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

Contraindications for Paxlovid (Nirmatrelvir/Ritonavir)

Paxlovid is absolutely contraindicated in patients with clinically significant hypersensitivity to nirmatrelvir or ritonavir, severe hepatic impairment (Child-Pugh Class C), and when co-administered with drugs primarily metabolized by CYP3A where elevated concentrations cause serious/life-threatening reactions or with strong CYP3A inducers that would compromise antiviral efficacy. 1, 2

Absolute Contraindications

Patient-Specific Factors

• Severe hepatic impairment (Child-Pugh Class C) is an absolute contraindication due to unpredictable drug metabolism and accumulation 2, 1
• History of clinically significant hypersensitivity reactions including toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome to nirmatrelvir, ritonavir, or any product component 1

Drug-Drug Interactions: Contraindicated Medications

Because ritonavir is a potent CYP3A4 inhibitor, the following drug classes are absolutely contraindicated due to risk of serious/life-threatening adverse events from elevated plasma concentrations 1:

Cardiovascular Agents

• Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine 1
• Antianginal: ranolazine 1
• Alpha-1 blockers: alfuzosin, silodosin 1
• Cardiovascular agents: eplerenone, ivabradine, finerenone 1
• PDE5 inhibitor: sildenafil when used for pulmonary arterial hypertension (Revatio®) 1

Lipid-Lowering Agents

• HMG-CoA reductase inhibitors: lovastatin, simvastatin (these can be temporarily discontinued during the 5-day Paxlovid course) 1
• Microsomal triglyceride transfer protein inhibitor: lomitapide 1

Central Nervous System Agents

• Antipsychotics: lurasidone, pimozide 1
• Sedative/hypnotics: triazolam, oral midazolam 1
• Serotonin agents: flibanserin 1

Migraine Medications

• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine 1
• Triptans and CGRP antagonists: eletriptan, ubrogepant 1

Other Agents

• Anti-gout: colchicine (in patients with renal and/or hepatic impairment) 1
• Immunosuppressants: voclosporin 1
• Opioid antagonists: naloxegol 1
• Vasopressin receptor antagonists: tolvaptan 1

Strong CYP3A Inducers (Contraindicated)

These medications significantly reduce nirmatrelvir/ritonavir plasma concentrations, risking loss of virologic response and potential resistance 1:

• Anticonvulsants: carbamazepine, phenobarbital, primidone, phenytoin 1, 3
• Antimycobacterials: rifampin, rifapentine 1
• Anticancer drugs: apalutamide, enzalutamide 1
• Cystic fibrosis drugs: lumacaftor/ivacaftor 1
• Herbal products: St. John's Wort (hypericum perforatum) 1, 4

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

Dose Adjustments Required (Not Contraindications, But Essential)

Renal Impairment

• Moderate renal impairment (eGFR 30-59 mL/min): Reduce dose to 150 mg nirmatrelvir/100 mg ritonavir every 12 hours for 5 days 2, 5
• Severe renal impairment (eGFR <30 mL/min): Use with extreme caution; limited data available 2, 5
• eGFR <30 mL/min/1.73 m²: Some guidelines recommend avoiding use 6

Hepatic Impairment

• Mild to moderate hepatic impairment (Child-Pugh Class A or B): No dose adjustment needed 2
• Severe hepatic impairment (Child-Pugh Class C): Contraindicated 2, 1

High-Risk Drug Interactions Requiring Management

Immunosuppressants

• Tacrolimus: Should be discontinued or given as a microdose on day 1 of Paxlovid due to drastic CYP3A inhibition 7
• Cyclosporine: Reduce dosage to 20% of initial dose during antiviral treatment 7
• mTOR inhibitors: Require dosage adjustment 7

Antiretroviral Therapy

• Ritonavir- or cobicistat-boosted regimens: Contraindicated or require careful management due to additive CYP3A inhibition 8
• NNRTIs (efavirenz, etravirine, nevirapine): Contraindicated as they induce CYP3A and reduce Paxlovid efficacy 8
• Integrase inhibitors without boosters: Preferred HIV regimen during Paxlovid therapy 8

Hepatitis C DAAs

• Protease inhibitor-containing DAA regimens: Contraindicated with ritonavir-containing regimens 2
• Tenofovir-based regimens: Relatively contraindicated when combined with lopinavir-ritonavir due to increased tenofovir exposure and renal toxicity risk 8, 2

Practical Considerations

Timing

• Must be initiated within 5 days of symptom onset for maximum effectiveness 2
• CYP3A4 inhibition persists for several days after completing the 5-day course, extending the period of potential drug interactions 2

Drug Interaction Checking

• Use the Liverpool COVID-19 drug interaction tool (www.hep-druginteractions.org) before prescribing to identify all potential interactions 2, 9
• The FDA label provides guidance but is not comprehensive; consult specialized resources 1

Alternative Therapy

• Remdesivir should be considered for patients with contraindications to Paxlovid, especially those with significant drug-drug interactions or severe hepatic impairment 2, 6

Special Populations

• Women of childbearing age: Ethinylestradiol-containing contraception is contraindicated with some DAAs but specific guidance for Paxlovid alone is limited; progestogen-only contraception is safer 8
• Patients on anticoagulants: Warfarin, dabigatran, and other anticoagulants require careful monitoring due to potential interactions 8