Paxlovid, Nirmatrelvir + Ritonavir

by Michael S. Saag, M.D. last updated 2022-01-07 09:49:06.194795-05:00 © Antimicrobial Therapy, Inc.
Paxlovid, Nirmatrelvir + Ritonavir
Paxlovid
  • 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 ≥ 60 yrs regardless of comorbidities
  • 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.
  • 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.
  • Age ≥12 years of age, weighing ≥40 kg: use adult dose.
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
  • 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.
  • Dysgeusia
  • Diarrhea
  • Hypertension
  • Myalgia
  • Hepatic transaminase elevations, clinical hepatitis, jaundice
  Nirmatrelvir Ritonavir
Class  Protease inhibitor Boosting agent
PK/PD Index  No data No data
Pharmaceutical
Preparation		  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
Oral
Absorption2 (%)		  No data No data
Tmax (hr)  3 3.98
Peak Serum Level3
(μg/mL)		  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 
CSF/Blood
Penetration6 (%)		   No data   No data
Therapeutic Levels in CSF7   No data  No data 
Volume of Distribution8
(Vd)		  104.7 (Vz/F)  112.4 (Vz/F)
AUC9
(μg*hr/mL)		 23.01 (AUC0-inf)  No data
CYP450, Transporter
Interactions

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
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