Drug Interactions between dabigatran and nirmatrelvir / ritonavir

ADJUST DOSE: Coadministration of dabigatran etexilate mesylate with nirmatrelvir-ritonavir may increase the plasma concentrations of dabigatran, the resultant active moiety following oral absorption and hydrolysis by esterases in the liver and plasma. The proposed mechanism is inhibition by ritonavir and possibly also nirmatrelvir (based on in vitro data) of the intestinal P-glycoprotein (P-gp)-mediated efflux of dabigatran etexilate, the prodrug of dabigatran. When a single 75 mg dose of dabigatran etexilate mesylate was administered following pretreatment with nirmatrelvir-ritonavir 300 mg-100 mg for 5 doses in 24 study subjects, mean dabigatran peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 2.3- and 1.9-fold, respectively.

MANAGEMENT: The potential for increased bleeding risk should be considered when dabigatran etexilate mesylate is administered with nirmatrelvir-ritonavir, particularly in patients with renal impairment or advanced age. Depending on dabigatran indication and renal function, reducing the dosage of dabigatran, separating the times of administration of each medication by several hours, or avoiding concomitant use may be advisable. Alternative antiviral agents such as molnupiravir or remdesivir may be considered if dabigatran cannot be withheld, substituted, or safely given with nirmatrelvir-ritonavir. The prescribing information for dabigatran and local or institutional guidelines should be consulted for further information and guidance.

MONITOR: Coadministration with ritonavir may increase the plasma concentrations of dabigatran, particularly in patients with renal impairment. The mechanism is inhibition of P-glycoprotein (P-gp) by ritonavir. In a single-center, two-arm, single-sequence, open-label study, dabigatran etexilate (150 mg) and ritonavir (100 mg) were administered simultaneously and separately (2 hours apart). When administered together, thrombin time (TT) at 24 hours post-dose increased by 31% (p-value less than 0.05) while no significant changes in dabigatran pharmacokinetic parameters were observed. When dabigatran was given 2 hours before ritonavir, dabigatran AUC decreased by 29% (p-value less than 0.05) while no significant changes in TT were observed.

MANAGEMENT: Coadministration of dabigatran with ritonavir is not recommended in certain patients with renal impairment. If concomitant use is necessary, clinical and laboratory monitoring is recommended and the dabigatran dosage should be adjusted as necessary. Patients should be monitored closely for the development of bleeding complications.