DUBLIN and BUDAPEST, Hungary, May
28, 2019 /PRNewswire/ -- Allergan plc (NYSE: AGN)
and Gedeon Richter Plc. today announced that the U.S. Food and
Drug Administration (FDA) has approved a supplemental New Drug
Application (sNDA) for VRAYLAR® (cariprazine) for
expanded use to treat depressive episodes associated with bipolar I
disorder (bipolar depression) in adults. VRAYLAR is also approved
in the U.S. to treat manic or mixed episodes associated with
bipolar I disorder in adults. There are nearly 11 million adults in
the U.S. living with bipolar disorder,1 a condition that
causes extreme shifts in mood, energy, and activity
levels.2
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"Treating bipolar disorder can be very difficult because people
living with the illness experience a range of depressive and manic
symptoms, sometimes both at the same time, and this FDA approval
gives healthcare providers a new option to treat the full spectrum
of bipolar I disorder symptoms, specifically manic, mixed, and
depressive episodes, with just one medication," said Dr.
Stephen Stahl, Professor of
Psychiatry at the University of California San
Diego and lead author of the post hoc analysis,
Cariprazine Efficacy in Patients with Bipolar Depression and
Concurrent Manic Symptoms. "Treating depression, mania and
mixed episodes with a single medication is important for people
living with, and healthcare providers treating, this complex
illness. This approval can streamline a treatment decision while
helping to stabilize the disorder."
Seventy percent of people living with bipolar disorder receive
at least one misdiagnosis and consult an average of four doctors
over approximately 10 years before being accurately
diagnosed.3 Many patients take multiple medications to
treat the symptoms of this condition.
The FDA approval for the expanded indication of VRAYLAR is based
on three pivotal trials, including RGH-MD-53, RGH-MD-54 and
RGH-MD-56, in which cariprazine demonstrated greater improvement
than placebo for the change from baseline to week six on the
Montgomery Asberg Depression Rating scale (MADRS) total score. In
all three studies, the VRAYLAR 1.5 mg dose demonstrated statistical
significance over placebo; additionally, in RGH-MD-54, the VRAYLAR
3 mg dose demonstrated statistical significance over placebo.
Common adverse events reported in the pivotal trials were nausea,
akathisia, restlessness, and extrapyramidal symptoms.
"This approval represents an important milestone in our efforts
to help patients and prescribing healthcare providers effectively
manage bipolar I disorder and demonstrates our ongoing focus on
mental health," said David
Nicholson, Chief Research & Development Officer at
Allergan. "We are committed to developing therapies for
complex mental health disorders, including VRAYLAR, which is
currently in Phase 3 clinical trials for the treatment of major
depressive disorder."
"This approval is considered a notable achievement in the
development process of cariprazine, our flagship product," said Dr.
István Greiner, Research Director of Gedeon Richter Plc. "We are
pleased that more and more patient groups suffering from
psychiatric disorders will get access to cariprazine as a treatment
option."
About VRAYLAR® (cariprazine)
VRAYLAR is an
oral, once daily atypical antipsychotic approved for the acute
treatment of adults with manic or mixed episodes associated with
bipolar I disorder (3 to 6 mg/day) and for the treatment of
depressive episodes associated with bipolar I disorder (bipolar
depression) in adults (1.5 or 3 mg/day). VRAYLAR is also approved
for the treatment of schizophrenia in adults (1.5 to 6 mg/day).
While the mechanism of action of VRAYLAR is unknown, the
efficacy of VRAYLAR could be mediated through a combination of
partial agonist activity at central dopamine D₂ and serotonin
5-HT1A receptors and antagonist activity at
serotonin 5-HT2A receptors. Pharmacodynamic studies
with cariprazine have shown that it acts as a partial agonist with
high binding affinity at dopamine D3, dopamine
D2, and serotonin 5-HT1A receptors.
Cariprazine demonstrated up to ~8-fold greater in
vitro affinity for dopamine D3 vs
D2 receptors. Cariprazine also acts as an
antagonist at serotonin 5-HT2B and
5-HT2A receptors with high and moderate binding
affinity, respectively as well as it binds to the histamine
H1 receptors.
