FDA Approves Seroquel XR for Maintenance Treatment of Schizophrenia

Seroquel XR Receives Approval From FDA for Maintenance Treatment of Schizophrenia

WILMINGTON, Del., November 16, 2007 /PRNewswire-FirstCall/ -- AstraZeneca today announced that the U.S. Food and Drug Administration (FDA) has approved once-daily Seroquel XR (quetiapine fumarate) Extended-Release Tablets for maintenance treatment of schizophrenia in adult patients. On May 17, 2007, the FDA approved Seroquel XR for the acute treatment of schizophrenia in adult patients.

Schizophrenia patients experience high rates of symptom relapse, and as a result, there is an important need for long-term treatment options for schizophrenia to help reduce the risk of the recurrence of acute psychotic episodes. (1,2)

In the clinical trial supporting this approval, patients with schizophrenia who were treated with Seroquel XR experienced a significantly longer time to relapse, compared with patients receiving placebo. Patients receiving Seroquel XR demonstrated an 84% reduction in the relative risk of relapse (hazard ratio 0.16; p<0.0001). Results showed the estimated risk of relapse after six months was 14.3% in the Seroquel XR group versus 68.2% in the placebo group (p<0.0001). Differences in relapse rate between active treatment and placebo were large enough to require the study to be stopped early. The complete results of the clinical trial appear in the November issue of the journal Psychiatry 2007.(3)

"Today's FDA approval helps address the need for longer-term treatment options for patients with schizophrenia," said Mark Scott, Ph.D., Executive Director for Development, AstraZeneca. "The clinical trial results provided compelling evidence for reducing the risk of relapse when these patients are treated with Seroquel XR."

Schizophrenia is a serious brain disorder with symptoms including distorted perceptions of reality, hallucinations and delusions, illogical thinking, and flat or blunted emotions, affecting over 2 million American adults -- about 1% of the population 18 years and older.(4,5)

The FDA approval for maintenance treatment of schizophrenia was based on clinical trial results in which patients who had responded to Seroquel XR for the treatment of schizophrenia for 16 weeks (n=197) were randomized and either continued on Seroquel XR (n=94; 400-800 mg/day, flexibly dosed) or were switched to placebo (n=103). The primary endpoint was the time from randomization to psychiatric relapse (hospitalization for worsening schizophrenia, increase in PANSS* Total score Greater Than or Equal To 30%, Clinical Global Impression-Global Improvement [CGI-I]** score Greater Than or Equal To 6, or need for additional antipsychotic medication to treat psychosis).(3)

* Schizophrenic symptomatology is measured on 30-item Positive and Negative Syndrome Scale (PANSS) scale. Each symptom was rated on a severity scale from 1-7. PANSS positive (7 items), negative (7 items), and general psychopathology (16 items) subscale scores were summarized to give the PANSS total score.(8)

** The Clinical Global Impression (CGI) consists of 3 global scales or items (Severity of Illness; Global Improvement; Efficacy Index). For the primary endpoint of Study 004, item 2, the Global Improvement scale, was used to evaluate patients. The Global Improvement scale involves the physician rating total improvement whether or not, in the physician's judgment, it is due entirely to drug treatment (1=very much improved to 7=very much worse).(9)

The adverse reactions reported for Seroquel XR in the longer-term placebo- controlled schizophrenia trial were generally consistent with those reported in the short-term placebo-controlled schizophrenia trials. The most common (Greater Than or Equal To 5% of patients) treatment emergent adverse events for the Seroquel XR group versus placebo group in the randomized phase were insomnia (8.5% vs 17.5%) and headache (7.4% vs 4.9%).(3,6)

Launched in 1997, Seroquel has been prescribed to millions of patients worldwide. It is approved in 88 countries for the treatment of schizophrenia, in 77 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 US 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.(3)

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%), headache (7% vs 5%), 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 Schizophrenia

Schizophrenia is a serious brain disorder with symptoms including distorted perceptions of reality, hallucinations and delusions, illogical thinking, and flat or blunted emotions.(4) Schizophrenia affects men and women with equal frequency, but the first signs of schizophrenia typically emerge earlier in men (in late teens or early twenties) compared to women (in twenties or early thirties). Approximately 2.4 million American adults -- about 1.1 % of the population age 18 and older -- suffer from schizophrenia.(5) Medications are important in the management of symptoms. While there is no cure for schizophrenia, it is a highly treatable and manageable illness. Medications are classified into two categories -- "conventional" and "atypical" antipsychotics.(7)

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of $26.47 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

In the United States, AstraZeneca is a $12.44 billion healthcare business with more than 12,000 employees. For nearly three decades, AstraZeneca has offered drug assistance programs side by side with its medicines, and over the past five years, has provided over $3 billion in savings to more than 1 million patients throughout the US and Puerto Rico. AstraZeneca has been named one of the "100 Best Companies for Working Mothers" by Working Mother magazine and is the only large pharmaceutical company named to FORTUNE magazine's 2007 list of "100 Best Companies to Work For." In 2006, for the fifth consecutive year, Science magazine named AstraZeneca a "Top Employer" on its ranking of the world's most respected biopharmaceutical employers.

For more information about AstraZeneca, please visit: www.astrazeneca-us.com.

The statements herein include forward-looking statements. By their nature, forward-looking statements and forecasts involve risk and uncertainty. For a discussion of those risks and uncertainties please see the company's Annual Report/Form 20-F for 2006.

References:
(1) Altamura AC, Bobo WV, Meltzer HY. Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment. Int Clin Psychopharmacol. 2007;22:249-267.
(2) Robinson D, Woerner MG, Alvir JMJ, et al. Predictors of Relapse Following Response From a First Episode of Schizophrenia or Schizoaffective Disorder. "Arch Gen Psychiatry. 1999; 56: 241-247.
(3) Peuskens J, Trivedi J, Malyarov S, et al. Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: A randomized, placebo-controlled trial in clinically stable patients. Psychiatry 2007. 2007; 4(11):34-50.
(4) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Fourth Edition. Arlington, VA, 2000: 299.
(5) National Alliance for the Mentally Ill: About Mental Illness/Schizophrenia fact sheet. Reviewed by Kenneth Duckworth, MD: February 2007. Accessed on September 24, 2007 at http://www.nami.org/PrinterTemplate.cfm?Section=By_Illness&Template=/ TaggedPage/TaggedPageDisplay.cfm&TPLID=54&ContentID=23036&lstid=327.
(6) Seroquel XR Prescribing Information.
(7) National Institutes of Mental Health. The Numbers Count: Mental Disorders in America. NIH Publication No. 06-4584. December 2006. Accessed on September 24, 2007 at http://www.nimh.nih.gov/publicat/numbers.cfm.
(8) Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13: 261-276.
(9) Guy, W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ. No. ADM 76-338). Rockville, MD: National Institute of Mental Health; 1976: 218- 222.

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//

Company News On-Call: http://www.prnewswire.com/comp/985887.html /

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Posted: November 2007

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