Teachable Moment
Less Is More
February 20, 2023
Safely Prescribing Nirmatrelvir and Ritonavir—Avoiding Drug-Drug Interactions
Roshni Culas, Sridesh Nath, Sarath Nath
JAMA Intern Med. 2023;183(4):362-363. doi:10.1001/jamainternmed.2022.6834
Story From the Front Lines
A72-year-old man called his primary care physician (PCP) after 2 days of throat pain, myalgia, mild shortness of breath, and fever. A home COVID-19 antigen test result was positive. He had received 3 doses of the BNT162b2 vaccine (Pfizer-BioNTech COVID-19 vaccine); the most recent dose was 6 months prior. Considering a history of recent coronary artery bypass graft, hypertension, diabetes, and the patient’s age, his PCP prescribed nirmatrelvir and ritonavir (Paxlovid) for 5 days. The patient called his PCP after 2 days with active complaints of worsening myalgia. On medication review, the patient’s active medications included atorvastatin, 80 mg daily; metformin, 1000 mg twice a day; aspirin, 81 mg daily; and dapagliflozin, 10 mg daily.
The patient was advised to stop nirmatrelvir-ritonavir use, hold atorvastatin use, and have his creatinine kinase levels checked. The patient’s creatinine kinase levels came back within normal limits. With rest and over-the-counter analgesics, the patient’s symptoms improved without further interventions. His COVID-19–related symptoms resolved within 5 days. He was restarted on atorvastatin therapy 1 week after finishing nirmatrelvir-ritonavir treatment, with no recurrence of myalgias.
Teachable Moment
Nirmatrelvir and ritonavir combination (Paxlovid) was approved for emergency use authorization by the US Food and Drug Administration in December 2021 for the treatment of mild to moderate COVID-19 in adults who are also at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir-ritonavir use in unvaccinated high-risk patients showed a significant reduction (89%) in progression to severe COVID-19.1 In ambulatory patients with mild to moderate COVID-19 at high risk for progression to severe disease, the Infectious Diseases Society of America guideline panel suggests that nirmatrelvir/ritonavir be initiated within 5 days of symptom onset irrespective of the vaccination status. Since approval, as of September 18, 2022, 4 799 532 courses of nirmatrelvir-ritonavir have been prescribed in the US.2
As mentioned, Paxlovid consists of 2 medications: nirmatrelvir and ritonavir. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), and ritonavir is an inhibitor of cytochrome P450 3A4 (CYP3A4), which decreases nirmatrelvir metabolism and thus increases its serum levels. As ritonavir is a CYP3A4 inhibitor, ritonavir has substantial and complex drug-drug interactions leading to increased levels and toxic effects of some commonly used drugs.
It is estimated that of all reported adverse drug events, 26% are due to drug-drug interactions.3 Generally, drug interactions are classified under risk ratings that consist of 5 groups. A clinician should be vigilant for interactions with risk ratings of C (monitor therapy), D (consider drug modification), and X (avoid combination). Cytochrome P450 3A4 is a member of the cytochrome P450 superfamily of enzymes. Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism.4 With medications like nirmatrelvir-ritonavir, which contains a CYP3A4 inhibitor, a prescriber should be vigilant to check for interactions. Common drug interactions with nirmatrelvir-ritonavir are summarized in the Table.
Table. Common Drug Interactions With Nirmatrelvir-Ritonavir
Statins, also known as β-hydroxy-β-methylglutaryl-CoA inhibitors, are a class of lipid-lowering medications. The CYP3A4 isoenzyme is responsible for the metabolism of statins, and hence strong CYP3A4 inhibitors such as protease inhibitors (eg, ritonavir) can increase levels of drugs metabolized by the CYP3A4 pathway, leading to harmful adverse effects. One of the major adverse effects related to statin use is muscle toxicity, which can be of varying severity. About 15% of patients receiving statin therapy develop myalgias; however, true statin-induced myopathy is thought to occur in less than 1% of patients. Statin-related myopathy, when it does occur, is often due to drug-drug interaction. It is estimated that 60% of cases of statin-induced rhabdomyolysis (most severe presentation of myopathy) are due to drug interactions. In cases where myopathy is due to a reversible cause, statin therapy can be restarted with close monitoring once the cause is resolved.5
The Food and Drug Administration nirmatrelvir-ritonavir emergency use authorization fact sheet for health care clinicians recommends temporarily discontinuing medications metabolized by CYP3A4, such as atorvastatin, during treatment with nirmatrelvir-ritonavir. Statin therapy can often be restarted 3 to 5 days after discontinuing use of nirmatrelvir-ritonavir or another CYP3A4 inhibitor, since these drugs will be metabolized by that time.
As this case illustrates, nirmatrelvir-ritonavir has clinically significant interactions with many commonly prescribed drugs (Table). Our Teachable Moment emphasizes 2 things. First, nirmatrelvir-ritonavir has significant benefit for high-risk patients, as it can substantially reduce their risk of progressing to severe disease or death. Thus, rather than avoiding prescribing nirmatrelvir-ritonavir altogether for high-risk patients, clinicians should simply consider drug-drug interactions and understand how to temporarily modify the dosing of drugs or hold them preemptively for the duration of nirmatrelvir-ritonavir administration. Second, drug-drug interactions provide an important rationale for avoiding the use of nirmatrelvir-ritonavir in low-risk patients (eg, a healthy patient younger than 40 years who is fully vaccinated). For the current patient, the best approach may have been to prescribe a full 5-day course of nirmatrelvir-ritonavir and asking him to hold atorvastatin use for the next 8 to 10 days.
