XERAVA Powder for solution for injection Ref.[10284] Active ingredients: Eravacycline

The AUC divided by the MIC of eravacycline has been shown to be the best predictor of activity. Based on the flat exposure-response relationship observed in clinical studies, eravacycline exposure achieved with the recommended dosage regimen appears to be on the plateau of the exposure-response curve.

Cardiac Electrophysiology

The effect of XERAVA on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 60 healthy adult subjects. At the 1.5 mg/kg single dose (1.5 times the maximum approved recommended dose), XERAVA did not prolong the QTc interval to any clinically relevant extent.

Following single-dose intravenous administration, eravacycline AUC and C_max increase approximately dose-proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved dose).

The mean exposure of eravacycline after single and multiple intravenous infusions (approximately 60 minutes) of 1 mg/kg administered to healthy adults every 12 hours is presented in Table 2.

There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours.

Table 2. Mean (%CV) Plasma Exposure of Eravacycline After Single and Multiple Intravenous Dose in Healthy Adults:

Abbreviations: C_max = maximum observed plasma concentration, CV = coefficient of variation; AUC_0-12 = area under the plasma concentration-time curve from time 0 to 12 hours.
^a AUC of day 1 equals AUC_0-12 after the first dose of eravacycline.
^b AUC of day 10 equals steady state AUC_0-12.

Distribution

Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L.

Elimination

The mean elimination half-life is 20 hours.

Metabolism

Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation.

Excretion

Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites.

Specific Populations

No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, and race.

Patients with Renal Impairment

The geometric least square mean C_max for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC_0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI -14.0, 12.3 [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment

Eravacycline C_max was 13.9%, 16.3%, and 19.7% higher in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child‑Pugh Class C) hepatic impairment versus healthy subjects, respectively. Eravacycline AUC_0-inf was 22.9%, 37.9%, and 110.3% higher in subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54% [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

Concomitant use of itraconazole (strong CYP3A inhibitor) increased eravacycline C_max by 5% and AUC by 32%, and decreased eravacycline clearance by 32%.

In Vitro Studies

Eravacycline is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Eravacycline is not an inducer of CYP1A2, 2B6, or 3A4.

Eravacycline is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter peptide (OATP)1B1, OATP1B3, organic ion transporter (OAT)1, OAT3, OCT1, OCT2, multidrug and toxin extrusion (protein) (MATE)1, or MATE2-K transporters.

Eravacycline is not an inhibitor of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K transporters.

Mechanism of Action

Eravacycline is a fluorocycline antibacterial within the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.

In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been demonstrated against certain strains of Escherichia coli and Klebsiella pneumoniae.

Resistance

Eravacycline resistance in some bacteria is associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux, and target-site modifications such as to the 16s rRNA or certain 30S ribosomal proteins (e.g., S10).

The C7 and C9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including in vitro activity against gram-positive and gram-negative strains expressing certain tetracycline-specific resistance mechanism(s) [i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded by tet(M) and tet(Q)].

Activity of eravacycline was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended spectrum β-lactamases, and AmpC. However, some beta-lactamase-producing isolates may confer resistance to eravacycline via other resistance mechanisms.

The overall frequency of spontaneous mutants in the gram-positive organisms tested was in the range of 10^-9 to 10^-10 at 4 times the eravacycline Minimum Inhibitory Concentration (MIC). Multistep selection of gram-negative strains resulted in a 16- to 32-times increase in eravacycline MIC for one isolate of Escherichia coli and Klebsiella pneumoniae, respectively. The frequency of spontaneous mutations in K. pneumoniae was 10^-7 to 10^‑8 at 4 times the eravacycline MIC.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between XERAVA and other commonly used antibacterial drugs for the indicated pathogens.

Antimicrobial Activity

XERAVA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]:

Aerobic bacteria:

Gram-positive bacteria:

Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Streptococcus anginosus group

Gram-negative bacteria:

Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae

Anaerobic bacteria:

Gram-positive bacteria:

Clostridium perfringens

Gram-negative bacteria:

Bacteroides caccae
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Parabacteroides distasonis

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 eravacycline against isolates of similar genus or organism group. However, the efficacy of eravacycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria:

Gram-positive bacteria:

Streptococcus salivarius group

Gram-negative bacteria:

Citrobacter koseri
Enterobacter aerogenes

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.

Carcinogenicity studies with eravacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).

Eravacycline was not genotoxic in a standard battery of assays, including an in vitro mammalian cell mutation assay, an in vitro clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.

