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Abilify for Pediatric Patients
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U.S. Food and Drug Administration Approves ABILIFY
(R)(aripiprazole) for the Acute Treatment of Manic
and Mixed Episodes Associated With Bipolar I
Disorder in Pediatric Patients (10 to 17 Years of
Age)
- Otsuka-sponsored Study Evaluated Use of ABILIFY In This Patient
Population -
TOKYO and PRINCETON, N.J., Feb. 29 -- Otsuka
Pharmaceutical Co., Ltd. and Bristol-Myers Squibb Company (NYSE: BMY)
announced today that the U.S. Food and Drug Administration (FDA) approved
the supplemental New Drug Application for ABILIFY(R) (aripiprazole) for the
acute treatment of manic and mixed episodes associated with Bipolar I
Disorder, with or without psychotic features in pediatric patients (10 to
17 years old). ABILIFY has been approved for the acute and maintenance
treatment of manic and mixed episodes associated with Bipolar I Disorder
with or without psychotic features in adults since September 2004 and March
2005, respectively.
"Pediatric bipolar illness is a serious condition," said Christoph
Correll, M.D., Medical Director, Recognition and Prevention Program, The
Zucker Hillside Hospital and Assistant Professor of Psychiatry and
Behavioral Sciences, Albert Einstein College of Medicine, Glen Oaks, New
York. "The availability of an additional treatment option that can help
guide decisions in managing Bipolar I Disorder in children and adolescents
is welcome news."
The approval is based on results from a four-week, multicenter,
randomized, double-blind, placebo-controlled study in pediatric patients
(10 to 17 years old) with Bipolar I Disorder that demonstrated efficacy
with ABILIFY compared to placebo on the primary efficacy endpoint, mean
change from baseline to Week 4 on the Young-Mania Rating Scale (Y-MRS)
Total Score.
"We are pleased that the FDA has approved ABILIFY to treat pediatric
patients aged 10 to 17 years suffering from Bipolar I Disorder," said Taro
Iwamoto, Ph.D., Chief Executive Officer, President and Chief Operating
Officer, Otsuka Pharmaceutical Development and Commercialization, Inc. "The
approval of this new indication for ABILIFY provides clinicians with
expanded treatment options that can help address the therapeutic needs of
this population."
"We are committed to developing innovative new medicines to their
fullest potential," said Elliott Sigal, M.D., Ph.D., Executive Vice
President, Chief Scientific Officer and President, Research and
Development, Bristol-Myers Squibb. "Expanding the clinical use of an
important therapy such as ABILIFY gives pediatric patients with Bipolar I
Disorder and their caregivers a new treatment option in their fight against
this serious disease."
Clinical Trial Design and Findings
These findings are from a four-week, multicenter, randomized,
double-blind, placebo-controlled study, which evaluated the efficacy and
safety of ABILIFY in 296 pediatric patients (10 to 17 years old) with a
DSM-IV diagnosis of Bipolar I Disorder, manic or mixed episodes, with or
without psychotic features. Diagnosis was made by a trained child and
adolescent psychiatrist and confirmed by a separate diagnostic interview.
This study was conducted on an outpatient basis with the possibility of
inpatient hospitalization, as needed. This clinical trial was sponsored by
Otsuka Pharmaceutical Co., Ltd. and its U.S. subsidiary, Otsuka
Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ) with
enrollment at 54 U.S. centers.
After a screening period of up to four weeks, pediatric patients (10 to
17 years old) who scored greater than or equal to 20 on the Y-MRS* were
randomly assigned to receive one of two fixed doses of ABILIFY [10 mg/day
(n=98) or 30 mg/day (n=99)] or placebo (n=99). ABILIFY was initiated at a
starting dose of 2 mg/day and titrated to the target dose of 10 mg/day or
30 mg/day.
The primary efficacy endpoint was the mean change in the Y-MRS Total
Score from baseline to Week 4. Safety evaluations included incidence of
adverse reactions, discontinuation due to adverse reactions, laboratory
measures and body weight.
