RECARBRIO™

(imipenem, cilastatin, and relebactam) for injection 1.25 g

In Vitro Activity

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In the Study for Monitoring Antimicrobial Resistance Trends (SMART),

RECARBRIO demonstrated potent in vitro activity1

The Study for Monitoring Antimicrobial Resistance Trends (SMART) represents the commitment of Merck to monitor the in vitro susceptibility of clinical bacterial Gram-negative isolates to antimicrobials in intra-abdominal (since 2002), urinary tract (since 2009), respiratory (since 2015), and bloodstream infections (since 2019). SMART was initiated in 2002 and is a global study.

The limitations of SMART surveillance include the small number of sites per country, changes over time in the sites participating in SMART, and the relatively small number of isolates tested each year, n=250. In addition, the lack of clinical information does not allow for confirmation of isolates as being “community-acquired” vs “hospital-acquired.”

The following breakpoints were used to test for the susceptibility of RECARBRIO for P. aeruginosa (MICs [mcg/mL]): 2/4 (susceptible), and of Enterobacteriaceae: <1/4 (susceptible).

Enterobacteriaceae: C. freundii, E. cloacae, E. coli, K. aerogens, K. oxytoca, K. pneumoniae, S. marcescens

Susceptibility rates for P. aeruginosa isolates in surveillance data (2019–2020)a

P. aeruginosa (n=1641) Pip/tazo NS P. aeruginosa (n=345) 71% 0% Imipenem/relebactam Piperacillin/tazobactam 0 20 40 60 80 100 90% 79% Percentage of susceptible pathogens
a Isolates collected from both ICU and non-ICU settings in the United States from 2019–2020 for the SMART surveillance program.
  • Culture and susceptibility information and local epidemiology should be considered in modifying antibacterial therapy.
  • The clinical significance of in vitro data is unknown.

Susceptibility rates for Enterobacteriaceae isolates in surveillance data (2019–2020)a

Imipenem/relebactam Piperacillin/tazobactam 0 20 40 60 80 100 Percentage of susceptible pathogens Enterobacteriaceae (n=6339) Pip/tazo NS Enterobacteriaceae (n=584) K. pneumoniae(n=1268) Pip/tazo NSK. pneumoniae(n=108) Pip/tazo NSE. coli (n=126) E. coli (n=2769) 97% 91% 99% 99% 92% 94% 0% 0% 0% 100% 100% 96%
a Isolates collected from both ICU and non-ICU settings in the United States from 2019–2020 for the SMART surveillance program.
  • Culture and susceptibility information and local epidemiology should be considered in modifying antibacterial therapy.
  • The clinical significance of in vitro data is unknown.

Susceptibility rates for K. pneumoniae isolates in surveillance data (2016–2020)a

KPC+ K. pneumoniae (n=76) K. pneumoniae (n=3333) Imipenem/relebactam Piperacillin/tazobactam 0 20 40 60 80 100 Percentage of susceptible pathogens 93% 0% 99% 90%
aIsolates collected from both ICU and non-ICU settings in the United States from 2016–2020 for the SMART surveillance program.
  • Culture and susceptibility information and local epidemiology should be considered in modifying antibacterial therapy.
  • The clinical significance of in vitro data is unknown.

Susceptibility rates for ESBL+ Enterobacteriaceae isolates in surveillance data (2019–2020)a,b

Imipenem/relebactam Piperacillin/tazobactam 0 20 40 60 80 100 Percentage of susceptible pathogens ESBL+ Enterobacteriaceae (n=1244) ESBL+ E. coli (n=585) ESBL+ K. pneumoniae (n=233) Enterobacteriaceae (n=6339) E. coli (n=2769) K. pneumoniae (n=1268) 98% 67% 100% 86% 97% 64% 91% 99% 100% 96% 99% 92%
aESBL+ phenotype was defined by the criteria of MIC ≥2 ug/ml for aztreonam OR ceftazidime OR ceftriaxone.
bIsolates collected from both ICU and non-ICU settings in the United States from 2019–2020 for the SMART surveillance program.
  • Culture and susceptibility information and local epidemiology should be considered in modifying antibacterial therapy.
  • The clinical significance of in vitro data is unknown.
Reference

1. Data available on request from Merck & Co., Inc., Professional Services DAP, WP1-27, PO Box 4, West Point, PA 19846-0004. Please specify information package US-TIX-00522.

Indications

RECARBRIO is indicated 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.

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 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 is based on limited clinical safety and efficacy data for RECARBRIO.

Usage

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.

Selected Safety Information

  • 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 (eg, 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) 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: The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%).
  • The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI 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%).
US-TIX-0057810/22