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News Release - November 20, 2007
U.S. Food and Drug Administration Approves ABILIFY(R) (aripiprazole) as the First Medication for Add-On Treatment of Major Depressive Disorder (MDD)ABILIFY Used With Another Antidepressant Can Help Adults Living With Depression Who Have Failed to Achieve Adequate Symptom Relief -(1)
PRINCETON, N.J. and TOKYO, Nov. 20 (HSMN NewsFeed) -- Bristol-Myers Squibb Company (NYSE: BMY ) and Otsuka Pharmaceutical Co., Ltd. announced today that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application for ABILIFY® (aripiprazole) as adjunctive, or add-on, treatment to antidepressant therapy (ADT) in adults with major depressive disorder (MDD). ABILIFY is the first medication approved by the FDA as add-on treatment for MDD.
"The approval of this new add-on treatment option is critical for adults suffering from depression who cannot find sufficient relief for their symptoms with antidepressants alone," said Madhukar Trivedi, M.D., Professor and Chief- Division of Mood Disorders, University of Texas Southwestern Medical School, Dallas, Texas. "Now physicians have a proven new option they can add to their patients' antidepressant treatments to help them feel better and relieve unresolved depressive symptoms."
The approval is based on results from two six-week, double-blind, randomized, placebo-controlled, multicenter studies (n=743). The results from both studies demonstrated significant improvement in depressive symptoms in adult patients with a primary diagnosis of major depressive disorder who had experienced an inadequate response* to monotherapy with one or more ADTs in the current episode and then added ABILIFY to their treatment regimens.
"We are committed to helping those who suffer from depression, one of the leading causes of disability in the United States and worldwide," said Elliott Sigal, M.D., Ph.D., Executive Vice President, Chief Scientific Officer and President, Research and Development, Bristol-Myers Squibb. "This approval is a reflection of our ongoing commitment to provide innovative therapies, such as ABILIFY, to help adults living with depression."
"We are pleased that ABILIFY has achieved this important milestone as the first medication approved as adjunctive treatment for adults with major depressive disorder," said Taro Iwamoto, Ph.D., Chief Executive Officer, President and Chief Operating Officer, Otsuka Pharmaceutical Development and Commercialization, Inc. "This new add-on treatment option for depression represents hope for many adults suffering from this debilitating illness."
Major depressive disorder affects millions of U.S. adults at some point in their lives.(2) A recent study evaluated different treatment approaches, including adjunctive medications and switching strategies, in patients with MDD.(1) The study found that 63 percent of patients did not achieve adequate relief of depressive symptoms following the initial treatment with an antidepressant alone.(1) Additionally, the study demonstrated that the use of adjunctive medications in treatment may be useful to improve unresolved depressive symptoms.(1)
Clinical Trial Design and Findings
Two six-week, double-blind, randomized, placebo-controlled, multicenter studies evaluated the efficacy and safety of add-on ABILIFY in adult patients with a primary diagnosis of major depressive disorder who had experienced an inadequate response to prior antidepressant therapy (one to three courses) in the current episode.
After an eight-week prospective treatment phase with one ADT plus single- blind placebo to confirm inadequate response to ADT, 743 participants entered a six-week randomized treatment phase during which they continued their ADT plus double-blind adjunctive placebo or adjunctive ABILIFY. All study participants received one of the commonly prescribed ADTs, including selective serotonin reuptake inhibitors (SSRIs): Lexapro® (escitalopram), Prozac® (fluoxetine), Paxil CR® (paroxetine controlled-release), Zoloft® (sertraline); or a serotonin-norepinephrine reuptake inhibitor (SNRI): Effexor XR® (venlafaxine extended release). The dosage range for adjunctive ABILIFY was 2-20 mg/day (15 mg/day was the maximum dose for patients receiving ABILIFY as an adjunct to Paxil CR or Prozac).
The primary efficacy endpoint was the mean change from baseline -- the end of the prospective treatment phase -- to the end of the randomized treatment phase in a standard measure called Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess depressive symptoms. A reduction in MADRS Total Score represents an improvement in depressive symptoms. The key secondary endpoint was the Sheehan Disability Scale (SDS), a three-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life and family life) with each item scored from zero (not at all) to 10 (extreme). Safety evaluations included incidence of adverse reactions, discontinuation rate due to adverse reactions and laboratory measures.
For the primary endpoint, both studies showed that taking ABILIFY plus an ADT provided superior improvement in depressive symptoms to ADT alone at study endpoint (week six), as measured by the reduction of the MADRS Total Scores.(3) For the secondary endpoint, ABILIFY plus an ADT was also superior to placebo plus ADT in reducing the mean SDS Total Score in one study.
In these studies, adjunctive ABILIFY demonstrated no clinically important differences on metabolic parameters, including prolactin, fasting glucose, HDL, LDL and total cholesterol. The median percent change from baseline in triglycerides was 5 percent for adjunctive ABILIFY-treated patients vs 0 percent for adjunctive placebo-treated patients. In the studies, weight gain greater than or equal to 7 percent increase from baseline was seen in 5 percent of adult patients treated with adjunctive ABILIFY and 1 percent of adjunctive placebo-treated patients. The mean change from baseline in weight was 1.7 kilograms (kg) for adjunctive ABILIFY and 0.4 kg for adjunctive placebo.
