VIBATIV: Package Insert and Label Information (Page 4 of 5)

12.4 Microbiology

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)

Entero coccus 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

13.2 Animal Toxicology and/or Pharmacology

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 CLINICAL STUDIES

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

VIBATIV (N=884) 1 Vancomycin (N=910) 1
Type of infection
Major Abscess 375 (42.4%) 397 (43.6%)
Deep/Extensive Cellulitis 309 (35.0%) 337 (37.0%)
Wound Infection 139 (15.7%) 121 (13.3%)
Infected Ulcer 45 (5.1%) 46 (5.1%)
Infected Burn 16 (1.8%) 9 (1.0%)

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

Trial 1 Trial 2
VIBATIV Vancomycin Difference VIBATIV Vancomycin Difference
% (n/N) % (n/N) (95% CI) 1 % (n/N) % (n/N) (95% CI) 1
ATe 72.5% (309/426) 71.6% (307/429) 0.9 (-5.3, 7.2) 74.7% (342/458) 74.0% (356/481) 0.7 (-5.1, 6.5)
CE 84.3% (289/343) 82.8% (288/348) 1.5 (-4.3, 7.3) 83.9% (302/360) 87.7% (315/359) -3.8 (-9.2, 1.5)

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).

VIBATIV % (n/N) Vancomycin % (n/N)
Staphylococcus aureus (MRSA) 87.0% (208/239) 85.9% (225/262)
Staphylococcus aureus (MSSA) 82.0% (132/161) 85.1% (131/154)
Enterococcus faecalis 95.6% (22/23) 80.0% (28/35)
Streptococcus pyogenes 84.2% (16/19) 90.5% (19/21)
Streptococcus agalactiae 73.7% (14/19) 86.7% (13/15)
Streptococcus anginosus group 76.5% (13/17) 100.0% (9/9)

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.

Trial 1 Trial 2
VIBATIV Vancomycin VIBATIV Vancomycin
All Patients Mortalitya 28.7%N=187 24.3%N=180 24.3%N=224 22.3%N=206
Difference (95% CI) 4.4% (-4.7%, 13.5%) 2.0% (-6.1%, 10%)
CrCl 50 mL/min Mortalitya 41.8% N=63 35.4% N=68 43.9% N=53 29.6% N=58
Difference (95% CI) 6.4% (-10.4, 23.2) 14.3% (-3.6, 32.2)
CrCl > 50 mL/min Mortalitya 22.0%N=124 17.6%N=112 18.2%N=171 19.3%N=148
Difference (95% CI) 4.4% (-5.9, 14.7) -1.1% (-9.8, 7.6)

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

Trial 1 Trial 2
VIBATIV Vancomycin VIBATIV Vancomycin
ATa Difference(95% CI) 57.5% (214/372) 59.1% (221/374) 60.2% (227/377) 60.0% (228/380)
-1.6% (-8.6%, 5.5%) 0.2% (-6.8%, 7.2%)
CEb Difference(95% CI) 83.7% (118/141) 80.2% (138/172) 81.3% (139/171) 81.2% (138/170)
3.5% (-5.1%, 12.0%) 0.1% (-8.2%, 8.4%)

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.

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