What are the contraindications for Paxlovid (nirmatrelvir/ritonavir) in patients with a history of hypersensitivity, impaired renal function, or hepatic impairment?

Paxlovid Contraindications

Paxlovid is absolutely contraindicated in patients with clinically significant hypersensitivity to nirmatrelvir or ritonavir (including toxic epidermal necrolysis or Stevens-Johnson syndrome), those taking drugs highly dependent on CYP3A clearance where elevated levels cause serious/life-threatening reactions, those on potent CYP3A inducers that would compromise antiviral efficacy, and patients with severe hepatic impairment (Child-Pugh Class C). 1

Absolute Contraindications by Category

Hypersensitivity History

• Any history of clinically significant hypersensitivity reactions to nirmatrelvir or ritonavir, including toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome, absolutely prohibits Paxlovid use 1
• If signs of anaphylaxis or severe hypersensitivity develop during treatment, immediately discontinue Paxlovid and initiate supportive care 1

Severe Hepatic Impairment

• Paxlovid is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) due to lack of dosing data and increased risk of hepatotoxicity 1
• Ritonavir has been associated with hepatic transaminase elevations, clinical hepatitis, and jaundice 1

Severe Renal Impairment (Specific Circumstances)

• Paxlovid is contraindicated in patients with eGFR <30 mL/min who are NOT on hemodialysis, as standard dosing cannot be safely administered 1, 2
• For patients with eGFR <30 mL/min on hemodialysis, dose adjustment is required (not contraindicated, but requires modified dosing) 1

Drug-Drug Interaction Contraindications

Cardiovascular Medications

• Alfuzosin, amiodarone, dronedarone, flecainide, propafenone, quinidine, ranolazine - risk of life-threatening cardiac arrhythmias 3, 4, 1
• Eplerenone, ivabradine, finerenone - excessive cardiovascular effects 1
• Sildenafil (Revatio) for pulmonary arterial hypertension - risk of excessive vasodilation and hypotension 3, 4, 1
• Salmeterol - serious cardiovascular adverse events 4, 1

Statins

• Lovastatin and simvastatin - severe risk of rhabdomyolysis due to CYP3A inhibition; must be discontinued at least 12 hours before starting Paxlovid 3, 4, 1
• Atorvastatin should also be avoided due to increased rhabdomyolysis risk 3

Sedatives/Hypnotics

• Oral midazolam and triazolam - risk of prolonged sedation and respiratory depression 3, 4, 1

Ergot Derivatives

• Dihydroergotamine, ergotamine, methylergonovine - acute ergot toxicity causing vasospasm and ischemia 4, 1

Antipsychotics

• Lurasidone, pimozide, quetiapine - increased risk of serious toxicity including QT prolongation 3, 1

Other High-Risk Medications

• Colchicine in patients with renal or hepatic impairment - risk of life-threatening toxicity 1
• Naloxegol, silodosin, voclosporin, lomitapide, tolvaptan, flibanserin, eletriptan, ubrogepant - serious adverse effects from elevated drug levels 1

CYP3A Inducer Contraindications

Strong CYP3A inducers significantly reduce nirmatrelvir/ritonavir plasma concentrations, leading to loss of antiviral efficacy and potential viral resistance. 1

Contraindicated Inducers:

• Anticonvulsants: carbamazepine, phenobarbital, primidone, phenytoin 3, 1
• Antimycobacterials: rifampin, rifapentine 1
• Anticancer drugs: apalutamide, enzalutamide 1
• Herbal products: St. John's wort (hypericum perforatum) 3, 1
• Cystic fibrosis drugs: lumacaftor/ivacaftor 1

Critical caveat: Paxlovid cannot be started immediately after discontinuing these CYP3A inducers due to delayed offset of enzyme induction effects 1

Clinical Management Imperatives

Pre-Prescribing Requirements

• Conduct comprehensive medication review using drug interaction databases (Liverpool COVID-19 Drug Interaction tool) before prescribing Paxlovid 3, 5, 4
• Screen for renal function (eGFR) and hepatic function (Child-Pugh score) 5, 1
• Assess for history of hypersensitivity to nirmatrelvir or ritonavir 1

Common Pitfall

The most frequent error is prescribing Paxlovid without recognizing contraindicated drug interactions, particularly with statins, sedatives, and cardiovascular medications 2. In one study, 87.1% of patients required pharmacist intervention to prevent drug-related problems, with 17% having severe drug interactions 2.