; Not Applicable
Clostridium difficilea
ATCC 70057 0.12-1 Not Applicable
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime studies in animals have not been performed to eva luate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg·hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.
13.2 Animal Toxicology and/or Pharmacology
In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg·hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.
14 CLINICAL STUDIES
14.1 Complicated Skin and Skin Structure Infections
TYGACIL was eva luated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically eva luable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 6. Clinical cure rates at TOC by pathogen in the microbiologically eva luable patients are presented in Table 7.
Table 6. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy TYGACILa
n/N (%) Vancomycin/Aztreonamb
n/N (%)
a 100 mg initially, followed by 50 mg every 12 hours
b Vancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)
Study 300
CE 165/199 (82.9) 163/198 (82.3)
c-mITT 209/277 (75.5) 200/260 (76.9)
Study 305
CE 200/223 (89.7) 201/213 (94.4)
c-mITT 220/261 (84.3) 225/259 (86.9)
Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically eva luable Patients with Complicated Skin and Skin Structure Infectionsa Pathogen TYGACIL
n/N (%) |
