Merck Planning Regulatory Submissions in the
U.S. for EMEND® in Pediatric Setting Including New
Suspension Formulation in Second Half of 2014
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced results from a global, investigational
Phase 3 study to evaluate the safety and efficacy of EMEND®
(aprepitant) in the prevention of chemotherapy-induced nausea and
vomiting (CINV) in pediatric cancer patients, aged 6 months to 17
years. In this study in pediatric cancer patients undergoing very
highly, highly, or moderately emetogenic (vomit-inducing)
chemotherapy, the use of the EMEND regimen for CINV prevention was
significantly more effective than a control regimen in achieving
Complete Response, defined as no vomiting or retching and no use of
rescue medication for nausea and vomiting, in all phases of CINV
(acute, delayed, and overall). These new data were presented in an
oral session at the Multinational Association of Supportive Care in
Cancer/International Society of Oral Oncology (MASCC/ISOO) Annual
International Symposium on Supportive Care in Cancer (Abstract
#0286) by Dr. Hyoung Jin Kang, M.D., Ph.D., lead investigator and
associate professor, Department of Pediatrics, Cancer Research
Institute, Seoul National University College of Medicine, Seoul,
Korea.
“Nausea and vomiting are common complications of cancer
chemotherapy and can be particularly distressful and debilitating
to pediatric cancer patients,” said Dr. Stuart Green, vice
president, clinical research, Merck Research Laboratories. “In this
large pediatric study, adding EMEND to a standard regimen for
prevention of CINV resulted in significant reduction of emetic
events.”
Based on these data, Merck plans worldwide regulatory
submissions for EMEND (aprepitant), beginning in the United States,
for use in the prevention of CINV in pediatric and adolescent
cancer patients (ages 6 months to 17 years). In the United States,
Merck plans to submit a New Drug Application (NDA) for a new
pediatric formulation (powder for suspension) and a supplemental
NDA for use of the current formulation (capsules). Both filings are
planned for the second half of 2014.
EMEND, a Substance P/Neurokinin-1 (NK1) receptor antagonist
approved for use in combination with other antiemetic agents, is
indicated in adults for the prevention of acute and delayed nausea
and vomiting associated with initial and repeat courses of highly
emetogenic cancer chemotherapy, including high-dose cisplatin; and
for prevention of nausea and vomiting associated with initial and
repeat courses of moderately emetogenic cancer chemotherapy. EMEND
has not been studied for treatment of established nausea and
vomiting. Chronic continuous administration of EMEND is not
recommended. Safety and efficacy of EMEND in pediatric patients
have not been established.
Efficacy and Safety Findings for Investigational, Phase 3
CINV Prevention Study of EMEND in Pediatric Patients
The Phase 3 randomized, double-blind, active-comparator study of
302 participants evaluated EMEND for prevention of CINV in children
(ages 6 months to 17 years of age). In the study, patients
receiving emetogenic chemotherapy were randomly assigned to receive
an EMEND plus ondansetron regimen (n=152) or a control regimen
(placebo plus ondansetron) (n=150). The EMEND regimen included
either EMEND capsules or an investigational powder for suspension
formulation of aprepitant dosed based on weight. Ondansetron dosing
was based on the approved pediatric dose (as per the local label).
The primary endpoint of the study was complete response (no
vomiting, no retching, and no use of rescue medication for nausea
and vomiting) in the delayed phase (25 to 120 hours following
initiation of chemotherapy). The secondary endpoints were complete
response in the acute phase (0 to 24 hours) and overall phase
(0-120 hours), and no vomiting in the overall phase. In both
groups, the first dose of EMEND (plus ondansetron) was administered
on day 1 of chemotherapy, then subsequently (without ondansetron)
later on days 2 and 3. Dexamethasone could be administered
intravenously per investigator discretion (the dose was based on
weight). Administration of dexamethasone was similar in patients
receiving the EMEND regimen and the control regimen (44 vs. 42
patients, respectively).
EMEND Regimen Increased Complete Response in Days 2 through 5
(primary endpoint)
In the study, 51 percent of patients receiving the EMEND
(aprepitant) regimen achieved the primary endpoint of complete
response in the delayed phase of CINV, versus 26 percent of those
in the control group (p <0.0001). For the secondary endpoints,
66 percent of patients receiving the EMEND regimen achieved a
complete response in the acute phase of CINV, versus 52 percent of
those receiving the control regimen (p = 0.0135). In addition,
complete response in the overall phase was higher in patients
receiving the EMEND regimen versus the control regimen (40% vs.
20%, p =0.0002). No vomiting in the overall phase was observed in
47 percent vs. 21 percent of patients receiving the EMEND regimen
compared to the control regimen, respectively (p <0.0001).
Overall, 79 percent of patients receiving the EMEND regimen and
77 percent receiving the control regimen experienced one or more
adverse events. The most common adverse events (across all grades)
with the EMEND regimen compared to the control regimen included
anemia (17% vs. 25%), febrile neutropenia (16% for both groups),
vomiting (15% for both groups), neutropenia (14% vs. 12%),
thrombocytopenia (10% vs. 11%), decreased neutrophil count (9% vs.
13%), nausea (9% vs. 11%), and a decreased platelet count (8% vs.
