RECARBRIO is Indicated to Treat Multiple
Infections Caused by Susceptible Gram-Negative Bacteria in
Adults
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, announced today that the U.S. Food and Drug Administration
(FDA) has approved a supplemental New Drug Application (sNDA) for
RECARBRIO™ (imipenem, cilastatin, and relebactam) for the treatment
of patients 18 years of age and older with hospital-acquired
bacterial pneumonia and ventilator-associated bacterial pneumonia
(HABP/VABP), caused by the following susceptible Gram-negative
microorganisms: Acinetobacter calcoaceticus-baumannii complex,
Enterobacter cloacae, Escherichia coli, Haemophilus influenzae,
Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae,
Pseudomonas aeruginosa and Serratia marcescens. To reduce the
development of drug-resistant bacteria and maintain the
effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO
should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria.
RECARBRIO is contraindicated in patients with a history of known
severe hypersensitivity to any component of RECARBRIO. See Selected
Safety Information below.
“Hospital-acquired infections continue to be a significant cause
of illness and death despite advances in our understanding of the
contributing factors and prevention of these diseases,” said Dr.
Keith Kaye, professor of medicine and director of research for the
division of infectious diseases, University of Michigan Health
System, and a principal investigator in the clinical program.
“Because these infections are often caused by difficult to treat
Gram-negative organisms, new therapeutic options such as RECARBRIO
are urgently needed for patients.”
RECARBRIO is a combination of imipenem, a carbapenem
antibacterial, cilastatin, a renal dehydropeptidase inhibitor, and
relebactam, a beta-lactamase inhibitor. Relebactam protects
imipenem from degradation by certain serine beta-lactamases such as
SHV (Sulfhydryl Variable), TEM (Temoneira), CTX-M
(Cefotaximase-Munich), P99 (Enterobacter cloacae P99), PDC
(Pseudomonas-derived cephalosporinase), and KPC
(Klebsiella-pneumoniae carbapenemase).
The additional indication in HABP/VABP is based on results of
the pivotal Phase 3 RESTORE-IMI 2 trial that compared RECARBRIO
1.25 grams (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) to
piperacillin/tazobactam 4.5 grams (PIP/TAZ, piperacillin 4000
mg/tazobactam 500 mg), each administered intravenously every six
hours for seven to 14 days, for the treatment of adult patients
with HABP/VABP. RECARBRIO met the primary and key secondary
endpoints, demonstrating non-inferiority to PIP/TAZ in 28-day
all-cause mortality and clinical response at early follow-up,
respectively. The RESTORE-IMI 2 study abstract was published by the
30th European Congress of Clinical Microbiology & Infectious
Diseases (ECCMID).
“At a time of great public health concern about the need for new
treatments to meet the evolving challenges posed by Gram-negative
bacteria, we are proud to continue bringing new therapeutic options
to health care practitioners in an effort to help them overcome the
challenges in patient care,” said Dr. Nicholas Kartsonis, senior
vice president, clinical research, infectious diseases and
vaccines, Merck Research Laboratories. “Today’s approval is further
affirmation of Merck’s steadfast commitment to meeting the needs of
the health care community.”
RECARBRIO is also indicated in adults who have limited or no
alternative treatment options for complicated urinary tract
infections (cUTI), including pyelonephritis, and complicated
intra-abdominal infections (cIAI) caused by susceptible
Gram-negative bacteria, as described below. RECARBRIO is
administered via intravenous injection.
Clinical Data Supporting Use of RECARBRIO (imipenem,
cilastatin, and relebactam) in HABP/VABP
The FDA approval of the use of RECARBRIO in HABP/VABP was based
on the RESTORE-IMI 2 trial (NCT02493764), a Phase 3, multinational,
randomized, double-blind, non-inferiority study evaluating the
efficacy and safety of RECARBRIO (imipenem 500 mg/cilastatin 500
mg/relebactam 250 mg) compared with PIP/TAZ (piperacillin 4000
mg/tazobactam 500 mg) in adults with HABP/VABP. In the study, 535
hospitalized adults with HABP/VABP in 113 trial sites were
randomized 1:1 to receive a dose of RECARBRIO or PIP/TAZ, each
given intravenously every six hours for seven to 14 days. The
primary efficacy endpoint was incidence of all-cause mortality
through Day 28 in the modified intent-to-treat (MITT) population,
which is defined as all randomized participants who received at
least one dose of trial treatment and did not have only
Gram-positive cocci on Gram stain of a baseline lower respiratory
tract (LRT) specimen. The key secondary endpoint was clinical
response at early follow-up (seven to 14 days after completing
therapy) in the MITT population.
