ORBACTIV Powder for solution for injection Ref.[10366] Active ingredients: Oritavancin

The antimicrobial activity of oritavancin appears to correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) based on animal models of infection.

Exposure-response analyses from both preclinical and clinical studies support the treatment of clinically relevant Gram-positive microorganisms (e.g. S. aureus and S. pyogenes) causative of ABSSSI with a single 1200 mg dose of ORBACTIV.

Cardiac Electrophysiology

In a thorough QTc study of 135 healthy subjects at a dose 1.3 times the 1200 mg recommended dose, ORBACTIV did not prolong the QTc interval to any clinically relevant extent.

The population PK analysis was derived using data from the two Phase 3 ABSSSI clinical trials in 297 patients. The mean pharmacokinetic parameters of oritavancin in patients following a single 1200 mg dose are presented in Table 3.

Table 3. Mean PK parameters for patients receiving a single 1200 mg dose for ABSSSI (n=297):

C_max, Maximum plasma concentration; AUC_0-24, Area under the plasma concentration-time curve from time zero to 24 hours, AUC_0-∞ = Area under the plasma concentration time curve from time zero to infinity; CV% = Percent Coefficient of variation.

Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg. The mean, population-predicted oritavancin concentration-time profile displays a multi-exponential decline with a long terminal plasma half-life.

Distribution

Oritavancin is approximately 85% bound to human plasma proteins.

Based on population PK analysis, the population mean total volume of distribution is estimated to be approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.

Exposures of oritavancin in skin blister fluid were approximately 20% of those in plasma (AUC_0-24) after single 800 mg dose in healthy subjects.

Metabolism/Excretion

Non-clinical studies including in vitro human liver microsome studies indicated that oritavancin is not metabolized. No mass balance study has been conducted in humans. In humans, oritavancin is slowly excreted unchanged in feces and urine with less than 1% and 5% of the dose recovered in feces and urine, respectively, after 2 weeks of collection.

Oritavancin has a terminal half-life of approximately 245 hours and a clearance of 0.445 L/h based on population pharmacokinetic analyses.

Specific Populations

No dosage adjustments of ORBACTIV are required for patients with mild to moderate renal or mild to moderate hepatic impairment or other subpopulations including age, gender, race and weight.

Renal Impairment

The pharmacokinetics of oritavancin was examined in the Phase 3 ABSSSI trials in patients with normal renal function, CrCL ≥80 mL/min (n=238), mild renal impairment, CrCL 50-79 mL/min (n=48), and moderate renal impairment, CrCL 30-49 mL/min (n=11). Population pharmacokinetic analysis indicated that mild to moderate renal impairment had no clinically relevant effect on the exposure of oritavancin. No dedicated studies in dialysis patients have been conducted.

Dosage adjustment of ORBACTIV is not needed in patients with mild or moderate renal impairment. The pharmacokinetics of oritavancin in patients with severe renal impairment have not been evaluated.

Hepatic Impairment

The pharmacokinetics of oritavancin were evaluated in study of subjects with moderate hepatic impairment (Child-Pugh Class B) (n=20) and compared with healthy subjects (n=20) matched for gender, age and weight. There were no relevant changes in pharmacokinetics of oritavancin in subjects with moderate hepatic impairment.

Dosage adjustment of ORBACTIV is not needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of oritavancin in patients with severe hepatic insufficiency has not been studied.

Pediatric

The pharmacokinetics of ORBACTIV in pediatric populations (<18 years of age) has not been studied [see Use in Specific Populations (8.4)].

Age, Gender, Weight and Race

Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that gender, age, weight or race had no clinically relevant effect on the exposure of ORBACTIV. No dosage adjustment is warranted in these subpopulations.

Drug Interactions

In vitro studies with human liver microsomes showed that oritavancin inhibited the activities of cytochrome P450 (CYP) enzymes 1A2, 2B6, 2D6, 2C9, 2C19, and 3A4. The observed inhibition of multiple CYP isoforms by oritavancin in vitro is likely to be reversible and noncompetitive. In vitro studies indicate that oritavancin is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp).

