What are the primary medicines contraindicated for Paxlovid (nirmatrelvir/ritonavir)?

Primary Medicines Contraindicated for Paxlovid

Paxlovid (nirmatrelvir/ritonavir) is absolutely contraindicated with strong CYP3A4 inducers and numerous medications metabolized by CYP3A4 due to ritonavir's potent enzyme inhibition, which can either cause loss of antiviral efficacy or life-threatening toxicity from elevated drug levels.

Strong CYP3A4 Inducers (Loss of Paxlovid Efficacy)

These medications reduce Paxlovid effectiveness and must be avoided:

• Anticonvulsants: Carbamazepine, phenobarbital, phenytoin, and primidone are absolutely contraindicated because they induce CYP3A4 metabolism of nirmatrelvir, causing loss of virologic response and potential viral resistance 1, 2
• Antimycobacterials: Rifampicin and rifabutin are contraindicated due to strong CYP3A4 induction 3
• Herbal products: St. John's wort is contraindicated as it significantly reduces nirmatrelvir plasma concentrations 3

Medications with Dangerous Elevation Risk (Toxicity from CYP3A4 Inhibition)

Cardiovascular Agents

Ritonavir's CYP3A4 inhibition causes marked increases in these drugs:

• Alpha-blockers: Alfuzosin is contraindicated because ritonavir increases exposure 2.3-fold for Cmax and 3.2-fold for AUC, risking severe hypotension 4
• Antiarrhythmics: Amiodarone is contraindicated due to risk of life-threatening cardiac arrhythmias 3
• Antiarrhythmics: Quinidine is contraindicated because elevated plasma exposure leads to serious cardiac adverse events 3
• Ergot derivatives: All ergot alkaloids are contraindicated due to risk of acute ergot toxicity including peripheral vasospasm and ischemia 3

Anticoagulants

Direct oral anticoagulants require extreme caution or avoidance:

• Rivaroxaban (Xarelto): Classified as "red" contraindicated interaction—ritonavir increases rivaroxaban AUC by 150% and Cmax by 70%, creating unpredictable anticoagulation and severe bleeding risk 5
• Apixaban (Eliquis): Requires either switching to low molecular weight heparin during the 5-day Paxlovid course or 25% dose reduction with close bleeding monitoring, particularly in patients >75 years 6
• Dabigatran: Contraindicated when combined with velpatasvir/voxilaprevir due to near 3-fold AUC increase from P-gp inhibition 3

Lipid-Lowering Agents

Statins metabolized by CYP3A4 are contraindicated:

• Lovastatin and simvastatin: Absolutely contraindicated because markedly elevated plasma concentrations lead to serious adverse events including rhabdomyolysis 3
• Atorvastatin: Contraindicated due to excessive exposure risk 3

Psychotropic Medications

Sedatives and antipsychotics with narrow therapeutic windows:

• Benzodiazepines: Oral midazolam and triazolam are contraindicated due to excessive sedation and respiratory depression risk 3
• Antipsychotics: Pimozide is contraindicated because ritonavir inhibits CYP3A4 metabolism, and two sudden deaths occurred when similar interactions prolonged QT intervals 7
• Antipsychotics: Quetiapine is contraindicated due to markedly increased plasma concentrations 3
• Antipsychotics: Clozapine toxicity risk is enhanced by concomitant Paxlovid administration 8

Pulmonary and GI Agents

• Bronchodilators: Salmeterol is contraindicated because elevated exposure leads to serious cardiovascular adverse events 3
• Sildenafil: When used for pulmonary arterial hypertension (not erectile dysfunction), sildenafil is contraindicated due to excessive vasodilation risk 3
• GI motility agents: Cisapride is contraindicated due to risk of QT prolongation and cardiac arrhythmias 3

Anti-Infectives

• Macrolide antibiotics: Clarithromycin, erythromycin, azithromycin are contraindicated as they inhibit CYP3A4 and could impede pimozide metabolism when combined with ritonavir 7
• Azole antifungals: Itraconazole and ketoconazole are contraindicated because they inhibit CYP3A4 and increase paritaprevir exposure when combined with ritonavir 3

Immunosuppressants Requiring Dramatic Dose Reduction

These are not contraindicated but require extreme caution:

• Tacrolimus: Should be discontinued or given as a microdose on day 1 of Paxlovid due to drastic CYP3A inhibition 9
• Cyclosporine: Dosage must be reduced to 20% of initial dose during antiviral treatment 9
• mTOR inhibitors: Dosages require adjustment while mycophenolic acid and corticosteroids are less impacted 9

Additional High-Risk Interactions

• Antihistamines: Astemizole and terfenadine are contraindicated due to cardiac arrhythmia risk 3
• Oncology agents: Multiple chemotherapy agents including imatinib, irinotecan, lapatinib are not recommended due to BCRP substrate effects 3
• Ranolazine: Risk of toxicity is enhanced by concomitant Paxlovid administration 8

Critical Clinical Pitfalls

Monitor for these common errors:

• Failing to check for CYP3A4-metabolized medications before prescribing Paxlovid—87.1% of patients required interventions to prevent drug-related problems in one analysis 10
• Not recognizing that 81.4% of patients on Paxlovid had at least one drug-drug interaction, with 17% having severe interactions 10
• Overlooking renal impairment combined with DDIs, which occurred in 24.3% of cases and compounds risk 10
• Continuing anticonvulsants without switching to alternatives—consider alternate oral or intravenous COVID-19 treatments instead 1
• Not educating patients on bleeding signs when continuing anticoagulants: unusual bruising, blood in urine/stool, prolonged bleeding from cuts, severe headache, coughing up blood 6