The mean age of patients in the study was 60 years, 43% of
patients were 65 years of age and older, 31% were female, and 22%
had polymicrobial infection. The mean Acute Physiology and Chronic
Health Evaluation (APACHE) II score was 15, and 48% of patients had
an APACHE II score greater than or equal to 15 at baseline.
Overall, 260 (49%) patients were ventilated at enrollment,
including 194 (36%) patients with VABP and 66 (12%) patients with
ventilated HABP. Concurrent bacteremia was present at baseline in
5.8% of patients.
RECARBRIO met the primary and key secondary endpoints,
demonstrating non-inferiority to PIP/TAZ. For patients treated with
RECARBRIO, 28-day all-cause mortality was 15.9% (42/264) and 21.3%
(57/267) in those treated with PIP/TAZ, for a treatment difference
of -5.3% (95% confidence interval [CI]: -11.9, 1.2). Clinical
response at early follow-up was 61% (161/264) for RECARBRIO and
55.8% (149/267) for PIP/TAZ group, for a treatment difference of 5%
(95% CI: -3.2, 13.2).
In the subgroup of patients with ventilated HABP/VABP at
enrollment, a favorable response in 28-day all-cause mortality was
observed at 19.7% (24/122) for RECARBRIO and 30.9% (42/136) for
PIP/TAZ, for a treatment difference of -11.2% (95% CI: -21.6,
-0.5). In the subgroup of patients with non-ventilated HABP at
enrollment, 28-day all-cause mortality was 12.7% (18/142) for
RECARBRIO and 11.5% (15/131) for PIP/TAZ, for a treatment
difference of 1.2% (95% CI: -6.8, 9.1).
Serious adverse reactions occurred in 27% (71/266) of patients
receiving RECARBRIO and 32% (86/269) of patients receiving PIP/TAZ.
Deaths were reported in 15% (40/266) of patients receiving
RECARBRIO and 21% (57/269) of patients receiving PIP/TAZ. Adverse
reactions leading to discontinuation occurred in 5.6% (15/266) of
patients receiving RECARBRIO and 8.2% (22/269) of patients
receiving PIP/TAZ. The most frequently reported adverse reactions
occurring in 4% or greater of patients treated with RECARBRIO were
increased aspartate aminotransferase (11.7%), anemia (10.5%),
increased alanine aminotransferase (9.8%), diarrhea (7.9%),
hypokalemia (7.9%), hyponatremia (6.4%), constipation (4.1%),
pyrexia (4.1%) and rash (4.1%).
RECARBRIO was also studied in patients with cIAI, cUTI, and
HABP/VABP caused by imipenem-nonsusceptible pathogens, in a
non-inferential trial which used colistin (loading dose to achieve
300 mg colistin base activity, followed by maintenance doses up to
150 mg colistin base activity, every 12 hours) plus imipenem (500
mg every 6 hours) as the active comparator (RESTORE-IMI 1;
NCT02452047). This trial, which included 47 patients, provided only
limited efficacy and safety information.
Selected Safety Information about RECARBRIO (imipenem,
cilastatin, and relebactam)
Hypersensitivity Reactions: RECARBRIO is contraindicated
in patients with a history of known severe hypersensitivity (severe
systemic allergic reaction such as anaphylaxis) to any component of
RECARBRIO. Serious and occasionally fatal hypersensitivity
(anaphylactic) reactions have been reported in patients receiving
therapy with beta-lactams. Before initiating therapy with
RECARBRIO, careful inquiry should be made concerning previous
hypersensitivity reactions to carbapenems, penicillins,
cephalosporins, other beta-lactams, and other allergens. If a
hypersensitivity reaction to RECARBRIO occurs, discontinue the
therapy immediately.
