Paxlovid, Nirmatrelvir + Ritonavir

by Michael S. Saag, M.D. last updated 2022-06-02 19:51:48.948278-04:00 © Antimicrobial Therapy, Inc.
Paxlovid, Nirmatrelvir + Ritonavir

Usage and Dosing

  • Nirmatrelvir tablets and ritonavir tablets (Paxlovid, co-packaged) are for the treatment of mild-to-moderate COVID-19 disease in adults and pediatric patients (≥12 years, weight ≥40 kg) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.  
  • High risk includes those with one of the following:
    • diabetes
    • overweight (BMI >25)
    • chronic lung disease (including asthma)
    • chronic kidney disease
    • current smoker
    • immunosuppressive disease or immunosuppressive treatment
    • cardiovascular disease
    • hypertension
    • sickle cell disease
    • neurodevelopmental disorders
    • active cancer
    • medically-related technological dependence
    • age ≥ 65 yrs regardless of co-morbidities
  • Best if given within 2 - 3 days of onset of symptoms.  Not very effective when given > 5 days after onset of symptoms.  Patients should be advised to test for SARS-CoV-2 as soon as possible after onset of symptoms and notify their provider ASAP after symptoms develop.
  • Clinical trials demonstrated a 5.6-fold reduction in COVID-19 related hospitalization or death (any cause). US FDA EUA on 22 Dec 2021.
  • Nirmatrelvir is a protease inhibitor, targeting 3CLpro of SARS-CoV-2. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, boosting its plasma concentrations. It is not active against 3CLpro.
  • Caution: numerous drug interactions (see Major Drug Interactions chart below, not all-inclusive).  CHECK FOR DRUG-DRUG INTERACTIONS BEFORE PRESCRIBING
  • No dosage adjustment required if co-administered with other products containing ritonavir or cobicistat.

Adult Dose

  • Nirmatrelvir 300 mg twice daily + ritonavir 100 mg twice daily (taken together, with or without food) for five days.
  • Initiate treatment as soon as possible after COVID-19 diagnosis, and within five days of symptom onset.

Pediatric Dose

  • Age ≥12 years of age, weighing ≥40 kg: use adult dose.

Renal Adjustment

eGFR (mL/min) Recommended dosage
 ≥60 Nirmatrelvir 300 mg bid + ritonavir 100 mg bid (both x5 days)
≥30 to <60 Nirmatrelvir 150 mg bid + ritonavir 100 mg bid (both x5 days)
<30 Not recommended (no data)
  • Source: EUA fact sheet

Hepatic Adjustment

  • No dosage adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
  • No data regarding use in severe hepatic impairment (Child-Pugh Class C), therefore not recommended.

Adverse Effects

  • Dysgeusia
  • Diarrhea
  • Hypertension
  • Myalgia
  • Hepatic transaminase elevations, clinical hepatitis, jaundice


  Nirmatrelvir Ritonavir
Class  Protease inhibitor Boosting agent
PK/PD Index  No data No data
 150 mg tablets  100 mg tablets
Usual Adult Dose 300 mg bid 100 mg bid
Pregnancy Risk Summary
 No human data. Evidence of embryo-fetal toxicity in animals.  No evidence of toxicity in humans or animals.
Food Effect1  Take with or without food   Take with or without food
Absorption2 (%)
 No data No data
Tmax (hr)  3 3.98
Peak Serum Level3
 2.21 (SD) No data
Protein Binding (%)  69  98-99
Average Serum
Half-life4 (hr)
 6.05 6.15
Elimination  Renal Metabolized mainly by 3A4, metabolites eliminated in feces
Biliary Penetration5 (%)   No data  No data 
Penetration6 (%)
  No data   No data
Therapeutic Levels in CSF7   No data  No data 
Volume of Distribution8
 104.7 (Vz/F)  112.4 (Vz/F)
23.01 (AUC0-inf)  No data
CYP450, Transporter

Substrate for 3A4, PGP

Inhibits 3A4, PGP

Substrate for 3A4, 2D6, PGP

Inhibits 2D6, 3A4, PGP

May induce long-term: 1A2, 2B6, 2C9, 2C19, 3A4, PGP, UGT1A1

  • Notes:
    • 1 Adult preparations unless otherwise noted.
    • 2 Absorption under optimal conditions.
    • 3 Total drug; adjust for protein binding to determine free drug concentration.
      • SD = after single dose
      • SS = steady state after multiple doses
    • 4 Assumes CrCl > 80 mL/min
    • 5 Peak concentration in bile/peak concentration in serum x 100
    • 6 CSF levels with inflammation
    • 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
    • 8 Volume of Distribution (Vd):
      • V/F = Vd/oral bioavailability
      • Vss = Vd at steady state
      • Vss/F = Vd at steady state/oral bioavailability
    • 9 Area under the plasma concentration versus time curve

