Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved ISENTRESS® HD, a new 1200 mg once-daily dose of
the company’s integrase inhibitor, ISENTRESS® (raltegravir), to be
administered orally as two 600 mg film-coated tablets with or
without food, in combination with other antiretroviral agents, for
the treatment of HIV-1 infection in adults, and pediatric patients
weighing at least 40 kg, who are treatment-naïve or whose virus has
been suppressed on an initial regimen of ISENTRESS 400 mg given
twice daily.
“ISENTRESS has been used as a component of treatment regimens
for patients diagnosed with HIV-1 for almost a decade,” said Dr.
Michael S. Saag, associate dean for global health, and director of
the Center for AIDS Research at the University of Alabama at
Birmingham School of Medicine. “The addition of a convenient
once-daily version with a comparable efficacy and safety profile at
48 weeks to the existing twice-daily version of ISENTRESS provides
physicians with a new therapeutic option for some patients with
HIV-1 infection.”
ISENTRESS and ISENTRESS HD do not cure HIV-1 infection or AIDS.
Severe, potentially life-threatening and fatal skin reactions have
been reported. This includes cases of Stevens-Johnson syndrome,
hypersensitivity reaction, and toxic epidermal necrolysis.
Immediately discontinue treatment with ISENTRESS or ISENTRESS HD
and other suspect agents if severe hypersensitivity, severe rash,
or rash with systemic symptoms or liver aminotransferase elevations
develop and monitor clinical status, including liver
aminotransferases closely. For more information, see “Selected
Safety Information” below.
The FDA approval of once-daily ISENTRESS HD (raltegravir) is
supported by data from the pivotal Phase 3 ONCEMRK trial. At Week
48, 89 percent (N=531) of treatment-naïve HIV-1 infected patients
receiving ISENTRESS HD 1200 mg (2 x 600 mg) once a day achieved
viral suppression of HIV-1 RNA <40 copies/mL compared to 88
percent (N=266) of patients receiving ISENTRESS 400 mg twice a day,
each in combination therapy with emtricitabine + tenofovir
disoproxil fumarate, with a treatment difference of 0.5 percent,
and a 95 percent confidence interval of -4.2, 5.2. This was
consistent across demographic groups at initiation of therapy and a
variety of patient populations, including those with high viral
load (HIV-1 RNA >100,000 copies/mL).
“Because of improvements in the effectiveness of antiretroviral
therapies and with appropriate access to care, HIV infection can
now be managed as a chronic disease,” said Carl Schmid, deputy
executive director of the AIDS Institute. “For people living with
HIV, having a wide range of effective therapies is important
because it provides options to fit patients’ individual needs and
lifestyles.”
In ONCEMRK, through 48 weeks, the rate of discontinuation of
therapy due to adverse events was low (1 percent in patients
receiving ISENTRESS HD 1200 mg once daily and 2 percent in patients
receiving ISENTRESS 400 mg twice daily). There were no drug-related
clinical adverse reactions of moderate to severe intensity
occurring in ≥2 percent of patients in either treatment group.
Clinical adverse reactions of all intensities (mild, moderate, and
severe) occurring in ≥2 percent of patients on ISENTRESS HD or
ISENTRESS included abdominal pain, diarrhea, vomiting, and
decreased appetite. Treatment-emergent viral mutations leading to
any drug resistance were detected in less than 1 percent (4/531) of
those treated with ISENTRESS HD once daily.
ISENTRESS HD can be co-administered with a wide range of
antiretroviral agents and non-antiretroviral agents. The potential
for drug-drug interactions must be considered prior to and during
therapy. The co-administration of ISENTRESS HD with aluminum and/or
magnesium-containing antacids, calcium carbonate antacids,
rifampin, tipranavir/ritonavir, etravirine, and other strong
inducers of drug metabolizing enzymes (e.g., carbamazepine,
phenobarbital, and phenytoin) is not recommended.
“ISENTRESS HD exemplifies Merck’s unwavering commitment to
innovation in HIV therapy, and we are pleased to be able to offer
this option to a broad range of appropriate adult and pediatric
patients weighing at least 40 kg who are living with HIV,” said Dr.
Eliav Barr, senior vice president, global clinical development,
infectious diseases and vaccines, Merck Research Laboratories.
The price of ISENTRESS HD will be the same as ISENTRESS twice
daily. Merck anticipates ISENTRESS HD to be available in pharmacies
in approximately four weeks.
About ONCEMRK
The ONCEMRK study is an ongoing Phase 3 multicenter,
double-blind, randomized, active comparator-controlled clinical
trial designed to evaluate the efficacy and safety of once-daily
ISENTRESS HD 1200 mg, given as two 600 mg oral tablets, compared to
twice-daily ISENTRESS 400 mg, each in combination therapy with
emtricitabine + tenofovir disoproxil fumarate in previously
untreated adults with HIV-1 infection with HIV-1 RNA ≥1000
copies/mL. The primary efficacy objective was the proportion of
patients achieving HIV-1 RNA <40 copies/mL at Week 48.