Seizures and Other Central Nervous System (CNS) Adverse
Reactions: CNS adverse reactions, such as seizures, confusional
states, and myoclonic activity, have been reported during treatment
with imipenem/cilastatin, a component of RECARBRIO, especially when
recommended dosages of imipenem were exceeded. These have been
reported most commonly in patients with CNS disorders (e.g., brain
lesions or history of seizures) and/or compromised renal function.
Anticonvulsant therapy should be continued in patients with known
seizure disorders. If CNS adverse reactions including seizures
occur, patients should undergo a neurological evaluation to
determine whether RECARBRIO should be discontinued.
Increased Seizure Potential Due to Interaction with Valproic
Acid: Concomitant use of RECARBRIO, with valproic acid or
divalproex sodium may increase the risk of breakthrough seizures.
Avoid concomitant use of RECARBRIO with valproic acid or divalproex
sodium or consider alternative antibacterial drugs other than
carbapenems.
Clostridioides difficile-Associated Diarrhea (CDAD):
Clostridioides difficile-associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including
RECARBRIO, and may range in severity from mild diarrhea to fatal
colitis. Careful medical history is necessary since CDAD has been
reported to occur over two months after the administration of
antibacterial agents. If CDAD is suspected or confirmed, ongoing
antibacterial drug use not directed against C. difficile may need
to be discontinued.
Development of Drug-Resistant Bacteria: Prescribing
RECARBRIO in the absence of a proven or strongly suspected
bacterial infection or prophylactic indication is unlikely to
provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Adverse Reactions: In the cUTI and cIAI trials, the most
frequently reported adverse reactions occurring in ≥2% of patients
treated with RECARBRIO were diarrhea (6%), nausea (6%), headache
(4%), vomiting (3%), alanine aminotransferase increased (3%),
aspartate aminotransferase increased (3%), phlebitis/infusion site
reactions (2%), pyrexia (2%) and hypertension (2%). In the
HABP/VABP study, the most frequently reported adverse reactions
occurring in ≥4% of patients treated with RECARBRIO were increased
aspartate aminotransferase (11.7%), anemia (10.5%), increased
alanine aminotransferase (9.8%), diarrhea (7.9%), hypokalemia
(7.9%), hyponatremia (6.4%), constipation (4.1%), pyrexia (4.1%)
and rash (4.1%).
About RECARBRIO (imipenem, cilastatin, and
relebactam)
RECARBRIO is indicated for the treatment of patients 18 years of
age and older with hospital-acquired bacterial pneumonia and
ventilator-associated bacterial pneumonia, caused by the following
susceptible Gram-negative microorganisms: Acinetobacter
calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia
coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella
oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia
marcescens.
RECARBRIO is also indicated in patients 18 years of age and
older who have limited or no alternative treatment options, for the
treatment of complicated urinary tract infections (cUTI), including
pyelonephritis, caused by the following susceptible Gram-negative
microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella
aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa.
RECARBRIO is also indicated in patients 18 years of age and
older who have limited or no alternative treatment options, for the
treatment of complicated intra-abdominal infections (cIAI) caused
by the following susceptible gram-negative microorganisms:
Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus,
Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides
uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter
cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella
aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae,
Parabacteroides distasonis and Pseudomonas aeruginosa.
Approval of the cUTI and cIAI indications are based on limited
clinical safety and efficacy data for RECARBRIO.
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of RECARBRIO and other antibacterial
drugs, RECARBRIO should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information is available,
they should be considered in selecting or modifying antibacterial
therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of
therapy.
About Merck
For more than 125 years, Merck, known as MSD outside of the
United States and Canada, has been inventing for life, bringing
forward medicines and vaccines for many of the world’s most
challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. 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 the recent global outbreak of novel coronavirus
disease (COVID-19); 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 2019
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 RECARBRIO (imipenem,
cilastatin, and relebactam) at
https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf
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