SEROQUEL (quetiapine) tablet, film coated
AstraZeneca Pharmaceuticals LP

AstraZeneca Pharmaceuticals LP
AstraZeneca PLC
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
LACTOSE MONOHYDRATE
WATER
peach
biconvex
SEROQUEL;25
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
LACTOSE MONOHYDRATE
WATER
FERRIC OXIDE YELLOW
biconvex
SEROQUEL;50
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
WATER
biconvex
SEROQUEL;100
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
WATER
biconvex
SEROQUEL;200
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
WATER
biconvex
SEROQUEL;300
SEROQUEL
quetiapine
QUETIAPINE FUMARATE
QUETIAPINE
POVIDONE, UNSPECIFIED
DIBASIC CALCIUM PHOSPHATE DIHYDRATE
MICROCRYSTALLINE CELLULOSE
SODIUM STARCH GLYCOLATE TYPE A POTATO
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
WATER
biconvex
SEROQUEL;400

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Warnings and Precautions (5.1)]. SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Suicidal Thoughts and Behaviors

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.2)].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.2)].

SEROQUEL is not approved for use in pediatric patients under ten years of age [see Use in Specific Populations (8.4)].

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SEROQUEL is not approved for elderly patients with dementia-related psychosis (5.1)

Suicidal Thoughts and Behaviors

  • Increased risk of suicidal thoughts and behavior in children, adolescents and young adults taking antidepressants (5.2)
  • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.2)

1 INDICATIONS AND USAGE

SEROQUEL is an atypical antipsychotic indicated for the treatment of:

  • Schizophrenia (1.1)
  • Bipolar I disorder manic episodes (1.2)
  • Bipolar disorder, depressive episodes (1.2)

1.1 Schizophrenia

SEROQUEL is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13-17 years). The effectiveness of SEROQUEL for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14.1)].

1.2 Bipolar Disorder

SEROQUEL is indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10-17 years) [see Clinical Studies (14.2)].

SEROQUEL is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [see Clinical Studies (14.2)].

SEROQUEL is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was established in two maintenance trials in adults. The effectiveness of SEROQUEL as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14.2)].

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

2 DOSAGE AND ADMINISTRATION

  • SEROQUEL can be taken with or without food (2.1)

Indication

Initial Dose

  •   Recommended Dose
  •   Maximum Dose

Schizophrenia - Adults (2.2)

25 mg twice daily

  •  150-750 mg/day
  •  750 mg/day

Schizophrenia - Adolescents (13-17 years) (2.2)

25 mg twice daily

  •  400-800 mg/day
  •  800 mg/day

Bipolar Mania - Adults Monotherapy or as an adjunct to lithium or divalproex (2.2)

50 mg twice daily

  •  400-800 mg/day
  •  800 mg/day

Bipolar Mania - Children and Adolescents (10-17 years), Monotherapy (2.2)

25 mg twice daily

  •  400-600 mg/day
  •  600 mg/day

Bipolar Depression - Adults (2.2)

50 mg once daily at bedtime

  •  300 mg/day
  •  300 mg/day
  • Geriatric Use: Consider a lower starting dose (50 mg/day), slower titration and careful monitoring during the initial dosing period in the elderly (2.3, 8.5)
  • Hepatic Impairment: Lower starting dose (25 mg/day) and slower titration may be needed (2.4, 8.7, 12.3)

2.1 Important Administration Instructions

SEROQUEL can be taken with or without food.

2.2 Recommended Dosing

The recommended initial dose, titration, dose range and maximum SEROQUEL dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies (14.1 and 14.2)].

Table 1: Recommended Dosing for SEROQUEL

Indication

Initial Dose and Titration

Recommended Dose

Maximum Dose

Schizophrenia - Adults

Day 1: 25 mg twice daily.

Increase in increments of 25 mg-50 mg divided two or three times on Days 2 and 3 to range of 300-400 mg by Day 4.

Further adjustments can be made in increments of 25–50 mg twice a day, in intervals of not less than 2 days.

150-750 mg/day

750 mg/day

Schizophrenia - Adolescents (13-17 years)

Day 1: 25 mg twice daily.

Day 2: Twice daily dosing totaling 100 mg.

Day 3: Twice daily dosing totaling 200 mg.

Day 4: Twice daily dosing totaling 300 mg.

