The FDA ( Food and Drug Administration ) 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.

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

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.
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 ) ( > 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% ).

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.
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 ) ( > 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% ).

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.

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

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 neuroleptic malignant syndrome 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/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. Tardive dyskinesia 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 > 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 ).

Source: AstraZeneca, 2008

XagenaMedicine2008



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