Seroquel XR

Dosage Forms And Strengths

• 50 mg extended-release tablets are peach, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 50” on one side and plain on the other side
• 150 mg extended-release tablets are white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 150” on one side and plain on the other side
• 200 mg extended-release tablets are yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 200” on one side and plain on the other side
• 300 mg extended-release tablets are pale yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 300” on one side and plain on the other side
• 400 mg extended-release tablets are white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 400” on one side and plain on the other side

Storage And Handling

50 mg Tablets (NDC 0310-0280) peach, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 50” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.

150 mg Tablets (NDC 0310-0281) white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 150” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.

200 mg Tablets (NDC 0310-0282) yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 200” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.

300 mg Tablets (NDC 0310-0283) pale yellow, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 300” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.

400 mg Tablets (NDC 0310-0284) white, film-coated, capsule-shaped, biconvex, intagliated tablet with “XR 400” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.

Store SEROQUEL XR at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Feb 2017

Schizophrenia

SEROQUEL XR is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL XR in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13-17 years) treated with SEROQUEL.

Bipolar Disorder

SEROQUEL XR is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of SEROQUEL XR in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 – 17 years) with manic episodes associated with bipolar I disorder treated with SEROQUEL.

SEROQUEL XR is indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of SEROQUEL XR was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with SEROQUEL.

SEROQUEL XR is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with SEROQUEL. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials.

Adjunctive Treatment Of Major Depressive Disorder (MDD)

SEROQUEL XR is indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of SEROQUEL XR as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment.

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.

Important Administration Instructions

SEROQUEL XR tablets should be swallowed whole and not split, chewed or crushed. It is recommended that SEROQUEL XR be taken without food or with a light meal (approximately 300 calories).

SEROQUEL XR should be administered once daily, preferably in the evening.

Recommended Dosing

The recommended initial dose, titration, dose range and maximum SEROQUEL XR dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient .

Table 1: Recommended Dosing for SEROQUEL XR

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.

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. When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on SEROQUEL XR 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.

Dose Modifications In Hepatically Impaired Patients

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

Dose Modifications When Used With CYP3A4 Inhibitors

SEROQUEL XR 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 XR should be increased by 6 fold.

Dose Modifications When Used With CYP3A4 Inducers

SEROQUEL XR 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 tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of SEROQUEL XR should be reduced to the original level within 7-14 days.

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 XR for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off SEROQUEL XR for less than one week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.

Switching Patients From SEROQUEL Tablets To SEROQUEL XR Tablets

Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to SEROQUEL XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

Switching From Antipsychotics

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

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 XR is not approved for the treatment of patients with dementia-related psychosis.

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

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 nonpsychiatric. 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 nonpsychiatric, 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 XR 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 XR, 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.

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 XR is not approved for the treatment of patients with dementia-related psychosis.

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 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.

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.

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 treatment-emergent hyperglycemiarelated 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 Studies¹

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 treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent 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 quetiapine 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).

Table 4 shows the percentage of patients with shifts in blood glucose to ≥ 126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.

Table 4: Percentage of Patients with Shifts from Normal Baseline in Blood Glucose to ≥ 126 mg/dL (assumed fasting) in MDD Adjunct Therapy Trials by Dose

Children And Adolescents

Safety and effectiveness of SEROQUEL XR is supported from studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. 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.

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 treatment-emergent blood glucose level of ≥126 mg/dL.

Dyslipidemia

Adults

Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with SEROQUEL XR.

Table 5: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDLCholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

In SEROQUEL clinical trials for schizophrenia, the percentage of patients with shifts in cholesterol and triglycerides from baseline to clinically significant levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol parameters were not measured in these studies. In SEROQUEL clinical trials for bipolar depression, the following percentage of patients had shifts from baseline to clinically significant levels for the four lipid parameters measured: total cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol 6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were not measured in the bipolar mania studies.

Table 6 shows the percentage of patients in MDD adjunctive therapy trials with clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by dose.

Table 6: Percentage of Patients with Shifts in Total Cholesterol, Triglycerides, LDLCholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels in MDD Adjunctive Therapy Trials by Dose

Children And Adolescents

Safety and effectiveness of SEROQUEL XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.

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 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.

Table 7 shows the percentage of children and adolescents with shifts in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline to clinically significant levels by indication in clinical trials with SEROQUEL in adolescents (13–17 years) with schizophrenia and in children and adolescents (10–17 years) with bipolar mania.

