AstraZeneca submits sNDAs for SEROQUEL XR for bipolar symptoms

AstraZeneca has announced that the company has submitted two separate supplemental New Drug Applications (sNDAs) to the U.S. Food and Drug Administration (FDA) for once-daily SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets to seek approval for the treatment of manic episodes associated with bipolar disorder and the treatment of depressive episodes associated with bipolar disorder.

The bipolar mania submission is based on a clinical study of once-daily treatment with SEROQUEL XR, compared to placebo, with a primary endpoint of change in YMRS (Young Mania Rating Scale) total score (week 3), in 316 patients suffering from bipolar mania. The bipolar depression submission is supported by a clinical study of once-daily treatment with SEROQUEL XR, compared to placebo, with a primary endpoint of change from baseline in MADRS (Montgomery Asberg Depression Rating Scale) total score after 8 weeks of treatment, in 280 patients diagnosed with bipolar depression(1). Doses of SEROQUEL XR administered in both the bipolar mania (400 mg to 800 mg/day) and bipolar depression (300 mg/day) studies were comparable to the FDA-approved recommended doses for SEROQUEL (quetiapine fumarate) immediate release tablets in those indications(1,2). Both studies met their primary endpoint and it is expected that they will be presented at major scientific congresses in 2008.

SEROQUEL XR is currently approved in 8 countries including the U.S., Canada and The Netherlands, for the acute and maintenance treatment of schizophrenia in adults.

Launched in 1997, SEROQUEL has been prescribed to millions of patients worldwide. It is approved in 88 countries for the treatment of schizophrenia, in 79 countries for the treatment of bipolar mania, and in 11 countries including the U.S. for the treatment of bipolar depression. SEROQUEL XR was launched for the treatment of schizophrenia in the U.S. in 2007, and clinical development programs and regulatory filings are planned for a number of other indications.

Important Safety Information for SEROQUEL and SEROQUEL XR

SEROQUEL XR is indicated for the acute and maintenance treatment of schizophrenia. SEROQUEL is indicated for the treatment of depressive episodes in bipolar disorder; acute manic episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; and schizophrenia. Patients should be periodically reassessed to determine the need for treatment beyond the acute response.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death, compared to placebo (4.5% vs 2.6%, respectively). SEROQUEL and SEROQUEL XR are not approved for the treatment of patients with dementia-related psychosis. (See Boxed Warning.)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Patients of all ages started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL and SEROQUEL XR are not approved for use in patients under the age of 18 years. SEROQUEL XR is not approved for the treatment of depression; however, SEROQUEL is approved for the treatment of bipolar depression. (See Boxed Warning.)

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse events in patients treated with atypical antipsychotics. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

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 management of NMS should include immediate discontinuation of antipsychotic drugs.

Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of TD.

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

Warnings and Precautions also include the risk of orthostatic hypotension, cataracts, seizures and hyperlipidemia. 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.

The most commonly observed adverse events associated with the use of SEROQUEL monotherapy versus placebo in clinical trials for schizophrenia and bipolar disorder were dry mouth (9%-44% vs 3%-13%), sedation (30% vs 8%), somnolence (18%-28% vs 7%-8%), dizziness (11%-18% vs 5%-7%), constipation (8%- 10% vs 3%-4%), SGPT increase (5% vs 1%), dyspepsia (5%-7% vs 1%-4%), lethargy (5% vs 2%), and weight gain (5% vs 1%). The most commonly observed adverse events associated with the use of SEROQUEL versus placebo in clinical trials as adjunct therapy with lithium or divalproex in bipolar mania were somnolence (34% vs 9%), dry mouth (19% vs 3%), asthenia (10% vs 4%), constipation (10% vs 5%), abdominal pain (7% vs 3%), postural hypotension (7% vs 2%), pharyngitis (6% vs 3%), and weight gain (6% vs 3%). The most commonly observed adverse events associated with the use of SEROQUEL XR versus placebo in clinical trials for schizophrenia were dry mouth (12% vs 1%), constipation (6% vs 5%), dyspepsia (5% vs 2%), sedation (13% vs 7%), somnolence (12% vs 4%), dizziness (10% vs 4%), and orthostatic hypotension (7% vs 5%).

In long-term clinical trials of quetiapine, hyperglycemia (fasting glucose greater than or equal to 126 mg/dL) was observed in 10.7% of patients receiving quetiapine (mean exposure 213 days) vs 4.6% in patients receiving placebo (mean exposure 152 days).

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

About Bipolar Disorder

Approximately eight million American adults are affected by bipolar disorder, a serious psychiatric condition also known as manic depressive illness(3,4). Bipolar disorder consists of recurring episodes of mania and depression. Bipolar I disorder is characterized by one or more manic or mixed episodes, often with episodes of major depression, whereas bipolar II disorder is distinguished by one or more major depressive episodes accompanied by at least one hypomanic episode(5). In the long term, patients with bipolar I disorder experience depressive symptoms -- including prolonged periods of sadness, loss of energy, persistent lethargy, and recurring thoughts of death or suicide(6) - three times longer than manic symptoms(7). Similarly, patients with bipolar II disorder spend almost forty times longer in the depressed state than in hypomania(8). Bipolar disorder is often misdiagnosed as unipolar depression. This misdiagnosis can lead to unfocused treatment that may exacerbate the disease. In fact, many patients face up to ten years without appropriate treatment before a correct diagnosis is made(9). Up to 50 percent of patients with bipolar disorder attempt suicide, and approximately 15 to 20 percent complete suicide(10).