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  • Seroquel XR
  • SEROQUEL®
    (quetiapine fumarate)
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Safety and Tolerability

Most common adverse reactions in patients with acute depressive episodes of bipolar disorder¹

Short-term monotherapy trial for the acute depressive episodes of bipolar disorder¹

• In this 8-week, placebo-controlled study, the most commonly observed adverse reactions associated with the use of 300 mg/day SEROQUEL XR (quetiapine fumarate) (incidence of 5% or greater) and observed at a rate in 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%)¹
• In a short-term monotherapy trial, the incidence of discontinuation due to adverse reactions was 13.1% with SEROQUEL XR vs 3.6% with placebo²
• Somnolence* was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥2% with SEROQUEL XR in a trial for the acute depressive episodes of bipolar disorder (10.2% with SEROQUEL XR and 0% with placebo)^1,2

*Somnolence combines adverse reaction terms “somnolence” and “sedation.”

 

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Most-Common-Adverse-Reactionsa-Short-term-Monotherapy-Trial-in-Bipolar-Depression1b

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Most Common Adverse Reactions^a: Short-term Monotherapy Trial for the Acute Depressive Episodes of Bipolar Disorder^1,b

1. ^aIncidence ≥5% and at least twice that of placebo in the SEROQUEL XR dose group.
2. ^b Data from an 8-week, multicenter, randomized, double-blind, placebo-controlled monotherapy trial for the acute depressive episodes of bipolar disorder.
3. ^c Somnolence combines adverse reaction terms “somnolence” and “sedation.”

Effect on weight

Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.

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Percentage of Patients with Weight Gain ≥7% of Body Weight: Short-term Monotherapy Trial for the Acute Depressive Episodes of Bipolar Disorder^1,a

1. ^a Data from an 8-week, multicenter, randomized, double-blind, placebo-controlled monotherapy trial for the acute depressive episodes of bipolar disorder.

• The proportion of patients in adult clinical trials across approved indications meeting a weight gain criterion of ≥7% of body weight was 5%–23% for quetiapine vs 0%–7% for placebo^1,3

Effect on lipids

Undesirable alterations in lipids have been observed with quetiapine use. Increases in total cholesterol, LDL-cholesterol and triglycerides, and decreases in HDL-cholesterol have been reported in clinical trials. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of and periodically during treatment.

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Percentage of Patients with Shifts from Baseline in Lipids: Short-term Monotherapy Trial for the Acute Depressive Episodes of Bipolar Disorder^1,a

1. ^a Data from an 8-week, multicenter, randomized, double-blind, placebo-controlled monotherapy trial for the acute depressive episodes of bipolar disorder.
2. ^b Low-density lipoprotein.
3. ^c High-density lipoprotein.

• Clinically significant increases in total cholesterol (7%–18% for quetiapine vs 3%–9% for placebo), triglycerides (8%–22% for quetiapine vs 5%–16% for placebo), and LDL-cholesterol (4%–11% for quetiapine vs 2%–10% for placebo) and decreases in HDL-cholesterol (7%–19% for quetiapine vs 7%–14% for placebo) have been reported in adult clinical trials across approved indications^1,3

Effect on glucose

Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Enlarge

Percentage of Patients with Shifts from Baseline in Glucose: Short-term Monotherapy Trial for the Acute Depressive Episodes of Bipolar Disorder^4,a

1. ^a Data from an 8-week, multicenter, randomized, double-blind, placebo-controlled monotherapy trial for the acute depressive episodes of bipolar disorder.

Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

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Percentage of Patients with Shifts in Fasting Glucose to ≥126 mg/dL: Short-term (≤12 Weeks) Placebo-Controlled Studies Across Indications^1,3

• Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics

Extrapyramidal symptoms (EPS) adverse reactions

Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. Although much less commonly, TD can develop after relatively brief treatment periods at low doses or even after treatment discontinuation. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. SEROQUEL XR should be prescribed in a manner that is most likely to minimize the occurrence of TD, and discontinuation should be considered if signs and symptoms of TD occur.

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Percentage of Patients with Adverse Reactions Potentially Associated with EPS: Short-term Monotherapy Trial for the Acute Depressive Episodes of Bipolar Disorder^1,5,a

1. ^a Data from an 8-week, multicenter, randomized, double-blind, placebo-controlled monotherapy trial for the acute depressive episodes of bipolar disorder.
2. ^b Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration.
3. ^c Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia.
4. ^d Patients with the following terms were counted in this category: akathisia, psychomotor agitation.
5. ^e Patients with the following terms were counted in this category: restlessness, extrapyramidal disorder, movement disorder.

