FDA News: Issue 20, August 2019

Author: [AUTHOR] Published on 8/6/2019 10:09:00 AM

FDA Approves RECARBRIO (Imipenem, Cilastatin, and Relebactam) for Complicated Urinary Tract and Complicated Intra-Abdominal Infections

On July 16, 2019, the US Food and Drug Administration (FDA) approved RECARBRIO, a combination of imipenem, cilastatin, and relebactam, in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of the following infections caused by susceptible gram-negative bacteria:
  • Complicated urinary tract infections, including pyelonephritis (cUTI) caused by: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
  • Complicated intra-abdominal infections (cIAI) caused by: 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.
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 bacteria.

The approved recommended dosage of RECARBRIO is 1.25 grams (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) administered by intravenous infusion over 30 minutes every 6 hours in patients 18 years of age and older with creatinine clearance (CLcr) ≥ 90 mL/min. Reduce dosage in patients with CLcr < 90 mL/min based on recommendations in the full prescribing information linked below. The recommended duration of RECARBRIO treatment is 4 days to 14 days based on the severity and location of infection, as well as clinical response.

Additional information regarding important warnings and precautions about hypersensitivity reactions, seizures and other central nervous system adverse reactions, Clostridium difficile-associated diarrhea, and the development of drug-resistant bacteria can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: RECARBRIO is an antibacterial combination drug of imipenem, a penem antibacterial, cilastatin, a renal dehydropeptidase inhibitor, and relebactam, a beta lactamase inhibitor.
  • General PK: Accumulation of imipenem, cilastatin, and relebactam was minimal following multiple-dose administration in patients with CLcr ≥ 90 mL/min.
  • Distribution: Protein binding of imipenem and cilastatin is approximately 20% and 40%, respectively. Protein binding of relebactam is approximately 22% and is independent of concentration. The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively.
  • Elimination: Mean (± SD) half-life of imipenem and relebactam are 1 (± 0.5) hour and 1.2 (± 0.7) hours, respectively.
  • Metabolism: Low levels of imipenem are recovered in urine when administered alone because it is metabolized in the kidneys by dehydropeptidase. Concomitant administration with cilastatin effectively prevents renal metabolism of imipenem by inhibiting this enzyme, resulting in adequate concentrations of imipenem in the urine to enable antibacterial activity. Relebactam is minimally metabolized.
  • Excretion: Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys, involving both glomerular filtration and active tubular secretion. Following multiple-dose administration of imipenem, cilastatin, and relebactam to healthy male subjects, approximately 63%, 77%, and > 90% of the administered doses are excreted unchanged in urine, respectively.
  • PD: For imipenem, the % time of dosing interval that unbound plasma concentrations of imipenem exceed the imipenem/relebactam minimum inhibitory concentration (MIC) against the infecting organism best correlates with antibacterial activity in animal and in vitromodels of infection. For relebactam, the ratio of the 24-hour unbound plasma relebactam AUC to imipenem/relebactam MIC best predicts the activity of relebactam in animal and in vitromodels of infection.
Drug Interactions
Ganciclovir: Generalized seizures have been reported in patients who received ganciclovir concomitantly with imipenem/cilastatin, components of RECARBRIO. Avoid concomitant use of RECARBRIO with ganciclovir unless the potential benefits outweigh the risks.

Valproic Acid or Divalproex Sodium: Concomitant use of carbapenems (including imipenem/cilastatin, components of RECARBRIO) may decrease valproic acid concentrations which may increase the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems.

Use in Specific Populations
Mean AUC of imipenem, cilastatin, and relebactam increases with decreasing renal function. These drugs are also efficiently removed by hemodialysis. Therefore, reduce RECARBRIO dosage in patients with CLcr < 90 mL/min. ESRD patients on hemodialysis should receive RECARBRIO after hemodialysis session. Specific dosage adjustments can be found in the full prescribing information linked below.

Efficacy and Safety 
Efficacy and safety of RECARBRIO was supported in part by the previous findings of the efficacy and safety of imipenem/cilastatin for the treatment of cIAI and cUTI. The contribution of relebactam to RECARBRIO was primarily established in vitro and in animal models of infection. Imipenem/cilastatin plus relebactam was studied in cIAI and cUTI including pyelonephritis in randomized, blinded, active-controlled, multicenter trials. These trials provided only limited efficacy and safety information.

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.

RECARBRIO received FDA's Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, RECARBRIO was granted Priority Review under which the FDA's goal is to take action on an application within an expedited time frame.

Full prescribing information is available at https://go.usa.gov/xyw3F.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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