Merck Receives FDA Approval of ISENTRESS® HD (raltegravir), a New Once-Daily Option, in Combination with Other Antiretroviral Agents, for the Treatment of HIV-1 Infection in Appropriate Patients
May 30, 2017 6:00 am ET
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.
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
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
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
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Please see Prescribing Information for ISENTRESS (raltegravir) and
ISENTRESS HD (raltegravir) at
Patient Information for ISENTRESS and ISENTRESS HD (raltegravir) at
The Instructions for use also are available at
Pam Eisele, (267) 305-3558
Carmen de Gourville, (267) 305-4195
Teri Loxam, (908) 740-1986
Amy Klug, (908) 740-1898