Selected Safety Information about ISENTRESS HD (raltegravir)
and ISENTRESS (raltegravir)
Immune reconstitution syndrome can occur, including the
occurrence of autoimmune disorders with variable time to onset,
which may necessitate further evaluation and treatment.
ISENTRESS chewable tablets contain phenylalanine, a component of
aspartame, which may be harmful to patients with
phenylketonuria.
Co-administration of ISENTRESS or ISENTRESS HD with drugs that
induce uridine diphosphate glucuronosyltransferase (UGT) 1A1 may
result in reduced plasma concentrations of raltegravir.
Co-administration of ISENTRESS or ISENTRESS HD with drugs that
inhibit UGT1A1 may increase plasma levels of raltegravir.
Co-administration of ISENTRESS or ISENTRESS HD and other drugs
may alter the plasma concentration of raltegravir. The potential
for drug-drug interactions must be considered prior to and during
therapy. Co-administration or staggered administration of aluminum
and/or magnesium hydroxide-containing antacids and ISENTRESS or
ISENTRESS HD is not recommended. Co-administration of ISENTRESS HD
with calcium carbonate antacids, tipranavir/ritonavir, or
etravirine is also not recommended.
During co-administration with rifampin, the recommended dosage
of ISENTRESS in adults is 800 mg twice daily. Rifampin, a strong
inducer of UGT1A1, reduces plasma concentrations of ISENTRESS.
There are no data to guide co-administration of ISENTRESS with
rifampin in patients below 18 years of age.
Co-administration with rifampin is not recommended with
ISENTRESS HD.
The impact of other strong inducers of drug metabolizing enzymes
on raltegravir is unknown (e.g., Carbamazepine, Phenobarbital, and
Phenytoin). Co-administration of ISENTRESS or ISENTRESS HD with
other strong inducers is not recommended.
About ISENTRESS (raltegravir)
Approved in 2007, ISENTRESS was the first integrase inhibitor
developed for the treatment of HIV-1 infection. ISENTRESS is one of
the regimen options recommended by the Department of Health and
Human Services – in combination with other antiretroviral agents –
as a first-line therapy in treatment-naïve HIV-1 infected adults.
ISENTRESS chewable tablets and oral suspension, each in combination
therapy, are approved to treat pediatric patients aged at least
four weeks of age, and weighing less than 20 kg.
ISENTRESS works by inhibiting the insertion of HIV-1 DNA into
human DNA by the integrase enzyme and has demonstrated rapid
antiviral activity. Inhibiting integrase from performing this
essential function limits the ability of the virus to replicate and
infect new cells.
ISENTRESS is approved as part of combination therapy in 112
countries for treatment of HIV-1 infection in adult patients.
ISENTRESS, in combination therapy, for use in children and
adolescents with HIV-1 aged two years and older has also been
approved for use in 69 countries, and ISENTRESS oral suspension for
infants at least four weeks of age is approved for use in 33
countries.
Selected Safety Information about ISENTRESS HD (raltegravir)
and ISENTRESS (raltegravir) Continued
The most commonly reported (≥2 percent) drug-related clinical
adverse reactions of moderate to severe intensity in
treatment-naïve adult patients receiving ISENTRESS compared with
efavirenz were headache (4 percent vs. 5 percent), insomnia (4
percent vs. 4 percent), nausea (3 percent vs. 4 percent), dizziness
(2 percent vs. 6 percent), and fatigue (2 percent vs. 3 percent),
respectively. The most commonly reported (≥2 percent) clinical
adverse reactions of all intensities (Mild, Moderate, and Severe)
in treatment-naïve adult patients receiving ISENTRESS HD compared
with ISENTRESS through 48 weeks included abdominal pain, diarrhea,
vomiting, and decreased appetite. Intensities were defined as
follows: Mild (awareness of sign or symptom, but easily tolerated);
Moderate (discomfort enough to cause interference with usual
activity); or Severe (incapacitating with inability to work or do
usual activity).
Grade 2–4 creatine kinase laboratory abnormalities were observed
in subjects treated with ISENTRESS or ISENTRESS HD. Myopathy and
rhabdomyolysis have been reported with ISENTRESS. Use with caution
in patients at increased risk of myopathy or rhabdomyolysis, such
as patients receiving concomitant medications known to cause these
conditions and patients with a history of rhabdomyolysis, myopathy,
or increased serum creatine kinase.
There is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to ISENTRESS or ISENTRESS HD during
pregnancy. Healthcare providers are encouraged to register patients
by calling the Antiretroviral Pregnancy Registry (APR) at
1-800-258-4263.
Women infected with HIV-1 should be instructed not to breastfeed
if they are receiving ISENTRESS or ISENTRESS HD due to the
potential for HIV transmission.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been bringing forward medicines and vaccines for
many of the world's most challenging diseases. Through our
prescription medicines, vaccines, biologic therapies 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 health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer's disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’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 health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’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 the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company 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 the company’s 2016
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 ISENTRESS
(raltegravir) and ISENTRESS HD (raltegravir) at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf,
Patient Information for ISENTRESS and ISENTRESS HD (raltegravir) at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.
The Instructions for use also are available at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ifu.pdf.
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