US FDA approves SEROQUEL for the pediatric treatment of schizophrenia and bipolar mania

December 4, 2009 – Wilmington, DE – AstraZeneca (NYSE: AZN) today announced that the U.S. Food and Drug Administration (FDA) approved SEROQUEL (quetiapine fumarate) Tablets for the treatment of schizophrenia in adolescents (13-17 years of age) as monotherapy, and for the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age), both as monotherapy and as an adjunct to lithium or divalproex.¹

The SEROQUEL pediatric clinical program was undertaken to provide important clinical information for healthcare providers who treat pediatric patients with the serious diseases schizophrenia and bipolar mania. Studies were conducted to assess the safety and efficacy profile of SEROQUEL in the treatment of schizophrenia in adolescents (13-17 years of age), and the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age).¹ The pediatric studies for SEROQUEL were designed and initiated in consultation with FDA in accordance with a formal Written Request, pursuant to Section 505A of the Federal Food, Drug, and Cosmetic Act, for pediatric information on SEROQUEL.  

“Bipolar mania and schizophrenia in children and adolescents, while rare, are serious disorders and it is important to have treatments approved for use in this patient population,” said Howard Hutchinson, M.D., Chief Medical Officer of AstraZeneca.  “Because individuals respond differently to medications, patients and practitioners need proven treatment options that permit them to weigh safety and efficacy in individual circumstances. These new indications for SEROQUEL provide another FDA-approved option for treating pediatric patients suffering from these severe mental illnesses.”

The SEROQUEL pediatric approval is based on data from four studies. Three of the studies (Study 112, Study 149, and Study 150) evaluated the efficacy and safety of SEROQUEL in the treatment of adolescents with schizophrenia (13-17 years of age) or children and adolescents with bipolar I disorder (10-17 years of age). The fourth study (Study 28) assessed the pharmacokinetic profile of SEROQUEL in children and adolescents.^1,2 Doses of 400 mg to 800 mg of SEROQUEL were specifically studied in the pediatric program.¹

The most common adverse reactions (≥ to 5% and greater than placebo) in the clinical trials of SEROQUEL in children and adolescents in schizophrenia and bipolar mania and were somnolence (47% v. 15%), dizziness (15% vs. 4%), fatigue (9% vs. 4%), increased appetite (8% vs. 2%), nausea (8% vs. 4%), vomiting (7% vs. 6%), dry mouth (7% vs. 1%), tachycardia  (8% vs. 0%), and weight increased (5% vs.1%). The prescribing information for SEROQUEL has been updated to include safety information from the pediatric clinical trial program, including information in the Warnings and Precautions on hyperglycemia, hyperlipidemia, weight gain, hypothyroidism, hyperprolactinemia, and increases in blood pressure in children and adolescents. In addition, the Adverse Reactions section of the prescribing information was previously updated to include data on extrapyramidal symptoms and increased appetite.¹

The FDA has required that AstraZeneca implement a Risk Evaluation and Mitigation Strategy (REMS). The REMS for SEROQUEL requires a Medication Guide and periodic assessments that will include a survey of patients' understanding of the potential risks of SEROQUEL. The REMS applies to all approved indications.

About SEROQUEL
SEROQUEL was first approved in the US in 1997 and is currently approved for adults in 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; for the maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex; and for the treatment of schizophrenia in adult patients. SEROQUEL is also indicated for the treatment of schizophrenia in adolescents (13-17 years of age) as monotherapy, and the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age), both as monotherapy and as an adjunct to lithium or divalproex.¹ The safety of SEROQUEL has been evaluated in clinical trials with thousands of adult patients and continues to be reviewed by the FDA.

