Introduction
Paxlovid (nirmatrelvir co-packaged with ritonavir) is an oral antiviral medication developed by Pfizer for the treatment of COVID-19. It received Emergency Use Authorization (EUA) from the FDA in December 2021 for the treatment of mild-to-moderate COVID-19 in high-risk patients. This combination therapy represents a significant advancement in the outpatient management of SARS-CoV-2 infection.
Mechanism of Action
Paxlovid consists of two components: nirmatrelvir and ritonavir. Nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor that blocks viral replication by inhibiting the cleavage of polyprotein precursors into functional proteins required for viral replication. Ritonavir, a known CYP3A4 inhibitor, does not have antiviral activity against SARS-CoV-2 but serves as a pharmacokinetic enhancer by inhibiting the metabolism of nirmatrelvir, thereby increasing its plasma concentrations and therapeutic efficacy.
Indications
Paxlovid is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
Dosage and Administration
The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally twice daily for 5 days. Treatment should be initiated as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. The tablets should be swallowed whole and can be taken with or without food. Dosage adjustment is required in patients with moderate renal impairment (eGFR 30-60 mL/min): 150 mg nirmatrelvir with 100 mg ritonavir twice daily. Not recommended in severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment (Child-Pugh Class C).
Pharmacokinetics
Absorption: Nirmatrelvir reaches peak plasma concentrations within 3 hours. Co-administration with ritonavir significantly increases nirmatrelvir exposure. Distribution: Both components are highly protein-bound (>90%). Metabolism: Nirmatrelvir is primarily metabolized by CYP3A4, while ritonavir is metabolized by CYP3A4 and CYP2D6. Elimination: The elimination half-life of nirmatrelvir is approximately 6 hours when co-administered with ritonavir. Both drugs are primarily eliminated via feces.Contraindications
Paxlovid is contraindicated in patients with known hypersensitivity to nirmatrelvir, ritonavir, or any of its components. It is also contraindicated with drugs highly dependent on CYP3A4 for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions, including:
- Alpha1-adrenoreceptor antagonist: alfuzosin
- Analgesics: pethidine, propoxyphene
- Antianginal: ranolazine
- Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine
- Antipsychotics: lurasidone, pimozide, clozapine
- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: lovastatin, simvastatin
- PDE5 inhibitors: sildenafil (for pulmonary arterial hypertension)
- Sedative/hypnotics: triazolam, oral midazolam
Warnings and Precautions
Risk of serious adverse reactions due to drug interactions: The ritonavir component may cause significant drug interactions. Hepatotoxicity: Hepatic transaminase elevations have been observed. Monitor patients with pre-existing liver disease. HIV-1 resistance: Use in individuals with uncontrolled or undiagnosed HIV-1 infection may lead to HIV-1 resistance. Pregnancy and lactation: Use only if potential benefit justifies potential risk. Hypersensitivity reactions: Including anaphylaxis and skin reactions have been reported.Drug Interactions
Paxlovid has significant drug interaction potential due to ritonavir's strong inhibition of CYP3A4. Clinically significant interactions include:
- Contraindicated medications (as listed above)
- Immunosuppressants: cyclosporine, tacrolimus, sirolimus (require therapeutic drug monitoring)
- Anticoagulants: rivaroxaban, apixaban (avoid coadministration)
- Anticonvulsants: carbamazepine, phenobarbital, phenytoin (may reduce nirmatrelvir levels)
- Antidepressants: trazodone (increased risk of adverse effects)
- Benzodiazepines: alprazolam (requires dose reduction)
- Corticosteroids: budesonide, fluticasone (increased systemic exposure)
- Digoxin: requires therapeutic monitoring
- Statin therapy: atorvastatin, rosuvastatin (consider temporary discontinuation)
A comprehensive medication review is essential prior to initiating therapy.
Adverse Effects
Common adverse reactions (≥1% incidence):- Dysgeusia (altered taste) - 6%
- Diarrhea - 3%
- Hypertension - 1%
- Myalgia - 1%
- Hepatotoxicity
- Hypersensitivity reactions
- Immune reconstitution syndrome in patients with undiagnosed HIV
Monitoring Parameters
- COVID-19 symptoms and clinical status
- Renal function (eGFR) prior to and during treatment if indicated
- Liver function tests in patients with pre-existing liver disease
- Signs and symptoms of hypersensitivity reactions
- Potential drug interactions and adverse effects
- Pregnancy testing if clinically indicated
Patient Education
- Take Paxlovid exactly as prescribed, completing the full 5-day course
- Report any new symptoms or side effects to healthcare provider
- Inform all healthcare providers about Paxlovid use due to interaction potential
- Continue isolation measures according to CDC guidelines while symptomatic
- Notify provider if symptoms worsen or don't improve after treatment
- Use reliable contraception during treatment if of reproductive potential
- Do not share medication with others
References
1. FDA Emergency Use Authorization Fact Sheet for Paxlovid (December 2021) 2. Hammond J, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408 3. Pfizer Inc. Paxlovid Prescribing Information (2022) 4. NIH COVID-19 Treatment Guidelines: Antiviral Therapy 5. Marzolini C, et al. Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications. Clin Pharmacol Ther. 2022;112(6):1191-1200