Drugs that Inhibit or Induce CYP450 Enzymes

A screening drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1200 mg dose of ORBACTIV with probe substrates for several CYP450 enzymes. The results showed that ORBACTIV is a weak inducer of CYP3A4 (a decrease of 18% in the mean AUC of midazolam) and CYP2D6 (decrease of 31% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after administration of dextromethorphan). ORBACTIV was also a weak inhibitor of CYP2C19 (increase of 15% in the ratio of omeprazole to 5-OH-omeprazole concentrations in the plasma after administration of omeprazole) and also showed to be a weak inhibitor of CYP2C9 (with an increase of 31% in the mean AUC of warfarin) [see Warnings and Precautions (5.5), and Drug Interactions (7.1)].

In the screening drug-drug interaction study, co-administration of ORBACTIV resulted in an increase of 18% in the ratio of 1-methylxanthine + 1 methylurate + 5-acetylamino-6-formylamino-3-methyluracil (1X + 1U + AFMU) to 1,7-dimethylurate (17U) concentrations in the urine after administration of caffeine (CYP1A2 probe substrate), and an increase of 16% in the ratio of AFMU to (1X + 1U) concentrations in the urine after administration of caffeine (N-Acetyltransferase-2 probe substrate). Co-administration of ORBACTIV did not change the mean systemic exposure of caffeine metabolite (Xanthine oxidase probe substrate).

A study to assess the drug-drug interaction potential of a single 1200 mg dose of ORBACTIV on the pharmacokinetics of S-warfarin following a single dose was conducted in 36 healthy subjects. S-warfarin pharmacokinetics were evaluated following a single dose of warfarin 25 mg given alone, or administered at the start, 24, or 72 hours after a single 1200 mg ORBACTIV dose. The results showed no effect of ORBACTIV on S-warfarin C_max or AUC.

ORBACTIV is a semi-synthetic, lipoglycopeptide antibacterial drug. ORBACTIV exerts a concentration-dependent bactericidal activity in vitro against S. aureus, S. pyogenes, and E. faecalis.

Mechanism of Action

Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and cell death. These multiple mechanisms contribute to the concentration-dependent bactericidal activity of oritavancin.

Resistance

In serial passage studies, resistance to oritavancin was observed in isolates of S. aureus and E. faecalis. Resistance to oritavancin was not observed in clinical studies.

Interaction with Other Antimicrobial Agents

In in vitro studies, oritavancin exhibits synergistic bactericidal activity in combination with gentamicin, moxifloxacin or rifampicin against isolates of methicillin-susceptible S. aureus (MSSA), with gentamicin or linezolid against isolates of heterogeneous vancomycin-intermediate S. aureus (hVISA), VISA, and vancomycin-resistant S. aureus (VRSA), and with rifampin against isolates of VRSA. In vitro studies demonstrated no antagonism between oritavancin and gentamicin, moxifloxacin, linezolid or rifampin.

Antibacterial Activity

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

Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus dysgalactiae
Streptococcus pyogenes
Enterococcus faecalis (vancomycin-susceptible isolates only)

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 oritavancin against isolates of a similar organism group. However, the efficacy of oritavancin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria:

Enterococcus faecium (vancomycin-susceptible isolates only)

Susceptibility Testing 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.

Long term studies in animals have not been conducted to determine the carcinogenic potential of oritavancin.

No mutagenic or clastogenic potential of oritavancin was found in a battery of tests, including an Ames assay, in vitro chromosome aberration assay in Chinese hamster ovary cells, in vitro forward mutation assay in mouse lymphoma cells and an in vivo mouse micronucleus assay.

Oritavancin did not affect the fertility or reproductive performance of male rats (exposed to daily doses up to 30 mg/kg for at least 4 weeks) and female rats (exposed to daily doses up to 30 mg/kg for at least 2 weeks prior to mating). Those daily doses would be equivalent to a human dose of 300 mg, or 25% of clinical dose. Higher doses were not evaluated in nonclinical fertility studies.

