Otsuka America Pharmaceutical, Inc. (OAPI) and H. Lundbeck A/S
(Lundbeck) today announced the U.S. Food and Drug Administration
(FDA) has accepted for review a supplemental New Drug Application
(sNDA) for the proposed expanded labeling of Abilify Maintena
(aripiprazole) for extended-release injectable suspension to
support broader use of the drug for treatment of patients in the
acute phase of schizophrenia. Under the Prescription Drug User Fee
Act (PDUFA), the FDA has set a target date of December 7, 2014 to
complete its review.
The sNDA submission was based on a 12-week study of patients
with schizophrenia hospitalized and experiencing an acute
exacerbation of symptoms. The study demonstrated efficacy on the
primary endpoint of Positive and Negative Syndrome Scale (PANSS)
total score (p < 0.0001). Data showed Abilify Maintena was also
effective on the key secondary endpoint of Clinical Global
Impressions – Severity (CGI-S score, p < 0.0001). The three most
common adverse events reported by patients receiving Abilify
Maintena were weight gain, headache and akathisia. The full study
results have been submitted for publication in a scientific
journal.1
About Abilify Maintena® (aripiprazole)
Abilify Maintena (aripiprazole) for extended-release injectable
suspension is indicated for the treatment of schizophrenia.
Efficacy was demonstrated in a placebo-controlled,
randomized-withdrawal maintenance trial in patients with
schizophrenia. It is the first and only once-monthly injection of a
dopamine D2 partial agonist and was approved by the U.S. Food and
Drug Administration (FDA) on February 28, 2013.2,3
Abilify Maintena, an atypical antipsychotic, is an IM depot
formulation of aripiprazole. It is a sterile lyophilized powder
that, when reconstituted with sterile water for injection, forms an
injectable suspension that can be administered monthly. 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. It provides a treatment option to
address one of the most important considerations in the management
of schizophrenia – reducing the risk of relapse, or the
re-emergence or 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.2,4 Abilify Maintena became available for prescribing in the
U.S. on March 18, 2013.
About Schizophrenia
Schizophrenia is a disease characterized by a distortion in the
process of thinking and of emotional responsiveness. It most
commonly manifests as hallucinations, paranoid or bizarre
delusions, or disorganized speech and thinking, and is accompanied
by significant social or occupational dysfunction. Onset of
symptoms typically occurs in young adulthood and the condition is
chronic, often requiring life-long treatment to mitigate symptoms.
It has been estimated that schizophrenia affects approximately 1%
of the adult population in the U.S., and approximately 24 million
people worldwide.5,6 In the U.S., there are approximately 2.4
million adults with schizophrenia, prevalent equally in both
genders.7,8 While there is no cure for the disease, symptoms and
risk of relapse – the re-emergence or worsening of psychotic
symptoms9 – can be managed in most patients with appropriate
antipsychotic treatment.
IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA®
(aripiprazole) for extended-release injectable
suspension
Increased Mortality in Elderly Patients with Dementia-Related
Psychosis
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). Analyses
of 17 placebo-controlled trials (modal duration of 10 weeks),
largely in patients taking atypical antipsychotic drugs, revealed a
risk of death in drug-treated patients of between 1.6 to 1.7 times
the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug treated
patients was about 4.5%, compared to a rate of about 2.6% in the
placebo group. 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 (aripiprazole) 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
anaphylaxis.
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 oral aripiprazole.
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. There were no significant differences
between aripiprazole- and placebo-treated patients in the
proportion with changes from normal to clinically significant
levels for fasting/nonfasting total cholesterol, fasting
triglycerides, fasting low-density lipoproteins (LDLs), and
fasting/nonfasting high-density lipoproteins (HDLs).
- Weight Gain: Weight gain has
been observed. Clinical monitoring of weight is recommended.
Orthostatic Hypotension: Aripiprazole may cause
orthostatic hypotension. ABILIFY MAINTENA (aripiprazole) 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. Patients with
a history of clinically significant low white blood cell (WBC)
count or drug-induced leukopenia/neutropenia should have their
complete blood count monitored frequently during the first few
months of therapy while receiving ABILIFY MAINTENA. In such
patients, consider discontinuation of ABILIFY MAINTENA at the first
sign of a clinically significant decline in WBC count in the
absence of other causative factors.
Seizures/Convulsions: ABILIFY MAINTENA should be used
with caution in patients with a history of seizures or with
conditions that lower the seizure threshold.
Potential for Cognitive and Motor Impairment: ABILIFY
MAINTENA (aripiprazole) 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 dehydration.
Dysphagia: Esophageal dysmotility and aspiration have
been associated with ABILIFY MAINTENA; use caution in patients at
risk for aspiration pneumonia.
Alcohol: Advise patients to avoid alcohol while taking
ABILIFY MAINTENA.
