FDA Approves Once-Monthly ABILIFY MAINTENA™ (aripiprazole) for Extended-Release Injectable Suspension for the Treatment of

  FDA Approves Once-Monthly ABILIFY MAINTENA™ (aripiprazole) for
  Extended-Release Injectable Suspension for the Treatment of Schizophrenia

  *Approval provides patients with schizophrenia the ability to access the
    efficacy and safety profile of oral aripiprazole in a once-monthly
  *Relapse prevention is an important consideration in the treatment of
    patients with schizophrenia; ABILIFY MAINTENA met the Phase 3 clinical
    trial primary endpoint of significantly delaying time to relapse.
  *ABILIFY MAINTENA will be the first commercialized product from the global
    alliance between Otsuka and Lundbeck focused on developing Central Nervous
    System (CNS) therapies worldwide.

Business Wire

TOKYO & COPENHAGEN, Denmark -- February 28, 2013

Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck)
announced the U.S. Food and Drug Administration (FDA) has approved ABILIFY
MAINTENA™ (aripiprazole) for extended- release injectable suspension, an
intramuscular (IM) depot formulation indicated for the treatment of

(Photo: Business Wire)

(Photo: Business Wire)

ABILIFY MAINTENA is the first dopamine D2 partial agonist approved as a once-
monthly injection. It contributes a new treatment option to address the
ongoing need for relapse prevention in patients with schizophrenia – a
chronic, debilitating disease.

Efficacy was demonstrated in a 52-week, placebo-controlled, double-blind,
randomized-withdrawal, Phase 3 maintenance trial of ABILIFY MAINTENA in
patients with schizophrenia. The time to relapse was the primary endpoint. In
the trial, ABILIFY MAINTENA (n=269 adult patients) significantly delayed time
to relapse compared to placebo (n=134 adult patients; hazard ratio = 5.03, 95%
CI = 3.15-8.02, p<0.0001).^1 In a key secondary endpoint, the percentage of
subjects experiencing relapse (i.e., meeting clinical trial criteria for
exacerbation of psychotic symptoms/relapse) was also significantly lower with
ABILIFY MAINTENA compared to placebo at the end of the study (10% vs. 40%,
respectively; p<0.0001). Additional support for efficacy was derived from oral
aripiprazole trials.

Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. ABILIFY MAINTENA is not approved for
the treatment of patients with dementia-related psychosis. ABILIFY MAINTENA is
contraindicated in patients with a known hypersensitivity reaction to
aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis
(see Important Safety Information below).

ABILIFY MAINTENA will be the first commercialized product from the long-term
global alliance between Otsuka and Lundbeck to develop CNS medicines
worldwide. The companies expect the product will start becoming available in
the U.S. on March 18.

“Protection from relapse of schizophrenia is important for patients, their
families and the communities in which they live,” said study investigator John
M. Kane, M.D., Chairman of Psychiatry, The Zucker Hillside Hospital, and Vice
President, Behavioral Health Services, North Shore-LIJ Health System. “As a
strong believer in long-acting therapies for schizophrenia, I think it is
important for physicians to have a new and effective once-monthly treatment
option that can help reduce the risk of relapse and manage symptoms in

Results from the clinical trial of ABILIFY MAINTENA were published in the
Journal of Clinical Psychiatry and first presented in four poster
presentations at the 2012 American Psychiatric Association Annual Meeting in
May 2012.

The trial included adult patients who met DSM-IV-TR criteria for schizophrenia
and who were being treated with at least one antipsychotic medication.
Patients had at least a 3-year history of illness and a history of relapse or
symptom exacerbation when not receiving antipsychotic treatment. Patients in
the study received injections of ABILIFY MAINTENA or placebo once every four
weeks; the first injection was accompanied by two weeks of concomitant
administration of oral aripiprazole. The trial included a pre-planned interim
analysis which demonstrated a significantly longer time to relapse (p<0.001)
in patients randomized to the ABILIFY MAINTENA group compared to
placebo-treated patients. The trial was subsequently terminated early by an
independent data monitoring committee because maintenance of efficacy was
demonstrated. The final analysis demonstrated a statistically significantly
longer time to relapse in patients randomized to the ABILIFY MAINTENA group
than compared to placebo- treated patients (log-rank test p<0.0001).

