s for Dalbavancin Quality Control Strain
MIC Range (µg/mL)
Staphylococcus aureus ATCC ®29213
0.03-0.12
Streptococcus pneumoniae ATCC ®49619a
0.008-0.03
Enterococcus faecalis ATCC®29212
0.03‑0.12
ATCC® = American Type Culture Collection
a This organism may be used for validation of susceptibility test results when testing Streptococcus species other than S. pneumoniae.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals to determine the carcinogenic potential of dalbavancin have not been conducted.
Dalbavancin was not genotoxic in a mammalian HGPRT gene mutation assay, an in vitro chromosome aberration assay in Chinese Hamster Ovary cells, or an in vivo mouse micronucleus assay.
Impaired fertility in the rat was not observed at a dose of 15 mg/kg/day (1.2 times the human dose on an exposure basis). Reductions in male and female fertility and increased embryo resorptions occurred at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis), at which signs of parental toxicity were also observed.
13.2 Animal Toxicology and/or PharmacologyIncreases in serum levels of liver enzymes (ALT, AST), associated with microscopic findings in the liver were noted in toxicology studies in rats and dogs where dalbavancin was administered daily for 28 to 90 days. Hepatocellular necrosis was observed in dogs dosed at ≥10 mg/kg/day for longer than 2 months, i.e., at approximately 5 to 7 times the expected human dose on an exposure basis. Histiocytic vacuolation and hepatocyte necrosis were observed in rats dosed daily at 40 and 80 mg/kg/day, respectively, for 4 weeks, (approximately 3 and 6 times the expected human dose on an exposure basis, respectively). In addition, renal toxicity characterized by increases in serum BUN and creatinine and microscopic kidney findings was observed in rats and dogs at doses 5 to 7 times the expected human dose on an exposure basis. The relationship between these findings in the animal toxicology studies after 28 and 90 consecutive days of dosing to the indicated clinical dosing of 2 doses 7 days apart are unclear.
14 CLINICAL STUDIES
Acute Bacterial Skin and Skin Structure Infections: Adult patients with ABSSSI were enrolled in two Phase 3, randomized, double-blind, double-dummy clinical trials of similar design (Trial 1 and Trial 2). The Intent-to-Treat (ITT) population included 1,312 randomized patients. Patients were treated for two weeks with either a two-dose regimen of intravenous DALVANCE (1000 mg followed one week later by 500 mg) or intravenous vancomycin (1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). DALVANCE-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens.
Table 6. Clinical Response Rates in ABSSSI Trials at 48-72 Hours after Initiation of Therapy
DALVANCE
n/N (%)
Vancomycin/Linezolid
n/N (%)
Difference
(95%CI)3
Trial 1
240/288 (83.3%)
233/285 (81.8%)
1.5% (-4.6, 7.9)
Trial 2
285/371 (76.8%)
288/368 ( |