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 reaction: The safety
profile of ABILIFY MAINTENA is expected to be similar to that of
oral aripiprazole. In patients who tolerated and responded to oral
aripiprazole and single-blind ABILIFY MAINTENA and were then
randomized to receive ABILIFY MAINTENA or placebo injections, the
incidence of adverse reactions was similar between the two
treatment groups. The adverse reaction ≥ 5% incidence and at least
twice the rate of placebo for oral aripiprazole vs. placebo,
respectively, was:
- Akathisia (8% vs. 4%) in adult patients
with schizophrenia.
Injection Site Reactions: In the open-label,
stabilization phase of a study with ABILIFY MAINTENA in patients
with schizophrenia, the percent of patients reporting any injection
site- related adverse reaction was 6.3% for ABILIFY
MAINTENA-treated patients.
Dystonia is a class effect of antipsychotic drugs.
Symptoms of dystonia may occur in susceptible individuals during
the first days of treatment and at low doses.
Pregnancy/Nursing: Based on animal data, may cause fetal
harm. ABILIFY MAINTENA (aripiprazole) should be used during
pregnancy only if the potential benefit justifies the potential
risk to the fetus. Aripiprazole is excreted 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.
Please see accompanying FULL PRESCRIBING INFORMATION, including
Boxed WARNING, for ABILIFY MAINTENA.
About Otsuka America Pharmaceutical, Inc.
Otsuka America Pharmaceutical, Inc. (OAPI) is an innovative,
fast-growing healthcare company that commercializes
Otsuka-discovered and in-licensed products in the U.S. With a
strong focus on neuroscience, oncology, cardio-renal and medical
devices, OAPI is dedicated to improving the health and quality of
human life. For more information, visit www.otsuka-us.com.
OAPI is a subsidiary of Otsuka America, Inc. (OAI), a holding
company established in the U.S. in 1989. OAI is wholly owned by
Otsuka Pharmaceutical Co., Ltd. The Otsuka Group employs
approximately 42,000 people globally and its products are available
in more than 80 countries worldwide. Otsuka welcomes you to visit
its global website at https://www.otsuka.co.jp/en/.
About Lundbeck
H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is a global
pharmaceutical company specialised in brain diseases. For more than
50 years, we have been at the forefront of research within
neuroscience. Our development and distribution of pioneering
treatments continues to make a difference to people living with
brain diseases. Our key areas of focus are alcohol dependence,
Alzheimer's disease, depression/anxiety, epilepsy, Huntington's
disease, Parkinson's disease, schizophrenia and stroke. Lundbeck’s
U.S. business is based in Deerfield, Illinois. To learn more about
Lundbeck in the U.S., visit www.lundbeckus.com.
Our approximately 6,000 employees in 57 countries are engaged in
the entire value chain throughout research, development,
production, marketing and sales, and are committed to improving the
quality of life of people living with brain diseases. Our pipeline
consists of several late-stage development programmes and our
products are available in more 100 countries. We have research
centres in China, Denmark and the United States, and production
facilities in China, Denmark, France, Italy and Mexico. Lundbeck
generated revenue of approximately DKK 15 billion in 2013 (EUR 2.0
billion; USD 2.7 billion).
For further information please visit www.lundbeck.com.
References
- Data on file.
- Prescribing Information. ABILIFY
MAINTENA™ (aripiprazole) for extended-release injectable
suspension, for intramuscular use. February 2013.
- U.S. Food and Drug Administration
(FDA). FDA Approved Drug Products: All approvals February 2013.
Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.MonthlyApprovalsAll.
- 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.
- National Institute of Mental Health
(NIMH). Health Topics: Statistics. Available at
http://www.nimh.nih.gov/statistics/1SCHIZ.shtml. Accessed May 14,
2013.
- World Health Organization (WHO).
Schizophrenia Fact Sheet. 2010. Available at
http://www.who.int/mental_health/management/schizophrenia/en/.
Accessed May 14, 2013.
- National Institutes of Mental Health
(NIMH). The Numbers Count: Mental Disorders in America. Available
at
http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml.
Accessed May 14, 2013.
- Regier, Darrel et al. The de Facto US
Mental and Addictive Disorder Service System. Archives of General
Psychiatry. 1993; 50: 85-94.
- Almond, S et al. Relapse in
schizophrenia: costs, clinical outcomes and quality of life.
British Journal of Psychiatry, 2004; 184: 346-351.
April 2014 09US14EBC0040
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Otsuka America Pharmaceutical, Inc.
ContactMedia:Otsuka America Pharmaceutical, Inc.Kevin
WigginsHead of Corporate
CommunicationsKevin.wiggins@otsuka-us.com+1 609 524 1164orH.
Lundbeck A/S ContactsMedia:U.S.LundbeckAshleigh
Ducheneaduc@lundbeck.com+1 847 282 1164orEUROPELundbeckMads
Kronborgmavk@lundbeck.com+45 36 43 28
51orInvestors:LundbeckPalle Holm OlesenChief Specialist,
Investor Relationspalo@lundbeck.com+45 36 43 24 26
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