10%). Treatment-related adverse events were observed in 3 percent
(5/152) of patients receiving the EMEND regimen and in 2 percent
(3/150) of patients receiving the control regimen. Serious
treatment-related adverse events were observed in 1 percent (2/152)
of patients on an EMEND regimen and in 0 percent (0/150) of
patients receiving the control regimen.
Selected important safety information for EMEND
(aprepitant)
EMEND is contraindicated in patients who are hypersensitive to
any component of the product. EMEND is a dose-dependent inhibitor
of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used
concurrently with pimozide, terfenadine, astemizole, or cisapride.
Inhibition of CYP3A4 by aprepitant could result in elevated plasma
concentrations of these drugs, potentially causing serious or
life-threatening reactions.
EMEND should be used with caution in patients receiving
concomitant medications, including chemotherapy agents, that are
primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND
could result in elevated plasma concentrations of these concomitant
medications. Conversely, when EMEND is used concomitantly with
another CYP3A4 inhibitor, aprepitant plasma concentrations could be
elevated. When EMEND is used concomitantly with medications that
induce CYP3A4 activity, aprepitant plasma concentrations could be
reduced, and this may result in decreased efficacy of
aprepitant.
Chemotherapy agents that are known to be metabolized by CYP3A4
include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide,
imatinib, vinorelbine, vinblastine, and vincristine. In clinical
studies, EMEND (aprepitant) was administered commonly with
etoposide, vinorelbine, or paclitaxel. The doses of these agents
were not adjusted to account for potential drug interactions. In
separate pharmacokinetic studies, EMEND did not influence the
pharmacokinetics of docetaxel or vinorelbine.
Because a small number of patients in clinical studies received
the CYP3A4 substrates vinblastine, vincristine, or ifosfamide,
particular caution and careful monitoring are advised in patients
receiving these agents or other chemotherapy agents metabolized
primarily by CYP3A4 that were not studied.
Coadministration of EMEND with warfarin (a CYP2C9 substrate) may
result in a clinically significant decrease in International
Normalized Ratio (INR) of prothrombin time. In patients on chronic
warfarin therapy, the INR should be closely monitored in the 2-week
period, particularly at 7 to 10 days, following initiation of
fosaprepitant with each chemotherapy cycle.
The efficacy of hormonal contraceptives (including birth control
pills, skin patches, implants, and certain IUDs) may be reduced
upon coadministration and for 28 days following the last dose of
EMEND. Alternative or back-up methods of contraception should be
used during treatment with and for 1 month following the last dose
of EMEND.
Chronic continuous use of EMEND for prevention of nausea and
vomiting is not recommended because it has not been studied and
because the drug interaction profile may change during chronic
continuous use.
In clinical trials of EMEND in patients receiving highly
emetogenic chemotherapy, the most common adverse events reported at
a frequency greater than with standard therapy, and at an incidence
of 1% or greater, were hiccups (4.6% EMEND (aprepitant) vs. 2.9%
standard therapy), asthenia/fatigue (2.9% vs. 1.6%), increased ALT
(2.8% vs. 1.5%), increased AST (1.1% vs. 0.9%), constipation (2.2%
vs. 2.0%), dyspepsia (1.5% vs. 0.7%), diarrhea (1.1% vs. 0.9%),
headache (2.2% vs. 1.8%), and anorexia (2.0% vs. 0.5%).
In clinical trials of EMEND in patients receiving moderately
emetogenic chemotherapy, the most common adverse events reported at
a frequency greater than with standard therapy were eructation
(1.0% EMEND vs. 0.1% standard therapy) and fatigue (1.4% vs.
0.9%).
About CINV
Chemotherapy Induced Nausea and Vomiting (CINV) is a common side
effect of chemotherapy caused by injured stomach cells that start
the process of nausea and vomiting and can directly activate the
area of the brain responsible for producing nausea and
vomiting.
The two main types of CINV are acute and delayed. Acute happens
within the first 24 hours of receiving chemotherapy. Delayed
happens from day 2 to day 5 after chemotherapy. The amount and
timing of CINV can vary. Some chemotherapies cause acute nausea and
vomiting. Others cause acute nausea and vomiting followed by
another period of delayed nausea and vomiting.
About Merck
Today's Merck is a global healthcare leader working to help the
world be well. Merck is known as MSD outside the United States and
Canada. Through our prescription medicines, vaccines, biologic
therapies, and consumer care and animal health products, we work
with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit
www.merck.com and connect with us on Twitter, Facebook and
YouTube.
Forward-Looking Statement
This news release includes “forward-looking statements” within
the meaning of the safe harbor provisions of the United States
Private Securities Litigation Reform Act of 1995. These statements
are based upon the current beliefs and expectations of Merck’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include, but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and healthcare
legislation in the United States and internationally; global trends
toward healthcare cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; Merck’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of Merck’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
Merck undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in Merck’s 2013 Annual
Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for EMEND (aprepitant)
at
http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf
and Patient Information for EMEND (aprepitant) at
http://www.merck.com/product/usa/pi_circulars/e/emend/emend_ppi.pdf
EMEND® is a registered trademark of Merck & Co., Inc.,
Whitehouse Station, N.J., USA
MerckMedia:Pam Eisele, 267-305-3558orClaire Mulhearn,
908-423-7425orInvestors:Joseph Romanelli, 908-423-5185orJustin
Holko, 908-423-5088
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