Day 5: Twice daily dosing totaling 400 mg.

Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400-800 mg/day.

Based on response and tolerability, may be administered three times daily.

400-800 mg/day

800 mg/day

Schizophrenia - Maintenance

Not applicable.

400-800 mg/day

800 mg/day

Bipolar Mania - Adults Monotherapy or as an adjunct to lithium or divalproex

Day 1: Twice daily dosing totaling 100 mg.

Day 2: Twice daily dosing totaling 200 mg.

Day 3: Twice daily dosing totaling 300 mg.

Day 4: Twice daily dosing totaling 400 mg.

Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

400-800 mg/day

800 mg/day

Bipolar Mania - Children and Adolescents (10 to 17 years),

Monotherapy

Day 1: 25 mg twice daily.

Day 2: Twice daily dosing totaling 100 mg.

Day 3: Twice daily dosing totaling 200 mg.

Day 4: Twice daily dosing totaling 300 mg.

Day 5: Twice daily dosing totaling 400 mg.

Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400-600 mg/day.

Based on response and tolerability, may be administered three times daily.

400-600 mg/day

600 mg/day

Bipolar Depression - Adults

Administer once daily at bedtime.

Day 1: 50 mg

Day 2: 100 mg

Day 3: 200 mg

Day 4: 300 mg

300 mg/day

300 mg/day

Bipolar I Disorder Maintenance Therapy - Adults

Administer twice daily totaling 400-800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.

400-800 mg/day

800 mg/day

Maintenance Treatment for Schizophrenia and Bipolar I Disorder

Maintenance Treatment – Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].

2.3 Dose Modifications in Elderly Patients

Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on SEROQUEL 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

2.4 Dose Modifications in Hepatically Impaired Patients

Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day - 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.5 Dose Modifications when used with CYP3A4 Inhibitors

SEROQUEL dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of SEROQUEL should be increased by 6-fold [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].

2.6 Dose Modifications when used with CYP3A4 Inducers

SEROQUEL dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7-14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of SEROQUEL should be reduced to the original level within 7-14 days [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].

2.7 Re-initiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off SEROQUEL for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off SEROQUEL for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.

2.8 Switching from Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to SEROQUEL, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate SEROQUEL therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

3 DOSAGE FORMS AND STRENGTHS

  • 25 mg tablets are peach, round, biconvex, film-coated tablets, identified with 'SEROQUEL' and ‘25’ on one side and plain on the other side
  • 50 mg tablets are white, round, biconvex, film-coated tablets, identified with 'SEROQUEL' and ‘50’ on one side and plain on the other side
  • 100 mg tablets are yellow, round, biconvex, film-coated tablets, identified with 'SEROQUEL' and ‘100’ on one side and plain on the other side
  • 200 mg tablets are white, round, biconvex, film-coated tablets, identified with ‘SEROQUEL’ and ‘200’ on one side and plain on the other side
  • 300 mg tablets are white, capsule-shaped, biconvex, film-coated tablets, intagliated with ‘SEROQUEL’ on one side and ‘300’ on the other side
  • 400 mg tablets are yellow, capsule-shaped, biconvex, film-coated tablets, intagliated with ‘SEROQUEL’ on one side and ‘400’ on the other side

Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg (3)

4 CONTRAINDICATIONS

Hypersensitivity to quetiapine or to any excipients in the SEROQUEL formulation. Anaphylactic reactions have been reported in patients treated with SEROQUEL.

Known hypersensitivity to SEROQUEL or any components in the formulation. (4)

5 WARNINGS AND PRECAUTIONS

  • Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs (5.3)
  • Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring (5.4)
  • Metabolic Changes: Atypical antipsychotics have been associated with metabolic changes. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain (5.5)
    • ∘Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes
    • ∘Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically, during treatment
    • ∘Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended
  • Tardive Dyskinesia: Discontinue if clinically appropriate (5.6)
  • Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease (5.7)
  • Increased Blood Pressure in Children and Adolescents: Monitor blood pressure at the beginning of, and periodically during treatment in children and adolescents (5.9)
  • Leukopenia, Neutropenia and Agranulocytosis: Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenia/neutropenia and discontinue SEROQUEL at the first sign of a decline in WBC in absence of other causative factors (5.10)
  • Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment. Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment (5.11)
  • Anticholinergic(antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, or constipation (5.20)

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18-24

5 additional cases

Decreases Compared to Placebo

25-64

1 fewer case

≥65

6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SEROQUEL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including SEROQUEL, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

5.4 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including SEROQUEL. Rare cases of NMS have been reported with SEROQUEL. 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 creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. 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 metabolic profiles should be managed as clinically appropriate.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Adults:

Table 3: Fasting Glucose - Proportion of Patients Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled StudiesIncludes SEROQUEL and SEROQUEL XR data.

