TOKYO, Japan & VALBY, Denmark--(BUSINESS WIRE)--Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Lundbeck today announced
the U.S. Food and Drug Administration (FDA) has determined that the
supplemental New Drug Application (sNDA) for the expanded labeling of
ABILIFY MAINTENA® for the maintenance treatment of bipolar I disorder in
adult patients is sufficiently complete to permit a substantive review
and is considered filed. Under the Prescription Drug User Fee Act
(PDUFA), the FDA has set a target date of July 28, 2017, to complete its
“Otsuka – people creating new products for better health
About ABILIFY MAINTENA
ABILIFY MAINTENA is an extended-release injectable suspension, for
intramuscular use developed by Otsuka in Japan and is co-commercialized
by the alliance between Otsuka and H. Lundbeck. ABILIFY MAINTENA was
approved in the U.S. in 2013 for the treatment of adults with
schizophrenia.1 Efficacy and safety for ABILIFY MAINTENA is
supported by a short-term (12-week), randomized, double-blind,
placebo-controlled trial in acutely relapsed adults, as well as a longer
term (52-week) placebo-controlled, double-blind, randomized-withdrawal
study for the maintenance treatment of schizophrenia.2
ABILIFY MAINTENA, an atypical antipsychotic, is an intramuscular depot
formulation of aripiprazole.2 It is a sterile lyophilized
powder that, when reconstituted with sterile water for injection, forms
an injectable suspension that can be administered monthly.2
After an initial injection of ABILIFY MAINTENA along with an overlapping
14-day dosing of oral antipsychotic treatment, subsequent injections of
ABILIFY MAINTENA provide uninterrupted medication coverage for 30 days
at a time.2 It provides a treatment option to address two of
the most important considerations in the management of schizophrenia —
improving symptoms in patients with an acute relapse of their disease
and reducing the risk of relapse or the re-emergence of worsening of
symptoms.2 Depot formulations of antipsychotic agents provide
patients with concentrations of active drug that remain at a therapeutic
range for an extended period of time.3
About Bipolar I Disorder
Bipolar I disorder (BP-I) is a chronic mental illness.4
People with BP-I experience one or more episodes of mania, and may have
episodes of both mania and depression; however, an episode of depression
is not necessary for a BP-I diagnosis.4 The lifetime
prevalence of BP-I in the U.S. population is 2.6 percent with 89 percent
of these cases categorized as severe.5 If left untreated, the
manic and depressive symptoms may get worse.4
INDICATION and IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA®
ABILIFY MAINTENA is an atypical antipsychotic indicated for the
treatment of schizophrenia.
IMPORTANT SAFETY INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death
compared to placebo (4.5% vs 2.6%, respectively). Although the causes of
death were varied, most of the deaths appeared to be cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in
nature. ABILIFY MAINTENA is not approved for the treatment of patients
with dementia-related psychosis.
Contraindication: Known hypersensitivity reaction to
aripiprazole. Reactions have ranged from pruritus/urticaria to
Cerebrovascular Adverse Events, Including Stroke: Increased
incidence of cerebrovascular adverse events (e.g., stroke, transient
ischemic attack), including fatalities, have been reported in clinical
trials of elderly patients with dementia-related psychosis treated with
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom
complex sometimes referred to as NMS may occur with administration of
antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS
occurred during aripiprazole treatment. Signs and symptoms of NMS
include hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (e.g., 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: 1) immediate discontinuation of antipsychotic drugs and other
drugs not essential to concurrent therapy; 2) intensive symptomatic
treatment and medical monitoring; and 3) treatment of any concomitant
serious medical problems for which specific treatments are available.
Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of
abnormal, involuntary movements) and the potential for it to become
irreversible are believed to increase as the duration of treatment and
the total cumulative dose of antipsychotic increase. The syndrome can
develop, although much less commonly, after relatively brief treatment
periods at low doses. Prescribing should be consistent with the need to
minimize TD. There is no known treatment for established TD, although
the syndrome may remit, partially or completely, if antipsychotic
treatment is withdrawn.
