Takeda and Lundbeck Announce FDA Approval of Brintellix™ (vortioxetine) for
Treatment of Adults with Major Depressive Disorder
OSAKA, Japan and COPENHAGEN, Denmark, Sept. 30, 2013
OSAKA, Japan and COPENHAGEN, Denmark, Sept. 30, 2013 /PRNewswire/ --Takeda
Pharmaceutical Company Limited (Takeda) and H. Lundbeck A/S (Lundbeck) jointly
announced today that the U.S. Food and Drug Administration (FDA) has approved
Brintellix (vortioxetine) for the treatment of adults with major depressive
disorder (MDD), a debilitating mental health illness affecting approximately
14 million adult Americans in a given year.^1 The mechanism of the
antidepressant effect of Brintellix is not fully understood. It is an
inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism
of its action. It is also an agonist at 5-HT1A receptors, a partial agonist
at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors.
The contribution of each of these activities to Brintellix's antidepressant
effect has not been established. It is considered to be the first and only
compound with this combination of pharmacodynamic activity. The clinical
relevance of this is unknown.
"MDD is a multifaceted disorder that encompasses emotional, physical and
cognitive symptoms that may make it challenging to treat," said Michael Thase,
M.D., professor of Psychiatry at the Perelman School of Medicine at the
University of Pennsylvania. "Because patients respond to treatments
differently, it is important to have additional new options available to help
address the overall symptoms of major depression."
The efficacy and safety of Brintellix were established across a comprehensive
global clinical trial program, including six positive 6-8 week short-term
studies – one of which was a dedicated study in the elderly – that
demonstrated statistically significant improvements in overall symptoms of
depression. The primary efficacy measure was the mean change from baseline to
endpoint in the Hamilton Depression Scale (HAMD-24) total score in two
short-term studies, including the elderly study, and the Montgomery-Asberg
Depression Rating Scale (MADRS) total score in the other studies. In addition,
the clinical trial program included a positive 24-64 week long-term
maintenance study in which Brintellix treatment resulted in a statistically
significant longer time to recurrence of depressive episodes (defined as a
MADRS total score >/= 22 or as judged by the investigator) compared to
placebo. Studies evaluated for safety included more than 4,700 patients aged
18 to 88 years. It is expected that Brintellix will be available to patients
by year end 2013.
"We are pleased that the FDA has approved Brintellix for the treatment of MDD,
a serious and complex condition," said Charlie Baum, M.D., vice president and
head, U.S. Medical and Scientific Affairs at Takeda Pharmaceuticals
International. "Together with our partner Lundbeck, we have been committed to
applying our collective expertise to develop new medicines that may help
people with depression."
According to The World Health Organization, fewer than half of people with
depression worldwide are receiving treatment, and the burden of depression is
expected to continue to rise globally. For those who do seek treatment,
discontinuation is not uncommon. MDD is a heterogeneous disorder that does not
consistently respond to therapy; thus it's important for patients to work with
a healthcare provider to help find a treatment plan that works for them.
"There are very few new antidepressant drugs currently in development even
though so many patients still struggle with depression. We are excited about
the approval of Brintellix and being able to offer a new option for patients,"
said Anders Gersel Pedersen, executive vice president and head, Research and
Development at Lundbeck. "This approval continues our six-decade history of
innovation in research and treatments for brain disorders, and underscores the
commitment of the Takeda and Lundbeck partnership to bring forward new
treatments for depression."
About Brintellix (vortioxetine)
The mechanism of the antidepressant effect of Brintellix is not fully
understood. It is an inhibitor of serotonin (5-HT) reuptake and that is
thought to be a mechanism of its action. It is also an agonist at 5-HT1A
receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3,
5-HT1D and 5-HT7 receptors. The contribution of each of these activities to
Brintellix's antidepressant effect has not been established. It is considered
to be the first and only compound with this combination of pharmacodynamic
activity. The clinical relevance of this is unknown.
Brintellix was discovered by Lundbeck researchers in Copenhagen, Denmark. The
clinical trial program in the U.S. was conducted jointly by Lundbeck and
Takeda, and Takeda holds the new drug application for the U.S. market.
Brintellix is a trademark of H. Lundbeck A/S and is used under license by
Takeda Pharmaceuticals America, Inc.
The World Health Organization has issued a new Anatomical Therapeutic Chemical
(ATC) code for Brintellix to be implemented in 2014.
