VIBATIV Powder for solution for injection Ref.[27433] Active ingredients: Telavancin

The antimicrobial activity of telavancin appears to best correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. Exposure-response analyses of the clinical trials support the dose of 10 mg/kg every 24 hours.

Cardiac Electrophysiology

The effect of telavancin on cardiac repolarization was assessed in a randomized, double-blind, multiple-dose, positive-controlled, and placebo-controlled, parallel study (n=160). Healthy subjects received VIBATIV 7.5 mg/kg, VIBATIV 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from VIBATIV 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebocorrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for VIBATIV 10 mg/kg and 22 msec for the positive control (Table 7). By 1 hour after infusion the maximum QTc prolongation was 6-9 msec for VIBATIV and 15 msec for the positive control.

Table 7. Mean and Maximum QTcF Changes from Baseline Relative to Placebo:

¹ Fridericia corrected; ²Upper Confidence Limit (CL) from a 2-sided 90% Confidence Interval (CI) on difference from placebo (msec)

ECGs were performed prior to and during the treatment period in patients receiving VIBATIV 10 mg/kg in 3 cSSSI studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with VIBATIV and 164 of 1033 (16%) allocated to vancomycin received concomitant medications known to prolong the QTc interval and known to be associated with definite or possible risk of torsades de pointes. The incidence of QTc prolongation >60 msec was 1.5% (15 patients) in the VIBATIV group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 VIBATIV patients received concomitant medications known to prolong the QTc interval and definitely or possibly associated with a risk of torsades de pointes, compared with 1 of the 6 patients who received vancomycin. A similar number of patients in each treatment group (<1%) who did not receive a concomitant medication known to prolong the QTc interval experienced a prolongation >60 msec from baseline. In a separate analysis, 1 patient in the VIBATIV group and 2 patients in the vancomycin group experienced QTc >500 msec. No cardiac adverse events were ascribed to prolongation of the QTc interval. In the Phase 3 HABP/VABP studies, the incidence of QTc prolongation >60 msec or mean value >500 msec was 8% (52 patients) in the telavancin group and 7% (48 patients) in the vancomycin group.

The mean pharmacokinetic parameters of telavancin (10 mg/kg) after a single and multiple 60-minute intravenous infusions (10 mg/kg every 24 hours) are summarized in Table 8.

Table 8. Pharmacokinetic Parameters of Telavancin in Healthy Adults, 10 mg/kg:

C_max = maximum plasma concentration; AUC = area under concentration-time course; t_1/2 = terminal elimination half-life; Cl = clearance; V_ss = apparent volume of distribution at steady state; --¹ Data not available

In healthy young adults, the pharmacokinetics of telavancin administered intravenously were linear following single doses from 5 to 12.5 mg/kg and multiple doses from 7.5 to 15 mg/kg administered once daily for up to 7 days. Steadystate concentrations were achieved by the third daily dose.

Distribution

Telavancin binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The mean binding is approximately 90% and is not affected by renal or hepatic impairment.

Concentrations of telavancin in pulmonary epithelial lining fluid (ELF) and alveolar macrophages (AM) were measured through collection of bronchoalveolar lavage fluid at various times following administration of VIBATIV 10 mg/kg once daily for 3 days to healthy adults. Telavancin concentrations in ELF and AM exceeded the MIC₉₀ for S. aureus (0.5 mcg/mL) for at least 24 hours following dosing.

Concentrations of telavancin in skin blister fluid were 40% of those in plasma (AUC_0-24hr ratio) after 3 daily doses of 7.5 mg/kg VIBATIV in healthy young adults.

Metabolism

No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11. The clearance of telavancin is not expected to be altered by inhibitors of any of these enzymes.

In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for <10% of the radioactivity in urine and <2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.

Excretion

Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and <1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.

Specific Populations

Geriatric Patients

The impact of age on the pharmacokinetics of telavancin was evaluated in healthy young (range 21-42 years) and elderly (range 65-83 years) subjects. The mean CrCl of elderly subjects was 66 mL/min. Age alone did not have a clinically meaningful impact on the pharmacokinetics of telavancin [see Use in Specific Populations (8.5)].

Pediatric Patients

The pharmacokinetics of telavancin in patients less than 18 years of age have not been studied.