Metabolic Changes: Atypical antipsychotic drugs have been
associated with metabolic changes that include:
Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases
extreme and associated with ketoacidosis, coma, or death, has been
reported in patients treated with atypical antipsychotics including
aripiprazole. Patients with diabetes should be regularly monitored for
worsening of glucose control; those with risk factors for diabetes
should undergo baseline and periodic fasting blood glucose testing.
Any patient treated with atypical antipsychotics should be monitored
for symptoms of hyperglycemia including polydipsia, polyuria,
polyphagia, and weakness. Patients who develop symptoms of
hyperglycemia should also undergo fasting blood glucose testing. In
some cases, hyperglycemia has resolved when the atypical antipsychotic
was discontinued; however, some patients required continuation of
anti-diabetic treatment despite discontinuation of the suspect drug.
Dyslipidemia: Undesirable alterations in lipids have been
observed in patients treated with atypical antipsychotics.
Weight Gain: Weight gain has been observed with atypical
antipsychotic use. Clinical monitoring of weight is recommended.
Pathological Gambling and Other Compulsive Behaviors: Intense
urges, particularly for gambling, and the inability to control these
urges have been reported while taking aripiprazole. Other compulsive
urges (e.g., eating, sexual, or shopping) have been reported less
frequently. Prescribers should ask patients or their caregivers
specifically about, and closely monitor for, the development of new or
intense compulsive urges. Consider dose reduction or stopping
aripiprazole, if such urges develop.
Orthostatic Hypotension: ABILIFY MAINTENA may cause orthostatic
hypotension and should be used with caution in patients with known
cardiovascular disease, cerebrovascular disease, or conditions which
would predispose them to hypotension.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia,
neutropenia, and agranulocytosis have been reported. In patients with a
history of clinically significant low white blood cell count
(WBC)/absolute neutrophil count (ANC) or history of drug-induced
leukopenia/neutropenia, perform a complete blood count (CBC) frequently
during the first few months of therapy. Consider discontinuing
ABILIFY MAINTENA at the first sign of a clinically significant decline
in WBC in the absence of other causative factors. Monitor patients with
clinically significant neutropenia for fever or other symptoms or signs
of infection and treat promptly if such symptoms or signs occur.
Discontinue ABILIFY MAINTENA in patients with severe neutropenia (ANC
<1000/mm3) and follow their WBC counts until recovery.
Seizures: ABILIFY MAINTENA should be used with caution in
patients with a history of seizures or with conditions that lower the
Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA
may impair judgment, thinking, or motor skills. Instruct patients to
avoid operating hazardous machinery, including automobiles, until they
are certain ABILIFY MAINTENA does not affect them adversely.
Body Temperature Regulation: Disruption of the body’s ability to
reduce core body temperature has been attributed to antipsychotic
agents. Advise patients regarding appropriate care in avoiding
overheating and dehydration. Appropriate care is advised for patients
who may exercise strenuously, may be exposed to extreme heat, receive
concomitant medication with anticholinergic activity, or are subject to
Dysphagia: Esophageal dysmotility and aspiration have been
associated with ABILIFY MAINTENA; use caution in patients at risk for
Alcohol: Advise patients to avoid alcohol while taking ABILIFY
Concomitant Medication: Dosage adjustments are recommended in
patients who are CYP2D6 poor metabolizers and in patients taking
concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14
days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the
ABILIFY MAINTENA dosage may need to be increased. Avoid the concomitant
use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days
because the blood levels of aripiprazole are decreased and may be below
the effective levels. Dosage adjustments are not recommended for
patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or
CYP3A4 inducers for less than 14 days.
Most Commonly Observed Adverse Reactions: Based on the
placebo-controlled trial of ABILIFY MAINTENA in schizophrenia, the most
commonly observed adverse reactions associated with the use of ABILIFY
MAINTENA (incidence of 5% or greater and aripiprazole incidence at least
twice that for placebo) were increased weight (16.8% vs 7.0%), akathisia
(11.4% vs 3.5%), injection site pain (5.4% vs 0.6%), and sedation (5.4%
Injection Site Reactions: In the data from the short-term,
double-blind, placebo-controlled trial with ABILIFY MAINTENA in patients
with schizophrenia, the percent of patients reporting any injection
site-related adverse reaction (all reported as injection site pain) was
5.4% for patients treated with gluteal administered ABILIFY MAINTENA and
0.6% for placebo. In an open label study comparing
bioavailability of ABILIFY MAINTENA administered in the deltoid or
gluteal muscle, injection site pain was observed in both groups at
approximately equal rates.
