What are the contraindications for Paxlovid (nirmatrelvir/ritonavir)?

Paxlovid Contraindications

Absolute Contraindications

Paxlovid is absolutely contraindicated in patients with clinically significant hypersensitivity reactions (toxic epidermal necrolysis or Stevens-Johnson syndrome) to nirmatrelvir or ritonavir, severe hepatic impairment (Child-Pugh Class C), and when co-administered with specific medications that pose serious safety risks. 1

Patient-Specific Contraindications

• Severe hepatic impairment (Child-Pugh Class C) is an absolute contraindication, as no pharmacokinetic or safety data exist for this population 2, 1
• Clinically significant hypersensitivity to nirmatrelvir, ritonavir, or any product components (including history of TEN or Stevens-Johnson syndrome) 1

Drug-Drug Interaction Contraindications

The following medications are absolutely contraindicated due to life-threatening risks when combined with Paxlovid's potent CYP3A inhibition:

Cardiovascular Agents

• Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine (risk of life-threatening cardiac arrhythmias) 3, 1
• Antianginal agents: ranolazine 1
• Cardiovascular agents: eplerenone, ivabradine 1
• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine (risk of acute ergot toxicity) 3, 1
• Mineralocorticoid receptor antagonists: finerenone 1

Lipid-Lowering Agents

• HMG-CoA reductase inhibitors: lovastatin, simvastatin (risk of rhabdomyolysis and serious adverse events; these can be temporarily discontinued during Paxlovid treatment) 3, 1

Psychotropic Medications

• Sedative/hypnotics: triazolam, oral midazolam (risk of excessive sedation and respiratory depression) 3, 1
• Antipsychotics: lurasidone, pimozide, quetiapine (markedly increased plasma concentrations) 3, 1
• Serotonin receptor agents: flibanserin 1

Urogenital Agents

• Alpha-1 adrenoreceptor antagonists: alfuzosin 1
• Benign prostatic hyperplasia agents: silodosin 1
• PDE5 inhibitors: sildenafil (Revatio) when used for pulmonary arterial hypertension (risk of excessive vasodilation) 3, 1
• Opioid antagonists: naloxegol 1

Migraine Medications

• Migraine agents: eletriptan, ubrogepant 1

Other Agents

• Anti-gout: colchicine in patients with renal and/or hepatic impairment 1
• Immunosuppressants: voclosporin 1
• Microsomal triglyceride transfer protein inhibitors: lomitapide 1
• Vasopressin receptor antagonists: tolvaptan 1

Strong CYP3A Inducers (Loss of Efficacy)

Paxlovid cannot be co-administered with strong CYP3A inducers, as these significantly reduce nirmatrelvir/ritonavir concentrations, leading to loss of virologic response and potential resistance. 1

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

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

Relative Contraindications and Special Precautions

Renal Impairment

• Severe renal impairment (eGFR <30 mL/min) including hemodialysis is a relative contraindication requiring modified dosing (300 mg nirmatrelvir/100 mg ritonavir on day 1, then 150 mg/100 mg once daily on days 2-5) 1
• Paxlovid was contraindicated in 2.1% of patients due to severe renal impairment in real-world practice 4
• Moderate renal impairment (eGFR 30-59 mL/min) requires dose reduction to 150 mg nirmatrelvir/100 mg ritonavir twice daily 5, 2, 1

Hepatic Impairment

• Moderate hepatic impairment (Child-Pugh Class B): No dose adjustment needed, but use with caution as trials excluded severe liver impairment 5, 1
• Mild hepatic impairment (Child-Pugh Class A): No dose adjustment needed 1

Antiretroviral Therapy Considerations

• Ritonavir- or cobicistat-boosted regimens: Contraindicated or require careful management due to additive CYP3A inhibition 2
• NNRTIs (efavirenz, etravirine, nevirapine): Contraindicated as they induce CYP3A and reduce Paxlovid efficacy 2
• Preferred HIV regimen: Integrase inhibitors without boosters during Paxlovid therapy 2

Hepatitis Treatment Interactions

• Protease inhibitor-containing DAA regimens for hepatitis C with lopinavir-ritonavir: Contraindicated 2
• Tenofovir disoproxil fumarate or tenofovir alafenamide for HBV with lopinavir-ritonavir: Relatively contraindicated 2

Critical Clinical Considerations

• Always use the Liverpool COVID-19 Drug Interaction Tool before prescribing Paxlovid, as the contraindicated drug list is not comprehensive 5, 2, 1
• Ritonavir's CYP3A4 inhibition persists for several days after treatment completion, extending the period of potential drug interactions beyond the 5-day treatment course 2
• In real-world practice, 87.1% of patients required pharmacist interventions to prevent drug-related problems, with DDIs being the most common issue (57.1% of cases) 4
• Severe drug interactions occurred in 17% of patients in observational studies, highlighting the critical importance of interaction screening 4