Clinical Overview: Paxlovid for COVID-19

Nirmatrelvir and ritonavir (Paxlovid; Pfizer) is an investigational medication used to treat COVID-19 in adults and children [12 years of age and older weighing at least 88 pounds (40 kg)] with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.¹ In December 2021, the FDA issued an emergency use authorization (EUA) for Paxlovid in high-risk patients with COVID-19.¹

Earlier this week, Pfizer announced that it would stop enrollment in a trial for Paxlovid in standard-risk patients following the results of a study showing a statistically insignificant risk reduction in this patient population. The drug‘s EUA is for high-risk groups, for whom the drug has been effective in lowering hospitalizations and deaths.

Limitations of Authorized Use:

• Paxlovid is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19.¹
• Paxlovid is not authorized for pre- or post-exposure prophylaxis for the prevention of COVID-19.¹
• Paxlovid is not authorized for use longer than 5 consecutive days.¹

Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro; also known as 3C-like protease or nsp5 protease). Inhibition of Mpro subsequently results in inhibiting viral replication by preventing the processing of polyprotein precursors. Ritonavir is a pharmacokinetic enhancer with no activity against SARS-CoV-2 Mpro. Ritonavir inhibits CYP3A-mediated metabolism of nirmatrelvir, resulting in increased nirmatrelvir plasma concentrations.⁴

Dosing and Administration

Paxlovid consists of 2 oral antiviral drugs, nirmatrelvir and ritonavir, that must be taken together. It is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at an increased risk of progression to severe disease.³

The recommended dosage of Paxlovid is two 150 mg tablets of nirmatrelvir plus a 100 mg tablet of ritonavir taken together twice daily for 5 days. Treatment should start as soon as possible after a positive SARS-CoV-2 test and within 5 days of symptom onset. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course per the health care provider’s discretion.¹

No dosage adjustment is needed in patients with mild renal impairment (eGFR 60 to 90 mL/min). In patients with moderate renal impairment (eGFR 30 to 60 mL/min), the dosage of Paxlovid is 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days. Paxlovid is not recommended in patients with severe renal impairment (eGFR 30 mL/min) at this time.¹

Clinical Studies

EPIC-HR: There was a phase 2/3, randomized, double-blind, placebo-controlled study in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Subjects were randomized in a 1:1 ratio to receive Paxlovid or placebo orally every 12 hours for 5 days.

The researchers evaluated COVID-19-related hospitalization or death from any cause through day 28, viral load, and safety. The trial found that treatment of symptomatic COVID-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe COVID-19 that was 89% lower than the risk with placebo, without evident safety concerns.⁵

Contraindications

Paxlovid is contraindicated in patients with a history of clinically significant hypersensitivity reactions (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome) to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product. Paxlovid is also contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevate concentrations are associated with serious and/or life-threatening reactions.

Paxlovid is contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.¹

Warnings and Precautions

In May 2022, the CDC issued a Health Alert Network Health Advisory on the potential for COVID-19 recurrence. COVID-19 rebound has been reported to occur between 2 and 8 days after initial recovery and is characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. A brief return of symptoms may be part of the natural history of SARS-CoV-2 infection in some individuals, independent of treatment with Paxlovid and regardless of vaccination status.⁴

There are limited clinical data available for Paxlovid. Serious and unexpected adverse events may occur that have not been previously reported with Paxlovid use.¹

Drug Interactions

Paxlovid is an inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Co-administration of Paxlovid with drugs highly dependent on CYP3A for clearance for with elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring.¹

Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce Paxlovid’s therapeutic effect.¹

Use in Special Populations

Pregnancy: There are no data available on the use of nirmatrelvir in pregnant women to inform a drug-associated risk. Based on data available on ritonavir, use in pregnant women has not shown an increase in the risk of major birth defects.¹

Lactation: There are no data available on the presence of nirmatrelvir in human milk effects on the breastfed infant, or effects on milk production. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production.¹

Females and Males of Reproductive Potential: Regarding contraception, use of ritonavir may reduce the efficacy of combined hormonal contraceptives. It is advised for patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.¹

Pediatric Use: Paxlovid is not authorized for use in patients younger than 12 years of age or weighing less than 40 kg. The safety and efficacy of Paxlovid have not been established in pediatric patients.¹

Geriatric Use: There is no difference in safety or efficacy in geriatric patients compared to younger patients.¹

Renal Impairment: There are dosage adjustments needed in patients with mild renal impairment (eGFR 60 to 90 mL/min). In patients with moderate renal impairment (eGFR 30 to 60 mL/min), the dosage of Paxlovid is reduced to 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days. Paxlovid is not recommended in patients with severe renal impairment (eGFR 30 mL/min) at this time.¹

Hepatic Impairment: There are no dose adjustments needed for patients with mild-moderate hepatic impairment. There are no data available in patients with severe hepatic impairment, therefore Paxlovid is not recommended for use in these patients.¹

Adverse Events (AEs)

Dysgeusia, diarrhea, hypertension, and myalgia were the most common AEs. These AEs occurred in 1% of patients being treated with Paxlovid. The most common AE was dysgeusia.¹

Storage and Handling

Paxlovid should be stored at room temperature, between 68F and 77F.

About the Author

Theresa Ha Doan is a PharmD candidate at Duquesne University School of Pharmacy, anticipated to graduate in spring 2023, and completed this article while on an Advanced Pharmacy Practice Rotation at STACK. For more information about their APPE rotation program, please visit www.managewithstack.com.

References

1. FDA. Fact sheet for health care providers: Emergency Use Authorization for Paxlovid. April 14, 2022. Available at: https://www.fda.gov/media/155050/download. Accessed May 27, 2022.
2. FDA. Fact sheet for patients, parents, and caregivers: Emergency Use Authorization for Paxlovid. April 14, 2022. Available at: https://labeling.pfizer.com/ShowLabeling.aspx?id=16473. Accessed May 27, 2022.
3. Chaplin, Steve. Paxlovid: antiviral combination for the treatment of COVID-19. Prescriber Volume: 33 Issue 3-4 (2022). March/April 2022. https://wchh.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/psb.1979. Accessed May 27, 2022.
4. Nirmatrelvir and Ritonavir (Lexi-drugs). http://www.crlonline.com.authenticate.library.duq.edu/lco/action/doc/retrieve/docid/patch_f/7185660?cesid=27XVLVsc31H&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dpaxlovid%26t%3Dname%26acs%3Dtrue%26acq%3Dpaxlov#rfs. Accessed June 1, 2022.
5. Hammond, Jennifer, Ph.D. Oral Nirmatrelvir for High-Risk, Non-hospitalized Adults with COVID-19. https://www.nejm.org/doi/full/10.1056/NEJMoa2118542. Accessed June 3, 2022.