AstraZeneca submits sNDA for SEROQUEL XR for treatment of major depressive disorder

AstraZeneca has announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for once- daily SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets to seek approval for the treatment of major depressive disorder (MDD) as monotherapy, adjunct therapy, and maintenance therapy in adult patients.

MDD affects 15 million American adults -- between 5 and 8 percent of the population each year -- and today it is often treated with generic or branded antidepressants. Studies have shown that at least one-third of patients with MDD treated with antidepressants fail to achieve a satisfactory response. The American Psychiatric Association Practice Guidelines recommend switching to a medication in another class when two medications from the same class have proven ineffective. AstraZeneca has investigated the use of SEROQUEL XR, an atypical antipsychotic, in the treatment of MDD, aiming to develop another potential treatment option, including treatment for patients who have failed or had an inadequate response to another antidepressant therapy.

The MDD submission is based on seven Phase III, placebo-controlled studies that assessed the efficacy and safety of once-daily treatment with SEROQUEL XR in patients diagnosed with MDD. Studies 1, 2, 3, and 4 were acute monotherapy studies involving 2,116 patients; Studies 6 and 7 were acute adjunct therapy studies (with ongoing antidepressant therapy) involving 939 patients who had an inadequate response to an antidepressant therapy; and Study 5 was a longer-term (up to 78 weeks) monotherapy maintenance study involving 1,854 patients. The acute studies included in this submission used the Montgomery-Asberg Depression Rating Scale (MADRS)* as the primary assessment of depression symptoms. In the longer-term study (Study 5), the primary assessment was time to a depressed event using criteria including the MADRS. Doses of 50 mg, 150 mg and 300 mg of SEROQUEL XR were studied in the MDD program.

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. Last month, 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. The FDA has not completed its review of these submissions. In addition to the submission for MDD, clinical development programs are ongoing and regulatory filings are planned for SEROQUEL XR in other indications.

Launched in 1997, SEROQUEL(R) (quetiapine fumarate tablets) has been prescribed to millions of patients worldwide. It is approved in 88 countries for the treatment of schizophrenia, in 79 countries for the treatment of bipolar mania, and in 11 countries including the U.S. for the treatment of bipolar depression.

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.

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%), and orthostatic hypotension (7% vs 5%).

In long-term clinical trials of quetiapine, hyperglycemia (fasting glucose 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 (http://www1.astrazeneca-us.com/pi/seroquel.pdf) and SEROQUEL XR (http://www1.astrazeneca-us.com/pi/seroquelxr.pdf).

About Major Depressive Disorder

Major depressive disorder is a serious medical illness affecting 15 million American adults, or approximately 5 to 8 percent of the adult population in a given year. Depression occurs twice as frequently in women as in men. Unlike normal emotional experiences of sadness, loss, or passing mood states, major depressive disorder is persistent and can significantly interfere with an individual's thoughts, behavior, mood, activity, and physical health. Among all medical illnesses, major depressive disorder is the leading cause of disability in the U.S. and many other developed countries.

Symptoms of major depressive disorder characteristically represent a significant change from how a person functioned before the illness. The symptoms of depression include: persistently sad or irritable mood; pronounced changes in sleep, appetite, and energy; difficulty thinking, concentrating, and remembering; physical slowing or agitation; lack of interest in or pleasure from activities that were once enjoyed; feelings of guilt, worthlessness, hopelessness, and emptiness; recurrent thoughts of death or suicide; and persistent physical symptoms for two or more weeks that do not respond to treatment, such as headaches, digestive disorders, and chronic pain. Symptomatically, a major depressive episode in MDD is similar to a depressive episode of bipolar disorder with the major distinguishing feature between the disorders being the absence of manic or hypomanic symptoms in MDD. It has been reported that 69 percent of patients with bipolar disorder were misdiagnosed, with the most frequent misdiagnosis being MDD.

Without treatment, the frequency of depressive illness as well as the severity of symptoms tends to increase over time. Left untreated, depression can lead to suicide.