FDA Approves Seroquel for Maintenance Treatment in Bipolar Disorder

FDA Approves AstraZeneca's Seroquel for Maintenance Treatment in Bipolar Disorder

WILMINGTON, Del., May 14, 2008 /PRNewswire-FirstCall/ -- AstraZeneca today announced that the U.S. Food and Drug Administration (FDA) has approved Seroquel (quetiapine fumarate tablets) for the maintenance treatment of patients with bipolar I disorder, as adjunct therapy to lithium or divalproex. Seroquel is approved by the FDA for the treatment of schizophrenia, and is also the only single agent approved by the FDA for the treatment of both depressive episodes in bipolar disorder and acute manic episodes associated with bipolar I disorder. (1,2)

Considered one of the most severe forms of mental illness, bipolar disorder currently affects about 8 million adults in the U.S.(3-5) Bipolar I disorder is a lifelong psychiatric condition characterized by manic or mixed mood episodes, interspersed with major depressive episodes. (6) It is estimated that 0.4 percent to 1.6 percent of individuals will develop bipolar I disorder in their lifetime. (6)

"This new indication for Seroquel marks an important milestone in the treatment of bipolar I disorder because it provides patients with another option over the long-term. In fact, despite the number of currently available treatments, many patients with bipolar I disorder do not receive effective therapy and some 20 to 30 percent of patients continue to display residual mood symptoms of bipolar I disorder," said Mark Scott, Executive Director, Clinical Development, Seroquel. "The studies showed that Seroquel, with lithium or divalproex, can provide clinicians with a safe and effective long-term treatment option that reduced the risk of relapse of both manic and depressive mood events in bipolar I disorder."

The FDA approval was based on two multicenter, randomized, double-blind, placebo-controlled clinical trials that evaluated Seroquel when used as an adjunct therapy to lithium or divalproex in the maintenance treatment of adult patients with bipolar I disorder (n=703, n=623 respectively). (7,8) The rigorous study design included a 12 to 36 week stabilization phase which was followed by a longer-term, randomized, double-blind treatment phase that had a mean duration of exposure of 213.2 days for Seroquel and 152.4 days for placebo. (9)

In both studies, patients with bipolar I disorder whose most recent episode was manic, depressed, or mixed, were treated with either Seroquel (flexible dosing between 400 and 800 mg per day in divided doses) plus lithium-or-divalproex or placebo plus lithium-or-divalproex. (9) The primary endpoint, which was time to recurrence of a depressive, manic, or mixed mood event, was significant for Seroquel compared with placebo in both studies. (9) Pooled study results indicated that patients treated with Seroquel plus lithium-or-divalproex (n=646) had a risk reduction of 70% relative to those treated with placebo plus lithium-or-divalproex (n=680) for time to recurrence of a mood event (HR: 0.30; 95% CI: 0.24, 0.37; p<0.001). (9) This reduction in risk was significant for both recurrence of manic episodes (HR: 0.30; 95% CI: 0.22, 0.41; p less than 0.001) and recurrence of depressive episodes (HR: 0.30; 95% CI: 0.23, 0.40; p less than 0.001). The proportion of patients who relapsed when treated with Seroquel was 19.3% [125/646] versus 50.4% [343/680] of patients on placebo. (9)

Adverse events in these trials, which were monitored during both the open-label stabilization phase and the randomized controlled-phase, were generally consistent with those reported in short term, placebo-controlled trials for Seroquel. In the pooled data of the two clinical studies, a greater incidence of blood glucose increases to hyperglycemic levels (Greater Than or Equal to 126mg/dL) was observed in patients randomized to Seroquel plus lithium-or-divalproex than in patients randomized to placebo plus lithium-or-divalproex. The Seroquel prescribing information was updated in July 2007 to reflect the increases in blood glucose levels observed in these trials.

"To date, long-term controlled studies of maintenance therapies have been relatively few and typically focused on either the manic or depressive phase of the illness, but not on both," said Mark Scott, Executive Director, Clinical Development, Seroquel. "Seroquel is the only single agent to offer proven efficacy in both the manic and depressive episodes in bipolar disorder, and now has demonstrated proven efficacy as an adjunct treatment for the maintenance treatment of bipolar I disorder."

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.

Important Safety Information for Seroquel

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; maintenance treatment of bipolar I disorder, as adjunct 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 is 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 is not approved for use in patients under the age of 18 years. 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 reactions in patients treated with atypical antipsychotics. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

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 less than 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 reactions 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 reactions 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 reactions 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.

About Bipolar Disorder

Approximately eight million American adults are affected by bipolar disorder, a serious psychiatric condition also known as manic depressive illness. (4,5) 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. (6) 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 three times longer than manic symptoms (10,11) Similarly, patients with bipolar II disorder spend almost forty times longer in the depressed state than in hypomania. (12) Bipolar disorder is often misdiagnosed as unipolar depression. This misdiagnosis can lead to treatment that may exacerbate the disease. In fact, many patients face up to ten years without appropriate treatment before a correct diagnosis is made. (13) Up to 50 percent of patients with bipolar disorder attempt suicide, and approximately 10 to 15 percent complete suicide. (14) Bipolar Disorder is typically managed through a treatment strategy with several phases -- including acute and maintenance phases. In the acute phase, the aim is to improve the acute symptoms of the patient; the maintenance treatment phase aims to reduce the risk of recurrence of future episodes. (3,15)

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of $29.55 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.35 billion dollar healthcare business with 12,200 employees committed to improving people's lives. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

For more information visit http://www.astrazeneca-us.com.

The statements contain herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report/Form 20-F for 2007. Nothing contained herein should be construed as a profit forecast.

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    262387 5/08

CONTACT: Jim Minnick, +1-302-886-5135, , orAbigail Baron, +1-302-885-3578, , both ofAstraZeneca jim.minnick@astrazeneca.com abigail.baron@astrazeneca.com

Web site: http://www.astrazeneca-us.com/

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Posted: May 2008

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