Laboratory Analyte

Category Change (At Least Once) from Baseline

Treatment Arm

N

Patients

n (%)

Fasting

Glucose

Normal to High

(<100 mg/dL to

≥126 mg/dL)

Quetiapine

2907

71 (2.4%)

Placebo

1346

19 (1.4%)

Borderline to High

(≥100 mg/dL and <126 mg/dL to

≥126 mg/dL)

Quetiapine

572

67 (11.7%)

Placebo

279

33 (11.8%)

In a 24-week trial (active-controlled, 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at Week 24 the incidence of a post-glucose challenge glucose level ≥200 mg/dL was 1.7% and the incidence of a fasting blood glucose level ≥126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for SEROQUEL and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for SEROQUEL (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents:

In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a blood glucose level of ≥126 mg/dL.

In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10-17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for SEROQUEL XR (n=60) compared to placebo (n=62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the SEROQUEL XR or placebo-treated groups with a baseline normal fasting glucose level (<100 mg/dL) that had an increase in blood glucose level >126 mg/dL. There was one patient in the SEROQUEL XR group with a baseline borderline fasting glucose level (>100 mg/dL and <126 mg/dL) who had an increase in blood glucose level of >126 mg/dL compared to zero patients in the placebo group.

Dyslipidemia

Adults:

Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline by indication in clinical trials with SEROQUEL.

Table 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

Laboratory Analyte

Indication

Treatment Arm

N

Patients

n (%)

Total Cholesterol ≥240 mg/dL

Schizophrenia6 weeks duration

SEROQUEL

137

24 (18%)

Placebo

92

6 (7%)

Bipolar

Depression8 weeks duration

SEROQUEL

463

41 (9%)

Placebo

250

15 (6%)

Triglycerides ≥200 mg/dL

Schizophrenia

SEROQUEL

120

26 (22%)

Placebo

70

11 (16%)

Bipolar

Depression

SEROQUEL

436

59 (14%)

Placebo

232

20 (9%)

LDL-

Cholesterol

≥160 mg/dL

Schizophrenia

SEROQUEL

naParameters not measured in the SEROQUEL registration studies for schizophrenia.

na

Placebo

na

na

Bipolar

Depression

SEROQUEL

465

29 (6%)

Placebo

256

12 (5%)

HDL- Cholesterol

≤40 mg/dL

Schizophrenia

SEROQUEL

na

na

Placebo

na

na

Bipolar

Depression

SEROQUEL

393

56 (14%)

Placebo

214

29 (14%)

Children and Adolescents:

Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline in clinical trials with SEROQUEL.

Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels

Laboratory

Analyte

Indication

Treatment Arm

N

Patients

n (%)

Total Cholesterol ≥200 mg/dL

Schizophrenia13-17 years, 6 weeks duration

SEROQUEL

107

13 (12%)

Placebo

56

1 (2%)

Bipolar Mania10-17 years, 3 weeks duration

SEROQUEL

159

16 (10%)

Placebo

66

2 (3%)

Triglycerides

≥150 mg/dL

Schizophrenia

SEROQUEL

103

17 (17%)

Placebo

51

4 (8%)

Bipolar Mania

SEROQUEL

149

32 (22%)

Placebo

60

8 (13%)

LDL-Cholesterol ≥130 mg/dL

Schizophrenia

SEROQUEL

112

4 (4%)

Placebo

60

1 (2%)

Bipolar Mania

SEROQUEL

169

13 (8%)

Placebo

74

4 (5%)

HDL-Cholesterol ≤40 mg/dL

Schizophrenia

SEROQUEL

104

16 (15%)

Placebo

54

10 (19%)

Bipolar Mania

SEROQUEL

154

16 (10%)

Placebo

61

4 (7%)

In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL), and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for SEROQUEL XR vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for SEROQUEL XR vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for SEROQUEL XR vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for SEROQUEL XR vs. 15% (11/74) for placebo.