Table 7: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

Weight Gain

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

Adults

Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.

Table 8: Percentage of Patients with Weight Gain ≥7% of Body Weight (Adults) by Indication

In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%).

Table 9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.

Table 9: Percentage of Patients with Weight Gain ≥7% of Body Weight in MDD Adjunctive Therapy Trials by Dose (Adults)

Children and Adolescents: Safety and effectiveness of SEROQUEL XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. 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.

Weight gain was greater in patients 10-12 years of age compared to patients 13-17 years of age. The percentage of patients 10-12 years of age with weight gain ≥7% at any time was 28% (7/25) for SEROQUEL XR vs. 0% (0/28) for placebo. The percentage of patients 13-17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for SEROQUEL XR vs. 13.9% (10/72) for placebo.

Table 10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with SEROQUEL in adolescents (13 – 17 years) with schizophrenia and in children and adolescents (10 – 17 years) with bipol

SIDE EFFECTS

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

• Increased mortality in elderly patients with dementia-related psychosis
• Suicidal thoughts and behaviors in adolescents and young adults
• Cerebrovascular adverse reactions, including stroke in elderly patients with dementiarelated psychosis
• Neuroleptic Malignant Syndrome (NMS)
• Metabolic changes (hyperglycemia, dyslipidemia, weight gain)
• Tardive dyskinesia
• Hypotension
• Falls
• Increases in blood pressure (children and adolescents)
• Leukopenia, neutropenia and agranulocytosis
• Cataracts
• QT Prolongation
• Seizures
• Hypothyroidism
• Hyperprolactinemia
• Potential for cognitive and motor impairment
• Body temperature regulation
• Dysphagia
• Discontinuation Syndrome

Clinical Studies Experience

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

Adults

The information below is derived from a clinical trial database for SEROQUEL XR consisting of approximately 3400 patients exposed to SEROQUEL XR for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses and ECG results.

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

Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term, Placebo- Controlled Trials

Schizophrenia

There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in schizophrenia trials.

Bipolar I Disorder, Manic Or Mixed Episodes

There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in the bipolar mania trial.

Bipolar Disorder, Depressive Episode

In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on SEROQUEL XR discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence² was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in SEROQUEL XR in the bipolar depression trial.

MDD, Adjunctive Therapy

In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on SEROQUEL XR discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in SEROQUEL XR in MDD trials.

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

In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%).

Adverse Reactions Occurring At An Incidence Of 2% Or More Among SEROQUEL XR Treated Patients In Short-Term, Placebo-Controlled Trials

Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with SEROQUEL XR (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 12: Adverse Reactions in 6-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia

In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%).

Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with SEROQUEL XR (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 13: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania

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

Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with SEROQUEL XR 300 mg/day where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients.

Table 14: Adverse Reactions in an 8-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Depression

In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater and observed at a rate on SEROQUEL XR and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation (300 mg only: 11%) and weight increased (300 mg only: 5%).

Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with SEROQUEL XR (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebotreated patients.

Table 15: Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose

Adverse Reactions In Clinical Trials With Quetiapine And Not Listed Elsewhere In The Label

Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), and priapism.

Extrapyramidal Symptoms (EPS)

Dystonia

Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS.

Adults

In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo.

In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 8% for SEROQUEL XR and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group.

At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients.

In Tables 16 – 19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.

Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo- Controlled Clinical Trials for Schizophrenia

In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 6.6% for SEROQUEL XR and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction.

Table 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo- Controlled Clinical Trial for Bipolar Mania

In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 4.4% for SEROQUEL XR and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction.

Table 18: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo- Controlled Clinical Trial for Bipolar Depression

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

Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose:

Table 19: Adverse Reactions Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration)

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 adolescents (13 – 17 years old) 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 quetiapinetreated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse reaction leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).

Bipolar I Mania

The incidence of discontinuation due to adverse reactions for quetiapinetreated 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 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%.

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

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

Adverse Reactions Occurring At An Incidence Of ≥ 2% Among 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 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with SEROQUEL (doses of 400 or 800 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 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%).

