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
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)