VRAYLAR shows lower binding affinity to the serotonin
5-HT2C and α1A- adrenergic receptors and
has no appreciable affinity for cholinergic muscarinic receptors.
The clinical significance of these in vitro data
is unknown.
VRAYLAR was discovered and co-developed by Gedeon Richter
Plc and is licensed by Allergan, in the U.S.
and Canada. For more than a decade both companies have
conducted over 20 clinical trials enrolling thousands of
patients worldwide to evaluate the efficacy and safety of
cariprazine for people living with a broad range of mental health
illnesses.
Visit www.vraylar.com for more information.
About Bipolar I Disorder and Bipolar I Depression
There are nearly 11 million adults in the U.S. living with
bipolar disorder,1 a condition that causes periods of
severe changes in mood, energy, and activity levels.2
These periods are often called "episodes." Experiencing just one
manic episode is enough to be diagnosed with bipolar I disorder.
Although there is no known cure, its symptoms may be
managed.4
Bipolar depression refers to the depressive episodes of bipolar
I disorder. People living with bipolar I disorder can have manic
and depressive episodes, as well as mixed episodes that feature
both manic and depressive symptoms at the same time. Depressive
symptoms are three times more prevalent than manic symptoms and
constitute a larger portion of the patient's life spent
unwell.5 Bipolar I depression typically lasts at least
two weeks and can be difficult to differentiate from major
depression during diagnosis. If misdiagnosed with major depressive
disorder, people may be given an antidepressant which, when taken
as a monotherapy by someone with bipolar disorder, can induce a
manic episode.6
INDICATION AND USAGE
VRAYLAR is an oral, once daily atypical
antipsychotic approved for the acute treatment of adults with manic
or mixed episodes associated with bipolar I disorder (3 to 6
mg/day) and for the treatment of depressive episodes associated
with bipolar I disorder (bipolar depression) in adults (1.5 or 3
mg/day). VRAYLAR is also approved for the treatment of
schizophrenia in adults (1.5 to 6 mg/day).
IMPORTANT SAFETY INFORMATION
|
WARNINGS:
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS
|
Elderly patients
with dementia-related psychosis treated with antipsychotic drugs
are at an increased risk of death. VRAYLAR is not approved for
treatment of patients with dementia-related
psychosis.
Antidepressants
increased the risk of suicidal thoughts and behaviors in pediatric
and young adult patients in short-term studies. Closely monitor
antidepressant-treated patients for clinical worsening, and for
emergence of suicidal thoughts and behaviors. Safety and
effectiveness of VRAYLAR have not been established in pediatric
patients.
|
Contraindication: VRAYLAR is contraindicated in patients
with known hypersensitivity. Reactions have included rash,
pruritus, urticaria, and events suggestive of angioedema.
Cerebrovascular Adverse Reactions, Including Stroke: In
clinical trials with antipsychotic drugs, elderly subjects with
dementia had a higher incidence of cerebrovascular adverse
reactions, including fatalities vs placebo. VRAYLAR is not approved
for the treatment of patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially
fatal symptom complex, has been reported with antipsychotic drugs.
NMS may cause hyperpyrexia, muscle rigidity, delirium, and
autonomic instability. Additional signs may include elevated
creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute
renal failure. Manage with immediate discontinuation,
intensive symptomatic treatment, and monitoring.
Tardive Dyskinesia (TD): Risk of developing TD (a
syndrome of potentially irreversible, involuntary, dyskinetic
movements) and the likelihood it will become irreversible may
increase with the duration of treatment and the cumulative dose.
The syndrome can develop after a relatively brief treatment period,
even at low doses, or after treatment discontinuation. If signs and
symptoms of TD appear, drug discontinuation should be
considered.
Late-Occurring Adverse Reactions: Adverse events may
first appear several weeks after initiation of VRAYLAR, probably
because plasma levels of cariprazine and its major metabolites
accumulate over time. As a result, the incidence of adverse
reactions in short-term trials may not reflect the rates after
longer term exposures. Monitor for adverse reactions, including
extrapyramidal symptoms (EPS) or akathisia, and patient response
for several weeks after starting VRAYLAR and after each dosage
increase. Consider reducing the dose or discontinuing the drug.
