Nirmatrelvir Ritonavir

Nirmatrelvir with ritonavir is an oral fixed combination for early treatment of mild to moderate COVID-19 in adults and adolescents at high risk of progression. Nirmatrelvir inhibits the SARS-CoV-2 main protease; ritonavir has no antiviral effect against SARS-CoV-2 here but inhibits CYP3A4 to boost nirmatrelvir. The boosting causes many serious drug interactions, which are the main prescribing hazard.

Class. Protease inhibitor antiviral with pharmacokinetic booster.

Mechanism. Nirmatrelvir inhibits the viral 3CL main protease, preventing cleavage of viral polyproteins. Ritonavir is a strong CYP3A4 inhibitor that raises nirmatrelvir exposure.

Pharmacokinetics. Absorbed orally with ritonavir boosting; half life of nirmatrelvir about 6 hours; excreted mainly in urine (as nirmatrelvir) when boosted. Ritonavir inhibits CYP3A4 and P-glycoprotein.

Mild to moderate COVID-19, high risk of progression (adults and adolescents aged 12 years and over, 40 kg or more).

• Nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg orally twice daily for 5 days.
• Start within 5 days of symptom onset.
• Loading dose: none. Maximum: 600 mg of nirmatrelvir daily.

Dose adjustment for kidney function.

• eGFR 30 to 59 mL/min: no adjustment in recent labelling (earlier labels reduced the dose).
• eGFR under 30 mL/min: nirmatrelvir 150 mg with ritonavir 100 mg twice daily on day 1, then once daily on days 2 to 5; in haemodialysis, give after dialysis.

Hepatic adjustment. Not advised in Child-Pugh C; no adjustment in A or B.

Main alternatives. Remdesivir (3 days) when interactions preclude nirmatrelvir with ritonavir, or other antivirals where available.

Contraindications. Hypersensitivity, severe kidney disease where dosing cannot be adjusted, Child-Pugh C liver impairment, and co-prescription of drugs that depend on CYP3A4 for clearance with risk of life-threatening effects:

• amiodarone
• dronedarone
• flecainide
• propafenone
• quinidine
• ranolazine
• lovastatin
• simvastatin
• lurasidone
• pimozide
• ergot alkaloids
• oral midazolam
• triazolam
• sildenafil for pulmonary hypertension
• colchicine in kidney or liver impairment
• strong inducers (carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort)

Serious adverse effects. Anaphylaxis, severe skin reactions, hepatotoxicity, and the effects of raised levels of interacting drugs.

Common adverse effects. Taste disturbance (dysgeusia), diarrhoea, hypertension, myalgia and nausea.

Interactions.

• Anticoagulants: avoid rivaroxaban and apixaban at high dose; monitor warfarin INR.
• Atorvastatin and rosuvastatin: withhold during the 5 days and for 3 days after.
• Immunosuppressants (tacrolimus, ciclosporin, sirolimus): specialist-led dose reduction and levels.
• Combined oral contraceptives may be less effective; use additional contraception.

Common prescribing errors. No drug history, treating after 5 days of symptoms, not adjusting for kidney function, and missing rebound after the course.

Special groups.

• Pregnancy: use if benefit outweighs risk; limited data.
• Breastfeeding: acceptable.
• Children: from 12 years and 40 kg.
• Older adults: usual dose; high interaction burden.
• Kidney impairment: eGFR 30 to 59 mL/min usual dose; eGFR under 30: nirmatrelvir 150 mg with ritonavir 100 mg twice daily on day 1, then once daily on days 2 to 5.
• Liver impairment: avoid in Child-Pugh C.

Regional points. In people with undiagnosed or untreated HIV infection, ritonavir given alone for a short course carries a theoretical risk of protease inhibitor resistance; HIV status should be known where possible, and antiretroviral interactions need review in the many patients on treatment.

Formulations. Co-packaged tablets: nirmatrelvir 150 mg (two tablets) and ritonavir 100 mg (one tablet) in a single dose pack.

Administration. Swallow tablets whole with or without food, twice daily 12 hours apart.

Baseline. Full drug history and interaction check, eGFR, liver tests if disease, pregnancy test, HIV status where known.

Monitoring. Symptoms at 24 to 48 hours; INR in warfarin users; blood pressure; review for rebound after day 5.

Stopping thresholds. Stop for anaphylaxis, severe skin reaction or clinical hepatotoxicity.

Referral and escalation. Admission for hypoxia or deterioration; specialist review for transplant recipients and complex interaction cases.