Digoxin and Nirmatrelvir: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Digoxin
Nirmatrelvir
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased digoxin exposure, an increased risk of digoxin toxicity, and an increased risk of PR interval
Interaction Deep Dive
Use caution with coadministration of digoxin with nirmatrelvir/ritonavir and monitor serum digoxin levels as appropriate4. Coadministration of digoxin (P-gp substrate with NTI) and nirmatrelvir/ritonavir (P-gp inhibitor) may increase digoxin exposure. To reduce digoxin exposure, reduce the digoxin dose by 30% to 50% or modify the dosing frequency, monitor digoxin levels 51, and monitor for potential signs and symptoms of clinical toxicity when initiating, adjusting, or discontinuing nirmatrelvir/ritonavir 23. Additionally, concomitant use with both ritonavir and digoxin increases the PR interval 51.
Why it happens (mechanism)
Inhibition of P-gp mediated efflux transport of digoxin; additive increase of PR interval
Literature reports
2 reports — tap to read
a) Concomitant administration of ritonavir with IV digoxin significantly reduced digoxin total clearance and increased digoxin bioavailability. In a randomized, double-blind, cross-over study, healthy men (N=12) received either ritonavir 300 mg twice daily or placebo on study days 1 through 11. Twenty minutes after an oral dose of ritonavir 300 mg was given on study day 3, each subject received a single IV dose of digoxin 0.5 mg, after which digoxin pharmacokinetics were assessed in a serial manner over the next 216 hours. An oral water overload (200 mL/hr) was imposed over the first 12 hours after dosing in order to minimize renal tubular reabsorption of digoxin. Each subject crossed over the opposing study arm after a minimum washout period of 20 days. Concurrent administration of ritonavir with digoxin significantly decreased digoxin renal clearance by 35% and nonrenal clearance by 48% and significantly increased digoxin AUC (0 to infinity) by 86%, steady-state Vd by 77%, and t(1/2) by 156% 6.
b) In a 2 treatment, 2 period, single sequence, longitudinal drug interaction study lasting 32 days, 9 out of 12 healthy subjects showed decreased nonrenal clearance of a 0.4 mg single oral dose of digoxin by 30% after 13 days of ritonavir 200 mg twice daily. In the 72 hours after the digoxin dose, ritonavir significantly increased the digoxin AUC by 22%, from 26.2 to 31.96 nanograms x hour/mL. Renal clearance of digoxin was not significantly affected by the presence of ritonavir. The effects of ritonavir-associated P-gp inhibition on digoxin pharmacokinetics were comparable across the Multiple Drug Resistance Gene (MDR1) genotypes of the 12 subjects 7.
Common questions
Can I take Digoxin and Nirmatrelvir together?
Increased digoxin exposure, an increased risk of digoxin toxicity, and an increased risk of PR interval Always confirm with your pharmacist or prescriber before making any change.
How serious is the Digoxin and Nirmatrelvir interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Digoxin or Nirmatrelvir need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (7)
- Product Information: LANOXIN(R) oral tablets, digoxin oral tablets. Covis Pharmaceuticals, Inc. (per FDA), Cary, NC, 2013. DailyMed
- Product Information: DIGOXIN oral tablets, digoxin oral tablets. Aurobindo Pharma USA, Inc. (per Dailymed), East Windsor, NJ, May. DailyMed
- Product Information: DIGOXIN intravenous injection, digoxin intravenous injection. Hikma Pharmaceuticals USA Inc. (per Dailymed), Berkeley Heights, NJ, 2023. DailyMed
- Pfizer Inc: Fact sheet for healthcare providers: Emergency Use Authorization for PAXLOVID(TM). US Food & Drug Administration (FDA). Silver Spring, MD. 2021.
- Product Information: NORVIR oral capsules, ritonavir oral capsules. AbbVie Inc. (per FDA), North Chicago, IL, 2013. DailyMed
- Ding R, Tayrouz Y, Riedel KD, et al: Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 2004; 76(1):73-84.
- Penzak SR, Shen JM, Alfaro RM, et al: Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes. Ther Drug Monit 2004; 26(3):322-330. PubMed
Keep reading about Digoxin
Keep reading about Nirmatrelvir
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