ABILIFY MAINTENA 300-400 mg has been evaluated for safety in 1,287 adult
patients in clinical trials in schizophrenia, with approximately 1,281
patient-years of exposure to ABILIFY MAINTENA. A total of 832 patients were
treated with ABILIFY MAINTENA for at least 180 days (at least seven
consecutive injections) and 630 patients treated with ABILIFY MAINTENA had at
least one year of exposure (at least 13 consecutive injections). The safety
profile of ABILIFY MAINTENA is expected to be similar to that of oral
aripiprazole. In patients who tolerated and responded to treatment with oral
aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to
receive ABILIFY MAINTENA or placebo injections under double-blind conditions,
the incidence of adverse reactions was similar between the two treatment
groups. The only commonly observed adverse reaction associated with the use of
oral aripiprazole in patients with schizophrenia (incidence of 5% or greater
and aripiprazole incidence at least twice that for placebo) was akathisia
(aripiprazole 8%; placebo 4%).

“Our efforts to bring ABILIFY MAINTENA to market demonstrate our long-term
commitment to discover, develop and champion treatments for the most
challenging psychiatric diseases,” said Taro Iwamoto, President and
Representative Director, Otsuka Pharmaceutical Co., Ltd. “With this important
approval, more patients with schizophrenia will have access to the efficacy
and safety profile of ABILIFY in a once-monthly formulation. We are excited to
bring ABILIFY MAINTENA to market as part of our historic alliance with
Lundbeck. Both companies are deeply committed to supporting the comprehensive
needs of the mental health community, including patients, healthcare
providers, caregivers and advocates.”

Commenting on the first regulatory approval from the long-term alliance
established between Otsuka and Lundbeck, Ulf Wiinberg, Chief Executive
Officer, Lundbeck said, “ABILIFY MAINTENA represents an important treatment
option for patients and their physicians and caregivers seeking an alternative
long-term maintenance treatment for schizophrenia, and we are pleased to join
Otsuka in launching the first product as part of our extensive global
alliance. The launch of ABILIFY MAINTENA also represents Lundbeck’s first
entry into the U.S. psychiatry market, expanding our central nervous system
focus strategically in the U.S.”

On November 11, 2011 Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S
announced the formation of an alliance to collaborate on the development and
commercialization of up to five early- and late-stage compounds in
development. The two companies will co- commercialize ABILIFY MAINTENA in the
U.S. and will collaborate on the development and commercialization of
aripiprazole IM depot formulation in other markets worldwide.

About Schizophrenia and Disease Relapse

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 Europe, and approximately 24 million
people worldwide.^2,3 In the U.S., there are approximately 2.4 million adults
with schizophrenia, prevalent equally in both genders.^4,5 While there is no
cure for the disease, symptoms and risk of relapse can be managed in most
patients with appropriate antipsychotic treatment. However, when the disease
is not managed, patients are at increased risk of disease relapse, which can
cause the re-emergence or worsening of psychotic symptoms.^6

Relapse of schizophrenia can occur when a patient no longer responds to
antipsychotic medication or when patients stop taking their medication. There
are many reasons patients stop taking their medication and they include: poor
insight about their illness, side effects from their current treatment,
complicated medication regimens or lack of support from their family.

About ABILIFY MAINTENA (aripiprazole)

ABILIFY MAINTENA for extended-release injectable suspension, an IM depot
formulation of aripiprazole, is a sterile lyophilized powder that, when
reconstituted with sterile water for injection, forms an injectable suspension
that can be administered monthly. ABILIFY MAINTENA is indicated for the
treatment of schizophrenia.

