PAXLOVID

Paxlovid Generic Name & Formulations

Legal Class

General Description

Nirmatrelvir 150mg, co-packaged with ritonavir 100mg; tabs.

Pharmacological Class

SARS-CoV-2 main protease inhibitor + HIV-1 protease inhibitor/CYP3A inhibitor.

How Supplied

Blister packs—30 (150mg × 20 tabs + 100mg × 10 tabs); 20 (150mg × 10 tabs + 100mg × 10 tabs)

Manufacturer

Pfizer Inc.

Generic Availability

Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (M^pro), also referred to as 3C-like protease (3CL^pro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 M^pro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC₅₀ value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 M^pro active site by X-ray crystallography.

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 M^pro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

Paxlovid Indications

Indications

Mild to moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

Limitations of Use

Not for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19.

Paxlovid Dosage and Administration

Adult

Swallow whole. 300mg nirmatrelvir (2 × 150mg tabs) with 100mg ritonavir (1 × 100mg tab) twice daily for 5 days. Initiate 5-day treatment course as soon as possible after a diagnosis of COVID-19, and within 5 days of symptom onset. Moderate renal impairment (eGFR 30–<60mL/min): 150mg nirmatrevir with 100mg ritonavir twice daily for 5 days.

Children

Not established.

Paxlovid Contraindications

Contraindications

Concomitant alfuzosin HCl, ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, colchicine (in renal and/or hepatic impairment), lurasidone, pimozide, silodosin, eplerenone, ivabradine, ergots, lovastatin, simvastatin, voclosporin, lomitapide, eletriptan (within at least 72hrs of Paxlovid), ubrogepant, finerenone, naloxegol, sildenafil (as Revatio for PAH), oral midazolam, triazolam, flibanserin, tolvaptan, apalutamide, carbamazepine, phenobarbital, primidone, phenytoin, rifampin, rifapentine, lumacaftor/ivacaftor, St. John's Wort.

Paxlovid Boxed Warnings

Boxed Warning

Significant drug interactions with Paxlovid.

Paxlovid Warnings/Precautions

Warnings/Precautions

Potentially life-threatening drug-drug interactions (see Contraindications). Review all medications to assess potential drug-drug interactions and determine whether dose adjustment, interruption, and/or additional monitoring is required. Discontinue immediately and initiate appropriate medications and/or supportive care if signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur. Pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Severe renal (eGFR) <30mL/min), ESRD (eGFR <15mL/min), or severe hepatic (Child-Pugh Class C) impairment: not recommended. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception. Pregnancy. Nursing mothers.

Paxlovid Pharmacokinetics

Absorption

Median time to maximum concentration: 3 hours for nirmatrelvir; 3.98 hours for ritonavir.

Distribution

% bound to human plasma proteins: 69% for nirmatrelvir; 98–99% for ritonavir.
Mean apparent volume of distribution: 104.7 L for nirmatrelvir; 112.4 L for ritonavir.

Metabolism

Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal. Ritonair is metabolized primarily by CYP3A (minor CYP2D6).

Elimination

Nirmatrelvir: Renal (49.6%), fecal (35.3%). Ritonavir: Renal (11.3%), fecal (86.4%).
Mean half-life: 6.05 hours for nirmatrelvir; 6.15 hours for ritonavir.
Mean apparent clearance: 8.99 L/hr for nirmatrelvir; 13.92 L/hr for ritonavir.

Paxlovid Interactions

Interactions

See Contraindications. See full labeling. Potentiates tamsulosin, aliskiren, ticagrelor, vorapaxar, glecaprevir/pibrentasvir, calcineurin inhibitors (eg, cyclosporine, tacrolimus), mTOR inhibitors (eg, everolimus, sirolimus), salmeterol, rimegepant, suvorexant, tadalafil (as Adcirca), avanafil; avoid. Potentiates anticancer agents (eg, abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine), antifungals (eg, ketoconazole, isavuconazonium sulfate, itraconazole), antipsychotics (eg, quetiapine, clozapine), clarithromycin, erythromycin, rifabutin, bedaquiline; avoid or reduce doses (see full labeling). Potentiates disopyramide, lidocaine, digoxin, anti-HIV protease inhibitors (eg, atazanavir, darunavir, tipranavir), anti-HIV (eg, efavirenz, maraviroc, nevirapine, bictegravir, tenofovir), elbasvir/grazoprevir, ombitasvir/paritaprevir/ ritonavir and dasabuvir, sofosbuvir/velpatasvir/voxilaprevir, glucocorticoids (eg, dexamethasone, betamethasone, fluticasone, budesonide, ciclesonide, methyprednisolone, mometasone, triamcinolone; consider alternatives), narcotic analgesics (eg, fentanyl, hydrocodone, oxycodone, meperidine); monitor. Potentiates trazodone, clonazepam (monitor), cilostazol, CCBs (eg, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil), cystic fibrosis transmembrane conductance regulator potentiators (eg, ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor), saxagliptin, JAK inhibitors (eg, tofacitinib, upadacitinib), darifenacin (max 7.5mg/day), neuropsychiatric agents (eg, aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin), riociguat, sildenafil, tadalafil, vardenafil, sedative/hypnotics (eg, buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem, parenteral midazolam); may need dose reductions. Increased bleeding risk with rivaroxaban (avoid), dabigatran, apixaban; see full product labeling. Consider temporarily stopping atorvastatin and rosuvastatin during Paxlovid treatment. Antagonizes voriconazole, clopidogrel; avoid. Antagonizes oral contraceptives (eg, ethinyl estradiol); consider additional non-hormonal contraception during 5-day treatment course and until 1 menstrual cycle after stopping Paxlovid. Discontinue bosentan at least 36hrs prior to initiating Paxlovid. Monitor methadone, warfarin.

Paxlovid Adverse Reactions

Adverse Reactions

Dysgeusia, diarrhea.

Paxlovid Clinical Trials

See Literature

Paxlovid Note

Not Applicable

Paxlovid Patient Counseling