Author: [AUTHOR] Published on 7/28/2023 5:00:00 AM

FDA Approves PAXLOVID (Nirmatrelvir tablets and Ritonavir tablets, Co-packaged for Oral Use) for the Treatment of Mild-to-Moderate COVID-19 in Adults

On May 25, 2023, the US Food and Drug Administration (FDA) approved the oral antiviral PAXLOVID (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. 

PAXLOVID manufactured and packaged under the emergency use authorization (EUA) and distributed by the U.S. Department of Health and Human Services will continue to be available to ensure continued access for adults, as well as treatment of eligible children ages 12-18 who are not covered by this approval. PAXLOVID is not approved or authorized for use as a pre-exposure or post-exposure prophylaxis for prevention of COVID-19.

PAXLOVID should be initiated as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect. 

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together orally twice daily for 5 days. For patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the recommended dose is 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both tablets taken orally twice daily for 5 days. PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min).

The following boxed warning (in bold) is included in the prescribing information to underscore the potential for significant drug-drug interactions:

• PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events.
• Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring.
• Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed.

Additional information regarding dosage and administration, contraindications related to drugs that are primarily metabolized by CYP3A and drugs that are strong CYP3A inducers, as well as warnings and precautions about risk of significant adverse reactions due to drug interactions, hypersensitivity reactions, hepatotoxicity, and the risk of developing HIV-1 resistance can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK) 
MOA: Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro: also referred to as 3CL^pro or nsp5 protease) inhibitor. Ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor.

General PK: The PK of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19.

The PK properties of nirmatrelvir/ritonavir are displayed in Table 1.

Table 1: PK Properties of Nirmatrelvir and Ritonavir in Healthy Subjects

	Nirmatrelvir (When Given With Ritonavir)	Ritonavir
Absorption
Tmax (hr), median	3.00a	3.98a
Food Effect	Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinf and Cmax for nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively.b
Distribution
% bound to human plasma proteins	69%	98-99%
Blood-to-plasma ratio	0.60	0.14d
Vz/F (L), mean	104.7c	112.4c
Elimination
Major route of elimination	Renal eliminationd	Hepatic metabolism
Half-life (T½) (hr), mean	6.05a	6.15a
Oral clearance (CL/F) (L/hr), mean	8.99c	13.92c
Metabolism
Metabolic pathways	Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal.	Major CYP3A, Minor CYP2D6
Excretion
% drug-related material in feces	35.3%e	86.4%f
% of dose excreted as total (unchanged drug) in feces	27.5%e	33.8%f
% drug-related material in urine	49.6%e	11.3%f
% of dose excreted as total (unchanged drug) in urine	55.0%e	3.5%f

Abbreviations: CL/F=apparent clearance; hr=hour; L/hr=liters per hour; T½=terminal elimination half-life; T_max=the time to reach C_max; V_z/F=apparent volume of distribution.
^a Represents data after a single dose of 300 mg nirmatrelvir (2 x 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.
^b Following a single oral dose of nirmatrelvir 300 mg boosted ritonavir 100 mg at -12 hours, 0 hours and 12 hours, administered under fed (high fat and high calorie meal) or fasted conditions.
^c 300 mg nirmatrelvir (oral suspension formulation) co-administered with 100 mg ritonavir (tablet formulation) twice daily for 3 days. 
^d Red blood cell to plasma ratio.
^e Determined by ¹⁹F-NMR analysis following 300 mg nirmatrelvir oral suspension administered at 0 hr enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.
^f Determined by ¹⁴C analysis following 600 mg ¹⁴C-ritonavir oral solution (6 times the approved ritonavir dose).

Effect of Food: No clinically significant differences in the PK of nirmatrelvir were observed following administration of a high fat meal (800-1000 calories; 50% fat) to healthy subjects.

Drug Interactions

Potential for PAXLOVID to Affect Other Drugs: PAXLOVID is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse events. Co-administration of PAXLOVID with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Drugs listed below are a guide and not considered a comprehensive list of all drugs that may be contraindicated with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor like PAXLOVID.

Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions: 

• Alpha 1-adrenoreceptor antagonist: alfuzosin
• Antianginal: ranolazine
• Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
• Anti-gout: colchicine (in patients with renal and/or hepatic impairment) 
• Antipsychotics: lurasidone, pimozide
• Benign prostatic hyperplasia agents: silodosin
• Cardiovascular agents: eplerenone, ivabradine
• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use)
• Immunosuppressants: voclosporin
• Microsomal triglyceride transfer protein inhibitor: lomitapide
• Migraine medications: eletriptan, ubrogepant
• Mineralocorticoid receptor antagonists: finerenone
• Opioid antagonists: naloxegol
• PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH)
• Sedative/hypnotics: triazolam, oral midazolam
• Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
• Vasopressin receptor antagonists: tolvaptan

Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring, which can be found in further detail in the full prescribing information linked below.

Potential for Other Drugs to Affect PAXLOVID: Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer:

• Anticancer drugs: apalutamide
• Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
• Antimycobacterials: rifampin, rifapentine
• Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
• Herbal products: St. John’s Wort (hypericum perforatum)

Additional information regarding managing drug interactions with PAXLOVID can be found in the prescribing information linked below.

Use in Specific Populations

There were no clinically significant differences in the PK of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity.

Pediatric patients: The PK of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.

Renal impairment: Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively, following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg.

Hepatic impairment: The PK of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the PK of nirmatrelvir or ritonavir has not been studied.

Females and Males of Reproductive Potential (Contraception): Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to consider using an additional non-hormonal method of contraception during the 5 days of PAXLOVID treatment and until one menstrual cycle after stopping PAXLOVID.

Efficacy and Safety

Efficacy of PAXLOVID was demonstrated in a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common adverse reactions (incidence ≥1% and greater incidence than in the placebo group) are dysgeusia and diarrhea.

Visit the PAXLOVID (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) full prescribing information page to learn more about Paxlovid

Visit the Drugs@FDA Database for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at drug development and drug interactions - table of substrates, inhibitors and inducers webpage.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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