What medications should be held while initiating Paxlovid (nirmatrelvir/ritonavir)?

Medications to Hold or Adjust While on Paxlovid

Due to ritonavir's potent inhibition of CYP3A4 and P-glycoprotein, multiple medication classes require discontinuation, dose reduction, or temporary substitution during the 5-day Paxlovid treatment course to prevent serious toxicity. 1

High-Risk Medications Requiring Action

Direct Oral Anticoagulants (DOACs)

• Rivaroxaban (Xarelto): This combination is contraindicated—ritonavir increases rivaroxaban levels by approximately 2.5-fold (AUC increased 150%, Cmax increased 70%), creating severe bleeding risk. 2 Switch to low molecular weight heparin (LMWH) during the 5-day Paxlovid course. 3

• Apixaban (Eliquis): Temporarily switch to LMWH during Paxlovid treatment, or if continuation is absolutely necessary, reduce apixaban dose by 25% with intensive bleeding monitoring. 3 Monitor particularly closely in patients >75 years or those on concurrent antiplatelet therapy. 3

• Edoxaban: Represents the safest DOAC option with Paxlovid if switching anticoagulants is considered, as it demonstrates minimal clinically significant interactions. 3

Immunosuppressants

• Tacrolimus: Discontinue entirely or give only a microdose on day 1 of Paxlovid, as CYP3A inhibition causes drastic exposure increases. 4 Resume normal dosing after completing Paxlovid with therapeutic drug monitoring. 4

• Cyclosporine: Reduce dose to 20% of baseline during antiviral treatment. 4 Therapeutic drug monitoring is mandatory. 1

• Sirolimus and mTOR inhibitors: Require dose adjustments with therapeutic concentration monitoring. 1, 4

Statins

• Simvastatin and lovastatin: Contraindicated due to 27-fold increase in exposure with strong CYP3A4 inhibitors, risking severe myopathy and rhabdomyolysis. 1

• Atorvastatin and rosuvastatin: Hold during Paxlovid treatment or use the lowest possible dose with careful monitoring. 1, 5 Case reports document toxicity when continued at regular doses. 5

Antiarrhythmics

• Amiodarone: Hold during Paxlovid treatment—ritonavir significantly increases amiodarone levels, risking QT prolongation and torsades de pointes. 6, 5

• Flecainide and propafenone: Avoid concurrent use due to increased drug levels and arrhythmia risk. 6

• Ranolazine: Enhanced toxicity risk requires holding or significant dose reduction. 5

Sedatives and Benzodiazepines

• Triazolam and oral midazolam: Contraindicated due to potential for prolonged or increased sedation and respiratory depression. 1

• Diazepam, clorazepate, estazolam, flurazepam, zolpidem, buspirone: Reduce doses significantly to prevent excessive sedation. 1 Case reports document acute encephalopathy when benzodiazepines and narcotics were continued at regular doses with Paxlovid. 7

• Parenteral midazolam: Only use in monitored settings with dose reduction. 1

Calcium Channel Blockers

• Nifedipine, manidipine, verapamil: Case reports show enhanced toxicity; hold or reduce doses substantially during Paxlovid treatment. 5

Antipsychotics

• Clozapine and quetiapine: Enhanced toxicity risk requires holding or significant dose reduction during Paxlovid course. 5

PDE5 Inhibitors

• Sildenafil for pulmonary arterial hypertension (Revatio): Contraindicated. 1

• Avanafil: Do not use—no safe dosing regimen established. 1

• Sildenafil for erectile dysfunction: Maximum 25 mg every 48 hours. 1

• Tadalafil for erectile dysfunction: Maximum 10 mg every 72 hours. 1

• Vardenafil: Maximum 2.5 mg every 72 hours. 1

Corticosteroids

• Fluticasone, budesonide, ciclesonide, dexamethasone, methylprednisolone, mometasone, triamcinolone: Switch to beclomethasone or prednisolone (less affected by CYP3A inhibition) for long-term use to avoid Cushing's syndrome and adrenal suppression. 1

Colchicine

• Contraindicated in patients with renal or hepatic impairment: Ritonavir (a potent CYP3A4 inhibitor) dramatically increases colchicine exposure, risking life-threatening toxicity. 6 Hold colchicine during Paxlovid treatment in patients with CKD or liver disease. 6

Anticonvulsants

• Carbamazepine, phenobarbital, phenytoin, oxcarbazepine: These CYP3A inducers will decrease nirmatrelvir levels, reducing Paxlovid efficacy—avoid concurrent use. 6

Warfarin

• Reduce dose by 50% when initiating Paxlovid and monitor INR closely, as ritonavir affects warfarin metabolism. 6, 5

Digoxin

• Reduce dose by 30-50% and monitor digoxin concentrations, as ritonavir inhibits P-glycoprotein. 6

Contraceptives

• Ethinyl estradiol: Levels decrease with ritonavir—use alternate contraception methods during and after Paxlovid treatment. 1

Medications Safe to Continue

• Mycophenolic acid and corticosteroids: Expected to be less impacted by Paxlovid. 4

• Raltegravir, maraviroc, rilpivirine, tenofovir, emtricitabine, lamivudine, abacavir: No significant interactions with ritonavir. 6

• Daclatasvir and sofosbuvir: No clinically significant interactions with ritonavir. 6, 8

Critical Monitoring Parameters

• Bleeding signs: Monitor for unusual bruising, blood in urine/stool, prolonged bleeding from cuts, severe headache, coughing up blood throughout the 5-day course and 2-3 days after completion. 3

• Drug levels: Obtain therapeutic drug monitoring for immunosuppressants, digoxin, and warfarin (INR). 1, 4

• Renal function: Patients with CKD are at higher risk for drug interactions and toxicity. 2

Common Pitfalls to Avoid

• Assuming all DOACs are equivalent: Rivaroxaban has the most dangerous interaction and is contraindicated, while edoxaban is safest. 2, 3

• Continuing immunosuppressants at regular doses: This leads to severe toxicity—tacrolimus must be held or given as microdose only. 4

• Forgetting about herbal medicines: St. John's wort induces CYP3A and will reduce Paxlovid efficacy—must be discontinued. 6, 9

• Inadequate post-Paxlovid monitoring: Resume medications gradually with monitoring, as ritonavir effects persist 2-3 days after the last dose. 3