There are no human data on the effect of eravacycline on fertility. Eravacycline did not affect mating or fertility in male rats following intravenous administration at a dose approximating a clinical dose of 0.65 mg/kg/day (approximately 1.5 times the clinical exposure, based on AUC determined in a separate study), however, eravacycline administration at higher doses was associated with adverse reactions on male fertility and spermatogenesis that were at least partially reversible after a 70-day recovery period (1 spermatogenic cycle). Decreased sperm counts, abnormal sperm morphology, and reduced sperm motility were observed with testicular effects (impaired spermiation and sperm maturation). There were no adverse reactions on mating or fertility in female rats administered intravenous eravacycline at a dose approximating a clinical dose of 3.2 mg/kg/day (approximately 18 times the clinical exposure based on AUC determined in a separate study in unmated females).

Decreased sperm counts and eravacycline‑related lesions noted in the testes and epididymides were seen in general toxicology studies in rats and were reversible. These findings were anticipated effects for a tetracycline-class compound.

In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog and monkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dog and monkey) were observed with eravacycline. These findings were reversible or partially reversible during recovery periods of 3 to 7 weeks.

Bone discoloration, which was not fully reversible over recovery periods of up to 7 weeks, was observed in rats and monkeys after 13 weeks of dosing and in the juvenile rat study after dosing over Post-Natal Days 21-70.

Intravenous administration of eravacycline has been associated with a histamine response in rat and dog studies.

14.1 Complicated Intra-abdominal Infections in Adults

A total of 1,041 adults hospitalized with cIAI were enrolled in two Phase 3, randomized, double-blind, active-controlled, multinational, multicenter trials (Trials 1, NCT01844856, and Trial 2, NCT02784704). These studies compared XERAVA (1 mg/kg intravenous every 12 hours) with either ertapenem (1 g every 24 hours) or meropenem (1 g every 8 hours) as the active comparator for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis.

The microbiologic intent-to-treat (micro-ITT) population, which included all patients who had at least one baseline intra-abdominal pathogen, consisted of 846 patients in the two trials. Populations in Trial 1 and Trial 2 were similar. The median age was 56 years and 56% were male. The majority of patients (95%) were from Europe; 5% were from the United States. The most common primary cIAI diagnosis was intra-abdominal abscess(es), occurring in 60% of patients. Bacteremia at baseline was present in 8% of patients.

Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection at the Test of Cure (TOC) visit which occurred 25 to 31 days after randomization. Selected clinical responses were reviewed by a Surgical Adjudication Committee. Table 3 presents the clinical cure rates in the micro-ITT population. Clinical cure rates at the TOC visit for selected pathogens are presented in Table 4.

Table 3. Clinical Cure Rates at TOC in the Phase 3 cIAI Trials, Micro-ITT Population:

Abbreviations: CI = confidence interval; IV = intravenous; micro-ITT = all randomized subjects who had baseline bacterial pathogens that caused cIAI and against at least one of which the investigational drug has in vitro antibacterial activity; N = number of subjects in the micro-ITT population; n = number within a specific category with a clinical cure based on the Surgical Adjudication Committee assessment (if available); TOC = Test of Cure.
^a XERAVA dose equals 1 mg/kg every 12 hours IV.
^b Ertapenem dose equals1 g every 24 hours IV
^c Meropenem dose equals 1 g every 8 hours IV.
^d Treatment Difference = Difference in clinical cure rates (eravacycline minus ertapenem or meropenem). Confidence intervals are calculated using the unadjusted Miettinen-Nurminen method |

Table 4. Clinical Cure Rates at TOC by Selected Baseline Pathogens in Pooled Phase 3 cIAI Trials, Micro-ITT Population:

Abbreviations: IV = intravenous; N = Number of subjects in the micro-ITT Population; N1 = Number of subjects with a specific pathogen; n = Number of subjects with a clinical cure at the TOC visit. Percentages are calculated as 100 × (n/N1); TOC = Test of Cure
^a XERAVA dose equals 1 mg/kg every 12 hours IV.
^b Comparators include Ertapenem 1 g every 24 hours IV and Meropenem 1 g every 8 hours IV.
^c Includes Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius
^d Includes Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Parabacteroides distasonis.

14.2 Complicated Urinary Tract Infections (cUTI) in Adults

Two randomized, double-blind, active-controlled, clinical trials (Trial 4, NCT01978938, and Trial 5, NCT03032510) evaluated the efficacy and safety of once-daily intravenous eravacycline for the treatment of patients with complicated urinary tract infections (cUTI). Trial 4 included an optional switch from IV to oral therapy with eravacycline. The trials did not demonstrate the efficacy of XERAVA for the combined endpoints of clinical cure and microbiological success in the microbiological intent-to-treat (micro-ITT) population at the test-of-cure visit [see Indications and Usage (1)].