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Biopharmaceuticals FDA

 News Release - October 10, 2008

FDA Approves AstraZeneca's SEROQUEL XR(R) for the Treatment of Bipolar Depression and Bipolar Mania

WILMINGTON, Del., Oct. 10 (Healthcare Sales & Marketing Network) -- AstraZeneca (NYSE: AZN ) today announced that the U.S. Food and Drug Administration (FDA) has approved once-daily SEROQUEL XR® (quetiapine fumarate) Extended-Release Tablets for the acute treatment of the depressive episodes associated with bipolar disorder, the manic and mixed episodes associated with bipolar I disorder, and the maintenance treatment of bipolar I disorder as adjunctive therapy to lithium or divalproex. SEROQUEL XR is the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar disorder.(1)

"When people think about bipolar disorder it is important to remember how debilitating the depressive episodes of the disease can be. In fact, in the long term, patients with bipolar disorder experience depressive symptoms three times longer than manic symptoms," said Dr. Trisha Suppes, Professor of Psychiatry and Behavioral Sciences, Stanford University Medical Center and VA Palo Alto Health Care System. "With the approval of SEROQUEL XR for the treatment of bipolar depression and mania, we have a once-daily treatment that has been proven to help control the depressive and manic symptoms of bipolar disorder."

"These new indications for SEROQUEL XR mark an important milestone in the treatment of bipolar disorder," said Lisa Schoenberg, VP Specialty Care, AstraZeneca. "In addition to today's approval for the treatment of both the depressive and manic symptoms associated with this condition, SEROQUEL XR is now also approved as a long-term treatment option for bipolar I disorder."

About the SEROQUEL XR Bipolar Disorder Approval

Bipolar disorder, also known as manic depressive illness, is a serious psychiatric condition that consists of recurring episodes of depression and mania.(2) Approximately 8 million American adults may be affected by bipolar disorder.(3,4)

AstraZeneca submitted two separate supplemental new drug applications (sNDAs) to the FDA to seek approval for these indications. The bipolar depression submission was supported by a clinical study of treatment with SEROQUEL XR compared with placebo in 280 patients diagnosed with bipolar depression.(5,6) The primary endpoint was change from baseline in MADRS(*) (Montgomery-Asberg Depression Rating Scale) total score compared to placebo at week 8. In the study, SEROQUEL XR at 300 mg once-daily was significantly more effective than placebo. The mean change in MADRS total score from baseline to Week 8 was -17.4 for SEROQUEL XR compared with -11.9 for placebo (p<0.001). In the bipolar depression trial, the most common adverse events (AEs) (greater than or equal to 5% and at least twice placebo) associated with SEROQUEL XR compared with placebo were somnolence (combined adverse events terms somnolence and sedation) (52% vs. 13%), dry mouth (37% vs. 7%), increased appetite (12% vs. 6%), weight gain (7% vs. 1%), dyspepsia (7% vs. 1%), and fatigue (6% vs. 2%).(5)

The bipolar mania submission was based on a clinical study of treatment with SEROQUEL XR compared with placebo in 316 patients with bipolar mania or mixed episodes with or without psychotic features.(5,8) The primary endpoint was change from baseline in YMRS(**) (Young Mania Rating Scale) total score compared to placebo at week 3. The study showed that SEROQUEL XR at 400 mg to 800 mg (mean dose 604 mg) once-daily produced a significantly greater improvement in YMRS scores from baseline to endpoint compared with placebo (- 14.34 vs. -10.52; p<0.001). In the bipolar mania trial, the most common adverse events (AEs) (greater than or equal to 5% and at least twice placebo) associated with SEROQUEL XR compared with placebo were somnolence (combined adverse events terms somnolence and sedation) (50% vs. 12%), dry mouth (34% vs. 7%), dizziness (10% vs. 4%), constipation (10% vs. 3%), weight gain (7% vs. 1%), dysarthria (5% vs. 0%), and nasal congestion (5% vs. 1%).(5)

Important Safety Information for SEROQUEL XR

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

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 XR 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 XR is not approved for use in patients under the age of 18 years. (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.

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 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 XR should be discontinued in any patient if the absolute neutrophil count is < 1000/mm.(3)

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.

