CLARINEX-D 12 HOUR Extended Release Tablets (desloratadine/pseudoephedrine sulfate)(十一)
loratadine 3-hydroxydesloratadine
Cmax AUC
0–24 hrs Cmax AUC
0–24 hrs
Erythromycin
(500 mg Q8h) +24% +14% +43% +40%
Ketoconazole
(200 mg Q12h) +45% +39% +43% +72%
Azithromycin
(500 mg Day 1, 250 mg QD × 4 days) +15% +5% +15% +4%
Fluoxetine
(20 mg QD) +15% +0% +17% +13%
Cimetidine
(600 mg Q12h) +12% +19% -11% -3%CLOSE
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no animal or laboratory studies on the combination product of desloratadine and pseudoephedrine sulfate to eva luate carcinogenesis, mutagenesis, or impairment of fertility.
Carcinogenicity Studies:
The carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated desloratadine and desloratadine metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. The clinical significance of these findings during long-term use of desloratadine is not known.
In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day desloratadine, respectively, did not show significant increases in the incidence of any tumors. The estimated desloratadine and desloratadine metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.
Genotoxicity Studies:
In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).
Impairment of Fertility:
There was no effect on female fertility in rats at desloratadine doses up to 24 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). A male-specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral desloratadine dose of 12 mg/kg (estimated desloratadine and desloratadine metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies:
Desloratadine was not teratogenic in rats at doses up to 48 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were appro |
