in an 8-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Depression1

Body System/Preferred Term Placebo
(n=140)
SEROQUEL XR
(n=137)
Ear And Labyrinth Disorders
Ear Pain 1% 2%
Gastrointestinal Disorders
Dry Mouth 7% 37%
Constipation 6% 8%
Dyspepsia 1% 7%
Toothache 0% 3%
Abdominal Distension 0% 1%
General Disorders and Administration Site Conditions
Fatigue 2% 6%
Irritability 3% 4%
Immune System Disorders
Seasonal Allergy 1% 2%
Infections And Infestations
Viral Gastroenteritis 1% 4%
Urinary Tract Infection 0% 2%
Sinusitis 1% 2%
Investigations
Weight Gain 1% 7%
Heart Rate Increased 0% 2%
Metabolism and Nutrition Disorder
Increased Appetite 6% 12%
Decreased Appetite 1% 2%
Musculoskeletal And Connective Tissue Disorders
Arthralgia 1% 4%
Back Pain 1% 3%
Muscle Spasms 1% 3%
Myalgia 1% 2%
Neck Pain 0% 2%
Nervous System Disorders
Somnolence2 13% 52%
Extrapyramidal Symptoms3 1% 4%
Dizziness 11% 13%
Paraesthesia 2% 3%
Disturbance in Attention 1% 2%
Dysarthria 0% 2%
Akathisia 0% 2%
Hypersomnia 0% 2%
Mental Impairment 0% 2%
Migraine 1% 2%
Restless Legs Syndrome 1% 2%
Sinus Headache 1% 2%
Psychiatric Disorders
Abnormal Dreams 0% 3%
Anxiety 1% 2%
Confusional State 0% 2%
Disorientation 0% 2%
Libido Decreased 1% 2%
Renal And Urinary Disorders
Pollakiuria 1% 2%
Respiratory, Thoracic And Mediastinal Disorders
Sinus Congestion 1% 2%
Skin And Subcutaneous Tissue Disorders
Hyperhidrosis 1% 2%
Vascular Disorders
Orthostatic Hypotension 1% 2%
1Reactions for which the SEROQUEL XR incidence was 1% or more and equal to or less than placebo are not listed in the table, but included the following: headache insomnia, nausea, diarrhea, vomiting, nasopharyngitis, upper respiratory tract infection, influenza, pain in extremity, cough and nasal congestion.
2Somnolence combines adverse reaction terms somnolence and sedation.
3Extrapyramidal symptoms that were reported for SEROQUEL XR or placebo include the terms: akathisia, dystonia, extrapyramidal disorder, hypertonia, and tremor.

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 SEROQUEL XR (incidence of 5% or greater and observed at a rate on SEROQUEL XR 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 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 1% or more of patients treated with SEROQUEL XR (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 14: Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose1

Body System/Preferred Term Placebo
(n=309)
SEROQUEL XR 150 mg
(n=315)
SEROQUEL XR 300 mg
(n=312)
Ear And Labyrinth Disorders
Vertigo 1% 2% 2%
Eye Disorders
Vision Blurred 1% 2% 1%
Gastrointestinal Disorders
Dry Mouth 8% 27% 40%
Constipation 4% 6% 11%
Nausea 7% 7% 8%
Dyspepsia 2% 2% 3%
Abdominal Distension 0% 0% 1%
Vomiting 1% 3% 1%
General Disorders and Administration Site Conditions
Fatigue 4% 14% 11%
Irritability 3% 4% 2%
Chills 0% 1% 1%
Infections And Infestations
Upper Respiratory Tract Infection 2% 3% 2%
Influenza 0% 2% 1%
Injury, Poisoning And Procedural Complications
Fall 1% 2% 0%
Investigations
Weight Increased 0% 3% 5%
Metabolism And Nutrition Disorders
Increased Appetite 3% 3% 5%
Musculoskeletal And Connective Tissue Disorders
Back pain 1% 3% 3%
Muscle Spasms 1% 2% 1%
Nervous System Disorders
Somnolence2 9% 37% 43%
Dizziness 7% 11% 12%
Extrapyramidal Symptoms3 4% 4% 6%
Hypersomnia 0% 1% 2%
Dysarthria 0% 1% 1%
Dysgeusia 0% 1% 1%
Lethargy 1% 2% 1%
Akathisia 1% 2% 2%
Psychiatric Disorders
Abnormal Dreams 1% 2% 2%
Anxiety 1% 2% 2%
Restlessness 1% 1% 2%
Libido Decreased 0% 0% 1%
Depression 1% 2% 1%
1Reactions for which the SEROQUEL XR incidence was 1% or more but equal to or less than placebo are not listed in the table, but included the following: headache, insomnia, nausea, disturbance in attention, dysarthria, paraesthesia, tremor, diarrhea, upper abdominal pain, nightmare, nasopharyngitis, sinusitis, decreased appetite, myalgia, arthralgia, pain in extremity, hyperhidrosis, night sweats and nasal congestion.
2Somnolence combines adverse event terms somnolence and sedation.
3Extrapyramidal symptoms that were reported for SEROQUEL XR or placebo include the terms: akathisia, cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor.