In placebo-controlled adult clinical trials with quetiapine across all approved indications, the incidence of any adverse reactions potentially related to EPS ranged from 4%–11% with quetiapine and 1%–11% with placebo.¹

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Most common adverse reactions in patients with bipolar mania¹

• 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 in 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%)¹
• In this short-term monotherapy bipolar mania trial, the incidence of discontinuation due to adverse reactions was 4.6% with SEROQUEL XR vs 8.1% with placebo¹
• There were no adverse reactions leading to discontinuation that occurred at an incidence ≥2% for SEROQUEL XR in bipolar mania trials¹

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Most Common Adverse Reactions^a: Short-term Monotherapy Trial in Bipolar Mania^1,b

1. ^a Incidence ≥5% and at least twice that of placebo in the SEROQUEL XR dose group.
2. ^b Data from a 3-week, multicenter, randomized, double-blind, placebo-controlled monotherapy bipolar mania trial.
3. ^c Somnolence combines adverse reaction terms “somnolence” and “sedation.”

Effect on weight

Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.

Enlarge

Percentage of Patients with Weight Gain ≥7% of Body Weight: Short-term Monotherapy Trial in Bipolar Mania^1,a

1. ^a Data from a 3-week, multicenter, randomized, double-blind, placebo-controlled monotherapy bipolar mania trial.

• The proportion of patients in adult clinical trials across approved indications meeting a weight gain criterion of ≥7% of body weight was 5%–23% for quetiapine, vs 0%–7% for placebo^1,3

Effect on lipids

Undesirable alterations in lipids have been observed with quetiapine use. Increases in total cholesterol, LDL-cholesterol and triglycerides, and decreases in HDL-cholesterol have been reported in clinical trials. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of and periodically during treatment.¹

Enlarge

Percentage of Patients with Shifts from Baseline in Lipids: Short-term Monotherapy Trial in Bipolar Mania^1,a

1. ^a Data from a 3-week, multicenter, randomized, double-blind, placebo-controlled monotherapy bipolar mania trial.
2. ^b Low-density lipoprotein.
3. ^c High-density lipoprotein.

• Clinically significant increases in total cholesterol (7%–18% for quetiapine vs 3%–9% for placebo), triglycerides (8%–22% for quetiapine vs 5%–16% for placebo), and LDL-cholesterol (4%–11% for quetiapine vs 2%–10% for placebo) and decreases in HDL-cholesterol (7%–19% for quetiapine vs 7%–14% for placebo) have been reported in adult clinical trials across approved indications^1,3

Effect on glucose

Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Enlarge

Percentage of Patients with Shifts from Baseline in Glucose: Short-term Monotherapy Trial in Bipolar Mania^6,a

1. ^a Data from a 3-week, multicenter, randomized, double-blind, placebo-controlled monotherapy bipolar mania trial.

Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Enlarge

Percentage of Patients with Shifts in Fasting Glucose to ≥126 mg/dL: Short-term (≤12 Weeks) Placebo-Controlled Studies Across Indications^1,3

• In 2 long-term clinical trials of quetiapine for bipolar maintenance, hyperglycemia (fasting glucose ≥126 mg/dL) was observed in 10.7% of patients receiving quetiapine (mean exposure 213 days) vs 4.6% in patients receiving placebo (mean exposure 152 days)¹
• Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics¹

Extrapyramidal symptoms (EPS) adverse reactions

Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. Although much less commonly, TD can develop after relatively brief treatment periods at low doses or even after treatment discontinuation. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. SEROQUEL XR should be prescribed in a manner that is most likely to minimize the occurrence of TD, and discontinuation should be considered if signs and symptoms of TD occur.

Enlarge

Percentage of Patients with Adverse Reactions Potentially Associated with EPS: Short-term Monotherapy Trial in Bipolar Mania^1,a

1. ^a Data from a 3-week, multicenter, randomized, double-blind, placebo-controlled monotherapy bipolar mania trial.
2. ^b Patients with the following terms were counted in this category: nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration.
3. ^c Patients with the following terms were counted in this category: cogwheel rigidity, tremor, drooling, hypokinesia.
4. ^d Patients with the following terms were counted in this category: akathisia, psychomotor agitation.
5. ^e Patients with the following terms were counted in this category: restlessness, extrapyramidal disorder, movement disorder.

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HOW SEROQUEL XR IS THOUGHT TO WORK

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Indications

SEROQUEL XR is indicated in adults for (1) adjunctive therapy to antidepressants in major depressive disorder; (2) acute depressive episodes in bipolar disorder; (3) acute manic or mixed episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; (4) maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex; and (5) schizophrenia. SEROQUEL is indicated in adults for the treatment of (1) acute depressive episodes in bipolar disorder; (2) acute manic episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; (3) maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex, and (4) schizophrenia. Patients should be periodically reassessed to determine the need for treatment and the appropriate dose.

