Trivaris (Triamcinolone Acetonide Intravitreal) - Description and Clinical Pharmacology

DESCRIPTION

TRIVARIS™ (triamcinolone acetonide injectable suspension) 80 mg/mL is a synthetic glucocorticoid corticosteroid with anti-inflammatory action. This formulation is suitable for intravitreal, intramuscular, and intra-articular use. This formulation is not for intravenous injection. Each syringe of the sterile aqueous gel suspension contains 8 mg triamcinolone acetonide in 0.1 mL (8% suspension) in a HYLADUR™ vehicle containing w/w percents of 2.3% sodium hyaluronate; 0.63% sodium chloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate, monobasic; and water for injection. TRIVARIS™ is preservative-free with a pH of 7.0 to 7.4. The chemical name for triamcinolone acetonide is 9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone.

Its structural formula is:

MW 434.50 with a molecular formula of C₂₄H₃₁FO₆. Triamcinolone acetonide occurs as a white to cream-colored crystalline powder having not more than a slight odor, and is practically insoluble in water and very soluble in alcohol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Synthetic analogs such as triamcinolone are primarily used for their anti-inflammatory effects in disorders of many organ systems.

Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the bio-synthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure.

Intravitreal corticosteroids can down regulate the production of proinflammatory mediators, and can be used in ocular inflammatory conditions.

Pharmacokinetics

Aqueous humor pharmacokinetics of triamcinolone acetonide were 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 acetonide ranged from 2,151 to 7,202 ng/mL, the half-life ranged from 76 to 635 hours, and the area under the concentration-time curve (AUC_0-t) ranged from 231 to 1,911 μg∙h/mL. 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 acetonide was much faster (3.2 days) relative to patients that had not undergone vitrectomy.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis.

Triamcinolone acetonide was not mutagenic or clastogenic in the Ames bacterial reversion test and chromosomal aberration assay in Chinese hamster ovary (CHO) cells. Positive results were noted in the in vivo micronucleus test with triamcinolone acetonide in mice.

Steroids may increase or decrease motility and number of spermatozoa in some patients.