Adverse Reactions Occurring at an Incidence of 5% or More Among SEROQUEL XR Treated Patients in Long-Term, Placebo-Controlled Trials

In a longer-term placebo-controlled trial, adult patients with schizophrenia who remained clinically stable on SEROQUEL XR during open-label treatment for at least 4 months were randomized to placebo (n=103) or to continue on their current SEROQUEL XR (n=94) for up to 12 months of observation for possible relapse, the adverse reactions reported were generally consistent with those reported in the short-term, placebo-controlled trials. Insomnia (8.5%) and headache (7.4%) were the only adverse events reported by 5% or more patients.

Adverse Reactions that occurred in < 5% of patients and were considered drug-related (incidence greater than placebo and consistent with known pharmacology of drug class) in order of decreasing frequency: heart rate increased, hypotension, weight increased, tremor, akathisia, increased appetite, blurred vision, postural dizziness, pyrexia, dysarthria, dystonia, drooling, syncope, tardive dyskinesia, dysphagia, leukopenia, and rash.

Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label: nightmares, peripheral edema, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS).

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 potentially 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 SEROQUEL XR, the incidence of any adverse reactions potentially related to EPS was 8% for SEROQUEL XR and 8% for SEROQUEL (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 SEROQUEL in schizophrenia patients.

Table 15: Adverse Experiences Associated with Extrapyramidal Symptoms in Placebo-controlled Clinical Trials for Schizophrenia

Preferred term Placebo
(N=319)
SEROQUEL XR 300 mg/day
(N=91)
SEROQUEL XR 400 mg/day
(N=227)
SEROQUEL XR 600 mg/day
(N=310)
SEROQUEL XR 800 mg/day
(N=323)
All Doses
(N=951)
n % n % n % n % n % n %
Dystonic eventa 0 0.0 3 3.3 0 0.0 4 1.3 1 0.3 8 0.8
Parkinsonismb 4 1.3 1 1.1 3 1.3 11 3.6 7 2.2 22 2.3
Akathisiac 4 1.3 0 0.0 3 1.3 7 2.3 7 2.2 17 1.8
Dyskinetic eventd 2 0.6 2 2.2 1 0.4 1 0.3 1 0.3 5 0.5
Other extrapyramidal evente 7 2.2 3 3.3 4 1.8 7 2.3 12 3.7 26 2.7
a: Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration
b: Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia
c: Patients with the following terms were counted in this category: akathisia, psychomotor agitation
d: Patients with the following terms were counted in this category: tardive dyskinesia, dyskinesia, choreoathetosis
e: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder, movement disorder

In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of SEROQUEL XR, the incidence of any adverse reactions potentially related to EPS was 6.6% for SEROQUEL XR 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 16: Adverse Experiences Associated with Extrapyramidal Symptoms in a Placebo-controlled Clinical Trial for Bipolar Mania

Preferred term* Placebo (N=160) SEROQUEL XR (N=151)
n % n %
Dystonic eventa 0 0.0 1 0.7
Parkinsonismb 3 1.9 4 2.7
Akathisiac 1 0.6 2 1.3
Other extrapyramidal eventd 2 1.3 3 2.0
*: There were no adverse experiences with the preferred term of dyskinetic event.
a: Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration
b: Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia
c: Patients with the following terms were counted in this category: akathisia, psychomotor agitation
d: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder, movement disorder

