API Relebactam

Relebactam More Info

1. Drug Overview

Relebactam (development code: MK-7655) is a novel beta-lactamase inhibitor belonging to the diazabicyclooctane (DBO) class. It is marketed as a fixed-dose combination product with imipenem and cilastatin under the brand name Recarbrio®.

2. Chemical Information

The chemical properties of Relebactam include: CAS number 1174018-99-5; molecular formula C₁₂H₂₀N₄O₆S; molecular weight 348.38 g/mol; exact mass 348.1104; and it belongs to the diazabicyclo[3.2.1]octanone (DBO) series.

3. Mechanism of Action

Relebactam functions as a diazabicyclooctane beta-lactamase inhibitor (BLI) with the following characteristics. Relebactam lacks inherent antimicrobial activity. It covalently binds to the active site of class A and class C β-lactamases, forming a reversible acyl-enzyme intermediate that blocks substrate access. It targets class A β-lactamases including extended-spectrum β-lactamases (ESBLs) and KPC carbapenemases. It also targets class C β-lactamases including AmpC enzymes. By inhibiting these enzymes, relebactam restores the susceptibility of resistant bacteria to imipenem.

4. Spectrum of Activity

Relebactam enhances imipenem activity against Enterobacteriaceae producing KPC carbapenemases, Pseudomonas aeruginosa producing AmpC β-lactamases, and imipenem-nonsusceptible Gram-negative pathogens with limited treatment options. Relebactam shows no activity against metallo-β-lactamases such as NDM, IMP, VIM or efflux pump over-activity.

5. Approved Indications

Relebactam (as Recarbrio™: imipenem 500 mg / cilastatin 500 mg / relebactam 250 mg) is approved for complicated urinary tract infections (cUTI), including pyelonephritis. It is approved for complicated intra-abdominal infections (cIAI). It is also approved for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). It is approved for adult patients with limited or no alternative treatment options.

6. Dosing and Administration

The recommended dosage for adults with normal renal function is imipenem 500 mg plus cilastatin 500 mg plus relebactam 250 mg, administered intravenously as a 30-minute infusion, every 6 hours. The typical duration is 7-14 days depending on the indication.

For renal dose adjustment, patients with creatinine clearance of 90 mL/min or higher receive 500/500/250 mg every 6 hours. Patients with creatinine clearance of 60-89 mL/min receive 400/400/200 mg every 6 hours. Patients with creatinine clearance of 30-59 mL/min receive 300/300/150 mg every 6 hours. Patients with creatinine clearance of 15-29 mL/min receive 200/200/100 mg every 6 hours. Patients with end-stage renal disease on hemodialysis receive 200/200/100 mg every 6 hours, timed after dialysis. Patients with creatinine clearance below 15 mL/min should not receive Recarbrio unless hemodialysis is instituted within 48 hours.

7. Clinical Trial Evidence

The RESTORE-IMI 1 was a phase 3 trial for cUTI/cIAI that showed favorable clinical response rates comparable to imipenem-cilastatin. The RESTORE-IMI 2 was a phase 3 trial for HABP/VABP that compared Recarbrio to piperacillin-tazobactam, demonstrating non-inferiority. A meta-analysis of imipenem/cilastatin/relebactam showed clinical cure rates supporting efficacy against multidrug-resistant Gram-negative infections, with microbiologic response improved with the addition of relebactam.

8. Pharmacokinetics

Relebactam is well distributed to various body compartments and penetrates into most tissues. It undergoes extensive renal elimination, so dosage adjustment is required for renal impairment. Imipenem and relebactam are typically administered every 6 hours. Approximately 30-50% is removed by hemodialysis.

9. Storage and Handling

Keep in outer packaging to protect from light. After reconstitution, use immediately; infusion should not exceed 2 hours. It is compatible with 0.9% sodium chloride or 5% dextrose solution.

10. Safety Information

The most common adverse reactions occurring in 1-3% of patients include nausea, vomiting, diarrhea, rash, headache, and phlebitis. Carbapenem hypersensitivity incidence is estimated to be less than 3% in the general population. All carbapenems have been associated with seizures, with risk elevated in patients with renal failure and neurologic comorbidities. Relebactam is excreted into milk at approximately 5% of maternal plasma concentrations. Limited data support use in pregnant or lactating mothers. Renal tubular degeneration was observed in monkeys at AUC exposure 7 times the human maximum recommended dose, and it was reversible after discontinuation.

11. Regulatory Information

Relebactam was developed by Merck & Co., Inc. in the USA. It received FDA approval in February 2019 for cUTI/cIAI and in June 2020 for HABP/VABP. It received EU authorization on February 13, 2020, with authorization number EU/1/19/1420/001. It is protected by patent US 8487093.

12. Incompatibility

Relebactam is not compatible with Propofol in 5% dextrose or 0.9% sodium chloride solution. It is compatible with Dexmedetomidine, Dopamine, Epinephrine, Fentanyl, Heparin, Midazolam, Norepinephrine, and Phenylephrine.