14.1 Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

A total of 1987 adults with clinically documented ABSSSI suspected or proven to be due to Gram-positive pathogens were randomized into two identically designed, randomized, double-blind, multi-center, multinational, non-inferiority trials (Trial 1 and Trial 2) comparing a single 1200 mg intravenous dose of ORBACTIV to intravenous vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days. The primary analysis population (modified intent to treat, mITT) included all randomized patients who received any study drug. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. Patient demographic and baseline characteristics were balanced between treatment groups. Approximately 64% of patients were Caucasian and 65% were males. The mean age was 45 years and the mean body mass index was 27 kg/m². Across both trials, approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. A history of diabetes was present in 14% of patients. The types of ABSSSI across both trials included cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median infection area at baseline across both trials was 266.6 cm². The primary endpoint in both trials was early clinical response (responder), defined as cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibacterial drug at 48 to 72 hours after initiation of therapy.

Table 4 provides the efficacy results for the primary endpoint in Trial 1 and Trial 2 in the primary analysis population.

Table 4. Clinical Response Rates in ABSSSI Trials using Responders*,† at 48-72 Hours after Initiation of Therapy:

* Cessation of spread or reduction in size of baseline lesion, absence of fever (<37.7°C) and no rescue antibacterial drug at 48 to 72 hours.
^† Patients who died at 48 to 72 hours, after initiation of therapy or who had increase in lesion size at 48 to 72 hours, after initiation of therapy or who used non-study antibacterial therapy during first 72 hours or who had an additional, unplanned, surgical procedure or who had missing measurements during the first 72 hours from initiation of study drug were classified as non-responders.
^‡ 95% CI based on the Normal approximation to Binomial distribution.

A key secondary endpoint in these two ABSSSI trials evaluated the percentage of patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. Table 5 summarizes the findings for this endpoint in the two ABSSSI trials.

Table 5. Clinical Response Rates* in ABSSSI Trials using Reduction in Lesion Area of 20% or Greater at 48-72 Hours after Initiation of Therapy:

* Patients who died at 48 to 72 hours, after initiation of therapy or who had increase in lesion size at 48 to 72 hours, after initiation of therapy or who used non-study antibacterial therapy during first 72 hours or who had an additional, unplanned, surgical procedure or who had missing measurements during the first 72 hours from initiation of study drug were classified as non-responders.
^† 95% CI based on the Normal approximation to Binomial distribution.

Another secondary efficacy endpoint in the two trials was investigator-assessed clinical success at post therapy evaluation at Day 14 to 24 (7 to 14 days from end of blinded therapy). A patient was categorized as a clinical success if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibacterial drugs was needed.

Table 6 summarizes the findings for this endpoint in the mITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the post therapy visits. Therefore, comparisons of ORBACTIV to vancomycin based on clinical success rates at these visits cannot be utilized to establish non-inferiority conclusions.

Table 6. Clinical Success Rates* in ABSSSI Trials at the Follow-Up Visit (7-14 days after end of therapy):

³ mITT population consisted of all randomized patients who received study drug; CE population consisted of all mITT patients who did not have violations of inclusion and exclusion criteria, completed treatment and had investigator assessment at the Follow-Up Visit.
* Clinical success was defined if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms as described above.
^† 95% CI based on the Normal approximation to Binomial distribution.

Outcomes by Baseline Pathogen

Table 7 shows outcomes in patients with an identified baseline pathogen in the microbiological Intent-to-Treat (microITT) population in a pooled analysis of Trial 1 and Trial 2. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up study day 14 to 24.

Table 7. Outcomes by Baseline Pathogen (microITT):

* Early clinical response defined as a composite of the cessation of spread or reduction in size of baseline lesion, absence of fever and no rescue antibacterial drug at 48-72 hours.
^† Patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy.
^‡ Clinical success was defined if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms as described above.
^§ Baseline bacteremia in the oritavancin arm with relevant microorganisms causing ABSSSI included four subjects with MSSA and seven subjects with MRSA. Eight of these eleven subjects were responders at 48 to 72 hours after initiation of therapy.