EXBLIFEP Solution for injection Ref.[108537] Active ingredients: Cefepime Cefepime and Enmetazobactam

Similar to other beta-lactam antibacterial drugs, the percentage of time that unbound plasma concentrations of cefepime exceed the cefepime-enmetazobactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The percentage of time that enmetazobactam concentrations exceed a threshold concentration is the index that best predicts efficacy of enmetazobactam in combination with cefepime in animal and in vitro models of infection.

Cardiac Electrophysiology

At approximately 12 times the peak enmetazobactam concentrations of the maximum recommended dosing regimen of EXBLIFEP, clinically significant QTc interval prolongation was not observed.

Pharmacokinetic (PK) Parameters

The pharmacokinetic properties of cefepime and enmetazobactam are summarized in Table 5 as mean (SD) in patients with cUTI and eGFR greater than or equal to 60 mL/min.

Table 5. Pharmacokinetic Parameters (Mean [SD]) of Cefepime and Enmetazobactam:

¹ Pharmacokinetic parameters are presented at steady state (Day 7) in patients with cUTI and eGFR greater than or equal to 60 mL/min at a dosage of 2 g cefepime and 0.5 g enmetazobactam every 8 hours
² Approximately 7% of the cefepime dose is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide)
AUC_0-last = area under the plasma concentration time curve from time of dosing to the last measurable concentration; CL = clearance; C_max = maximum concentration; SD = standard deviation, T_1/2 = terminal half-life; V_ss = volume of distribution at steady state

Specific Populations

No clinically significant differences in the pharmacokinetics of cefepime or enmetazobactam were observed based on age (18–94 years), gender, or weight (45–135 kg). There was insufficient information to evaluate the effect of race on the pharmacokinetics of cefepime or enmetazobactam.

Patients with Renal Impairment

In a single-dose trial evaluating the effect of renal impairment on the pharmacokinetics of cefepime and enmetazobactam, dose-normalized systemic exposures of cefepime and enmetazobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min (Table 6). In subjects with creatinine clearance (CLcr) <15 mL/min on hemodialysis, the fraction of the dose removed by hemodialysis was 0.30 and 0.35 for cefepime and enmetazobactam, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Table 6. Dose Normalized Fold AUC Increase in Subjects with Renal Impairment Compared to Subjects with Creatinine Clearance (CLcr) ≥90 mL/min:

Patients with eGFR 130 mL/min or Greater

Increased cefepime and enmetazobactam clearance have been observed in patients with eGFR of 130 mL/min or greater. An EXBLIFEP (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h infused over 4 hours provided cefepime and enmetazobactam exposures comparable to those in patients with eGFR 90 to 129 mL/min who received EXBLIFEP (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h over 2 hours [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Cefepime and enmetazobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have a significant effect on cefepime or enmetazobactam exposures.

Drug Interactions

Clinical Studies

No drug-drug interactions were observed among cefepime, enmetazobactam and piperacillin in a clinical study in healthy subjects.

In vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Cytochrome P450 (CYP) Enzymes: At therapeutic plasma concentrations, enmetazobactam does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Enmetazobactam inhibits CYP2E1. Enmetazobactam does not induce CYP1A2, CYP2B6, or CYP3A4.

Membrane Transporter Systems: Enmetazobactam is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, BSEP, OAT1, OAT3, MATE1, or MATE2-K. In vitro data also indicated that enmetazobactam did not inhibit P-gp, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OAT3, BSEP, MRP3, MRP4 and NTCP.

No in vitro CYP450 enzyme or membrane transporter drug interaction studies were conducted with cefepime.

Mechanism of Action

The cefepime component of EXBLIFEP is a cephalosporin antibacterial drug. The bactericidal action of cefepime results from the inhibition of cell wall synthesis. Cefepime penetrates the cell wall of most grampositive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Cefepime is stable to hydrolysis by some beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of extended spectrum beta-lactamases (ESBL), some oxacillinases, and carbapenem hydrolyzing beta-lactamases.

The enmetazobactam component of EXBLIFEP is a beta-lactamase inhibitor that protects cefepime from degradation by certain serine beta-lactamases such as ESBL.

Resistance

Mechanisms of resistance to EXBLIFEP may include the production of beta-lactamases that are not inhibited by enmetazobactam, modification of PBPs by target alteration, overexpression of efflux pumps, and outer membrane porin mutations.

Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.

Cefepime-enmetazobactam demonstrated in vitro activity against Enterobacterales in the presence of some betalactamases and extended-spectrum beta-lactamases (ESBL) of the following groups: CTX-M, SHV, TEM, and VEB. EXBLIFEP is not active against bacteria that produce KPC, metallo-beta-lactamases or some oxacillinases (OXA). Cefepime is inherently stable to hydrolysis by some AmpC cephalosporinases and OXA48.

In the Phase 3 cUTI trial with EXBLIFEP, some isolates of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae species complex, Citrobacter braakii, Citrobacter freundii, and Proteus mirabilis, that produced beta-lactamases had a minimum inhibitory concentration ≤4 µg/mL for EXBLIFEP. These isolates carried genes for one or more beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, VEB, CMY, and OXA-48.

In the Phase 3 cUTI trial with EXBLIFEP, some beta-lactamases were also produced by isolates of K. pneumoniae and an isolate of E. cloacae that had a minimum inhibitory concentration ≥16 mcg/mL for EXBLIFEP. The K. pneumoniae isolates contained genes for NDM-1, OXA-48, or KPC-3 along with CTX-M, CMY, TEM, and/or SHV. The E. cloacae isolate encoded CTX-M.

No cross-resistance with other non-beta-lactam classes of antimicrobials has been identified. Some isolates resistant to carbapenems and to cephalosporins may be susceptible to EXBLIFEP.

