Liverpool COVID-19 Interactions

Potential Interaction

Nirmatrelvir/ritonavir (5 days)

Dabigatran

Quality of Evidence: Low

Summary:

Coadministration of dabigatran (75 mg single dose) and nirmatrelvir/ritonavir (300/100 mg twice daily for three doses) increased dabigatran Cmax and AUC by 133% and 94% (n=24). If nirmatrelvir/ritonavir treatment is needed, consider adjusting dabigatran dosage according to risk, indication and current dose. For treatment of atrial fibrillation with standard dabigatran dose (i.e., 150 mg twice daily), reduce dabigatran to 110 mg twice daily in patients with normal renal function and to 75 mg twice daily in patients with moderate renal impairment. For treatment of atrial fibrillation with low dose dabigatran (i.e., 110 mg twice daily), continue low dose on a case-by-case basis. For patients at high risk of venous/arterial thromboembolism (VTE/ATE), consider switching from dabigatran to low molecular weight heparin (LMWH); patients with a lower risk of VTE/ATE could be switched to aspirin on a case-by-case basis. The usual dabigatran treatment should be resumed 3 days after the last dose of nirmatrelvir/ritonavir. [These dosing recommendations are based on the interaction between dabigatran and darunavir/cobicistat as this is of a similar magnitude to ritonavir given for a short duration (i.e., only an inhibitory effect on P-gp with short duration ritonavir administration vs a mixed inhibitory/inducing effect with long-term ritonavir use)].

Description:

Coadministration of dabigatran (75 mg single dose) and nirmatrelvir/ritonavir (300/100 mg twice daily, 5 doses) increased dabigatran AUC Cmax and AUC by 133% and 94% (n=24). Increased bleeding risk with dabigatran. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to dabigatran Summary of Product Characteristics for further information.

Paxlovid GB Summary of Product Characteristics, Pfizer Ltd, December 2024.

Coadministration of nirmatrelvir/ritonavir increased dabigatran AUC and Cmax by 94% and 133%. Concomitant administration of Paxlovid is expected to increase dabigatran concentrations resulting in increased risk of bleeding. Reduce dose of dabigatran or avoid concomitant use.

Paxlovid EU Summary of Product Characteristics, Pfizer, February 2025.

Coadministration increased dabigatran concentrations. Coadministration of dabigatran (75 mg one dose) and nirmatrelvir/ritonavir (300/100 mg twice daily for four doses) was studied in 24 subjects. Dabigatran Cmax and AUC increased by 133% and 94%. Increased bleeding risk with dabigatran. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran product label for further information.

Paxlovid US Prescribing Information, Pfizer Inc, February 2025.

The pharmacokinetics and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with dabigatran (a P-gp substrate) were investigated in a phase 1, open-label, fixed-sequence study in 24 healthy adults. Single oral doses of dabigatran (75 mg) were administered alone and after steady-state (i.e., ≥2 days) of nirmatrelvir/ritonavir (300/100 mg twice daily for three doses) and ritonavir (100 mg twice daily for three doses). Coadministration with nirmatrelvir/ritonavir increased dabigatran AUC and Cmax by 1.9-fold and 2.3-fold. Coadministration with ritonavir alone increased both dabigatran AUC and Cmax by 1.7-fold. As dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with ritonavir alone, this suggests a minor incremental effect of nirmatrelvir on P-gp. Although dabigatran exposure was higher when coadministered with nirmatrelvir/ritonavir, this interaction can be managed for short treatment duration of nirmatrelvir/ritonavir by avoiding coadministration or reducing the dose of dabigatran treatment.

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants. Cox DS, Rehman M, Khan T, et al. Br J Clin Pharmacol, 2023, 89(11);3352-3363.

A population/physiologically based pharmacokinetic and pharmacodynamics analysis evaluated changes in dabigatran exposure in the presence of cobicistat and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within one year. The model indicated that coadministration of dabigatran and cobicistat should be avoided in subjects with severe renal impairment. The dabigatran dose should be reduced to 75 mg twice daily when coadministered with cobicistat in subjects with moderate renal impairment and should be reduced to 110 mg twice daily when coadministered with cobicistat in individuals with normal renal function.

Quantitative benefit-risk assessment of P-gp mediated drug-drug interactions (DDIs) of dabigatran co-administered with pharmacokinetic enhancers in patients with renal impairment. Lingineni K, Farhan N, Kim S, et al. Clin Pharmacol Ther, 2021; 109 (1):193-200.