The most commonly observed adverse events in MDD patients treated with
Brintellix in 6-8 week placebo-controlled studies (incidence >/= 5 percent and
at least twice the rate of placebo) were nausea, constipation and vomiting.
Overall, 5 to 8 percent of the patients who received Brintellix 5 to 20 mg/day
in short-term trials discontinued treatment due to an adverse reaction, the
most common being nausea, compared with 4 percent of placebo-treated patients
in these studies. Brintellix and other antidepressants may cause serious side
effects. See Important Safety Information below.
In clinical studies, Brintellix had no significant effect on body weight as
measured by the mean change from baseline in 6-8 week placebo-controlled
studies. In the 6-month, double-blind, placebo-controlled phase of a long-term
study in patients who had responded to Brintellix during the initial 12-week,
open-label phase, there was no significant effect on body weight between
Brintellix and placebo-treated patients. Brintellix has not been associated
with any clinically significant effects on vital signs, including systolic and
diastolic blood pressure and heart rate, as measured in placebo-controlled
The recommended starting dose of Brintellix is 10 mg once daily without regard
to meals. The dose should then be increased to 20mg/day, as tolerated, because
higher doses demonstrated better treatment effects in trials conducted in the
U.S. The available doses provide important flexibility for physicians to help
address the variability of patient needs.
Brintellix will be available as 5 mg, 10 mg and 20 mg tablets.
IMPORTANT SAFETY INFORMATION
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in
children, adolescents, and young adults in short-term studies. These studies
did not show an increase in the risk of suicidal thoughts and behavior with
antidepressant use in patients over age 24; there was a trend towards reduced
risk with antidepressant use in patients aged 65 and older.
In patients of all ages who are started on antidepressant therapy, monitor
closely for worsening, and for emergence of suicidal thoughts and behaviors.
Advise families and caregivers of the need for close observation and
communication with the prescriber.
BRINTELLIX has not been evaluated for use in pediatric patients.
Hypersensitivity: Hypersensitivity to vortioxetine or any components of the
BRINTELLIX formulation. Angioedema has been reported in patients treated with
Monoamine Oxidase Inhibitors (MAOIs): Due to an increased risk of serotonin
syndrome, do not use MAOIs intended to treat psychiatric disorders with
BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use
BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric
disorders. Do not start BRINTELLIX in a patient who is being treated with
linezolid or intravenous methylene blue.
WARNINGS AND PRECAUTIONS
Clinical Worsening and Suicide Risk: All patients being treated with
antidepressants for any indication should be monitored appropriately and
observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug
therapy, or at times of dose changes, either increases or decreases.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality (anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia, hypomania, and mania), especially if these symptoms
are severe, abrupt in onset, or were not part of the patient's presenting
symptoms. Families and caregivers of patients being treated with
antidepressants for MDD or other indications, both psychiatric and
nonpsychiatric, should be alerted about the need to monitor patients daily.
Serotonin Syndrome: The development of a potentially life-threatening
serotonin syndrome has been reported with serotonergic antidepressants (SNRIs,
SSRIs, and others), including BRINTELLIX, when used alone but more often when
used concomitantly with other serotonergic drugs (including triptans,
tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone,
and St. John's Wort), and with drugs that impair metabolism of serotonin (in
particular, MAOIs, both those intended to treat psychiatric disorders and also
others, such as linezolid and intravenous methylene blue). Serotonin syndrome
symptoms may include mental status changes (eg, agitation, hallucinations,
delirium, and coma), autonomic instability (eg, tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular
symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination),
seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea).
If such symptoms occur, discontinue BRINTELLIX and any concomitant
serotonergic agents, and initiate supportive symptomatic treatment. If
concomitant use of BRINTELLIX is clinically warranted, patients should be made
aware of and monitored for potential increased risk for serotonin syndrome,
particularly during treatment initiation and dose increases.
Abnormal Bleeding: Treatment with serotonergic antidepressants (SSRIs, SNRIs,
and others) may increase the risk of abnormal bleeding. Patients should be
cautioned about the increased risk of bleeding when BRINTELLIX is
coadministered with NSAIDs, aspirin, or other drugs that affect coagulation.
Activation of Mania/Hypomania: Activation of mania/hypomania can occur with
antidepressant treatment. Prior to initiating treatment with an
antidepressant, screen patients for bipolar disorder. As with all
antidepressants, use BRINTELLIX cautiously in patients with a history or
family history of bipolar disorder, mania, or hypomania.