Gender

The impact of gender on the pharmacokinetics of telavancin was evaluated in healthy male (n=8) and female (n=8) subjects. The pharmacokinetics of telavancin were similar in males and females. No dosage adjustment is recommended based on gender.

Renal Impairment

The pharmacokinetics of telavancin were evaluated in subjects with normal renal function and subjects with varying degrees of renal impairment following administration of a single dose of telavancin 7.5 mg/kg (n=28). The mean AUC_0-∞ values were approximately 13%, 29%, and 118% higher for subjects with CrCl >50 to 80 mL/min, CrCl 30 to 50 mL/min, and CrCl <30 mL/min, respectively, compared with subjects with normal renal function. Dosage adjustment is required in patients with CrCl ≤50 mL/min [see Dosage and Administration (2)].

Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:

CrCl = [140 – age (years)] x ideal body weight (kg)* / [72 x serum creatinine (mg/dL)] {x 0.85 for female patients}

^* Use actual body weight if < ideal body weight (IBW)

IBW (male) = 50 kg + 0.9 kg/cm over 152 cm height

IBW (female) = 45.5 kg + 0.9 kg/cm over 152 cm height

Following administration of a single dose of VIBATIV 7.5 mg/kg to subjects with end-stage renal disease, approximately 5.9% of the administered dose of telavancin was recovered in the dialysate following 4 hours of hemodialysis. The effects of peritoneal dialysis have not been studied.

Following a single intravenous dose of VIBATIV 7.5 mg/kg, the clearance of hydroxypropyl-beta-cyclodextrin was reduced in subjects with renal impairment, resulting in a higher exposure to hydroxypropyl-beta-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, the mean clearance values were 38%, 59%, and 82% lower, respectively, compared with subjects with normal renal function. Multiple infusions of VIBATIV may result in accumulation of hydroxypropyl-beta-cyclodextrin.

Hepatic Impairment

The pharmacokinetics of telavancin were not altered in subjects with moderate hepatic impairment (n= 8, Child-Pugh B) compared with healthy subjects with normal hepatic function matched for gender, age, and weight. The pharmacokinetics of telavancin have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Drug Interactions

In Vitro

The inhibitory activity of telavancin against the following CYP 450 enzymes was evaluated in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, and 3A4/5. Telavancin inhibited CYP 3A4/5 at potentially clinically relevant concentrations. Upon further evaluation in a Phase 1 clinical trial, telavancin was found not to inhibit the metabolism of midazolam, a sensitive CYP3A substrate (see below).

Midazolam

The impact of telavancin on the pharmacokinetics of midazolam (CYP 3A4/5 substrate) was evaluated in 16 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, intravenous midazolam 1 mg, and both. The results showed that telavancin had no impact on the pharmacokinetics of midazolam and midazolam had no effect on the pharmacokinetics of telavancin.

Aztreonam

The impact of telavancin on the pharmacokinetics of aztreonam was evaluated in 11 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, aztreonam 2 g, and both. Telavancin had no impact on the pharmacokinetics of aztreonam and aztreonam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or aztreonam is recommended when both drugs are coadministered.

Piperacillin-tazobactam

The impact of telavancin on the pharmacokinetics of piperacillin-tazobactam was evaluated in 12 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, piperacillin-tazobactam 4.5 g, and both. Telavancin had no impact on the pharmacokinetics of piperacillin-tazobactam and piperacillin-tazobactam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or piperacillin-tazobactam is recommended when both drugs are coadministered.

Telavancin is a semisynthetic, lipoglycopeptide antibiotic. Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive organisms in vitro, as demonstrated by time-kill assays and MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. In vitro studies demonstrated a telavancin post-antibiotic effect ranging from 1 to 6 hours against S. aureus and other Grampositive pathogens.

Mechanism of Action

Telavancin inhibits cell wall biosynthesis by binding to late-stage peptidoglycan precursors, including lipid II. Telavancin also binds to the bacterial membrane and disrupts membrane barrier function.

Interactions with Other Antibacterial Drugs

In vitro investigations demonstrated no antagonism between telavancin and amikacin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, rifampin, and trimethoprim/sulfamethoxazole when tested in various combinations against telavancin-susceptible staphylococci, streptococci, and enterococci. This information is not available for other bacteria.

