Nirmatrelvir co-administered with ritonavir (NMV/r), sold as Paxlovid by Pfizer, has shown a low reporting rate of drug-drug interactions (DDIs) in real-world clinical practice, according to a recent analysis of Pfizer’s global safety database (SDB). The study, which reviewed cases reported through October 31, 2023, found that only 0.005% of NMV/r-treated patients experienced DDIs with contraindicated drugs or drugs that can be used with caution. This finding supports the continued use of NMV/r as a critical tool in reducing COVID-19 morbidity and mortality, provided that DDI risks are effectively managed.
The analysis included 966 global cases, with 594 originating from the United States. Of these, 66.8% were classified as nonserious, while 33.2% were serious, including 1.4% with fatal outcomes. In the US, 77.3% of cases were nonserious, and 22.7% were serious, with 1.0% resulting in death. Hospitalizations were reported in 17.5% of global cases and 12.8% of US cases.
Common Drug Interactions
The most frequently implicated contraindicated drug globally was simvastatin (234 cases), followed by alfuzosin (45 cases) and flecainide (32 cases). Among drugs that can be used with caution, tacrolimus was the most commonly reported (212 cases), followed by atorvastatin (75 cases) and amlodipine (72 cases). In the US, similar trends were observed, with simvastatin (195 cases) and alfuzosin (36 cases) being the most common contraindicated drugs, and tacrolimus (67 cases), atorvastatin (45 cases), and amlodipine (38 cases) being the most common drugs used with caution.
Adverse Events
The most frequently co-reported adverse events (AEs) included dysgeusia (altered sense of taste), diarrhea, and cough. For drugs that can be used with caution, acute kidney injury and toxicity to various agents were also commonly reported. These AEs are generally consistent with the known safety profile of NMV/r and the adverse drug reactions associated with the interacting drugs.
Tacrolimus Interactions
Notably, a significant proportion of cases involving tacrolimus, an immunosuppressant, were serious (66.5% globally and 76.1% in the US). Tacrolimus is primarily metabolized by CYP3A4, and its co-administration with CYP3A4 inhibitors like ritonavir can lead to increased tacrolimus concentrations. The NMV/r label advises avoiding concomitant treatment with tacrolimus unless concentrations can be closely monitored and adjusted.
Fatal Outcomes
Fourteen reported interaction events were associated with fatal outcomes. These cases often involved multiple confounding factors, such as underlying comorbidities, concomitant medications, and COVID-19 infection. Three cases involved patients receiving contraindicated drugs (simvastatin, dronedarone hydrochloride, and primidone), while several fatal cases involved drugs that can be used with caution, including tacrolimus, apixaban, atorvastatin calcium, nifedipine, and verapamil hydrochloride.
Mitigation Strategies
To enhance awareness of potential DDIs and aid in the proper management of concomitantly administered drugs, Pfizer has implemented a robust program of risk mitigation activities and education. This includes detailed US and EU labels for NMV/r, letters disseminated to healthcare providers, an interactive Drug Interaction Checker, and a real-world evidence study assessing the potential for DDIs with NMV/r across the top 100 most prescribed drugs among high-risk patients.
Study Limitations
The study acknowledges several limitations, including potential underestimation of global patient exposure due to incomplete data from all countries and reliance on voluntarily submitted cases, which are subject to underreporting. Additionally, the analysis only included drugs currently listed in the NMV/r prescribing information, and it did not capture the potential for loss of effectiveness due to concomitant administration. The study also notes that case outcomes were not always a direct result of the DDI but could be attributed to confounding factors.
Conclusion
Despite these limitations, the study provides valuable insights into the real-world incidence and nature of DDIs associated with NMV/r. The low reporting rate and the availability of mitigation strategies support the continued use of NMV/r as a critical tool in reducing COVID-19 morbidity and mortality, provided that healthcare providers carefully select patients and manage concomitant medications.
