What are the contraindications to Paxlovid (nirmatrelvir/ritonavir) therapy?

Contraindications to Paxlovid (Nirmatrelvir/Ritonavir) Therapy

Paxlovid is contraindicated in patients with a history of clinically significant hypersensitivity reactions to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product, and in patients taking medications that have significant drug-drug interactions with ritonavir. 1

Major Contraindications

Hypersensitivity Reactions

• History of clinically significant hypersensitivity reactions (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome) to nirmatrelvir or ritonavir 1

Drug-Drug Interactions

Paxlovid is contraindicated with:

1. Drugs primarily metabolized by CYP3A where elevated concentrations can cause serious/life-threatening reactions: 1

   • Cardiovascular medications:

     • Alpha 1-adrenoreceptor antagonist: alfuzosin 1
     • Antianginal: ranolazine 1
     • Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine 1
     • Cardiovascular agents: eplerenone, ivabradine 1
     • Mineralocorticoid receptor antagonists: finerenone 1

   • Lipid-lowering medications:

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

   • Neuropsychiatric medications:

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

   • Other medications:

     • Anti-gout: colchicine (in patients with renal and/or hepatic impairment) 1
     • Benign prostatic hyperplasia agents: silodosin 1
     • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine 1
     • Immunosuppressants: voclosporin 1
     • Migraine medications: eletriptan, ubrogepant 1
     • Opioid antagonists: naloxegol 1
     • PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension 1
     • Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin 1
     • Vasopressin receptor antagonists: tolvaptan 1

2. Strong CYP3A inducers that may reduce nirmatrelvir/ritonavir concentrations: 1

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

Hepatic Impairment

• Severe hepatic impairment (Child-Pugh Class C) 2

Special Considerations

Renal Impairment

• Dose adjustment required for moderate renal impairment (eGFR 30-59 mL/min): 150 mg/100 mg orally every 12 hours for five days 2
• Limited data in severe renal impairment - use with caution 2

Hepatitis B/C Considerations

• Concomitant use of protease inhibitor-containing direct-acting antiviral (DAA) regimens for hepatitis C with lopinavir-ritonavir is contraindicated 2
• For patients on tenofovir disoproxil fumarate or tenofovir alafenamide for HBV, concomitant use with lopinavir-ritonavir is relatively contraindicated as drug concentration of tenofovir might be increased 2

Immunosuppressants

• Significant dose adjustments required for tacrolimus (discontinuation or microdose on day 1) and cyclosporine (reduce to 20% of initial dosage) when co-administered with nirmatrelvir/ritonavir 3

Clinical Pearls and Pitfalls

• Drug interaction management: The Liverpool COVID-19 drug interaction tool is recommended for checking potential interactions before prescribing Paxlovid 2

• Timing considerations: Paxlovid should be administered within 5 days of symptom onset for maximum effectiveness 2

• Age-related considerations: Patients older than 65 years may achieve higher plasma concentrations of nirmatrelvir and ritonavir, requiring closer monitoring for adverse effects 4

• Treatment duration impact: Even though Paxlovid is only a 5-day course, ritonavir's inhibition of CYP3A4 can persist for several days after treatment completion, extending the period of potential drug interactions 2, 5

• Medication reconciliation: A comprehensive review of all medications (including over-the-counter and herbal products) is essential before initiating Paxlovid therapy to identify potential interactions 5, 6

• Alternative options: For patients with contraindications to Paxlovid, remdesivir may be considered as an alternative, especially for those with significant drug-drug interactions 2

• Monitoring requirements: For patients on medications with potential interactions that cannot be temporarily discontinued, close monitoring for adverse effects is recommended if Paxlovid is administered 2, 5