About Schizophrenia
Schizophrenia is a serious psychiatric disorder with symptoms including distorted perceptions of reality, hallucinations and delusions, illogical thinking, and flat or blunted emotions.³ Medications are important in the management of symptoms.  While there is no cure for schizophrenia, it can be a treatable and manageable illness.⁴  

About Bipolar Mania
Bipolar mania is an essential feature of bipolar I disorder, and is characterized by abnormally and persistently elevated, expansive, or irritable mood; accompanied by symptoms including inflated self-esteem or grandiosity, decreased need for sleep, talkativeness, flight of ideas or racing thoughts, distractibility, increased goal-setting activity, psychomotor agitation, and excessive involvement in pleasurable activities such as buying sprees, sexual indiscretions, or foolish business investments.³ Bipolar disorder is a long-term illness that must be carefully managed throughout a person’s life.⁵ Bipolar disorder is often not recognized, and people may suffer for years before it is properly diagnosed and treated.⁶

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.¹

Indications 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; for the maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex; and schizophrenia in adult patients. SEROQUEL is also indicated for the treatment of schizophrenia in adolescents (13-17 years of age) as monotherapy, and for the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age), both as monotherapy and as an adjunct to lithium or divalproex. Patients should be periodically reassessed to determine the need for continued treatment and the appropriate dose.¹

Important Safety Information for SEROQUEL

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 and Indications.)

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 10 years.  (See Boxed Warning and Indications.)

A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with administration of antipsychotic drugs, including SEROQUEL. Rare cases of NMS have been reported with SEROQUEL. 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.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including SEROQUEL.  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.

Undesirable alterations in lipids have been observed with SEROQUEL use. Increases in total cholesterol, LDL-cholesterol and triglycerides, and decreases in HDL-cholesterol have been reported in clinical trials. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of and periodically during treatment.

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

Increases in blood pressure have been reported with SEROQUEL in children and adolescents.   Blood pressure should be measured at the beginning of and periodically during treatment in children and adolescents.  

Leukopenia, neutropenia, and agranulocytosis (including fatal cases), have been reported temporally related to atypical antipsychotics, including SEROQUEL.  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 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 should be discontinued in any patient if the absolute neutrophil count is <1000/mm³.  

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.  SEROQUEL 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, hyperprolactinemia, and dysphagia. 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 bipolar disorder, and close supervision of high risk patients should accompany drug therapy.

The most commonly reported adverse reactions associated with the use of SEROQUEL vs. placebo in adults in clinical trials for schizophrenia and bipolar disorder were somnolence (18%-57% vs. 8%-15%), dry mouth (9%-44% vs. 3%-13%), dizziness (9%-18% vs. 5%-7%), constipation (8%-10% vs. 3%-5%), asthenia (2%-10% vs. 1%-4%), abdominal pain (4%-7% vs. 1%-3%), postural hypotension (4%-7% vs. 1%-2%), pharyngitis (4%-6% vs. 3%), weight gain (4%-6% vs. 1%-3%), lethargy (5% vs. 2%), ALT increased (5% vs. 1%), and dyspepsia (4%-7% vs. 1%-4%).  

Please see Prescribing Information for SEROQUEL, including Boxed Warnings.

About AstraZeneca
AstraZeneca is engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and in the supply of healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with global healthcare sales of $ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines.  In the United States, AstraZeneca is a $13.5 billion dollar healthcare business.  

For more information about AstraZeneca in the US or our AZ&Me™ Prescription Savings programs, please visit: 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 2008.  Nothing contained herein should be construed as a profit forecast.. 

Media Contacts: 

• Kirsten Evraire, AstraZeneca: 302-885-0435
• Shannon Miller, AstraZeneca: 302-885-3623

References
1. SEROQUEL Prescribing Information.
2. Winters HR et al. Steady-State Pharmacokinetic, Safety, and Tolerability Profiles of Quetiapine, Norquetiapine, and Other Quetiapine Metabolites in Pediatric and Adult Patients with Psychotic Disorders. J Child Adol Psychopharmacol. 2008;18:81-98.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Fourth Edition. Arlington, VA, 2000. 299.
4. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia, Second Edition. February 2004. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2e_Inactivated_04-16-09. Accessed on December 2, 2009.
5. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Bipolar Disorder, Second Edition. April 2002. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Bipolar2ePG_05-15-06. Accessed on October 1, 2009.
6. 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.

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