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 RECARBRIO™ (imipenem, cilastatin, and
relebactam) for injection, 1.25 grams, a new combination
antibacterial. RECARBRIO is 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 or 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 these indications is 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 are
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.
Relebactam received FDA’s Qualified Infectious Disease Product
(QIDP) designation for the treatment of cUTI and cIAI. The New Drug
Application (NDA) for RECARBRIO received Priority Review
designation from the FDA. Merck anticipates making RECARBRIO
available later this year.
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.
Central nervous system (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 reactions have been reported most commonly in
patients with CNS disorders (such as brain lesions or a history of
seizures) and/or compromised renal function. Concominant use of
RECARBRIO, with valproic acid or divalproex sodium may increase the
risk of breakthrough seizures. Additionally, Clostridium
difficile-associated diarrhea (CDAD) has been reported with use of
nearly all antibacterial agents, including imipenem/cilastatin plus
relebactam and may range in severity from mild diarrhea to fatal
colitis. See Important Safety Information below.
RECARBRIO is a combination of imipenem/cilastatin and
relebactam. Imipenem is a penem antibacterial drug, cilastatin
sodium is a renal dehydropeptidase inhibitor, and relebactam is a
beta lactamase inhibitor. Cilastatin limits the renal metabolism of
imipenem and does not have antibacterial activity. The bactericidal
activity of imipenem results from binding to PBP 2 and PBP 1B in
Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent
inhibition of penicillin binding proteins (PBPs). Inhibition of
PBPs leads to the disruption of bacterial cell wall synthesis.
Imipenem is stable in the presence of some beta lactamases.
Relebactam has no intrinsic antibacterial activity. Relebactam
protects imipenem from degradation by certain serine beta
lactamases such as Sulhydryl Variable (SHV), Temoneira (TEM),
Cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99),
Pseudomonas-derived cephalosporinase (PDC), and
Klebsiella-pneumoniae carbapenemase (KPC).
“RECARBRIO provides an important addition to our toolkit in the
ongoing fight against infections caused by certain Gram-negative
pathogens,” said Dr. Keith Kaye, professor of medicine and director
of research for the division of infectious diseases, University of
Michigan Heath System, and a principal investigator in the clinical
program. “RECARBRIO offers an additional treatment option for
patients with cIAI and cUTI who have limited and, in some cases, no
alternative therapeutic options.”
“Today’s announcement is a great example of Merck’s longstanding
commitment to infectious diseases research and development, as we
continue to search for novel ways to approach difficult-to-treat
pathogens,” said Dr. Nick Kartsonis, senior vice president,
infectious diseases and vaccines, Merck Research Laboratories.
Important Safety Information about RECARBRIO (imipenem,
cilastatin, and relebactam)
CONTRAINDICATIONS
RECARBRIO is contraindicated in patients with a history of known
severe hypersensitivity (severe systemic allergic reaction such as
anaphylaxis) to any component of RECARBRIO.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions: 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.
Clostridium difficile-Associated Diarrhea (CDAD):
Clostridium difficile-associated diarrhea (CDAD) has been reported
with use of nearly all antibacterial agents, including
imipenem/cilastatin plus relebactam, and may range in severity from
mild diarrhea to fatal colitis. Treatment with antibacterial agents
alters the normal flora of the colon leading to overgrowth of C.
difficile.
C. difficile produces toxins A and B which contribute to the
development of CDAD. Hypertoxin producing strains of C. difficile
cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD
must be considered in all patients who present with diarrhea
following antibacterial drug use. 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.
Appropriate fluid and electrolyte management, protein
supplementation, antibacterial drug treatment of C. difficile, and
surgical evaluation should be instituted as clinically
indicated.
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: The most frequently reported adverse
reactions occurring in ≥2% of patients treated with
imipenem/cilastatin plus relebactam 250 mg were diarrhea, nausea,
headache, vomiting, alanine aminotransferase increased, aspartate
aminotransferase increased, phlebitis/infusion site reactions,
pyrexia, and hypertension.
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 inventing for life, 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 2018
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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