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RECARBRIO(imipenem, cilastatin, and relebactam) for injection(十三)
ity.
Patients with Renal Impairment
In a single-dose trial eva luating the effect of renal impairment on the PK of relebactam 125 mg co-infusedwith imipenem/cilastatin 250 mg (half the recommended dose in patients with normal renal function),mean AUC was higher in subjects with CLcr 60-89, 30-59, and 15-29 mL/min, respectively, compared to healthy subjects with CLcr 90 mL/min or greater (Table 5). In subjects with end stage renal disease(ESRD) on hemodialysis, imipenem, cilastatin, and relebactam are efficiently removed by hemodialysis,with extraction coefficients of 66 % to 87 % for imipenem, 46 % to 56 % for cilastatin and 67 % to 87 %for relebactam.
Table 5: Mean AUC Increase in Subjects with Renal Impairment Compared to Subjects with CLcr
90 mL/min or Greater
Estimated CLcr
(mL/min) Imipenem Cilastatin Relebactam
60 to 89 1.1-fold 1.2-fold 1.2-fold
30 to 59 1.7-fold 2.0-fold 2.2-fold
15 to 29 2.6-fold 5.5-fold 4.7-fold
To maintain systemic exposures similar to patients with normal renal function, dose adjustment isrecommended for patients with renal impairment [see Dosage and Administration (2.2)]. ESRD patientson hemodialysis should receive RECARBRIO after hemodialysis session [see Dosage and Administration(2.2)].
Patients with Hepatic Impairment
Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is notlikely to have any effect on RECARBRIO exposures.
Drug Interaction Studies
Clinical Studies
No drug-drug interaction was observed among imipenem, cilastatin, and relebactam in a clinical study in
healthy subjects.
No clinically significant differences in the pharmacokinetics of imipenem or relebactam were observedwhen RECARBRIO was used concomitantly with probenecid (Organic Anion Transporter 3 (OAT3)inhibitor).
In Vitro Studies
CYP Enzymes
Relebactam does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 orinduce CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes.
Transporter Systems
Relebactam does not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2, P-gp, BCRP, MATE1, MATE2K,or BSEP.
Relebactam is not a substrate of OAT1, OCT2, P-gp, BCRP, MRP2, or MRP4 transporters, but is asubstrate of OAT3, OAT4, MATE1, and MATE2K transporters.
The following antibacterial and antifungal drugs (piperacillin/tazobactam, ciprofloxacin, fluconazole,ampicillin, levofloxacin, metronidazole, vancomycin, linezolid, daptomycin, and cefazolin) did notsignificantly inhibit OAT3-mediated relebactam uptake.
12.4 Microbiology
Mechanism of Action
RECARBRIO is a combination of imipenem/cilastatin and relebactam. Imipenem is a penem antibacterialdrug, 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. Thebactericidal activity of imipenem results from binding to PBP 2 and PBP 1B in Enterobacteriaceae andPseudomonas aeruginosa and the subsequent inhibition of penicillin binding proteins (PBPs). Inhibition ofPBPs leads to the disruption of bacterial cell wall synthesis. Imipenem is stable in the presence of somebeta 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), Pse |
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