Weight Gain

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

Adults:

In clinical trials with SEROQUEL the following increases in weight have been reported.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults)

Vital Sign

Indication

Treatment Arm

N

Patients

n (%)

Weight Gain ≥7% of Body Weight

Schizophreniaup to 6 weeks duration

SEROQUEL

391

89 (23%)

Placebo

206

11 (6%)

Bipolar Mania (monotherapy)up to 12 weeks duration

SEROQUEL

209

44 (21%)

Placebo

198

13 (7%)

Bipolar Mania (adjunct therapy)up to 3 weeks duration

SEROQUEL

196

25 (13%)

Placebo

203

8 (4%)

Bipolar Depressionup to 8 weeks duration

SEROQUEL

554

47 (8%)

Placebo

295

7 (2%)

Children and Adolescents:

In two clinical trials with SEROQUEL, one in bipolar mania and one in schizophrenia, reported increases in weight are included in Table 7.

Table 7: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents)

Vital Sign

Indication

Treatment Arm

N

Patients

n (%)

Weight Gain ≥7% of Body Weight

Schizophrenia6 weeks duration

SEROQUEL

111

23 (21%)

Placebo

44

3 (7%)

Bipolar Mania3 weeks duration

SEROQUEL

157

18 (12%)

Placebo

68

0 (0%)

The mean change in body weight in the schizophrenia trial was 2.0 kg in the SEROQUEL group and -0.4 kg in the placebo group and in the bipolar mania trial, it was 1.7 kg in the SEROQUEL group and 0.4 kg in the placebo group.

In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with SEROQUEL. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on SEROQUEL met this criterion after 26 weeks of treatment.

In a clinical trial for SEROQUEL XR in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for SEROQUEL XR vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the SEROQUEL XR group vs. 0.6 kg in the placebo group.

When treating pediatric patients with SEROQUEL for any indication, weight gain should be assessed against that expected for normal growth.

5.6 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, SEROQUEL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on SEROQUEL, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL despite the presence of the syndrome.

5.7 Hypotension

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 1% (28/3265) of the patients treated with SEROQUEL, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs. Orthostatic hypotension, dizziness, and syncope may lead to falls.

SEROQUEL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see Dosage and Administration (2.2)]. If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.8 Falls

Atypical antipsychotic drugs, including SEROQUEL, may cause somnolence, postural hypotension, motor, and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Increases in Blood Pressure (Children and Adolescents)

In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

In a placebo-controlled SEROQUEL XR clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for SEROQUEL XR and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for SEROQUEL XR and 36.0% (36/100) for placebo.

5.10 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including SEROQUEL. Agranulocytosis has been reported.

Agranulocytosis (defined as absolute neutrophil count <500/mm3) has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. 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 at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue SEROQUEL and have their WBC followed until recovery.

5.11 Cataracts

The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology (13.2) ]. Lens changes have also been observed in adults, children, and adolescents during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, 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.

5.12 QT Prolongation

In clinical trials, quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (7.1)].

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure, and heart hypertrophy).

5.13 Seizures

During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. As with other antipsychotics, SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism

Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T4, in addition to clinical assessment, should be measured at baseline and at follow-up.

In the mania adjunct studies, where SEROQUEL was added to lithium or divalproex, 12% (24/196) of SEROQUEL treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels. Of the SEROQUEL treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels (free T4 <0.8 LLN).

About 0.7% (26/3489) of SEROQUEL patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were1: decrease in free T4 (<0.8 LLN), 2.0% (357/17513); decrease in total T4 (<0.8LLN), 4.0% (75/1861); decrease in free T3 (<0.8 LLN), 0.4% (53/13766); decrease in total T3 (<0.8LLN), 2.0% (26/1312), and increase in TSH (>5mIU/L), 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

____________

  •   1Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mlU/L at any time.
Table 8: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-Term Placebo-Controlled Clinical TrialsBased on shifts from normal baseline to potentially clinically important value at any time post-baseline. Shifts in total T4, free T4, total T3, and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mlU/L at any time. Includes SEROQUEL and SEROQUEL XR data.