Important Safety Information About SEROQUEL XR and SEROQUEL

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death, compared to placebo (4.5% vs 2.6%, respectively). SEROQUEL XR and SEROQUEL are not approved for the treatment of patients with dementia-related psychosis. (See Prescribing Information for complete Boxed Warnings.)

SUICIDALITY AND ANTIDEPRESSANT DRUGS: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Patients of all ages started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of drug therapy or when changing dose. Families and caregivers should be advised of the need for close observation and communication with the prescriber.
SEROQUEL XR is not approved for use in patients under the age of 18 years. SEROQUEL is not approved for use in patients under the age of 10 years. (See Prescribing Information for complete Boxed Warnings.)

Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex, sometimes referred to as NMS, has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment, and medical monitoring, and treatment of any concomitant serious medical problems.

Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Hyperlipidemia: Undesirable alterations in lipids have been observed with quetiapine use. Increases in total cholesterol, LDL-cholesterol and triglycerides, and decreases in HDL-cholesterol have been reported in clinical trials. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of and periodically during treatment.

Weight Gain: Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.

Tardive Dyskinesia (TD): TD, a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. Although much less commonly, TD can develop after relatively brief treatment periods at low doses or even after treatment discontinuation. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of TD, and discontinuation should be considered if signs and symptoms of TD occur.

Orthostatic Hypotension: Quetiapine may induce orthostatic hypotension with associated dizziness, tachycardia, and syncope, especially during the initial dose titration period and should be used with caution in patients predisposed to hypotension or with known cardiovascular or cerebrovascular disease.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis (including fatal cases), have been reported temporally related to atypical antipsychotics, including quetiapine. Patients with a pre-existing low white blood cell (WBC) count or a history of drug-induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy. In these patients, quetiapine should be discontinued at the first sign of a decline in WBC absent other causative factors. Patients with neutropenia should be carefully monitored, and quetiapine should be discontinued in any patient if the absolute neutrophil count is <1000/mm³.

Cataracts: Examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

QT Prolongation: Postmarketing cases show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase the QT interval. Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval.

Seizures: Quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, eg, Alzheimer’s dementia.

Potential for Cognitive and Motor Impairment: 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 or operating hazardous machinery, until they are reasonably certain that quetiapine therapy does not affect them adversely.

Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Use caution in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia.

Suicide: The possibility of a suicide attempt is inherent in schizophrenia, bipolar disorder, and depression, and close supervision of high risk patients should accompany drug therapy.

Warnings and Precautions Also Include: The risk of hypothyroidism, hyperprolactinemia, transaminase elevations, priapism, and withdrawal.

Common Adverse Reactions: The most commonly observed adverse reactions (incidence ≥ 5% and twice placebo) associated with the use of SEROQUEL XR versus placebo in clinical trials for all indications were somnolence (25%-52% vs 9%-13%), dry mouth (12%-40% vs 1%-8%), constipation (6%-11% vs 3%-6%), dizziness (10%-13% vs 4%-11%), increased appetite (2%-12% vs 0%-6%), dyspepsia (2%-7% vs 1%-4%), weight gain (3%-7% vs 0%-1%), fatigue (3%-14% vs 2%-4%), dysarthria (1%-5% vs 0%), and nasal congestion (2%-5% vs 1%). The most commonly reported adverse reactions associated with the use of SEROQUEL vs placebo in adults in clinical trials for all indications were somnolence (18%-57% vs 8%-15%), dry mouth (9%-44% vs 3%-13%), dizziness (9%-18% vs 5%-7%), constipation (8%-10% vs 3%-5%), asthenia (2%-10% vs 1%-4%), abdominal pain (4%-7% vs 1%-3%), postural hypotension (4%-7% vs 1%-3%), pharyngitis (4%-6% vs 3%), weight gain (4%-6% vs 1%-3%), lethargy (5% vs 2%), ALT increased (5% vs 1%) and dyspepsia (4%-7% vs 1%-4%).

Please see Full Prescribing Information for SEROQUEL XR and SEROQUEL , including Boxed Warnings.

REFERENCES:

• 1. SEROQUEL XR Prescribing Information.
• 2. Data on file, 272710, AstraZeneca Pharmaceuticals LP.
• 3. Data on file, 265022, AstraZeneca Pharmaceuticals LP.
• 4. Data on file, 273562, AstraZeneca Pharmaceuticals LP.
• 5. Suppes T, Datto C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010;121(1-2):106-115.
• 6. Data on file, 275152, AstraZeneca Pharmaceuticals LP.