Table 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients

Preferred Term	SEROQUEL 400 mg (n=73)	SEROQUEL 800 mg (n=74)	Placebo (n=75)
Somnolence1	33%	35%	11%
Dizziness	8%	15%	5%
Dry Mouth	4%	10%	1%
Tachycardia2	6%	11%	0%
I Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of SEROQUEL XR use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. SEROQUEL XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including SEROQUEL XR), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Animal Data When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses at doses up to 2.4 times the maximum recommended human dose (MRHD), for schizophrenia of 800 mg/day based on mg/m² body surface area. However, there was evidence of embryo-fetal toxicity. These included delays in skeletal ossification occurred at approximately 1 and 2 times the MRHD of 800 mg/day and in both rats and rabbits and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity observed as decreased body weights and/or death occurred at 2 times the MRHD in rats and at approximately 1-2 times the MRHD (all doses) in rabbits. In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day on mg/m² body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD. The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis Suicidal thoughts and behaviors in adolescents and young adults Cerebrovascular adverse reactions, including stroke in elderly patients with dementiarelated psychosis Neuroleptic Malignant Syndrome (NMS) Metabolic changes (hyperglycemia, dyslipidemia, weight gain) Tardive dyskinesia Hypotension Falls Increases in blood pressure (children and adolescents) Leukopenia, neutropenia and agranulocytosis Cataracts QT Prolongation Seizures Hypothyroidism Hyperprolactinemia Potential for cognitive and motor impairment Body temperature regulation Dysphagia Discontinuation Syndrome Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from a clinical trial database for SEROQUEL XR consisting of approximately 3400 patients exposed to SEROQUEL XR for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses and ECG results. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term, Placebo- Controlled Trials Schizophrenia There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in schizophrenia trials. Bipolar I Disorder, Manic Or Mixed Episodes There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for SEROQUEL XR in the bipolar mania trial. Bipolar Disorder, Depressive Episode In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on SEROQUEL XR discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in SEROQUEL XR in the bipolar depression trial. MDD, Adjunctive Therapy In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on SEROQUEL XR discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence2 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in SEROQUEL XR in MDD trials. Commonly Observed Adverse Reactions In Short-Term, Placebo-Controlled Trials In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%). Adverse Reactions Occurring At An Incidence Of 2% Or More Among SEROQUEL XR Treated Patients In Short-Term, Placebo-Controlled Trials Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with SEROQUEL XR (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients. Table 12: Adverse Reactions in 6-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia Preferred Term SEROQUELXR (n=951) Placebo (n=319) Somnolence1 25% 10% Dry Mouth 12% 1% Dizziness 10% 4% Extrapyramidal Symptoms2 8% 5% Orthostatic Hypotension 7% 5% Constipation 6% 5% Dyspepsia 5% 2% Heart Rate Increased 4% 1% Tachycardia 3% 1% Fatigue 3% 2% Hypotension 3% 1% Vision blurred 2% 1% Toothache 2% 0% Increased Appetite 2% 0% Muscle Spasms 2% 1% Tremor 2% 1% Akathisia 2% 1% Anxiety 2% 1% Schizophrenia 2% 1% Restlessness 2% 1% 1. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: akathisia, cogwheel rigidity, drooling, dyskinesia dystonia, extrapyramidal disorder, hypertonia, movement disorder, muscle rigidity, oculogyration, parkinsonism, parkinsonian gait, psychomotor hyperactivity, tardive dyskinesia, restlessness and tremor. In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%). Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with SEROQUEL XR (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients. Table 13: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania Preferred Term SEROQUEL XR (n=151) Placebo (n=160) Somnolence1 50% 12% Dry Mouth 34% 7% Dizziness 10% 4% Constipation 10% 3% Dyspepsia 7% 4% Fatigue 7% 4% Weight Gain 7% 1% Extrapyramidal Symptoms2 7% 4% Nasal Congestion 5% 1% Dysarthria 5% 0% Increased Appetite 4% 2% Back Pain 3% 2% Toothache 3% 1% Heart Rate Increased 3% 0% Abnormal Dreams 3% 0% Orthostatic Hypotension 3% 0% Tachycardia 2% 1% Vision blurred 2% 1% Sluggishness 2% 1% Lethargy 2% 1% 1. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, dystonia, extrapyramidal disorder, restlessness and tremor. In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater) and observed at a rate on SEROQUEL XR at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%). Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with SEROQUEL XR 300 mg/day where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebo-treated patients. Table 14: Adverse Reactions in an 8-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Depression Preferred Term SEROQUEL XR (n=137) Placebo (n=140) Somnolence1 52% 13% Dry Mouth 37% 7% Dizziness 13% 11% Increased Appetite 12% 6% Constipation 8% 6% Dyspepsia 7% 1% Weight Gain 7% 1% Fatigue 6% 2% Irritability 4% 3% Viral Gastroenteritis 4% 1% Arthralgia 4% 1% Extrapyramidal Symptoms2 4% 1% Paresthesia 3% 2% Back Pain 3% 1% Muscle Spasms 3% 1% Toothache 3% 0% Abnormal Dreams 3% 0% Ear Pain 2% 1% Seasonal Allergy 2% 1% Sinusitis 2% 1% Decreased Appetite 2% 1% Myalgia 2% 1% Disturbance in Attention 2% 1% Migraine 2% 1% Restless Legs Syndrome 2% 1% Anxiety 2% 1% Sinus Headache 2% 1% Libido Decreased 2% 1% Pollakiuria 2% 1% Sinus Congestion 2% 1% Hyperhidrosis 2% 1% Orthostatic Hypotension 2% 1% Urinary Tract Infection 2% 0% Heart Rate Increased 2% 0% Neck Pain 2% 0% Dysarthria 2% 0% Akathisia 2% 0% Hypersomnia 2% 0% Mental Impairment 2% 0% Confusional State 2% 0% Disorientation 2% 0% 1. Somnolence combines adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: muscle spasms, akathisia, dystonia, extrapyramidal disorder, hypertonia, and tremor. In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of SEROQUEL XR (incidence of 5% or greater and observed at a rate on SEROQUEL XR and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation (300 mg only: 11%) and weight increased (300 mg only: 5%). Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with SEROQUEL XR (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with SEROQUEL XR was greater than the incidence in placebotreated patients. Table 15: Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trials for the Treatment of MDD by Fixed Dose Preferred Term SEROQUELXR 150 mg (n=315) SEROQUEL XR 300 mg (n=312) Placebo (n=309) Somnolence1 37% 43% 9% Dry Mouth 27% 40% 8% Fatigue 14% 11% 4% Dizziness 11% 12% 7% Nausea 7% 8% 7% Constipation 6% 11% 4% Irritability 4% 2% 3% Extrapyramiaal Symptoms2 4% 6% 4% Vomiting 3% 1% 1% Upper Respiratory Tract Iniection 3% 2% 2% Weight Increasea 3% 5% 0% Increasea Appetite 3% 5% 3% Back pain 3% 3% 1% Vertigo 2% 2% 1% Vision Blurrea 2% 1% 1% Dyspepsia 2% 3% 2% Influenza 2% 1% 0% Fall 2% 0% 1% Muscle Spasms 2% 1% 1% Lethargy 2% 1% 1% Akathisia 2% 2% 1% ADnormal Dreams 2% 2% 1% Anxiety 2% 2% 1% Depression 2% 1% 1% 1. Somnolence combines the adverse reaction terms somnolence and sedation. 2. Extrapyramidal symptoms include the terms: muscle spasms, akathisia, cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness, and tremor. Adverse Reactions In Clinical Trials With Quetiapine And Not Listed Elsewhere In The Label Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), and priapism. Extrapyramidal Symptoms (EPS) Dystonia Class Effect Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS. Adults In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo. In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 8% for SEROQUEL XR and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group. At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients. In Tables 16 – 19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder. Table 16: Adverse Reactions Associated with Extrapyramidal Symptoms in Placebo- Controlled Clinical Trials for Schizophrenia Preferred term SEROQUELXR 300 mg/day (N=91) SEROQUELXR 400 mg/day (N=227) SEROQUELXR 600 mg/day (N=310) SEROQUELXR 800 mg/day (N=323) All Doses (N=951) Placebo (N=319) n % n % n % n % n % n % Dystonic event 3 3.3 0 0.0 4 1.3 1 0.3 8 0.8 0 0.0 Parkinsonism 1 1.1 3 1.3 11 3.6 7 2.2 22 2.3 4 1.3 Akathisia 0 0.0 3 1.3 7 2.3 7 2.2 17 1.8 4 1.3 Dyskinetic event 2 2.2 1 0.4 1 0.3 1 0.3 5 0.5 2 0.6 Other extrapyramidal event 3 3.3 4 1.8 7 2.3 12 3.7 26 2.7 7 2.2 In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 6.6% for SEROQUEL XR and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction. Table 17: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo- Controlled Clinical Trial for Bipolar Mania Preferred term1 SEROQUELXR (N=151) Placebo (N=160) n % n % Dystonic event 1 0.7 0 0.0 Parkinsonism 4 2.7 3 1.9 Akathisia 2 1.3 1 0.6 Other extrapyramidal event 3 2.0 2 1.3 1. There were no adverse experiences with the preferred term of dyskinetic event. In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 4.4% for SEROQUEL XR and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction. Table 18: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo- Controlled Clinical Trial for Bipolar Depression Preferred term1 SEROQUELXR (N=137) Placebo (N=140) n % n % Dystonic event 2 1.5 0 0.0 Parkinsonism 1 0.7 1 0.7 Akathisia 2 1.5 0 0.0 Other extrapyramidal event 1 0.7 0 0.0 1. There were no adverse experiences with the preferred term of dyskinetic event. In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of SEROQUEL XR, the incidence of any adverse reactions related to EPS was 5.1% for SEROQUEL XR and 4.2% for the placebo group. Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose: Table 19: Adverse Reactions Associated with EPS in MDD Trials by Dose, Adjunctive Therapy Clinical Trials (6 weeks duration) Preferred term SEROQUELXR 150 mg/day (N=315) SEROQUELXR 300 mg/day (N=312) All Doses (N=627) Placebo (N=309) n % n % n % n % Dystonic event 1 0.3 0 0.0 1 0.2 0 0.0 Parkinsonism 3 1.0 4 1.3 7 1.1 5 1.6 Akathisia 5 1.6 8 2.6 13 2.1 3 1.0 Dyskinetic event 0 0.0 1 0.3 1 0.2 0 0.0 Other extrapyramidal event 5 1.6 7 2.2 12 1.9 5 1.6 Children And Adolescents The information below is derived from a clinical trial database for SEROQUEL consisting of over 1000 pediatric patients. This database includes 677 adolescents (13 – 17 years old) 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 quetiapinetreated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse reaction leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo). Bipolar I Mania The incidence of discontinuation due to adverse reactions for quetiapinetreated 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 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%. In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%). In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). Adverse Reactions Occurring At An Incidence Of ≥ 2% Among 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 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with SEROQUEL (doses of 400 or 800 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 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%). Table 20: Adverse Reactions in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients < Human Experience In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose. There were also very rare reports of overdose of SEROQUEL alone resulting in death or coma. Management Of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of SEROQUEL XR. Similarly it is reasonable to expect that the α-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension. There is no specific antidote to SEROQUEL XR. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since β stimulation may worsen hypotension in the setting of quetiapine-induced α blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D1 and D2, serotonin 5HT1A and 5HT2A, histamine H1, muscarinic M1, and adrenergic α1b and α2 receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M1 receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors. Table 24: Receptor Affinities (Ki, nM) for Quetiapine and Norquetiapine Preferred Term SEROQUEL 400 mg (n=73) SEROQUEL 800 mg (n=74) Placebo (n=75) Somnolence1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia2 6% 11% 0% Irritability Receptor Quetiapine Norquetiapine Dopamine D1 428 99.8 Dopamine D2 626 489 Serotonin 5HT1A 1040 191 Serotonin 5HT2A 38 2.9 Norepinephrine transporter >10000 34.8 Histamine H1 4.41 1.15 Adrenergic α1b 14.6 46.4 Adrenergic α2 617 1290 Muscarinic M1 1086 38.3 Benzodiazepine >10000 > 10000 Effect On QT Interval 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 , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. Adults Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of norquetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. SEROQUEL XR is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes. Children And Adolescents At steady state, the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and Cmax of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults. Absorption Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. SEROQUEL XR dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the SEROQUEL XR Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that SEROQUEL XR be taken without food or with a light meal. Distribution Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine. Metabolism And Elimination Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine. Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine. Age Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n = 9) compared to young patients (n = 12), and dosing adjustment may be necessary. Gender There is no gender effect on the pharmacokinetics of quetiapine. Race There is no race effect on the pharmacokinetics of quetiapine. Smoking Smoking has no effect on the oral clearance of quetiapine. Renal Insufficiency Patients with severe renal impairment (CLcr=10-30 mL/min/1.73m², n=8) had a 25% lower mean oral clearance than normal subjects (CLcr>80 mL/min/1.73m², n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients. Hepatic Insufficiency Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed. Feb 2017 Seroquel XR price Average cost of Seroquel XR 150 mg per unit in online pharmacies is from 2.08$ to 5.58$, per pack from 125$ to 635$. 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