Warnings and Precautions also include the risk of orthostatic hypotension, cataracts, seizures, hyperlipidemia, and possibility of suicide attempts. 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 possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high risk patients should accompany drug therapy.

The most commonly observed adverse reactions associated with the use of SEROQUEL XR versus placebo in clinical trials for schizophrenia and bipolar disorder somnolence (25-52% vs. 10-13%), dry mouth (12-37% vs. 1-7%), constipation (6-10% vs. 3-6%), dyspepsia (5-7% vs. 1-4%), dizziness (10-13% vs. 4-11%), orthostatic hypotension (7% vs. 5%), weight gain (7% vs. 1%), increased appetite (12% vs. 6%), fatigue (6-7% vs. 2-4%), dysarthria (5% vs. 0%), and nasal congestion (5% vs. 1%).

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 XR. (

About Bipolar Disorder

Approximately 8 million American adults may be 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.(2) Bipolar I disorder is characterized by one or more manic or mixed episodes, often with one or more episodes of major depression, whereas bipolar II disorder is distinguished by one or more major depressive episodes accompanied by at least one hypomanic episode.(2) Patients with bipolar I disorder experience depressive symptoms -- approximately three times longer than manic symptoms.(10) Similarly, patients with bipolar II disorder spend almost forty times longer in the depressed state than in hypomania.(11) Bipolar disorder is often misdiagnosed as major depressive disorder. This misdiagnosis can lead to unfocused treatment that may exacerbate the disease. In fact, many patients face up to ten years before a correct diagnosis is made.(12) Up to 50 percent of patients with bipolar disorder attempt suicide, and approximately 15 to 20 percent complete suicide.(13) 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.(14)

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.

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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.


* Montgomery-Asberg Depression Rating Scale: a 10-item scale that measures severity of symptoms on a scale of 0 to 6.(7)

** Young Mania Rating Scale: an 11-item scale that measures severity of manic symptoms. Four core symptoms (irritability, speech, content, and disruptive/aggressive behavior) were measured on an 8-point scale; the remaining items were measured on a 4-point scale.(9)

1. Data on file, DA-SXR-270636.

2. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington,

DC: APA; 2000; pp. 382-397.

3. Hirschfeld RMA, Calabrese JR, Weissman MM, et al. Screening for Bipolar in the Community. J Clin Psychiatry. 2003; 64:53-59.

4. US Bureau of the Census. Available at:

Accessed October 8, 2008.

5. SEROQUEL XR(TM) (quetiapine fumarate) Prescribing Information.

6. Suppes T, Datto C, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression [poster]. Presented at the 48th Annual New Clinical Drug Evaluation Meeting; May 27-30, 2008; Phoenix, Arizona, USA.

7. Montgomery S, Asberg M. A New Depression Scale Designed to be Sensitive to Change. Brit. J. Psychiat (1979), 134, 382-9.

8. Cutler A, Datto C, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar mania [poster]. Presented at the 161st Annual Meeting of the American Psychiatry Association; May 3-8, 2008; Washington DC, USA.

9. Young E.C, Biggs T et al. A Rating Scale for Mania: Reliability, Validity and Sensitivity. Brit. J. Psychiat. (1978), 133, 429-35.

10. Judd LL, Akiskal HS, Schettler PJ, et al. The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder. Arch Gen Psychiatry. 2002; 59:530-537.

11. Judd LL, Akiskal HS, Schettler PJ, et al. A Prospective Investigation of the Natural History of the Long-term Weekly Symptomatic Status of Bipolar II Disorder. Arch Gen Psychiatry. 2003; 60:26 -269.

12. Hirschfeld RMA, Lewis L, Vornik LA. Perceptions and Impact of Bipolar Disorder: How Far Have We Really Come? Results of the National Depressive and Manic- Depressive Association 2000 Survey of Individuals With Bipolar Disorder. J Clin Psychiatry. 2003; 64:161- 174.

13. Oquendo MA, Chaudhury SR, Mann JJ. Pharmacotherapy of Suicidal Behavior in Bipolar Disorder. Archives of Suicide Research. 2005; 9(3):237- 250.

14. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Bipolar Disorder, Second Edition. April 2002. Bipolar2ePG_05-15-06 (Due to length of URL, please cut and paste into browser).

Source: AstraZeneca

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