Metabolic Changes: Atypical antipsychotics have caused
metabolic changes, such as:
- Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in
some cases associated with ketoacidosis, hyperosmolar coma, or
death, has been reported in patients treated with atypical
antipsychotics. Assess fasting glucose before or soon after
initiation of treatment, and monitor periodically during long-term
treatment.
- Dyslipidemia: Atypical antipsychotics cause adverse
alterations in lipids. Before or soon after starting an
antipsychotic, obtain baseline fasting lipid profile and monitor
periodically during treatment.
- Weight Gain: Weight gain has been observed with VRAYLAR.
Monitor weight at baseline and frequently thereafter.
Leukopenia, Neutropenia, and Agranulocytosis:
Leukopenia/neutropenia have been reported with antipsychotics,
including VRAYLAR. Agranulocytosis (including fatal cases) has been
reported with other antipsychotics. Monitor complete blood count in
patients with pre-existing low white blood cell count
(WBC)/absolute neutrophil count or history of drug-induced
leukopenia/neutropenia. Discontinue VRAYLAR at the first sign of a
clinically significant decline in WBC and in severely neutropenic
patients.
Orthostatic Hypotension and Syncope: Atypical
antipsychotics cause orthostatic hypotension and syncope, with the
greatest risk during initial titration and with dose increases.
Monitor orthostatic vital signs in patients predisposed to
hypotension and in those with cardiovascular/cerebrovascular
diseases.
Falls: VRAYLAR may cause somnolence, postural
hypotension, motor and sensory instability, which may lead to falls
and, consequently, fractures, or other injuries. For patients with
diseases, conditions, or medications that could exacerbate these
effects, complete fall risk assessments when initiating
antipsychotics and recurrently for patients on long-term
therapy.
Seizures: Use VRAYLAR with caution in patients with
history of seizures or with conditions that lower the seizure
threshold.
Potential for Cognitive and Motor Impairment: Somnolence
was reported with VRAYLAR. Caution patients about performing
activities requiring mental alertness (eg, operating hazardous
machinery or a motor vehicle).
Body Temperature Dysregulation: Use VRAYLAR with caution
in patients who may experience conditions that increase body
temperature (eg, strenuous exercise, extreme heat, dehydration, or
concomitant anticholinergics).
Dysphagia: Esophageal dysmotility and aspiration have
been associated with antipsychotics. Antipsychotic drugs, including
VRAYLAR, should be used cautiously in patients at risk for
aspiration.
Drug Interactions: Strong CYP3A4 inhibitors increase
VRAYLAR concentrations, so VRAYLAR dose reduction is recommended.
Concomitant use with CYP3A4 inducers is not recommended.
Adverse Reactions: In clinical trials, the most common
adverse reactions (≥5% and at least twice the rate of placebo) are
listed below:
- Schizophrenia: The incidences within the
recommended dose range (VRAYLAR 1.5 – 3 mg/day and 4.5 – 6 mg/day
vs placebo) were: EPS (15%, 19% vs 8%) and akathisia (9%, 13%
vs 4%).
- Bipolar mania: The incidences within the
recommended dose range (VRAYLAR 3 – 6 mg/day vs placebo) were: EPS
(26% vs 12%), akathisia (20% vs 5%), vomiting (10% vs 4%),
dyspepsia (7% vs 4%), somnolence (7% vs 4%), and restlessness (7%
vs 2%).
- Bipolar depression: The incidences within the
recommended doses (VRAYLAR 1.5 mg/day or 3 mg/day vs placebo) were:
nausea (7%, 7% vs 3%), akathisia (6%, 10% vs 2%), restlessness (2%,
7% vs 3%), and EPS (4%, 6% vs 2%).
Please also see full Prescribing Information, including Boxed
Warnings.