In a pool of two placebo-controlled trials of patients, the rate of discontinuation due to adverse reactions with the use of adjunctive ABILIFY compared to placebo plus ADT was 6 percent vs 2 percent, respectively. The most commonly observed adverse reactions (incidence greater than or equal to 5 percent and at least twice the incidence of placebo plus ADT) associated with the use of adjunctive ABILIFY were akathisia (25 percent vs 4 percent), restlessness (12 percent vs 2 percent), insomnia (8 percent vs 2 percent), constipation (5 percent vs 2 percent), fatigue (8 percent vs 4 percent) and blurred vision (6 percent vs 1 percent).
About Major Depressive Disorder
Major depressive disorder is a serious mental illness(4)characterized by one or more major depressive episodes.(5) Depression affects approximately 13 to 14 million adults,(2) or about 6.7 percent of the adult population in a given year,(6) and is one of the most common mental health disorders.(7) Depression is one of the leading causes of disability in the U.S.(8) In 2000, the total economic burden of treating depression in the U.S. was $83.1 billion, with workplace costs, including missed days and lack of productivity due to illness, accounting for the majority of the total economic burden (62 percent).(9) Other economic burdens in 2000 included $26.1 billion (31 percent) for treatment costs and $5.4 billion (7 percent) for suicide- related costs.(9)
The first and only available dopamine partial agonist, ABILIFY is indicated as adjunctive treatment to antidepressant therapy in adults with major depressive disorder.
Initially approved in November 2002, over 12.5 million prescriptions have been written for ABILIFY in the U.S.(10) through June 2007.
ABILIFY is available by prescription only. ABILIFY Tablets should be taken once daily with or without food and are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths. As adjunctive treatment to antidepressant therapy in adults with major depressive disorder, ABILIFY Oral starting dose is 2 mg/day to 5 mg/day with a maximum dose of 15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week.
IMPORTANT SAFETY INFORMATION and INDICATIONS for ABILIFY
-- ABILIFY is indicated for use as an adjunctive treatment to antidepressants for major depressive disorder in adults.
IMPORTANT SAFETY INFORMATION:
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ABILIFY is not approved for the treatment of patients with dementia-related psychosis (see Boxed WARNING).
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD). Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of therapy, or at times of dose changes. ABILIFY is not approved for use in pediatric patients with depression (See Boxed WARNING).
Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, have been reported at an increased incidence in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY
Neuroleptic malignant syndrome (NMS)-As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with ABILIFY. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. If signs and symptoms appear, immediate discontinuation is recommended
Tardive dyskinesia (TD)-The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered since TD may remit, partially or completely
Hyperglycemia and diabetes mellitus-Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including ABILIFY. Patients with diabetes should be monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. There have been few reports of hyperglycemia with ABILIFY
ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.
As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.
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.
The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy.
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY; use caution in patients at risk for aspiration pneumonia.
Physicians should advise patients to avoid alcohol while taking ABILIFY.
Strong CYP3A4 or CYP2D6 inhibitors increase ABILIFY drug concentrations when used concomitantly.
CYP3A4 inducers decrease ABILIFY drug concentrations when used concomitantly.
Commonly observed adverse reactions (greater than or equal to 5 percent incidence and at least twice the rate of placebo for adjunctive ABILIFY vs adjunctive placebo, respectively):
-- Adult patients with major depressive disorder: akathisia (25 percent vs 4 percent), restlessness (12 percent vs 2 percent), insomnia (8 percent vs 2 percent), constipation (5 percent vs 2 percent), fatigue (8 percent vs 4 percent), and blurred vision (6 percent vs 1 percent).
Please see FULL PRESCRIBING INFORMATION, including Boxed WARNING, for ABILIFY.
About Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd.
Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. are collaborative partners in the development and commercialization of ABILIFY in the United States and major European countries.
ABILIFY was discovered by Otsuka Pharmaceutical Co., Ltd. Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: "Otsuka - people creating new products for better health worldwide." Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment. The Otsuka Pharmaceutical Group comprises 99 companies and employs approximately 31,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned U.S. $7.2 billion in annual revenues in fiscal 2006.
Bristol-Myers Squibb is a global pharmaceutical and related healthcare products company whose mission is to extend and enhance human life.
For more information and FULL PRESCRIBING INFORMATION, including Boxed WARNING, visit: www.abilify.com Visit Bristol-Myers Squibb at: www.bms.com Visit Otsuka Pharmaceutical Co., Ltd. at: www.otsuka-global.com
* Inadequate response for prospective treatment was defined as less than 50 percent improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement.
(1) Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psych. 2006;163:1905-1917.
(2) Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA. June 18 2003;289(23):3095-3105.
(3) Berman RM, Marcus RN, Swanink R, et al. The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2007;68:843-853.
(4) National Alliance on Mental Illness (NAMI) Web site. About Mental Illness: Major Depression. 2006. Accessed August 2007.
(5) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text revision. Washington DC, American Psychiatric Association, 2000.
(6) Kessler RC, Chiu WT, Demler OD, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry. 2005;62:617-627.
(7) Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
(8) Michaud CM, McKenna MT, Begg S, et al. The burden of disease and injury in the United States 1996. Population Health Metrics. 2006;4:11.
(9) Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: How did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-1475.
(10) IMS Auditrac NGPS: ABILIFY total monthly retail prescriptions: Data accessed July 2007.
Source: Bristol-Myers Squibb
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