Ritonavir-boosted nirmatrelvir
- Combination of oral protease inhibitors
- Preferred option for СΟVΙD-19-specific therapy for symptomatic outpatients with risk for progression to severe disease
- Substantially reduces the risk of hospitalization and mortality in some high-risk outpatients who have mild to moderate СOVID-19 (i.e., no hypoxia).
Indications
- Confirmed COVID-19 (at home or in-clinic test).
- Patients who are at highest risk for progressing to severe disease.
- Initiated within 5 days of symptom onset.
Particularly recommended for those who:
- Are 65 years or older, or
- Are immunocompromised, or
- Have multiple medical comorbidities.
Dosing
Adult Dosing
- eGFR ≥ 60 mL/min: 300 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
- eGFR ≥ 60 mL/min: 150 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
- eGFR < 30 mL/min: Not recommended.
Pediatric Dosing
Children ≥ 12 years old, weighing ≥40 kg:
- eGFR ≥ 60 mL/min: 300 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
- eGFR ≥ 60 mL/min: 150 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
- eGFR < 30 mL/min: Not recommended.
Drug Interactions
Nirmatrelvir-ritonavir:
- An inhibitor of metabolic enzymes and transporters such as the CYP3A enzyme (predominantly because of the ritonavir component), and
- A substrate of CYP3A [1].
Prior to prescribing, review the patient's medications' list and assess specific drug interactions and potential ways to mitigate them. For example:
- Drug interactions program included with UpToDate
- Drug interaction checker from the University of Liverpool
Adverse Reactions
- 1% to 10%: Gastrointestinal: Diarrhea (3%), dysgeusia (5%)
Postmarketing:
- Cardiovascular: Bradycardia, hypertension, syncope
- Dermatologic: Pruritus, severe dermatological reaction (including Stevens-Johnson syndrome and toxic epidermal necrolysis), skin rash
- Gastrointestinal: Abdominal pain, nausea, pancreatitis, vomiting
- Hypersensitivity: Anaphylaxis, hypersensitivity reaction
- Nervous system: Headache, malaise
- Respiratory: Dyspnea
Rebound
- Viral rebound with or without mild recurrent symptoms occurs in a minority of patients following initial improvement with nirmatrelvir-ritonavir.
- Viral rebound warrants extension of the isolation period.
- Advise patients of this possibility, but, for patients at risk for progression to severe disease, the potential benefits of treatment greatly outweigh any potential inconvenience from rebound.
Special Populations
Pregnancy Rating
- US FDA pregnancy category: Not assigned.
- Nirmatrelvir-ritonavir should not be used during pregnancy unless the benefit outweighs the risk to the fetus.
Lactation risk
- Information related to COVID-19 and breastfeeding is available from the World Health Organization
Renal Dosing
Addressed above in "Dosing" section.
Hepatic Dosing
- Adult:
- Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
- Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
- Pediatric (≥12 years old, weighing ≥40 kg):
- Mild or moderate impairment: No dosage adjustment necessary.
- Severe impairment: Not recommended for use (has not been studied).
Contraindications
- Allergy to class/drug
- Many drug interactions
- E.g. Plavix, Phenytoin, Tacrolimus, Tramadol, Statins, Hydro/oxycodone/Codeine, Diazepam/Clonazepam/Alprazolam, Fentanyl, Tamsulosin
Pharmacology
- Metabolism: Νirmatrelvir (when given with ritonavir): Minimal; Ritonavir: Hepatic via CYP3A4 (major) and CYP2D6 (minor).
- Time to peak: Νirmаtrelvir (when given with ritonavir): 3 hours; Ritonavir: 3.98 hours.
- Half-life: Νirmаtrelvir (when given with ritonavir): 6.05 hours; Ritonavir: 6.15 hours.
- Excretion: Nirmаtrelvir (when given with ritonavir): Feces (27.5%); urine (55%); Ritonavir: Feces (86.4%); urine (3.5%).
Mechanism of Action
- Nirmаtrelvir blocks the activity of the ЅΑRS-CoV-2-3CL protease, an enzyme required for viral replication.
- Co-administration of nirmаtrelvir with ritonavir slows the metabolism of ոirmatrelvir so it remains active in the body for longer and at higher concentrations.
Comments
- 89% reduction in hospitalization or death in high risk population, and 70% reduction in hospitalizations with no deaths in standard risk population.
See Also
References
- Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions (https://pubmed.ncbi.nlm.nih.gov/35226530/)
- UpToDate: Nirmatrelvir and ritonavir: Drug information (https://www.uptodate.com/contents/nirmatrelvir-and-ritonavir-drug-information)
- UpToDate: COVID-19: Management of adults with acute illness in the outpatient setting (https://www.uptodate.com/contents/covid-19-management-of-adults-with-acute-illness-in-the-outpatient-setting)