In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of SEROQUEL XR, the incidence of any adverse reactions potentially related to EPS was 4.4% for SEROQUEL XR 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 17: Adverse Experiences Associated with Extrapyramidal Symptoms in a Placebo-controlled Clinical Trial for Bipolar Depression

Preferred term* Placebo (N=140) SEROQUEL XR (N=137)
n % n %
Dystonic eventa 0 0.0 2 1.5
Parkinsonismb 1 0.7 1 0.7
Akathisiac 0 0.0 2 1.5
Other extrapyramidal eventd 0 0.0 1 0.7
*: There were no adverse experiences with the preferred term of dyskinetic event.
a: Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration
b: Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia
c: Patients with the following terms were counted in this category: akathisia, psychomotor agitation
d: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder, movement disorder

In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of SEROQUEL XR, the incidence of any adverse reactions potentially related to EPS was 5.1% for SEROQUEL XR and 4.2% for the placebo group.

Table 18 shows the percentage of patients experiencing adverse reactions potentially associated with EPS in adjunct clinical trials for MDD by dose:

Table 18: Adverse Reactions Potentially Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration)

Preferred term Placebo (N=309) SEROQUEL XR 150 mg/day (N=315) SEROQUEL XR 300 mg/day (N=312) All Doses
n % n % n % n %
Dystonic eventa 0 0.0 1 0.3 0 0.0 1 0.2
Parkinsonismb 5 1.6 3 1.0 4 1.3 7 1.1
Akathisiac 3 1.0 5 1.6 8 2.6 13 2.1
Dyskinetic eventd 0 0.0 0 0.0 1 0.3 1 0.2
Other extrapyramidal evente 5 1.6 5 1.6 7 2.2 12 1.9
a: Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration
b: Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia
c: Patients with the following terms were counted in this category: akathisia, psychomotor agitation
d: Patients with the following terms were counted in this category: tardive dyskinesia, dyskinesia, choreoathetosis
e: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder, movement disorder

Children and Adolescents: Safety and effectiveness of SEROQUEL XR have not been established in pediatric patients and SEROQUEL XR is not approved for patients under the age of 18 years. In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% for SEROQUEL and 5.3% for placebo, though the incidence of the individual adverse events (eg, akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% for SEROQUEL and 1.1% for placebo.

Table 19 below presents a listing of patients with adverse experiences potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

Table 19 : Adverse experiences potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6­week duration).

Preferred term Placebo (N=75) SEROQUEL 400 mg/day (N=73) SEROQUEL 800 mg/day (N=74) All SEROQUEL (N=147)
n % n % n % n %
Dystonic eventa 0 0.0 2 2.7 0 0.0 2 1.4
Parkinsonismb 2 2.7 4 5.5 4 5.4 8 5.4
Akathisiac 3 4.0 3 4.1 4 5.4 7 4.8
Dyskinetic eventd 0 0.0 2 2.7 0 0.0 2 1.4
Other extrapyramidal evente 0 0.0 2 2.7 2 2.7 4 2.7
a: Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity
b: Patients with the following terms were counted in this category: cogwheel rigidity, tremor
c: Patients with the following terms were counted in this category: akathisia
d: Patients with the following terms were counted in this category: tardive dyskinesia, dyskinesia, choreoathetosis
e: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder

Table 20 below presents a listing of patients with Adverse Experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration)

Table 20: Adverse experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration)

Preferred term* Placebo (N=90) SEROQUEL 400mg/day (N=95) SEROQUEL 600 mg/day (N=98) All SEROQUEL (N=193)
n % n % n % n %
Parkinsonisma 1 1.1 2 2.1 1 1.0 3 1.6
Akathisiab 0 0.0 1 1.0 1 1.0 2 1.0
Other extrapyramidal eventc 0 0.0 1 1.1 1 1.0 2 1.0
*: There were no adverse experiences with the preferred term of dystonic or dyskinetic events.
a: Patients with the following terms were counted in this category: cogwheel rigidity, tremor
b: Patients with the following terms were counted in this category: akathisia
c: Patients with the following terms were counted in this category: restlessness; extrapyramidal disorder

Children and Adolescents: Safety and effectiveness of SEROQUEL XR have not been established in pediatric patients and SEROQUEL XR is not approved for patients under the age of 18 years. In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increased appetite was 7.6% for SEROQUEL compared to 2.4% for placebo. In a 26-week open-label study that enrolled patients from the above two pediatric trials, the incidence of increased appetite was 7% for SEROQUEL.