Cross-Resistance

Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. There is no known crossresistance between telavancin and other classes of antibacterial drugs.

Antibacterial Activity

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

Gram-Positive Bacteria:

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

Greater than 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the telavancinsusceptible breakpoint for organisms of similar genus. The safety and effectiveness of telavancin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria:

Enterococcus faecium (vancomycin-susceptible isolates only)
Staphylococcus haemolyticus
Streptococcus dysgalactiae subsp. equisimilis
Staphylococcus epidermidis

Susceptibility Testing

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 to determine the carcinogenic potential of telavancin have not been performed.

Neither mutagenic nor clastogenic potential of telavancin was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion), an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.

Telavancin did not affect the fertility or reproductive performance of adult male rats (up to 100 mg/kg/day for at least 4 weeks prior to mating) or female rats (up to 150 mg/kg/day for at least 2 weeks prior to mating).

Male rats given 50 or 100 mg/kg/day telavancin for 6 weeks, at exposure levels similar to those measured in clinical studies, displayed altered sperm parameters that were reversible following an 8-week recovery period. A longer dosing period showed that telavancin caused histopathological changes in the seminiferous tubules and epididymides of the rat testis after 13 weeks of administration at 50 or 100 mg/kg/day. These changes were reversible at the end of a 4 week recovery period.

Two-week administration of telavancin in rats produced minimal renal tubular vacuolization with no changes in BUN or creatinine. These effects were not seen in studies conducted in dogs for similar duration. Four weeks of treatment resulted in reversible elevations in BUN and/or creatinine in association with renal tubular degeneration that further progressed following 13 weeks of treatment.

These effects occurred at exposures (based on AUCs) that were similar to those measured in clinical trials.

The potential effects of continuous venovenous hemofiltration (CVVH) on the clearance of telavancin were examined in an in vitro model using bovine blood. Telavancin was cleared by CVVH and the clearance of telavancin increased with increasing ultrafiltration rate [see Overdosage (10)].

14.1 Complicated Skin and Skin Structure Infections

Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) were enrolled in two randomized, multinational, multicenter, double-blinded trials (Trial 1 and Trial 2) comparing VIBATIV (10 mg/kg IV every 24 hours) with vancomycin (1 g IV every 12 hours) for 7 to 14 days. Vancomycin dosages could be adjusted per site-specific practice. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. These trials were identical in design, enrolling approximately 69% of their patients from the United States.

The trials enrolled adult patients with cSSSI with suspected or confirmed MRSA as the primary cause of infection. The all-treated efficacy (ATe) population included all patients who received any amount of study medication according to their randomized treatment group and were evaluated for efficacy. The clinically evaluable population (CE) included patients in the ATe population with sufficient adherence to the protocol.

The ATe population consisted of 1,794 patients. Of these, 1,410 (79%) patients were clinically evaluable (CE). Patient baseline infection types were well-balanced between treatment groups and are presented in Table 9.

Table 9. Baseline Infection Types in cSSSI Trials 1 and 2 – ATe Population:

¹ Includes all patients randomized, treated, and evaluated for efficacy

The primary efficacy endpoints in both trials were the clinical cure rates at a follow-up (Test-of-Cure) visit in the ATe and CE populations. Clinical cure rates in Trials 1 and 2 are displayed for the ATe and CE population in Table 10.

Table 10. Clinical Cure at Test-of-Cure in cSSSI Trials 1 and 2 – ATe and CE Populations:

¹ 95% CI computed using a continuity correction

The cure rates by pathogen for the microbiologically evaluable (ME) population are presented in Table 11.

Table 11. Clinical Cure Rates at the Test-of-Cure for the Most Common Pathogens in cSSSI Trials 1 and 2 – ME Population¹:

¹ The ME population included patients in the CE population who had Gram-positive pathogens isolated at baseline and had central identification and susceptibility of the microbiological isolate(s).

Of the 1784 patients in the ATe population in the two cSSSI trials, 32 patients had baseline S. aureus bacteremia: 21 patients (2.4%, including 13 with MRSA) were treated with VIBATIV and 11 patients (1.2%, including 4 with MRSA) were treated with vancomycin. In these bacteremic patients, the clinical cure rate at Test-of-Cure was 57.1% (12/21) for the VIBATIV-treated patients and 54.6% (6/11) for the vancomycin-treated patients. Given the limited sample size in this subgroup, the interpretation of these results is limited.