For the primary endpoint, both doses of ABILIFY demonstrated
statistically significant improvement in symptoms when compared to placebo
(p-value less than 0.0001) as measured by the mean change from baseline to
endpoint (Week 4) on the Y-MRS Total Score. The efficacy of ABILIFY for the
maintenance treatment of Bipolar I Disorder in the pediatric population has
not been evaluated.
Approximately 80% of patients completed the four-week study (ABILIFY 10
mg: 86%; ABILIFY 30 mg: 78%; placebo: 77%). There was a low rate of
discontinuation due to adverse reactions at Week 4 (ABILIFY: 7%; placebo:
2%).
During the study, the most commonly observed adverse reactions (greater
than or equal to 5% in combined ABILIFY groups and at least twice the rate
of placebo) associated with ABILIFY were: somnolence (ABILIFY: 23%;
placebo: 3%), extrapyramidal disorder (ABILIFY: 20%; placebo: 3%), fatigue
(ABILIFY: 11%; placebo: 4%), nausea (ABILIFY: 11%; placebo: 4%), akathisia
(ABILIFY: 10%; placebo: 2%), blurred vision (ABILIFY: 8%; placebo: 0%),
salivary hypersecretion (ABILIFY: 6%; placebo: 0%) and dizziness (ABILIFY:
5%; placebo: 1%). Four common adverse reactions had a possible
dose-response relationship at Week 4: extrapyramidal disorder (ABILIFY 10
mg: 12.2%; ABILIFY 30 mg: 27.3%; placebo: 3.1%), somnolence (ABILIFY 10 mg:
19.4%; ABILIFY 30 mg: 26.3%; placebo: 3.1%), akathisia (ABILIFY 10 mg:
8.2%; ABILIFY 30 mg: 11.1%; placebo: 2.1%) and salivary hypersecretion
(ABILIFY 10 mg: 3.1%; ABILIFY 30 mg: 8.1%; placebo: 0%). Children and
adolescents might be more sensitive than adults in developing
antipsychotic-related adverse events.(1)
In the study, weight gain greater than or equal to 7% change from
baseline was seen in 3.2%, 9.4% and 3.3% for the ABILIFY 10 mg, ABILIFY 30
mg and placebo groups, respectively. The mean change from baseline to Week
4 in body weight was 0.6 kilograms (kg) for ABILIFY 10 mg, 0.9 kg for
ABILIFY 30 mg and 0.5 kg for placebo.
In this study, ABILIFY demonstrated no clinically important differences
on prolactin and the following metabolic parameters: triglyceride, HDL-C,
LDL-C and total cholesterol. All treatment groups showed a reduction in
mean serum prolactin levels at last visit relative to baseline.
About ABILIFY(R) (aripiprazole)
The first and only available dopamine partial agonist, ABILIFY is
indicated for the treatment of acute manic or mixed episodes associated
with Bipolar I Disorder in adults and pediatric patients (10 to 17 years
old). ABILIFY(R) (aripiprazole) Injection is indicated for the treatment of
adults with agitation associated with Bipolar I Disorder, manic or mixed.
Initially approved in November 2002, over 14.9 million prescriptions
have been written for ABILIFY in the U.S.(2) through December 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. ABILIFY(R) DISCMELT(TM)
(aripiprazole) Orally Disintegrating Tablets are available in 10 mg and 15
mg strengths. In addition, ABILIFY is available in a 1 mg/mL
nonrefrigerated Oral Solution and as a single-dose, ready-to-use solution
for intramuscular injection 7.5 mg/mL. In adult patients, the recommended
ABILIFY(R) (aripiprazole) Oral target dose is 15 mg/day to 30 mg/day in
Bipolar I Disorder. In pediatric patients (10 to 17 years old) with Bipolar
I Disorder, the recommended ABILIFY Oral target dose is 10 mg/day (with a
starting dose of 2 mg/day which was titrated to 5 mg/day after 2 days and
to the target dose of 10 mg/day after 2 additional days). In adult patients
with agitation associated with bipolar mania, the ABILIFY Injection initial
dose is 9.75 mg/1.3 mL. If ongoing ABILIFY therapy is clinically indicated,
oral ABILIFY in a range of 10 mg/day to 30 mg/day should replace ABILIFY
Injection as soon as possible. The safety of doses of ABILIFY Oral or
ABILIFY Injection above 30 mg/day has not been evaluated in clinical
trials.
