Dabigatran Etexilate Mesylate 126.83 mg · Hard-gelatin capsules

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy adult subjects and adult patients in the range of doses from 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor in adults and pediatrics is approximately two.

Absorption — The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at 1-hour post-administration in the fasted state.

Coadministration of Dabigatran Etexilate Capsules with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; Dabigatran Etexilate Capsules may be administered with or without food.

The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation based on a single-dose relative bioavailability study. Dabigatran Etexilate Capsules should therefore not be broken, chewed, or opened before administration.

Dabigatran Etexilate Capsules is available in capsules. The approved indications and intended age groups are not the same. Oral absorption of dabigatran etexilate is formulation-dependent. At steady-state, dabigatran etexilate oral pellets show 37% higher relative bioavailability in healthy adults compared to dabigatran etexilate capsules based on a multiple-dose relative bioavailability study. In addition, the relative bioavailability between the two dosage forms is age-dependent. The relative bioavailability observed in adults cannot be translated to pediatrics.

Distribution — Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L.

Elimination — Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces.

The half-life of dabigatran in healthy adult subjects is 12 to 17 hours. Population pharmacokinetic simulation shows that the elimination half-life in pediatric patients is 12 to 14 hours.

Metabolism — After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation, forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

Specific Populations — Pediatric Patients The pharmacokinetics of dabigatran was characterized in two clinical studies (DIVERSITY and Study 2) following multiple doses in pediatric patients from birth to less than 18 years old. In pediatric patients taking age- and weight-adjusted dosages of Dabigatran Etexilate Capsules (aged 8-18 years), the observed geometric mean steady-state trough concentration was 97.9 ng/m L (63.7 to 151 ng/m L, 10th to 90th percentile) compared to the steady-state geometric mean trough concentration of 59.7 ng/m L (26.3 to 146 ng/m L, 10th to 90th percentile) observed in adult patients with DVT/PE.

Renal Impairment — An open, parallel-group, single-center study compared dabigatran pharmacokinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving a single dose of Dabigatran Etexilate Capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 10). Similar findings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.

Hepatic Impairment — Administration of Dabigatran Etexilate Capsules in adult patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.