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
Pharmacology
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
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 |