dose prefilled syringe is clear to opalescent, colorless to pale yellow,sterile, and preservative-free solution, and is formulated at pH 6.2 ± 0.3.
Table 5. Contents of Eticovo
Presentation Active Ingredient Content Inactive Ingredients Content
Eticovo 50 mg prefilled syringe 50 mg etanercept-ykro in 1 mL 8.18 mg sodium chloride
0.665 mg sodium phosphate dibasic
heptahydrate
1.038 mg sodium phosphate
monobasic monohydrate
10 mg sucrose
Water for Injection, USP
Eticovo 25 mg prefilled syringe 25 mg etanercept-ykro in 0.5 mL 4.09 mg sodium chloride0.333 mg sodium phosphate dibasic
heptahydrate
0.519 mg sodium phosphate
monobasic monohydrate
5 mg sucrose
Water for Injection, USP
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays animportant role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology.
In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involvedtissues and fluids of patients with RA, JIA, PsA, AS, and PsO.
Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), existnaturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent uponbinding to either cell surface TNFR.
Etanercept products are dimeric soluble forms of the p75 TNF receptor that can bind TNF molecules. Etanerceptproducts inhibit binding of TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNFbiologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells
expressing transmembrane TNF (that binds etanercept products) are not lysed in the presence or absence ofcomplement.
12.2 Pharmacodynamics
Etanercept products can modulate biological responses that are induced or regulated by TNF, including expression ofadhesion molecules responsible for leukocyte migration (eg, E-selectin, and to a lesser extent, intercellular adhesionmolecule-1 [ICAM-1]), serum levels of cytokines (eg, IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3or stromelysin). Etanercept products have been shown to affect several animal models of inflammation, including
murine collagen-induced arthritis.
12.3 Pharmacokinetics
After administration of 25 mg of etanercept by a single SC injection to 25 patients with RA, a mean ± standarddeviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serumconcentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following
a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2- to 7-fold increase in peak serum concentrations and approximately4-fold increase in AUC0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months.
In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with50 mg etanercept once weekly and those treated with 25 mg etanercept twice weekly. The mean (± standard deviati |