Total T4

Free T4

Total T3

Free T3

TSH

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

Quetiapine

Placebo

3.4 %

(37/1097)

0.6%

(4/651)

0.7%

(52/7218)

0.1%

(4/3668)

0.5%

(2/369)

0.0%

(0/113)

0.2%

(11/5673)

0.0%

(1/2679)

3.2%

(240/7587)

2.7%

(105/3912)

In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.

Children and Adolescents:

In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts for thyroid function values at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively, and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the SEROQUEL treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.

5.15 Hyperprolactinemia

Adults: During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents:

In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; >26 µg/L females at any time) was 13.4% (18/134) for SEROQUEL compared to 4% (3/75) for placebo in males and 8.7% (9/104) for SEROQUEL compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D2 receptors, SEROQUEL elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary, and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see Nonclinical Toxicology (13.1)].

5.16 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse event reported in patients treated with SEROQUEL especially during the 3-5 day period of initial dose-titration. In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on SEROQUEL compared to 11% (22/206) of placebo patients. In acute bipolar mania trials using SEROQUEL as monotherapy, somnolence was reported in 16% (34/209) of patients on SEROQUEL compared to 4% of placebo patients. In acute bipolar mania trials using SEROQUEL as adjunct therapy, somnolence was reported in 34% (66/196) of patients on SEROQUEL compared to 9% (19/203) of placebo patients. In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on SEROQUEL compared to 15% (51/347) of placebo patients. Since SEROQUEL 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 SEROQUEL therapy does not affect them adversely. Somnolence may lead to falls.

5.17 Body Temperature Regulation

Although not reported with SEROQUEL, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL 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. SEROQUEL 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 SEROQUEL. In short-term placebo-controlled, monotherapy clinical trials with SEROQUEL XR 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 SEROQUEL XR 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 withdrawal 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 SEROQUEL is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. SEROQUEL 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.

SEROQUEL 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:

  • Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia (6.1)
  • Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Study Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults:

The information below is derived from a clinical trial database for SEROQUEL consisting of over 4300 patients. This database includes 698 patients exposed to SEROQUEL for the treatment of bipolar depression, 405 patients exposed to SEROQUEL for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to SEROQUEL for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of SEROQUEL for the treatment of schizophrenia.

Of these approximately 4,300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with SEROQUEL varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed.

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

Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for SEROQUEL vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence (0.8% SEROQUEL vs. 0% placebo) and hypotension (0.4% SEROQUEL vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.7 and 5.19)].

Bipolar Disorder:

Mania: Overall, discontinuations due to adverse reactions were 5.7% for SEROQUEL vs. 5.1% for placebo in monotherapy and 3.6% for SEROQUEL vs. 5.9% for placebo in adjunct therapy.

Depression: Overall, discontinuations due to adverse reactions were 12.3% for SEROQUEL 300 mg vs. 19.0% for SEROQUEL 600 mg and 5.2% for placebo.

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials:

In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of SEROQUEL monotherapy (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%).

Adverse Reactions Occurring at an Incidence of 2% or More Among SEROQUEL Treated Patients in Short-Term, Placebo-Controlled Trials:

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence in the population studied.

Table 9 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2% or more of patients treated with SEROQUEL (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.

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

Preferred Term

SEROQUEL (n=719)

PLACEBO (n=404)

Headache

21%

14%

Agitation

20%

17%

Somnolence

18%

8%

Dizziness

11%

5%

Dry Mouth

9%

3%

Constipation

8%

3%

Pain

7%

5%

Tachycardia

6%

4%

Vomiting

6%

5%

Asthenia

5%

3%

Dyspepsia

5%

1%

Weight Gain

5%

1%

ALT Increased

5%

1%

Anxiety

4%

3%

Pharyngitis

4%

3%

Rash

4%

2%

Abdominal Pain

4%

1%

Postural Hypotension

4%

1%

Back Pain

3%

1%

AST Increased

3%

1%

Rhinitis

3%

1%

Fever

2%

1%

Gastroenteritis

2%

0%

Amblyopia

2%

1%

In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%).

Table 10 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2% or more of patients treated with SEROQUEL (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.