Major Drug Interactions

Drug Effect on concentration (or other) Suggested management
Abemaciclib ↑ abemaciclib  Avoid co-administration 
Alfuzosin ↑ alfuzosin Contraindicated
Amiodarone  ↑ amiodarone Contraindicated
Apalutamide  ↓ nirmatrelvir or ↓ ritonavir Contraindicated
Atorvastatin ↑ atorvastatin  Avoid co-administration 
Bedaquiline ↑ bedaquiline Monitor, seek further info
Bictegravir/FTC/TAF ↑ bictegravir, ↑ tenofovir Monitor, seek further info
Bosentan ↑ bosentan Avoid co-administration
Bupropion ↓ bupropion, ↓ hydroxybupropion Monitor
Calcium channel blockers ↑ calcium channel blocker Monitor, adjust dosage
Carbamazepine  ↓ nirmatrelvir/ritonavir, ↑ carbamazepine Contraindicated
Ceritinib ↑ ceritinib  Avoid co-administration 
Clarithromycin ↑ clarithromycin Monitor, adjust dosage
Clozapine ↑ clozapine Contraindicated
Colchicine ↑ colchicine Contraindicated
Corticosteroids ↑ corticosteroid  Avoid co-administration 
Cyclosporine ↑ cyclosporine Monitor
Dasatinib ↑ dasatinib  Avoid co-administration 
Didanosine ↑ didanosine Monitor, seek further info
Digoxin ↑ digoxin Monitor, adjust dosage
Dihydroergotamine ↑ dihydroergotamine Contraindicated
Dronedarone ↑ dronedarone Contraindicated
Efavirenz ↑ efavirenz Monitor, seek further info
Elbasvir/Grazoprevir ↑ antiviral Monitor, seek further info
Encorafenib ↑ encorafenib Avoid co-administration
Ergotamine ↑ ergotamine Contraindicated
Erythromycin ↑ erythromycin Monitor, adjust dosage
Ethinyl estradiol ↓ ethinyl estradiol Use non-hormonal contraception
Fentanyl ↑ fentanyl Monitor, adjust dosage
Flecainide ↑ flecainide Contraindicated
Glecaprevir/Pibrentasvir ↑ antiviral Avoid co-administration
Ibrutinib ↑ ibrutinib Avoid co-administration
Isavuconazole ↓ nirmatrelvir/ritonavir, ↑ isavuconazole Avoid co-administration
Itraconazole ↓ nirmatrelvir/ritonavir, ↑ itraconazole Avoid co-administration
Ivosedenib ↑ ivosedenib Avoid co-administration
Ketoconazole ↓ nirmatrelvir/ritonavir, ↑ ketoconazole Avoid co-administration
Lovastatin ↑ lovastatin Contraindicated
Lurasidone ↑ lurasidone Contraindicated
Maraviroc ↑ maraviroc Monitor, seek further info
Meperidine  ↑ meperidine Contraindicated
Methadone ↓ methadone Monitor, adjust dosage
Methylergonovine ↑ methylergonovine Contraindicated
Midazolam (oral) ↑ midazolam Contraindicated
Midazolam (parenteral) ↑ midazolam Monitor, adjust dosage
Neratinib ↑ neratinib Avoid co-administration 
Nilotinib ↑ nilotinib Avoid co-administration  
Ombitasvir/Paritaprevir/RTV/Dasabuvir ↑ antiviral Monitor, seek further info
Phenobarbital  ↓ nirmatrelvir/ritonavir, ↓ phenobarbital Contraindicated
Phenytoin  ↓ nirmatrelvir/ritonavir, ↓ phenytoin Contraindicated
Pimozide ↑ pimozide Contraindicated
Piroxicam  ↑ piroxicam Contraindicated
Propafenone ↑ propafenone Contraindicated
Propoxyphene ↑ propoxyphene Contraindicated
Quetiapine ↑ quetiapine Monitor, adjust dosage
Quinidine ↑ quinidine Contraindicated
Raltegravir ↑ raltegravir Monitor, seek further info
Ranolazine ↑ ranolazine Contraindicated
Rifabutin ↑ rifabutin Monitor, seek further info
Rifampin  ↓ nirmatrelvir or ↓ ritonavir Contraindicated
Rivaroxaban ↑ rivaroxaban Avoid co-administration
Rosuvastatin ↑ rosuvastatin Avoid co-administration
Salmeterol ↑ salmeterol Avoid co-administration
Sildenafil (for PAH) ↑ sildenafil Contraindicated
Simvastatin ↑ simvastatin Contraindicated
Sirolimus ↑ sirolimus Avoid co-administration
Sofosbuvir/Velpatasvir/Voxilaprevir ↑ antiviral Monitor, seek further info
St John's wort  ↓ nirmatrelvir/ritonavir Contraindicated
Tacrolimus ↑ tacrolimus Monitor
Trazodone ↑ trazodone Monitor, adjust dosage
Triazolam ↑ triazolam Contraindicated 
Venetoclax ↑ venetoclax Avoid co-administration
Vinblastine  ↑ vinblastine Avoid co-administration  
Vincristine  ↑ vincristine Avoid co-administration 
Voriconazole ↓ nirmatrelvir/ritonavir, ↓ voriconazole Avoid co-administration  
Warfarin ↑↓ warfarin Monitor INR, adjust dosage
Zidovudine ↓ zidovudine Monitor, seek further info