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Press release from Business Wire

FDA Responds to AstraZeneca Citizen Petitions on Quetiapine Product Labeling

Friday, March 09, 2012

FDA Responds to AstraZeneca Citizen Petitions on Quetiapine Product Labeling02:27 EST Friday, March 09, 2012 WILMINGTON, Del. (Business Wire) -- AstraZeneca today announced that on March 7, 2012, the Food and Drug Administration (“FDA”) denied Citizen Petitions requesting that the FDA withhold finally approving any generic quetiapine product with labeling that omits certain hyperglycemia warning language that the FDA required AstraZeneca (NYSE: AZN) to include in the labeling for SEROQUEL® (quetiapine fumarate) tablets and SEROQUEL XR® (quetiapine fumarate) extended-release tablets. AstraZeneca is evaluating the FDA's decision and reasoning. Indications SEROQUEL XR is indicated in adults for (1) adjunctive therapy to antidepressants in major depressive disorder; (2) acute depressive episodes in bipolar disorder; (3) acute manic or mixed episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; (4) maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex; and (5) schizophrenia. SEROQUEL is indicated in adults for the treatment of (1) acute depressive episodes in bipolar disorder; (2) acute manic episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; (3) maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex, and (4) schizophrenia. SEROQUEL is also indicated (5) for the treatment of schizophrenia in adolescents (13-17 years of age) and (6) for the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years of age). Patients should be periodically reassessed to determine the need for treatment and the appropriate dose. Important Safety Information About SEROQUEL XR (quetiapine fumarate) and SEROQUEL (quetiapine fumarate)INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: 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 and SEROQUEL are not approved for the treatment of patients with dementia-related psychosis.(See Prescribing Information for complete Boxed Warnings.)SUICIDALITY AND ANTIDEPRESSANT DRUGS: 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, especially during the initial few months of drug therapy or when changing dose.Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL XR (quetiapine fumarate) is not approved for use in patients under the age of 18 years. SEROQUEL(quetiapine fumarate) is not approved for use in patients under the age of 10 years. (See Prescribing Information for complete Boxed Warnings.)Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex, sometimes referred to as 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. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment, and medical monitoring, and treatment of any concomitant serious medical problems. Hyperglycemia and DiabetesMellitus: 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. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. Hyperlipidemia: Undesirable alterations in lipids have been observed with quetiapine 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. Weight Gain: Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate. Tardive Dyskinesia (TD): 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. Although much less commonly, TD can develop after relatively brief treatment periods at low doses or even after treatment discontinuation. 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, and discontinuation should be considered if signs and symptoms of TD occur. Orthostatic Hypotension: Quetiapine may induce orthostatic hypotension with associated dizziness, tachycardia, and syncope, especially during the initial dose titration period and should be used with caution in patients predisposed to hypotension or with known cardiovascular or cerebrovascular disease. Increased Blood Pressure in Children and Adolescents: Increases in blood pressure have been reported with SEROQUEL (quetiapine fumarate) 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: 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, quetiapine should be discontinued at the first sign of a decline in WBC absent other causative factors. Patients with neutropenia should be carefully monitored, and quetiapine should be discontinued in any patient if the absolute neutrophil count is <1000/mm3. Cataracts: 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. QT Prolongation: Postmarketing cases show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase the QT interval. Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval. Seizures: Quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, eg, Alzheimer's dementia. Potential for Cognitive and Motor Impairment: Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, until they are reasonably certain that quetiapine therapy does not affect them adversely. Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Use caution in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Suicide: The possibility of a suicide attempt is inherent in schizophrenia, bipolar disorder, and depression, and close supervision of high risk patients should accompany drug therapy. Warnings and Precautions Also Include: The risk of hypothyroidism, hyperprolactinemia, transaminase elevations, priapism, and withdrawal.Common Adverse Reactions: The most commonly observed adverse reactions (incidence ≥5% and twice placebo) associated with the use of SEROQUEL XR versus placebo in clinical trials for all indications were somnolence (25%-52% vs 9%-13%), dry mouth (12%-40% vs 1%-8%), constipation (6%-11% vs 3%-6%), dizziness (10%-13% vs 4%-11%), increased appetite (2%-12% vs 0%-6%), dyspepsia (2%-7% vs 1%-4%), weight gain (3%-7% vs 0%-1%), fatigue (3%-14% vs 2%-4%), dysarthria (1%-5% vs 0%), and nasal congestion (2%-5% vs 1%). The most commonly reported adverse reactions associated with the use of SEROQUEL vs placebo in adults in clinical trials for all indications 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%-3%), 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%). The most commonly reported adverse reactions associated with the use of SEROQUEL vs placebo in children and adolescents in clinical trials for schizophrenia and bipolar disorder were somnolence (34%-53% vs 11%-14%), dizziness (12%-18% vs 2%-5%), fatigue (11% vs 4%), increased appetite (9% vs 1%), nausea (8% vs 4%), vomiting (8% vs 3%), dry mouth (7% vs 0%-1%), tachycardia (7% vs 0%), and weight gain (6% vs 0%). Please see full Prescribing Information for SEROQUEL XR(quetiapine fumarate) and SEROQUEL(quetiapine fumarate), including Boxed Warnings.NOTES TO EDITORSAbout the Citizen Petitions On September 9, 2011 AstraZeneca filed a Citizen Petition with the FDA for each of SEROQUEL and SEROQUEL XR, requesting the FDA withhold finally approving any generic quetiapine product that omits from its labeling certain hyperglycemia and suicidality warning language that FDA required AstraZeneca to include in the labeling for SEROQUEL and SEROQUEL XR. Data associated with the hyperglycemia warning language at issue is protected by marketing exclusivity periods expiring as late as December 2, 2012. The patent covering the active ingredient in SEROQUEL and SEROQUEL XR expired in September 2011, with pediatric exclusivity expiring March 26, 2012. SEROQUEL XR is covered by a formulation patent that expires in May 2017, with pediatric exclusivity expiring in November 2017. In 2011 AstraZeneca granted both Handa and Accord a license to enter the U.S. market with generic SEROQUEL XR on November 1, 2016, or earlier under certain circumstances. About AstraZeneca AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information about AstraZeneca in the U.S. or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363). 1718104 3/12 AstraZenecaMedia Inquiries US:Tony Jewell, +1-302-885-4594Julia Walker, +1-302-885-5172 Media Inquiries UK:Esra Erkal-Paler, +44 20 7604 8030Sarah Lindgreen, +44 20 7604 8033 Investor Enquiries UK:James Ward-Lilley, +44 20 7604 8122 mob: +44 7785 432613Karl Hård, +44 20 7604 8123 mob: +44 7789 654364Nicklas Westerholm, +44 20 7604 8124 mob: +44 7585 404950 Investor Enquiries US:Ed Seage, +1-302-886-4065 mob: +1-302-373-1361Jorgen Winroth, +1-212-579-0506 mob: +1-917-612-4043