WILMINGTON, Del., May 8 /PRNewswire-FirstCall/ -- AstraZeneca (NYSE: AZN - News) today announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for SEROQUEL XR(TM) (quetiapine fumarate) Extended-Release Tablets to seek approval for the treatment of generalized anxiety disorder (GAD), including maintenance of antianxiety effect. It is the first time approval has been sought for an atypical antipsychotic medicine in GAD. The submission is based on a robust clinical development program involving more than three thousand patients. This week, at the 161st Annual Meeting of the American Psychiatric Association (APA) in Washington, D.C., data from two of the studies (Studies 9 and 12) supporting the submission were presented.
GAD, which affects approximately 6.8 million adults in the U.S., is characterized by persistent anxiety, exaggerated worry and tension. GAD is diagnosed when someone excessively worries about a number of everyday problems for at least 6 months.(1,2) Several classes of drugs have demonstrated efficacy in the treatment of GAD. Treatment typically includes selective- serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs); however, approximately 30 percent of patients do not achieve an adequate response to short-term treatment.(3) Benzodiazepines, commonly prescribed antianxiety medications, may be used for the rapid relief of anxiety symptoms, but long-term use of these agents is not generally recommended.(4)
The GAD submission is based on four Phase III efficacy and safety studies. Three short-term, multicenter, double-blind, randomized, placebo-controlled studies (Studies 9, 10, and 11) compared the safety and efficacy of SEROQUEL XR at doses of 50 mg, 150 mg and 300 mg to placebo for eight weeks in outpatients with GAD. Active controls were also used in Study 10 (escitalopram 10 mg daily) and Study 11 (paroxetine 20 mg daily). These short-term studies used the Hamilton Rating Scale for Anxiety (HAM-A)* as the primary assessment of anxiety symptoms.(5-8)
Study 12 was a long-term, multicenter, randomized-withdrawal, parallel- group, placebo-controlled, Phase III study that comprised four phases: an enrollment period of up to 28 days, an open-label run-in treatment period of four to eight weeks, an open-label stabilization treatment period of 12 to 18 weeks, and a randomized-withdrawal treatment period of up to 52 weeks. The SEROQUEL XR dose was flexible: 50 mg, 150 mg, or 300 mg once daily, based on the clinical judgment of the investigator. In this longer-term study, the primary assessment was time from randomization to an anxiety event.(8)
In 2007, SEROQUEL XR was approved in the U.S. for the treatment of schizophrenia in adult patients and for maintenance treatment of schizophrenia in adult patients. SEROQUEL XR is currently not approved for the treatment of bipolar disorder. In January 2008, AstraZeneca announced the submission of two separate sNDAs to the FDA for SEROQUEL XR to seek approval for the treatment of manic episodes associated with bipolar disorder and the treatment of depressive episodes associated with bipolar disorder. In February 2008, AstraZeneca filed a sNDA for SEROQUEL XR to seek approval for the treatment of MDD as monotherapy, adjunct therapy, and maintenance therapy. The FDA has not completed its review of these submissions.
IMPORTANT SAFETY INFORMATION FOR SEROQUEL XR
SEROQUEL XR is indicated for the acute and maintenance treatment of schizophrenia. Patients should be periodically reassessed to determine the need for maintenance 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. SEROQUEL XR is not approved for the treatment of depression; however, an immediate release form of quetiapine 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 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 less than 1000 per cubic millimeter.
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 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 XR.
About Generalized Anxiety Disorder (GAD)
GAD is characterized by chronic anxiety, exaggerated worry, and tension, even when there is little or nothing to provoke it.(1,2) People with GAD anticipate disaster and are overly concerned about health issues, money, family problems, or difficulties at work.
People with GAD can’t seem to get rid of their concerns, even though they usually realize that their anxiety is more intense than the situation warrants.(1,2) They can’t relax, startle easily, and have difficulty concentrating. Often they have trouble falling asleep or staying asleep. Physical symptoms that often accompany the anxiety include fatigue, headaches, muscle tension, muscle aches, difficulty swallowing, trembling, twitching, irritability, sweating, nausea, lightheadedness, having to go to the bathroom frequently, feeling out of breath, and hot flashes. GAD is diagnosed when someone excessively worries about a number of everyday problems for at least 6 months.
In the U.S. GAD affects about 6.8 million adults, with women twice as likely to develop GAD as men.(1,2) The disorder comes on gradually and can begin across the life cycle. GAD rarely occurs alone and is often accompanied by other anxiety disorders, depression, or substance abuse. Genetic factors are also thought to be involved.
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 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.
* The HAM-A rating scale consists of 14 items and measures the severity of symptoms such as anxiety, tension, depressed mood, palpitations, breathing difficulties, sleep disturbances, restlessness, and other physical symptoms.(9)
References 1. National Institute of Mental Health: Anxiety Disorders. NIH Publication No. 06-3879. Available at: (Due to URL length, please copy
and paste into browser) http://www.nimh.nih.gov/health/publications/anxiety-disorders/generalized- anxiety-disorder-gad.shtml
Accessed March 20, 2008.
2. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000:472-475.
3. Rickels K and Ryann M. Pharmacotherapy of Generalized Anxiety Disorder. J Clin Psychiatry. 2002;63 (suppl 14): 9-16.
4. Schmitt R, Gazalle FK, Silva de Lima M, et al. The efficacy of antidepressants for generalized anxiety disorder: a systematic review and meta-analysis. The Brazilian Journal of Psychiatry. 2005; 27(1):18-24.
5. Data on File, DA-SXR-15, AstraZeneca LP.
6. Joyce M, Khan A, Atkinson S, et al. Efficacy and safety of extended release Quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder (GAD) [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
7. Chouinard G, Bandelow B, Ahokas A, et al. Once-daily extended release of quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder: a Phases III, double-blind, placebo-controlled study [poster]. Presented at: The Annual Meeting of The American College of Neuropsychopharmacology; December 9-13, 2007, Boca Raton, FL.
8. Katzman M, Brawman-Mintzer O, Reyes E, et al. Extended Release quetiapine fumarate (quetiapine XR) monotherapy in maintenance treatment of generalized anxiety disorder (GAD): efficacy and tolerability results from a randomized, placebo-controlled trial [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
9. Lundbeck Institute. Psychiatric Rating Scales. PDF available at: http://www.brainexplorer.org/factsheets/Psychiatry%20Rating%20Scales.pdf. Accessed on May 2, 2008.
Source: AstraZeneca