IMPORTANT SAFETY INFORMATION and INDICATIONS for ABILIFY
INDICATIONS:
-- ABILIFY is indicated for acute and maintenance treatment of adults
with manic or mixed episodes associated with Bipolar I Disorder with
or without psychotic features
-- ABILIFY is indicated for acute treatment of pediatric patients (10 to
17 years old) with manic or mixed episodes associated with Bipolar I
Disorder with or without psychotic features
-- ABILIFY Injection is indicated for the treatment of adults with
agitation associated with Bipolar I Disorder, manic or mixed.
IMPORTANT SAFETY INFORMATION:
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). 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) and other
psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or
another antidepressant in a child, adolescent, or young adult must balance
this risk with the clinical need. Short-term studies did not show an
increased risk of suicidality in adults beyond age 24. Depression and
certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. 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. Families and caregivers should be advised for the need for close
observation and communication with the prescriber. ABILIFY is not approved
for use in pediatric patients with depression (See Boxed WARNING).
Contraindications: Known hypersensitivity reaction to ABILIFY.
Reactions have ranged from pruritus/urticaria to anaphylaxis.
Cerebrovascular adverse reactions (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.
Esophageal dysmotility and aspiration have been associated with
antipsychotic drug use, including ABILIFY; use caution in patients at risk
for aspiration pneumonia.
The possibility of a suicide attempt is inherent in psychotic
illnesses, bipolar disorder, and major depressive disorder, and close
supervision of high-risk patients should accompany drug therapy.
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%
incidence and at least twice the rate of placebo for ABILIFY vs placebo,
respectively):
-- Adult patients with bipolar mania: constipation (13% vs 6%), akathisia
(15% vs 3%), sedation (8% vs 3%), tremor (7% vs 3%), restlessness
(6% vs 3%), and extrapyramidal disorder (5% vs 2%)
-- Pediatric patients (10 to 17 years) with Bipolar I Disorder:
somnolence (23% vs 3%), extrapyramidal disorder (20% vs 3%), fatigue
(11% vs 4%), nausea (11% vs 4%), akathisia (10% vs 2%), blurred vision
(8% vs 0%), salivary hypersecretion (6% vs 0%), and dizziness
(5% vs 1%)
-- Adult patients with agitation associated with bipolar mania: nausea
(9% vs 3%)
Please see FULL PRESCRIBING INFORMATION, including Boxed WARNINGS, for
ABILIFY.
About Otsuka Pharmaceutical Co., Ltd. and Bristol-Myers Squibb
Otsuka Pharmaceutical Co., Ltd. and Bristol-Myers Squibb 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 18 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 biopharmaceutical and related
healthcare products company whose mission is to extend and enhance human
life.
For more information and FULL PRESCRIBING INFORMATION,
including Boxed WARNINGS, visit: http://www.abilify.com
Visit Otsuka Pharmaceutical Co., Ltd. at: http://www.otsuka-global.com
Visit Bristol-Myers Squibb at: http://www.bms.com
February 2008 0308N-0662
* The Y-MRS is a standard measure that is an 11-item rating scale used
by healthcare providers to assess the scope and severity of manic
symptoms.(1) Y-MRS Total Scores range from 0 (no manic symptoms) to 60
(severe mania).(2)
(1) Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for
mania: reliability, validity, and sensitivity. Br J Psychiatry.
1978;133:429-435.
(2) Rush AJ, et al. Handbook of Psychiatric Measures. Washington, DC:
American Psychiatric Association; 2000.
References
(1) Kumra S, Oberstar JV, Sikich L, Findling RL, McClellan JM, Vinogradov
S, Schulz SC. Efficacy and Tolerability of Second-Generation
Antipsychotics in Children and Adolescents With Schizophrenia.
Schizophrenia Bulletin. Published online October 8, 2007.
(2) IMS Auditrac NGPS: ABILIFY total monthly retail prescriptions: Data
accessed December 2007.
SOURCE Otsuka Pharmaceutical Co., Ltd.
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Reviewed: 02/2008
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