Hyponatremia: Hyponatremia has occurred as a result of serotonergic drugs and
in many cases, appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Elderly patients and patients taking
diuretics or who are otherwise volume-depleted can be at greater risk. More
severe or acute cases have included hallucination, syncope, seizure, coma,
respiratory arrest, and death. Discontinue BRINTELLIX in patients with
symptomatic hyponatremia and initiate appropriate medical intervention.
Adverse Reactions: The most commonly observed adverse reactions for BRINTELLIX
in 6- to 8-week placebo-controlled studies (incidence >/= 5% and at least
twice the rate of placebo) were by dose (5 mg, 10 mg, 15 mg, 20 mg) vs
placebo: nausea (21%, 26%, 32%, 32% vs 9%), constipation (3%, 5%, 6%, 6% vs
3%) and vomiting (3%, 5%, 6%, 6% vs 1%).
Drug Interactions: Concomitant administration of BRINTELLIX and strong CYP2D6
inhibitors or strong CYP inducers may require a dose adjustment of BRINTELLIX.
Please see full Prescribing Information and Medication Guide for BRINTELLIX.
The Science of Major Depression
The monoamine-deficiency theory posits that the underlying pathophysiological
basis of depression is a depletion of serotonin, norepinephrine or dopamine in
the central nervous system. The exact cause of MDD is unknown. Research
suggests that there are multiple serotonin receptors that may be important in
MDD and may influence many biologic and neurologic processes. The release of
bio-chemicals, such as serotonin, dopamine and norepinephrine enables impulses
to be passed from one cell to another in the nervous system.
Takeda and Lundbeck Alliance
In September 2007, Lundbeck and Takeda Pharmaceutical Company Limited formed a
strategic alliance for the exclusive co-development and co-commercialization
in the U.S. and Japan of several compounds in Lundbeck's pipeline for the
treatment of mood and anxiety disorders. The companies plan to co-promote
Brintellix in the U.S. for the commercial launch of the product. The
Lundbeck–Takeda alliance in the U.S. will benefit from the synergy of
Lundbeck's longstanding expertise and knowledge of psychiatry and Takeda's
understanding and established presence in the very important primary care
H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is a global pharmaceutical company
specialized 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
Our 5,800 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 programs and
our products are available in more than 100 countries. We have research
centers in China, Denmark and the United States, and production facilities in
China, Denmark, France, Italy and Mexico. Lundbeck generated revenue of
approximately DKK15 billion in 2012 (EUR 2 billion; USD 2.6 billion).
Lundbeck's shares are listed on the stock exchange in Copenhagen under the
symbol "LUN." Lundbeck has a sponsored Level 1 ADR program listed in the US
(OTC) under the symbol "HLUYY." For additional information, we encourage you
to visit our corporate site www.lundbeck.com.
About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its
main focus on pharmaceuticals. As the largest pharmaceutical company in Japan
and one of the global leaders of the industry, Takeda is committed to strive
towards better health for patients worldwide through leading innovation in
medicine. Additional information about Takeda is available through its
corporate website, www.takeda.com.
About Takeda Pharmaceuticals U.S.A., Inc. and Takeda Development Center
Based in Deerfield, Ill., Takeda Pharmaceuticals U.S.A., Inc. and Takeda
Development Center Americas, Inc. are subsidiaries of Takeda Pharmaceutical
Company Limited, the largest pharmaceutical company in Japan. The respective
companies currently market oral diabetes, insomnia, rheumatology,
gastroenterology and cardiovascular disease treatments and seek to bring
innovative products to people through a pipeline that includes compounds in
development for diabetes, gastroenterology, neurology and other conditions. To
learn more about these Takeda companies, visit www.takeda.us.
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Ashleigh Duchene Jessica Tuquero
Public Affairs Corporate Communications
Lundbeck Takeda Pharmaceuticals
Palle Holm Olesen Takeda Pharmaceutical
Chief Specialist, Head of Investor Relations Corporate Communications
H. Lundbeck A/S +81-3-3278-2037
^1 As estimated by the National Comorbidity Survey Replication (NCS-R),
conducted from February 2001 to December 2002.
SOURCE Takeda Pharmaceutical Company Limited; H. Lundbeck A/S
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