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 |