Vital Signs and Laboratory Values

Hyperglycemia, hyperlipidemia, weight gain, orthostatic hypotension and changes in thyroid hormone levels have been reported with quetiapine. Increases in blood pressure have also been reported with quetiapine in children and adolescents [see WARNINGS AND PRECAUTIONS].

Laboratory Changes
Neutrophil Counts

In three-arm SEROQUEL XR 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 SEROQUEL XR and 1.5% for SEROQUEL, 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. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue SEROQUEL XR at the first sign of a decline in WBC in absence of other causative factors [see WARNINGS AND PRECAUTIONS].

Decreased Hemoglobin

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

ECG Changes:

2.5% of SEROQUEL XR patients, and 2.3% of placebo patients, had tachycardia ( > 120 bpm) at any time during the trials. SEROQUEL XR 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 SEROQUEL. The incidence of adverse reactions of tachycardia was 1.9% for SEROQUEL XR compared to 0.5% for placebo. SEROQUEL 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].

Children and Adolescents: Safety and effectiveness of SEROQUEL XR have not been established in pediatric patients. In the acute (6week) schizophrenia trial in adolescents, potentially clinically significant increases in heart rate ( > 110 bpm) occurred in 5.2% of patients receiving SEROQUEL 400 mg and 8.5% of patients receiving SEROQUEL 800 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for SEROQUEL 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see WARNINGS AND PRECAUTIONS].

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% of patients receiving SEROQUEL 400 mg and 2.4% of patients receiving SEROQUEL 600 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for SEROQUEL 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [see WARNINGS AND PRECAUTIONS].

Post Marketing Experience

The following adverse reactions were identified during post approval use of SEROQUEL. 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 SEROQUEL therapy include anaphylactic reaction and galactorrhea.

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

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

Read the Seroquel XR (quetiapine fumarate extended-release tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

The risks of using SEROQUEL XR in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of SEROQUEL XR, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.

Because of its potential for inducing hypotension, SEROQUEL XR may enhance the effects of certain antihypertensive agents.

SEROQUEL XR may antagonize the effects of levodopa and dopamine agonists.

Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QT interval [see WARNINGS AND PRECAUTIONS].

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.

The Effect of Other Drugs on Quetiapine

Phenytoin

Coadministration of quetiapine (250 mg three times/day) and phenytoin (100 mg three times/day) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of SEROQUEL XR may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (eg, carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (eg, valproate) [see DOSAGE AND ADMINISTRATION].

Divalproex

Coadministration of quetiapine (150 mg twice daily) and divalproex (500 mg twice daily) increased the mean maximum plasma concentration of quetiapine at steady-state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine

Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.

Cimetidine

Administration of multiple daily doses of cimetidine (400 mg three times daily for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg three times daily). Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors

Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P450 3A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine. Caution (reduced dosage) is indicated when SEROQUEL XR is administered with ketoconazole and other inhibitors of cytochrome P450 3A (eg, itraconazole, fluconazole, erythromycin, protease inhibitors).

Fluoxetine, Imipramine, Haloperidol, and Risperidone

Coadministration of fluoxetine (60 mg once daily), imipramine (75 mg twice daily), haloperidol (7.5 mg twice daily), or risperidone (3 mg twice daily) with quetiapine (300 mg twice daily) did not alter the steady-state pharmacokinetics of quetiapine.

Effect of Quetiapine on Other Drugs

Lorazepam

The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times daily dosing.

Divalproex

The mean maximum concentration and extent of absorption of total and free valproic acid at steady-state were decreased by 10 to 12% when divalproex (500 mg twice daily) was administered with quetiapine (150 mg twice daily). The mean oral clearance of total valproic acid (administered as divalproex 500 mg twice daily) was increased by 11% in the presence of quetiapine (150 mg twice daily). The changes were not significant.

Lithium

Concomitant administration of quetiapine (250 mg three times daily) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine

Administration of multiple daily doses up to 750 mg/day (on a three times daily schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.

Drug Abuse And Dependence

Controlled Substance

SEROQUEL XR is not a controlled substance.

Abuse

SEROQUEL XR has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of SEROQUEL XR (eg, development of tolerance, increases in dose, drug-seeking behavior).

Read the Seroquel XR Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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