Is it safe to co‑administer Paxlovid (nirmatrelvir + ritonavir) with ranolazine?

Paxlovid and Ranolazine: Contraindicated Combination

Paxlovid (nirmatrelvir/ritonavir) should NOT be co-administered with ranolazine due to the risk of serious cardiac toxicity from excessive ranolazine exposure. 1, 2

Why This Combination Is Dangerous

Ritonavir is a potent CYP3A4 inhibitor that will dramatically increase ranolazine plasma concentrations, leading to potentially life-threatening cardiac complications. 3, 2

• Ranolazine is primarily metabolized by CYP3A4, and when this pathway is blocked by ritonavir, drug levels can rise to toxic concentrations 2, 4
• Ranolazine prolongs the QT interval, and elevated levels significantly increase the risk of torsades de pointes and other serious arrhythmias 1, 2
• Multiple case reports and pharmacokinetic studies have documented enhanced toxicity risk when ranolazine is combined with potent CYP3A4 inhibitors like ritonavir 2

Clinical Management Algorithm

If the patient is currently taking ranolazine:

1. Temporarily discontinue ranolazine before initiating Paxlovid 3, 4
2. Wait at least 24 hours after the last ranolazine dose before starting Paxlovid 4
3. Complete the full 5-day course of Paxlovid 3
4. Wait at least 3-5 days after completing Paxlovid before restarting ranolazine to allow ritonavir levels to decline 3, 4

If ranolazine cannot be safely discontinued:

• Do not prescribe Paxlovid 1, 3
• Consider alternative COVID-19 treatments based on patient risk stratification 5
• Consult the Liverpool COVID-19 Drug Interaction Tool for alternative antiviral options 5, 3

Critical Pitfalls to Avoid

Do not attempt dose reduction of ranolazine as a strategy to co-administer with Paxlovid—the magnitude of CYP3A4 inhibition by ritonavir is too profound to be managed by simple dose adjustment. 2, 4

Do not restart ranolazine immediately after completing Paxlovid—ritonavir's inhibitory effects persist for several days after the last dose, and premature reinitiation risks toxicity. 3, 4

Always use systematic interaction checking tools (Liverpool COVID-19 Drug Interaction Tool) before prescribing Paxlovid to any patient on cardiovascular medications, as this class has numerous contraindicated combinations. 5, 3, 4

Supporting Evidence Strength

The KDIGO 2024 guidelines explicitly list ritonavir/nirmatrelvir (Paxlovid) among potent CYP3A4 inhibitors that should not be used concomitantly with medications metabolized by this pathway. 1

Recent pharmacokinetic reviews (2025) specifically identify ranolazine as having enhanced toxicity risk when combined with Paxlovid, with documented adverse cardiovascular events. 2

Cardiovascular-focused drug interaction reviews emphasize that drugs with narrow therapeutic indices and predominant CYP3A4 metabolism—like ranolazine—require particular attention and often temporary discontinuation when Paxlovid is indicated. 4