Dystonia: Symptoms of dystonia may occur in susceptible
individuals during the first days of treatment and at low doses.
Pregnancy: Neonates exposed to antipsychotic drugs, including
ABILIFY MAINTENA, during the third trimester of pregnancy are at risk
for extrapyramidal and/or withdrawal symptoms. These complications have
varied in severity, from being self-limited to requiring intensive care
and prolonged hospitalization. ABILIFY MAINTENA should be used during
pregnancy only if the potential benefits justify the potential risks to
Lactation: Aripiprazole is present in human breast milk. A
decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother
and any potential risks to the infant.
To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America
Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).
Please see accompanying FULL
PRESCRIBING INFORMATION, including BOXED WARNING, for
ABILIFY MAINTENA (aripiprazole).
1. Drug Approval Reports. U.S. Food and Drug Administration (FDA). 2013.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.MonthlyApprovalsAll.
Accessed November 11, 2014.
2. ABILIFY MAINTENA US (aripiprazole) 2016 Full prescribing information.
Tokyo: Otsuka Pharmaceutical Co., Ltd.
3. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot
as maintenance treatment in patients with schizophrenia: a 52-week,
multicenter, randomized, double- blind, placebo-controlled study.
Journal of Clinical Psychiatry. 2012; 73(5): 617-624.
4. Bipolar Disorder. National Alliance on Mental Illness website. http://www.nami.org/Learn-More/Mental-
Accessed September 27, 2016.
5. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and
comorbidity of twelve-month DSM-IV disorders in the National Comorbidity
Survey Replication (NCS-R). Archives of General Psychiatry, 2005
About Otsuka Pharmaceutical Co., Ltd.
Otsuka Pharmaceutical 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 nutraceutical products for
the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leader in the challenging area of mental
health and also has research programs on several under-addressed
diseases including tuberculosis, a significant global public health
issue. These commitments illustrate how Otsuka is a “big venture”
company at heart, applying a youthful spirit of creativity in everything
Otsuka Pharmaceutical and related companies, which employ approximately
31,000 people worldwide, is a wholly owned subsidiary of Otsuka Holdings
Co., Ltd., the holding company for the Otsuka Group that is
headquartered in Tokyo, Japan. The Otsuka Group has business operations
in 28 countries and regions around the world, with consolidated sales of
approximately 1.45 trillion yen (or USD 11.9 billion or EUR 10.8
billion) in 2015. Otsuka welcomes you to visit its global website at https://www.otsuka.co.jp/en.
Lundbeck is a global pharmaceutical company specialized in brain
diseases. For more than 70 years, we have been at the forefront of
research within neuroscience. The key areas of focus are Alzheimer's
disease, depression, Parkinson's disease and psychosis. An estimated 700
million people worldwide are living with brain disease and far too many
suffer due to inadequate treatment, discrimination, a reduced number of
working days, early retirement and other unnecessary consequences. Every
day, we strive for improved treatment and a better life for people
living with brain disease – we call this Progress in Mind. Our
approximately 5,500 employees in 57 countries are engaged in the entire
value chain throughout research, development, production, marketing and
sales. Our pipeline consists of several late-stage development programs
and our products are available in more than 100 countries. We have
research centers in China and Denmark and production facilities in
China, Denmark, France and Italy. Lundbeck generated core revenue of DKK
14.6 billion in 2015 (EUR 2 billion; USD 2.2 billion). For additional
information, we encourage you to visit our corporate site www.lundbeck.com
and connect with us on Twitter at @Lundbeck. Lundbeck in the U.S. In the
U.S., Lundbeck employs more than 800 people focused solely on
accelerating therapies for brain diseases. With a special commitment to
the lives of patients, families and caregivers, Lundbeck US actively
engages in hundreds of initiatives each year that support our patient
communities. To learn more, visit us at www.LundbeckUS.com
and connect with us on Twitter at @LundbeckUS.