Maintenance therapy with the Bristol-Myers Squibb Company (NYSE: BMY) and
Otsuka Pharmaceutical Co., Ltd. atypical antipsychotic ABILIFY(R)
(aripiprazole) for nearly two years significantly delayed time to relapse
in adults with Bipolar I Disorder who had a recent manic or mixed episode
and were then stabilized with the medication for at least six weeks,
according to findings published in a supplement to Neuropsychopharmacology.
The results - from the longest double-blind, randomized, placebo-controlled
study reported to date investigating the treatment of Bipolar I Disorder
with ABILIFY - were based on rigorous criteria used to define stability for
Bipolar I Disorder.
"Bipolar I Disorder is a lifelong episodic illness. These findings are
important because they support existing ABILIFY data for delaying the
recurrence of mood symptoms," said Roger S. McIntyre, MD, Head, Mood
Disorders Psychopharmacology Unit, University Health Network, Associate
Professor of Psychiatry and Pharmacology, University of Toronto. "In fact,
a recent study showed that nearly 50 percent of individuals who responded
to initial treatment had relapses within two years, underscoring the
importance of long- term maintenance treatment."
Bipolar I Disorder can be treated with antipsychotic medications.
ABILIFY is indicated for the treatment of acute manic and mixed episodes
associated with Bipolar I Disorder, and for maintaining efficacy in adults
with Bipolar I Disorder with a recent manic or mixed episode who had been
stabilized and then maintained for at least six weeks. ABILIFY is one of
only two atypical antipsychotics indicated for maintenance therapy in
Bipolar I Disorder. Physicians who elect to use ABILIFY(R) (aripiprazole)
for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Study Design and Findings
In this double-blind, randomized, placebo-controlled long-term study,
adults with Bipolar I Disorder who had recently been hospitalized and
treated for a manic or mixed episode were initially stabilized with ABILIFY
monotherapy (15 or 30 mg/day for 6-18 weeks). In the open-label
stabilization phase, the adults in the study were required to maintain a
total score of 10 or less on the Young Mania Rating Scale (Y-MRS) and 13 or
less on the Montgomery-Asberg Depression Rating Scale (MADRS) for six
consecutive weeks prior to randomization into the double-blind phase. One
hundred and sixty one adults were randomly assigned to ABILIFY (n=78) or
placebo (n=83) in a double- blind fashion and monitored for relapse. The
primary endpoint was time to relapse for a manic, mixed, or depressive
episode up to and including Week 26. Relapse was defined by a
discontinuation from the study attributed to a lack of efficacy (indicated
by hospital admission for a mood episode, or addition to or increase in
psychotropic medication other than ABILIFY to treat affective symptoms).
Adults who completed the 26-week phase of the trial were allowed to
continue in a double-blind fashion with aripiprazole or placebo for an
additional 74 weeks (for a maximum of 100 weeks). This study was terminated
when a pre-determined number of subjects had relapsed for the primary
endpoint.
Of the 161 adults who entered the trial, 67 completed the 26-week phase
(ABILIFY n=39, placebo n=28). Sixty-six adults entered the 74-week phase
(ABILIFY n=39, placebo n=27). Of these adults, 30 discontinued due to
various reasons (ABILIFY n=18, placebo n=12), 24 discontinued prematurely
due to study termination (ABILIFY n=14, placebo n=10), and 12 completed the
additional 74 weeks of treatment (ABILIFY n=7, placebo n=5). Such drop-out
rates are common in long-term studies of people with Bipolar I Disorder.
The study showed in adults with up to 100 weeks of treatment, ABILIFY
continued to delay the time to relapse (manic, depressive, or mixed)
compared to placebo (hazard ratio=0.53, p-value equals 0.011). The majority
of the relapses were due to manic rather than depressive symptoms. There is
insufficient data to know whether ABILIFY is effective in delaying the time
to occurrence of depression in adults with Bipolar I Disorder.
These results were consistent with those previously reported in the 26-
week findings, which showed that ABILIFY delayed the time to relapse
(manic, depressive, or mixed) compared to placebo (hazard ratio=0.52,
p-value equals 0.02). In addition, compared to adults treated with placebo,
those treated with ABILIFY(R) (aripiprazole) experienced significantly
fewer relapses (25% vs 43%, p-value equals 0.013) and fewer manic relapses
(8% vs 23%, p-value equals 0.009).
In this study (up to and including 100 weeks of treatment), adverse
events reported at an incidence of 5% or more with ABILIFY and at least
twice the rate of placebo were the following: flu syndrome (5.2% vs 0%),
pharyngitis (5.2% vs 2.4%), abnormal thinking (5.2% vs 2.4%), vaginitis
(6.4% vs 0%), weight gain (6.5% vs 0%), hypertension (7.8% vs 3.6%), dry
mouth (7.8% vs 1.2%), akathisia (7.8% vs 1.2%), and tremor (9.1% vs 1.2%).
The safety profile was generally consistent with data reported in other
long-term placebo controlled trials of ABILIFY including changes in weight,
prolactin, QTc, and extrapyramidal symptoms.
About Bipolar Disorder
Bipolar disorder, formerly called manic-depressive illness, is a
condition that affects more than two million Americans. People who have
this illness tend to experience extreme mood swings, along with other
specific symptoms and behaviors. These mood swings or "episodes" can take
three forms: manic episodes, depressive episodes, or "mixed" episodes. The
symptoms of bipolar disorder are thought to be caused by an imbalance of
key chemicals in the brain. Although there is no cure for bipolar disorder,
medicine can play a key role in helping to manage symptoms and extreme mood
swings.