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. Depot formulations of antipsychotic agents provide patients with
concentrations of active drug that remain at a therapeutic range for an
extended period of time.^7,8

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 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 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

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 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

Pregnancy/Nursing: Based on animal data, may cause fetal harm. ABILIFY
MAINTENA 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

Please see accompanying FULL PRESCRIBING INFORMATION, including Boxed WARNING,

About 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

Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka
Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group
has business operations in 24 countries and regions around the world, with
consolidated sales of ¥1,154.6 billion for fiscal year 2011. For more
information, visit www.otsuka.co.jp/en.

About H. Lundbeck A/S

Lundbeck is a global pharmaceutical company highly committed to improving the
quality of life of people living with brain diseases. For this purpose,
Lundbeck is engaged in the entire value chain throughout research,
development, production, marketing and sales of pharmaceuticals across the
world. The company’s products are targeted at disorders such as depression and
anxiety, psychotic disorders, epilepsy, Huntington’s, Alzheimer’s and
Parkinson’s diseases. Lundbeck’s pipeline consists of several mid- to
late-stage development programs. Lundbeck’s U.S. business is based in
Deerfield, Illinois. To learn more about Lundbeck in the U.S., visit

Lundbeck employs more than 5,800 people worldwide, 2,000 of whom are based in
Denmark. We have research in 57 countries and our products are registered in
more than 100 countries. We have research centers in Denmark, China and the
United States and production facilities in Italy, France, Mexico, China and
Denmark. Lundbeck generated revenue of approximately DKK 15 billion in 2012.
For additional information, we encourage you to visit our corporate site


1.Kane, JM et al. “Aripiprazole Intramuscular Depot as Maintenance Treatment
    in Patients With Schizophrenia: A 52-Week, Multicenter, Randomized,
    Double-Blind, Placebo-Controlled Study.” J Clin Psychiatry
2.National Institute of Mental Health (NIMH). Health Topics: Statistics.
    Available at http://www.nimh.nih.gov/statistics/1SCHIZ.shtml. Accessed
    July 19, 2012.
3.World Health Organization (WHO). Schizophrenia Fact Sheet. 2010. Available
    at http://www.who.int/mental_health/management/schizophrenia/en/. Accessed
    July 16. 2012.
4.Regier, Darrel et al. The de Facto US Mental and Addictive Disorder
    Service System. Arch Gen Psychiatry. 1993; 50: 85-94.
5.National Institutes of Mental Health (NIMH). The Numbers Count: Mental
    Disorders in America. Available at
    mental-disorders-in-america/index.shtml. Accessed December 5, 2012.
6.Almond, S et al. Relapse in schizophrenia: costs, clinical outcomes and
    quality of life. British Journal of Psychiatry, 2004; 184: 346-351.
7.Patel MX, David AS. “Why aren’t depot antipsychotics prescribed more often
    and what can be done about it?” Adv Psychiatr Treat, 2005; 11: 203-213.
8.Kane, JM et al. “Guidelines for depot antipsychotic treatment in
    schizophrenia.” Eur Neuropsychopharmacol, 1998; 8(1): 55-66.

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Otsuka Pharmaceutical Co., Ltd. Contacts
Rose Weldon
Otsuka America Pharmaceutical, Inc.
+1 609 524 6879, +1 215 801 7644 (cell)
Jeffrey Gilbert
Otsuka Pharmaceutical Co., Ltd.
+81 3 6361 7379, +81 80 8728 6039 (cell)
Takuma Kimura
Investor Relations Department
Otsuka Holdings Co., Ltd.
+81 3 6361 7411
H. Lundbeck A/S Contacts
Ashleigh Duchene
+1 847 282 1164
Mads Kronborg Lundbeck
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+45 36 43 49 80
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Chief Specialist, Investor Relations
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Investor Relations Officer
+45 36 43 38 16
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