RECARBRIO

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

Efficacy

Clinical efficacy against HABP/VABP

Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

A total of 535 hospitalized adults with HABP/VABP were randomized and received trial medications in a multinational, double-blind trial (Trial 1, NCT02493764) comparing RECARBRIO 1.25 grams (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) intravenously every 6 hours to piperacillin and tazobactam (4.5 grams) for 7 to 14 days of therapy.

The modified intent-to-treat (MITT) population, which included all randomized patients who received at least one dose of trial treatment and did not have only gram-positive cocci on Gram stain of the baseline lower respiratory tract (LRT) specimen included 531 patients; the mean age was 60 and 43% were 65 years of age or older. The majority of patients were men (69%), white (78%), and from Europe (61%). The mean APACHE II score was 15 and 47% of the population had an APACHE II score of ≥15. At randomization, 66% of patients were admitted to the ICU, 77% had been in the hospital for ≥5 days, and 48% had a creatinine clearance of <90 mL/min. Concurrent bacteremia was present at baseline in 5.8% of patients.

The table below presents the incidence of all-cause mortality through Day 28 and clinical response at the early follow-up (EFU) visit (7 to 14 days after the end of therapy) in the MITT population. Overall results are presented along with subgroup results by pneumonia diagnosis.

Day 28 all-cause mortality and clinical response rates at EFU from Trial 1 of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) (MITT population)

  RECARBRIO Piperacillin/Tazobactam Treatment Difference
n/m (%) n/m (%) %a (95% CI)a
All-Cause Mortality Through Day 28b,d 42/264 (15.9) 57/267 (21.3) -5.3 (-11.9, 1.2)
Non-ventilated HABP 18/142 (12.7) 15/131 (11.5) 1.2 (-6.8, 9.1)
Ventilated HABP/VABP 24/122 (19.7) 42/136 (30.9) -11.2 (-21.6, -0.5)
Clinical Response at EFUc 161/264 (61.0) 149/267 (55.8) 5.0 (-3.2, 13.2)
Non-ventilated HABP 95/142 (66.9) 87/131 (66.4) 0.5 (-10.7, 11.7)
Ventilated HABP/VABP 66/122 (54.1) 62/136 (45.6) 8.5 (-3.7, 20.5)

aTreatment differences and 95% confidence intervals are based on Miettinen & Nurminen method.

bn/m = number of subjects with survival status of death or unknown / number of modified intent-to-treat subjects.

cn/m = number of subjects with a favorable clinical response / number of modified intent-to-treat subjects.

dOne subject in the RECARBRIO arm had unknown mortality status at Day 28 which was counted as a death.

Definitions

APACHE = acute physiology and chronic health evaluation.

EFU = early follow up.

In the MITT population, in patients with an APACHE II score <15, Day 28 all-cause mortality rates were 17/139 (12.2%) for RECARBRIO-treated patients and 12/140 (8.6%) for piperacillin/tazobactam-treated patients, clinical cure rates were 90/139 (64.7%) and 98/140 (70%), respectively. In patients with an APACHE II score ≥15, Day 28 all-cause mortality rates were 25/125 (20%) for RECARBRIO-treated patients and 45/127 (35.4%) for piperacillin/tazobactam-treated patients, clinical cure rates were 71/125 (56.8%) and 51/127 (40.2%), respectively.

Per pathogen favorable clinical response at EFU and Day 28 all-cause mortality were assessed in a microbiological modified intention to treat (mMITT) population, which consisted of all randomized MITT subjects who had at least one baseline LRT pathogen that was susceptible to both study treatments (see table below).

Day 28 all-cause mortality and favorable clinical response at EFU by baseline LRT pathogen from Trial 1 of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) (mMITT population)

Baseline LRT Pathogen Day 28 All-Cause Mortality Clinical Response at EFU
RECARBRIO n/ma (n%) Piperacillin/ Tazobactam n/ma (%) RECARBRIO n/mb (n%) Piperacillin/ Tazobactam n/mb (%)
Acinetobacter calcoaceticus-baumannii complex 0/5c (0.0) 1/10 (10.0) 4/5c (80.0) 6/10 (60.0)
Enterobacter cloacae 1/7c (14.3) 3/16 (18.8) 6/7c (85.7) 12/16 (75.0)
Escherichia coli 5/27 (18.5) 8/33 (24.2) 16/27 (59.3) 19/33 (57.6)
Haemophilus influenzaed 2/13 (15.4) 3/12 (25.0) 9/13 (69.2) 8/12 (66.7)
Klebsiella spp.e 6/42 (14.3) 8/41 (19.5) 25/42 (59.5) 28/41 (68.3)
Pseudomonas aeruginosa 7/26 (26.9) 5/35 (14.3) 12/26 (46.2) 20/35 (57.1)
Serratia marcescens 2/10 (20.0) 1/4 (25.0) 7/10 (70.0) 3/4 (75.0)

an/m = the number of subjects with survival status of death or unknown within each category / the number of microbiological modified intent-to-treat subjects who have the corresponding baseline pathogen from LRT culture.

bn/m = the number of subjects with a favorable clinical response within each category / the number of microbiological modified intent-to-treat subjects who have the corresponding baseline pathogen from LRT culture.

cSupportive evidence was derived from the imipenem and cilastatin prescribing information.

dAll H. influenzae isolates were susceptible to imipenem. The susceptible MIC breakpoint for PIP/TAZ is ≤1/4 mcg/mL. At the lowest concentration of PIP/TAZ tested (2/4 mcg/mL) there was no visible growth.

eIncludes Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae.

Definitions

EFU = early follow-up.

LRT = lower respiratory tract.

MIC = minimum inhibitory concentration.

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 ≥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%). 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%).
US-TIX-0010609/20