Paxlovid nirmatrelvir

Nirmatrelvir is an oral protease inhibitor that is active against Mpro, a viral protease that plays an essential role in viral replication by cleaving the two viral polyproteins. It has demonstrated antiviral activity against all coronaviruses that are known to infect humans. Nirmatrelvir is packaged with ritonavir, a strong CYP3A4 inhibitor and pharmacokinetic boosting agent that has been used to boost HIV protease inhibitors. Coadministration of ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic range. The US Food and Drug Administration (FDA) issued an Emergency Use Authorization for ritonavir-boosted nirmatrelvir on December 22, 2021, for the treatment of COVID-19. The living COVID-19 Treatment Guidelines by the US National Institutes of Health (NIH) recommend using ritonavir-boosted nirmatrelvir orally twice daily for 5 days in nonhospitalized adults and children older than 12 years and weighing more than 88.18 lb (40 kg) with mild to moderate COVID-19 who are at high risk of disease progression. Treatment should be initiated as soon as possible and within 5 days of symptom onset. In addition, ritonavir-boosted nirmatrelvir may be used in patients who are hospitalized for a diagnosis other than COVID-19 (in other words, COVID-19 was an incidental diagnosis), who present with mild to moderate COVID-19, who are at risk of progressing to severe disease, and who are within 5 days of symptom onset.

Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily because of the ritonavir component of the combination. Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient's concomitant medications, including over-the-counter medications, herbal supplements, and recreational drugs, to evaluate potential drug-drug interactions. Several medications, including metformin, lisinopril, or hydrochlorothiazide, do not have clinically relevant interactions and are not contraindicated in patients with COVID-19. There is a comprehensive list of safe medications and those with clinically relevant drug-drug interactions with ritonavir-boosted nirmatrelvir that requires careful consideration and pharmacy monitoring. Information on drug adjustments, continuation of concomitant medications, and monitoring adverse events are found in the references.

The coadministration of ritonavir-boosted nirmatrelvir (Paxlovid®) and amiodarone is contraindicated in patients with mild to moderate COVID-19 because of the potential high risk of amiodarone toxic levels (choice D is correct). Amiodarone is metabolized by cytochrome P450 (CYP3A4), and concentrations may be increased because of the inhibition of CYP3A4 by ritonavir-boosted nirmatrelvir, thereby increasing the risk of arrhythmias or other serious adverse events. It is important to recognize that amiodarone has a long elimination half-life and the risk of drug-drug interactions may not be overcome even by stopping amiodarone administration; an alternative treatment for COVID-19 should be considered.

The evidence to support the use of ritonavir-boosted nirmatrelvir comes from the EPIC-HR trial that enrolled adults with mild to moderate COVID-19 who were not hospitalized and were not vaccinated and who were at high risk of progressing to severe disease. The trial results demonstrated that starting ritonavir-boosted nirmatrelvir within 5 days of symptom onset reduced the risk of hospitalization or death through day 28 by 89% compared with results with placebo. The efficacy is comparable with that of remdesivir (87% relative reduction) and greater than that reported for molnupiravir (31% relative risk reduction, Lagevrio). However, these agents have not been directly compared in clinical trials.

Dysgeusia, diarrhea, hypertension, and myalgia are common adverse effects of ritonavir-boosted nirmatrelvir. Rare cases of anaphylaxis and other hypersensitivity reactions have been reported. Investigators in observational studies and the EPIC-HR trial found that SARS-CoV-2 viral rebound and the recurrence of COVID-19 symptoms occurred in some patients who completed the treatment course of ritonavir-boosted nirmatrelvir. Viral rebound and recurrence of COVID-19 symptoms could also occur in the absence of ritonavir-boosted nirmatrelvir treatment. Viral mutations that lead to substantial resistance to nirmatrelvir have been described.