Interaction with Other Antimicrobials

In vitro synergy studies did not demonstrate antagonism between EXBLIFEP and azithromycin, aztreonam, ceftazidime-avibactam, clindamycin, daptomycin, doxycycline, levofloxacin, linezolid, meropenem, metronidazole, trimethoprim-sulfamethoxazole, or vancomycin.

Activity against Cefepime Non-susceptible Bacteria in Animal Infection Models

Enmetazobactam restored activity of cefepime in animal models of infection (e.g., mouse thigh infection, urinary tract infection, pulmonary infection and sepsis) caused by cefepime-resistant, ESBL-producing (e.g., CTX-M, SHV, TEM) Enterobacterales.

Antimicrobial Activity

EXBLIFEP has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1)].

Gram-negative bacteria:

Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Proteus mirabilis
Enterobacter cloacae complex

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for EXBLIFEP against isolates of similar genus or organism group. However, the efficacy of EXBLIFEP in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria:

Citrobacter freundii
Klebsiella aerogenes
Klebsiella oxytoca
Providencia stuartii
Providencia rettgeri
Serratia marcescens

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis

Long-term carcinogenicity studies have not been performed with cefepime or enmetazobactam.

Mutagenesis

Cefepime

In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity.

Enmetazobactam

Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.

Impairment of Fertility

Cefepime

No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m² basis).

Enmetazobactam

In male and female fertility studies in rats, enmetazobactam was administered intravenously in doses of 125, 250, and 500 mg/kg/day in males for 28 days before mating and for 14 days before the start of the mating period, throughout the mating period, and until Gestation Day (GD) 7 in females. Enmetazobactam had no adverse effect on fertility in either sex and no effect on early embryonic development in female rats at doses up to 500 mg/kg/day, (approximately 7 times in males and 8 times in females the maximum recommended human dose (1.5 g/day) based on plasma AUC comparison).

14.1. Complicated Urinary Tract Infections, including Pyelonephritis

A total of 1041 adults with cUTI, including pyelonephritis, were randomized in a 1:1 ratio into in a multinational, double blind, noninferiority trial (Trial 1, NCT03687255), comparing EXBLIFEP (2 grams cefepime and 0.5 grams enmetazobactam) to piperacillin/tazobactam (4 grams piperacillin and 0.5 grams tazobactam) both administered intravenously every 8 hours (infused over 2 hours) for 7 days, or up to 14 days for patients with concurrent bacteremia. No switch from IV to oral antibacterial therapy was permitted.

The microbiological modified intent-to-treat population (mMITT) was the primary efficacy analysis population and included all randomized patients who received any study drug and had at least 1 baseline gram-negative pathogen ≥10⁵ colony-forming-units (CFU)/mL in urine culture or the same pathogen in blood and urine cultures that is not resistant to cefepime/enmetazobactam or piperacillin/tazobactam (defined as MIC ≤8/8 mcg/mL or MIC ≤64/4 mcg/mL, respectively). A total of 345 and 333 patients were included in the mMITT population in EXBLIFEP and piperacillin/tazobactam treatment groups, respectively.

Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. Approximately 95% of patients were Caucasian and 60% were female in both treatment groups. The mean age was 54 years with 38% and 31% of patients greater than 65 years of age in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. Mean body mass index was approximately 26.5 kg/m² in both treatment groups. Concomitant bacteremia was identified in 38 (11%) and 28 (8%) patients at baseline in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The proportion of patients with diabetes mellitus at baseline was 16% and 12% in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The majority of patients (93%) were enrolled from Europe. Overall, in both treatment groups, 51% of patients had pyelonephritis and 49% had cUTI, with 27% and 22% of patients having a non-removable and removable source of infection, respectively. Mean duration of treatment in both treatment groups was 8 days.

EXBLIFEP demonstrated efficacy with regard to composite response, defined as clinical cure and microbiological response, at the Test of Cure (TOC) visit (7 days after the end of treatment) in the mMITT population as shown in Table 7. Clinical cure was defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or pyelonephritis that were present at Screening (and no new urinary symptoms or worsening of symptoms). Microbiological response was defined as the baseline qualifying Gram-negative pathogen(s) reduced to <10³ colony-forming units/mL in urine culture and a negative blood culture for a Gram-negative pathogen that was identified as a uropathogen (if repeated after positive baseline blood culture).

Table 7. Composite Response (Clinical Cure, and Microbiological Response) Rates at TOC in Trial 1 of cUTI Including Pyelonephritis (mMITT Population):

CI = confidence interval.
^* The 95% CI was based on the stratified Newcombe method.

Composite response in patients with bacteremia at baseline was achieved in 27/38 (71%) patients in the EXBLIFEP group and 14/28 (50%) patients in the piperacillin/tazobactam group at the TOC visit in the mMITT population.

Composite response (microbiological and clinical cure) rates by pathogen for the m-MITT population are presented in Table 8.

Table 8. Composite Response (Microbiological Response and Clinical Cure) Rates at TOC by Pathogen in Trial 1 of cUTI Including Pyelonephritis (mMITT Population):

In a subset of the E. coli and K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g., TEM, CTX-M, SHV and OXA) in both treatment groups of the cUTI Trial 1. The proportion of patients with composite response at TOC was 56/76 (74%) and 34/66 (52%) in the EXBLIFEP group, and the piperacillin/tazobactam group, respectively, in patients with ESBL-producing bacteria at baseline.

A sensitivity analysis where patients with organisms resistant to piperacillin/tazobactam, according to the current FDA breakpoints (defined as MIC >16/4 mcg/mL for Enterobacterales and >64/4 mcg/mL for P. aeruginosa) and one patient with Stenotrophomonas maltophilia were excluded from the mMITT population, demonstrated similar efficacy results as in the mMITT population.