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

Preferred Term

SEROQUEL

(n=196)

PLACEBO

(n=203)

Somnolence

34%

9%

Dry Mouth

19%

3%

Headache

17%

13%

Asthenia

10%

4%

Constipation

10%

5%

Dizziness

9%

6%

Tremor

8%

7%

Abdominal Pain

7%

3%

Postural Hypotension

7%

2%

Agitation

6%

4%

Weight Gain

6%

3%

Pharyngitis

6%

3%

Back Pain

5%

3%

Hypertonia

4%

3%

Rhinitis

4%

2%

Peripheral Edema

4%

2%

Twitching

4%

1%

Dyspepsia

4%

3%

Depression

3%

2%

Amblyopia

3%

2%

Speech Disorder

3%

1%

Hypotension

3%

1%

Hormone Level Altered

3%

0%

Heaviness

2%

1%

Infection

2%

1%

Fever

2%

1%

Hypertension

2%

1%

Tachycardia

2%

1%

Increased Appetite

2%

1%

Hypothyroidism

2%

1%

Incoordination

2%

1%

Thinking Abnormal

2%

0%

Anxiety

2%

0%

Ataxia

2%

0%

Sinusitis

2%

1%

Sweating

2%

1%

Urinary Tract Infection

2%

1%

In bipolar depression studies (up to 8 weeks), the most commonly observed adverse reactions associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%).

Table 11 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2% or more of patients treated with SEROQUEL (doses of 300 and 600 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.

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

SEROQUEL

(n=698)

PLACEBO

(n=347)

SomnolenceSomnolence combines adverse reaction terms somnolence and sedation

57%

15%

Dry Mouth

44%

13%

Dizziness

18%

7%

Constipation

10%

4%

Fatigue

10%

8%

Dyspepsia

7%

4%

Vomiting

5%

4%

Increased Appetite

5%

3%

Lethargy

5%

2%

Nasal Congestion

5%

3%

Orthostatic Hypotension

4%

3%

Akathisia

4%

1%

Palpitations

4%

1%

Vision Blurred

4%

2%

Weight increased

4%

1%

Arthralgia

3%

2%

Paraesthesia

3%

2%

Cough

3%

1%

Extrapyramidal Disorder

3%

1%

Irritability

3%

1%

Dysarthria

3%

0%

Hypersomnia

3%

0%

Sinus Congestion

2%

1%

Abnormal Dreams

2%

1%

Tremor

2%

1%

Gastroesophageal Reflux Disease

2%

1%

Pain in Extremity

2%

1%

Asthenia

2%

1%

Balance Disorder

2%

1%

Hypoesthesia

2%

1%

Dysphagia

2%

0%

Restless Legs Syndrome

2%

0%

Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors.

Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials

Dose-related Adverse Reactions: Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of SEROQUEL (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain.

Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label:

The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity, and elevations in serum creatine phosphokinase (not associated with NMS), galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/or syncope) decreased platelets, somnambulism (and other related events), elevations in gamma-GT levels, hypothermia, dyspnea, eosinophilia, urinary retention, intestinal obstruction 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: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of SEROQUEL (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with SEROQUEL treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to EPS.

In Table 12, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.

Table 12: Adverse Reactions Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration)

Preferred Term

SEROQUEL

75 mg/day

(N=53)

SEROQUEL

150 mg/day

(N=48)

SEROQUEL

300 mg/day

(N=52)

SEROQUEL

600 mg/day

(N=51)

SEROQUEL

750 mg/day

(N=54)

Placebo

(N=51)

n

%

n

%

n

%

n

%

n

%

n

%

Dystonic event

2

3.8

2

4.2

0

0.0

2

3.9

3

5.6

4

7.8

Parkinsonism

2

3.8

0

0.0

1

1.9

1

2.0

1

1.9

4

7.8

Akathisia

1

1.9

1

2.1

0

0.0

0

0.0

1

1.9

4

7.8

Dyskinetic event

2

3.8

0

0.0

0

0.0

1

2.0

0

0.0

0

0.0

Other extrapyramidal event

2

3.8

0

0.0

3

5.8

3

5.9

1

1.9

4

7.8

Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1.0, -1.2; -1.6; -1.8, and -1.8. The rate of anticholinergic medication use to treat EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12%, and 11%.

In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of SEROQUEL, there were no differences between the SEROQUEL and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS.

In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of SEROQUEL, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity, and muscle rigidity) were generally low and did not exceed 4% in any treatment group.

The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups.