About Allergan plc
Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a global pharmaceutical
leader focused on developing, manufacturing and commercializing
branded pharmaceutical, device, biologic, surgical and regenerative
medicine products for patients around the world. Allergan
markets a portfolio of leading brands and best-in-class products
primarily focused on four key therapeutic areas including medical
aesthetics, eye care, central nervous system and gastroenterology.
As part of its approach to delivering innovation for better patient
care, Allergan has built one of the broadest pharmaceutical and
device research and development pipelines in the industry.
With colleagues and commercial operations in approximately 100
countries, Allergan is committed to working with physicians,
healthcare providers and patients to deliver innovative and
meaningful treatments that help people around the world live
longer, healthier lives every day.
For more information, visit Allergan's website
at www.Allergan.com.
About Gedeon Richter
Gedeon Richter Plc. (www.richter.hu), headquartered in
Budapest/Hungary, is a major
pharmaceutical company in Central Eastern Europe, with an expanding
direct presence in Western Europe,
in China, and in Latin America.
Having reached a market capitalization of EUR 3.2 billion (USD 3.6
billion) by the end of 2018, Richter's consolidated sales
were approximately EUR 1.4 billion
(USD 1.6 billion) during the same
year. The product portfolio of Richter covers many important
therapeutic areas, including Women's Healthcare, Central Nervous
System, and Cardiovascular areas.
Having the largest R&D unit in Central Eastern Europe,
Richter's original research activity focuses on CNS disorders. With
its widely acknowledged steroid chemistry expertise, Richter is a
significant player in the Women's Healthcare field worldwide.
Richter is also active in biosimilar product development.
Forward-Looking Statement
Statements contained in
this press release that refer to future events or other
non-historical facts are forward-looking statements that reflect
Allergan's current perspective on existing trends and information
as of the date of this release. Actual results may differ
materially from Allergan's current expectations depending upon a
number of factors affecting Allergan's business. These factors
include, among others, the difficulty of predicting the timing or
outcome of FDA approvals or actions, if any; the impact of
competitive products and pricing; market acceptance of and
continued demand for Allergan's products; the impact of uncertainty
around timing of generic entry related to key products, including
RESTASIS®, on our financial results; risks associated
with divestitures, acquisitions, mergers and joint ventures; risks
related to impairments; uncertainty associated with financial
projections, projected cost reductions, projected debt reduction,
projected synergies, restructurings, increased costs, and adverse
tax consequences; difficulties or delays in manufacturing; and
other risks and uncertainties detailed in Allergan's periodic
public filings with the Securities and Exchange Commission,
including but not limited to Allergan's Annual Report on Form 10-K
for the year ended December 31, 2018
and Allergan's Quarterly Report on Form 10-Q for the period ended
March 31, 2019. Except as expressly
required by law, Allergan disclaims any intent or obligation to
update these forward-looking statements.
References
1Harvard Medical School,
2007. National Comorbidity Survey (NSC). (2017, August 21). Retrieved from
https://www.hcp.med.harvard.edu/ncs/index.php. Data Table 1:
https://www.hcp.med.harvard.edu/ncs/ftpdir/table_ncsr_LTprevgenderxage.pdf Lifetime
prevalence DSM-IV/WMH-CIDI disorders by sex and cohort.
2National Institutes of Mental Health
(NIMH). Available at:
https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml.
Accessed May 13, 2019.
3Depression and Bipolar Support Alliance. Types of
Bipolar Disorder. Available at:
https://secure2.convio.net/dabsa/site/SPageServer/?pagename=education_bipolar_types.
Last Accessed May 13, 2019.
4The National Institute of Mental Health. Bipolar
Disorder.
https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml.
April 2016. Accessed May 13, 2019.
5 The long-term natural history of the weekly
symptomatic status of bipolar I disorder. Arch Gen
Psychiatry. 2002 Jun;59(6):530-7.
6American Journal of Psychiatry. Available at:
https://doi.org/10.1176/appi.pn.2014.8a5. Accessed May 13, 2019.
CONTACTS:
Allergan:
Investors:
Manisha Narasimhan, PhD
(862) 261-7162
Media:
Amy Rose
(862) 289-3072
Julie
Ciardiello
(732) 429-4909
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SOURCE Allergan plc