In the two cSSSI trials, clinical cure rates were similar across gender and race. Clinical cure rates in the VIBATIV clinically evaluable (CE) population were lower in patients ≥65 years of age compared with those <65 years of age. A decrease of this magnitude was not observed in the vancomycin CE population. Clinical cure rates in the VIBATIV CE population <65 years of age were 503/581 (87%) and in those ≥65 years were 88/122 (72%). In the vancomycin CE population clinical cure rates in patients <65 years of age were 492/570 (86%) and in those ≥65 years was 111/137 (82%). Clinical cure rates in the VIBATIV-treated patients were lower in patients with baseline CrCl ≤50 mL/min compared with those with CrCl >50 mL/min. A decrease of this magnitude was not observed in the vancomycintreated patients [see Warnings and Precautions (5.2)].

14.2 HABP/VABP

Adult patients with hospital-acquired and ventilator-associated pneumonia were enrolled in two randomized, parallelgroup, multinational, multicenter, double-blinded trials of identical design comparing VIBATIV (10 mg/kg IV every 24 hours) with vancomycin (1 g IV every 12 hours) for 7 to 21 days. Vancomycin dosages could be adjusted for body weight and/or renal function per local guidelines. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. The addition of piperacillin/tazobactam was also permitted for coverage of Gram-negative organisms if resistance to aztreonam was known or suspected. Patients with known or suspected infections due to methicillin-resistant Staphylococcus aureus were enrolled in the studies.

Of the patients enrolled across both trials, 64% were male and 70% were white. The mean age was 63 years. At baseline, more than 50% were admitted to an intensive care unit, about 23% had chronic obstructive pulmonary disease, about 29% had ventilator-associated pneumonia and about 6% had bacteremia. Demographic and baseline characteristics were generally well-balanced between treatment groups; however, there were differences between HABP/VABP Trial 1 and HABP/VABP Trial 2 with respect to a baseline history of diabetes mellitus (31% in Trial 1, 21% in Trial 2) and baseline renal insufficiency (CrCl _≤ 50 mL/min) (36% in Trial 1, 27% in Trial 2).

All-cause mortality was evaluated because there is historical evidence of treatment effect for this endpoint. This was a protocol pre-specified secondary endpoint. The 28-day all-cause mortality outcomes (overall and by baseline creatinine clearance categorization) in the group of patients who had at least one baseline Gram-positive respiratory pathogen are shown in Table 12. This group of patients included those who had mixed Gram-positive/Gram-negative infections.

Table 12. All-Cause Mortality at Day 28 in Patients with at Least One Baseline Gram- Positive Pathogen:

^a Mortality rates are based on Kaplan-Meier estimates at Study Day 28. There were 84 patients (5.6%) whose survival statuses were not known up to 28 days after initiation of study drug and were considered censored at the last day known to be alive. Thirty-five of these patients were treated with VIBATIV and 45 were treated with vancomycin.

The protocol-specified analysis included clinical cure rates at the TOC (7 to 14 days after the last dose of study drug) in the co-primary All-Treated (AT) and Clinically Evaluable (CE) populations (Table 13). Clinical cure was determined by resolution of signs and symptoms, no further antibacterial therapy for HABP/VABP after end-oftreatment, and improvement or no progression of baseline radiographic findings. However, the quantitative estimate of treatment effect for this endpoint has not been established.

Table 13. Clinical Response Rates in Trials 1 and 2 – AT and CE Populations:

^a All-Treated (AT) Population: Patients who received at least one dose of study medication
^b Clinically Evaluable (CE) Population: Patients who were clinically evaluable

Among the 797 patients with at least one Gram-positive respiratory pathogen at baseline, 73 patients had concurrent S. aureus bacteremia: 35 patients (8.5%, including 21 with MRSA) were treated with VIBATIV and 38 patients (9.8%, including 24 with MRSA) were treated with vancomycin. In these bacteremic patients, the 28-day all-cause mortality rate was 40.0% (14/35) for VIBATIV-treated patients and 39.5% (15/38) for vancomycin-treated patients. Given the limited sample size in this subgroup, the interpretation of these results is limited.