Children and Adolescents

The information below is derived from a clinical trial database for SEROQUEL consisting of over 1000 pediatric patients. This database includes 677 patients exposed to SEROQUEL for the treatment of schizophrenia and 393 children and adolescents (10-17 years old) exposed to SEROQUEL for the treatment of acute bipolar mania.

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

Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on SEROQUEL 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 SEROQUEL and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials

In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%).

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

In an acute (8-week) SEROQUEL XR trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater and at least twice that for placebo) were dizziness 7%, diarrhea 5%, fatigue 5%, and nausea 5%.

Adverse Reactions Occurring at an Incidence of ≥ 2% among SEROQUEL Treated Patients in Short-Term, Placebo-Controlled Trials

Schizophrenia (Adolescents, 13-17 years old)

The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.

Table 13 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 SEROQUEL (doses of 400 or 800 mg/day) where the incidence in patients treated with SEROQUEL was at least twice 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 13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

Preferred Term

SEROQUEL 400 mg

(n=73)

SEROQUEL
800 mg

(n=74)

Placebo

(n=75)

SomnolenceSomnolence combines adverse reaction terms somnolence and sedation.

33%

35%

11%

Dizziness

8%

15%

5%

Dry Mouth

4%

10%

1%

TachycardiaTachycardia combines adverse reaction terms tachycardia and sinus tachycardia.

6%

11%

0%

Irritability

3%

5%

0%

Arthralgia

1%

3%

0%

Asthenia

1%

3%

1%

Back Pain

1%

3%

0%

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 10-17 years old)

The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.

Commonly Observed Adverse Reactions

In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with SEROQUEL (doses of 400 or 600 mg/day) where the incidence in patients treated with SEROQUEL 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 14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients

Preferred Term

SEROQUEL

400 mg

(n=95)

SEROQUEL

600 mg

(n=98)

Placebo

(n=90)

SomnolenceSomnolence combines adverse reactions terms somnolence and sedation.

50%

57%

14%

Dizziness

19%

17%

2%

Nausea

6%

10%

4%

Fatigue

14%

9%

4%

Increased Appetite

10%

9%

1%

TachycardiaTachycardia combines adverse reaction terms tachycardia and sinus tachycardia.

6%

9%

1%

Dry Mouth

7%

7%

0%

Vomiting

8%

7%

3%

Nasal Congestion

3%

6%

2%

Weight Increased

6%

6%

0%

Irritability

3%

5%

1%

Pyrexia

1%

4%

1%

Aggression

1%

3%

0%

Musculoskeletal Stiffness

1%

3%

1%

Accidental Overdose

0%

2%

0%

Acne

3%

2%

0%

Arthralgia

4%

2%

1%

Lethargy

2%

2%

0%

Pallor

1%

2%

0%

Stomach Discomfort

4%

2%

1%

Syncope

2%

2%

0%

Vision Blurred

3%

2%

0%

Constipation

4%

2%

0%

Ear Pain

2%

0%

0%

Paresthesia

2%

0%

0%

Sinus Congestion

3%

0%

0%

Thirst

2%

0%

0%

Extrapyramidal Symptoms:

In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for SEROQUEL and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or SEROQUEL and 1.1% (1/90) for placebo.

Table 15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

In Tables 15-16, dystonic event included nuchal rigidity, hypertonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia, and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder.

Table 15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-Controlled Trial in Adolescent Patients with Schizophrenia (6-week duration)

Preferred Term

SEROQUEL

400 mg/day

(N=73)

SEROQUEL

800 mg/day

(N=74)

All

SEROQUEL

(N=147)

Placebo

(N=75)

n

%

n

%

n

%

n

%

Dystonic event

2

2.7

0

0.0

2

1.4

0

0.0

Parkinsonism

4

5.5

4

5.4

8

5.4

2

2.7

Akathisia

3

4.1

4

5.4

7

4.8

3

4.0

Dyskinetic event

2

2.7

0

0.0

2

1.4

0

0.0

Other Extrapyramidal Event

2

2.7

2

2.7

4

2.7

0

0.0

Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trial in Children and Adolescent Patients with Bipolar I Mania (3-week duration)

Preferred Term There were no adverse reactions with the preferred term of dystonic or dyskinetic events.

SEROQUEL

400 mg/day