About ABILIFY
The first and only available dopamine partial agonist, ABILIFY is
indicated for the treatment of schizophrenia including maintaining
stability in adults who had been symptomatically stable on other
antipsychotic medications for periods of three months or longer and
observed for relapse during a period of up to 26 weeks. ABILIFY is also
indicated for the treatment of acute manic and mixed episodes associated
with Bipolar I Disorder, and for maintaining efficacy in adults with
Bipolar I Disorder with a recent manic or mixed episode who had been
stabilized and then maintained for at least six (6) weeks. Physicians who
elect to use ABILIFY for extended periods should periodically re-evaluate
the long-term usefulness of the drug for the individual. Initially approved
in November 2002, ABILIFY is the fastest-growing atypical antipsychotic in
the United States with over nine million prescriptions written through May
2006.
ABILIFY(R) (aripiprazole) is available by prescription only. The
effective dose range for adults living with schizophrenia is 10-30 mg/day
and 15 or 30 mg/day for adults living with Bipolar I Disorder. ABILIFY
tablets are available in 2-, 5-, 10-, 15-, 20- and 30-mg strengths. ABILIFY
DISCMELT(TM) Orally Disintegrating Tablets are available in 10 mg and 15 mg
strengths. ABILIFY is also available in a 1 mg/mL nonrefrigerated oral
solution. The FDA recently approved ABILIFY Injection, an injectable form
of ABILIFY, for intramuscular use. The safety of doses of ABILIFY above 30
mg/day has not been evaluated in clinical trials.
ABILIFY is taken once daily with or without food. It is important to
talk to a healthcare professional for more information about ABILIFY.
IMPORTANT SAFETY INFORMATION for ABILIFY:
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).
-- 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
-- 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
-- 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(R) (aripiprazole)
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.
As antipsychotics have been associated with esophageal dysmotility and
aspiration, ABILIFY should be used cautiously in patients at risk for
aspiration pneumonia.
As the possibility of a suicide attempt is inherent in psychotic
illness and bipolar disorder, close supervision of high-risk patients
should accompany drug therapy. Prescriptions for ABILIFY should be written
for the smallest quantity consistent with good patient management to reduce
the risk of overdose.
Physicians should determine if a patient is pregnant or intends to
become pregnant while taking ABILIFY. Patients should be advised not to
breast-feed while taking ABILIFY.
Physicians should advise patients to avoid alcohol while taking
ABILIFY.
Both CYP3A4 and CYP2D6 are responsible for ABILIFY metabolism. Agents
that induce CYP3A4 (eg, carbamazepine) could cause an increase in ABILIFY
clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole)
or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit ABILIFY
elimination and cause increased blood levels.
Commonly observed adverse events (greater than or equal to 5% incidence
and at a rate at least twice the rate of placebo for ABILIFY vs placebo,
respectively):
ABILIFY Oral
In 3-week bipolar mania trials the following were reported: akathisia (15%
vs 3%), constipation (13% vs 6%), sedation (8% vs 3%), tremor (7% vs 3%),
restlessness (6% vs 3%), and extrapyramidal disorder (5% vs 2%).
In 4-6-week schizophrenia trials the following was reported: akathisia (8%
vs 4%).
A similar adverse event profile was observed in a 26-week trial in
schizophrenia except for a higher incidence of tremor (ABILIFY 8% vs.
placebo 2%)
ABILIFY Injection
In short-term (24-hour) trials in patients with agitation associated with
schizophrenia or bipolar mania the following was reported: nausea (9% vs
3%)
Treatment-emergent adverse events reported with:
ABILIFY Oral
In short-term trials of patients with schizophrenia (up to 6-weeks) or
bipolar disorder (up to 3-weeks) the following were reported at an
incidence greater than or equal to 10% and greater than placebo,
respectively, include headache (30% vs 25%), anxiety (20% vs 17%),
insomnia (19% vs 14%), nausea (16% vs 12%), vomiting (12% vs 6%),
dizziness (11% vs 8%), constipation (11% vs 7%), dyspepsia (10% vs 8%),
and akathisia (10% vs 4%).
ABILIFY Injection
Treatment-emergent adverse events reported with ABILIFY Injection in
short-term (24-hour) trials at an incidence greater than or equal to 5%
and greater than placebo, respectively, include headache (12% vs 7%),
nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).
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. The brand
name ABILIFY is registered to Otsuka Pharmaceutical Co., Ltd. Founded in
1964, Otsuka Pharmaceutical Co., Ltd. is a healthcare company with the
mission statement: "Otsuka - people creating new products for better health
worldwide." Otsuka researches, develops, manufactures and markets
innovative, original products, focusing its core businesses on
pharmaceutical products for the treatment of disease and consumer products
for the maintenance of everyday health. The Otsuka Pharmaceutical Group
comprises 87 companies and employs approximately 27,000 people in 17
countries and regions worldwide. Otsuka and its consolidated subsidiaries
earned US $6.8 billion in consolidated annual revenues in fiscal 2005.
Bristol-Myers Squibb is a global pharmaceutical and related health care
products company whose mission is to extend and enhance human life.
Bristol-Myers Squibb
bms
View drug information on Abilify.
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