ralocorticoid activity. For the purposes of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:
Cortisone, 25 Prednisone, 5 Paramethasone, 2
Hydrocortisone, 20 Methylprednisolone, 4 Betamethasone, 0.75
Prednisolone, 5 Triamcinolone, 4 Dexamethasone, 0.75
Corticosteroids have been demonstrated to depress the production of eosinophils and lymphocytes, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited.
12.3 Pharmacokinetics
Aqueous humor pharmacokinetics of triamcinolone have been assessed in 5 patients following a single intravitreal administration (4 mg) of triamcinolone acetonide. Aqueous humor samples were obtained from 5 patients (5 eyes) via an anterior chamber paracentesis on Days 1, 3, 10, 17 and 31 post injection. Peak aqueous humor concentrations of triamcinolone ranged from 2151 to 7202 ng/mL, half-life 76 to 635 hours, and the area under the concentration-time curve (AUC0-t) from 231 to 1911 ng.h/mL following the single intravitreal administration. The mean elimination half-life was 18.7 ± 5.7 days in 4 nonvitrectomized eyes (4 patients). In a patient who had undergone vitrectomy (1 eye), the elimination half-life of triamcinolone from the vitreous was much faster (3.2 days) relative to patients that had not undergone vitrectomy.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of mutagenicity was detected from in-vitro tests conducted with triamcinolone acetonide including a reverse mutation test in Salmonella bacteria and a forward mutation test in Chinese hamster ovary cells. With regard to carcinogenicity, in a two-year study in rats, triamcinolone acetonide caused no treatment-related carcinogenicity at oral doses up to 0.001mg/kg and in a two-year study in mice, triamcinolone acetonide caused no treatment-related carcinogenicity at oral doses up to 0.003 mg/kg (less than 1/25th of the recommended human dose). In male and female rats, triamcinolone acetonide caused no change in pregnancy rate at oral doses up to 0.015 mg/kg, but caused increased fetal resorptions and stillbirths and decreases in pup weight and survival at doses of 0.005 mg/kg (less than 1/10th of the recommended human dose).
13.2 Animal Toxicology and/or Pharmacology
Studies were conducted with triamcinolone acetonide, including those employing the proposed dosage form, i.e., 4.0% triamcinolone acetonide injectable suspension formulation containing 0.5% carboxymethylcellulose and 0.015% polysorbate-80 in a balanced salt solution.
Triamcinolone acetonide was demonstrated to be non-inflammatory when injected intravitreally in NZW rabbits, non-cytotoxic to mouse L-929 cells in an in-vitro assay and non-sensitizing in a guinea-pig maximization assay. Furthermore, the results of single-dose intravitreal injection studies with triamcinolone acetonide in both rabbits and monkeys demonstrate that the drug is well tolerated for up to one month with only minor findings of slight decrease in body weight gain and slight corneal thinning.
16 HOW SUPPLIED/STORAGE AND HANDLING
TRIESENCE® (triamcinolone a |
