Prescribing Nirmatrelvir–Ritonavir: How to Recognize and Manage Drug–Drug Interactions
American College of Physicians (ACP) Journals: Annals of Internal Medicine
Nirmatrelvir–ritonavir (NMV/r) is use in high-risk patients with mild to moderate COVID-19 who are likely to be receiving other medications. NMV/r administered within three days of symptom onset reduced the risk of COVID-19 related hospitalization and death from any cause by 88%, compared to placebo.
The use of ritonavir to boost plasma concentrations of nirmatrelvir through inhibition of cytochrome P450 (CYP) 3A4 confers a high potential for clinically significant drug–drug interactions (DDIs).
Interactions between NMV/r and comedications can be screened using specialized resources, such as the National Institutes of Health COVID-19 treatment guidelines or the University of Liverpool's website on COVID-19 drug interactions.
Significant DDIs with NMV/r: medications of concern
NMV/r is used for a short time (5 days), primarily in outpatients as post-exposure or therapeutic treatment of mild to moderate COVID-19. In spite of the short treatment duration, the propensity for DDI is clinically significant due to the rapid onset of cytochromes inhibition by ritonavir (i.e. reaching maximal inhibition 48 hours after ritonavir initiation).
Drug classes of particular concern are those prone to concentration-dependent toxicities or lack of efficacy (Type A adverse drug events), including -
immunosuppressant drugs, such as everolimus, sirolimus and tacrolimus, cyclosporine.
oral anticoagulants (rivaroxaban, apixaban),
antiplatelets (clopidogrel, ticagrelor),
anti-arrhythmic drugs (digoxin, amiodarone),
statins (simvastatin, lovastatin),
anti-psychotics (quetiapine, aripiprazole),
anti-epileptic drugs (carbamazepine, phenobarbital, phenytoin),
benzodiazepines (midazolam, triazolam, diazepam),
anti-migraine drugs,
anti-tuberculosis drugs (rifampicin, rifapentine)
sildenafil,
domperidone,
herbal (St. John's wort),
recreational drugs (amphetamines, ecstasy).
These drugs can significantly reduce NMV/r exposure, potentially jeopardizing its efficacy. Thus, patients on strong inducers would not qualify for NMV/r treatment.
Because of persistent induction after withdrawal of an inducer, DDIs with strong inducers cannot be avoided and require the use of an alternative COVID-19 treatment.
Strategies for Managing Potentially Clinically Relevant DDIs
The inhibitory effect of ritonavir takes several days to resolve. Thus, paused comedication therapy should be restarted 3 d after the last dose of nirmatrelvir–ritonavir. The same timeline applies for comedications whose dosage has been adjusted during nirmatrelvir–ritonavir treatment.
Clinically relevant DDIs with NMV/r can be managed in 4 ways:
The following strategies should be considered when managing DDIs with NMV/r:
(a) pausing the comedication if it is clinically appropriate to do so,
(b) monitoring or dose adjustment of the comedication (challenging to implement given the short treatment course of NMV/r),
(c) switch comedication,
(d) patient counselling about potential DDIs with advice to withhold temporarily a comedication if feeling unwell, or
(e) use of alternative COVID-19 therapy (sotrovimab, remdesivir, molnupiravir)Doctors Liked to Read More
Where possible, therapy with contraindicated comedications should be paused temporarily. If this is not appropriate—for example, if discontinuation poses too much risk, such as stopping clopidogrel treatment within 6 weeks of coronary stenting —then alternatives to NMV/r should be considered.
For example, a switch from clopidogrel to prasugrel reverses the deleterious effect of DDIs on platelet aggregation and, if feasible, should be considered in the 6-week period of highest risk after coronary stenting.
Most DDIs can be managed safely by temporarily withdrawing the problematic comedication. In some circumstances, DDIs cannot be prevented by this approach, either because of persisting effects (for example, residual induction with carbamazepine or rifampicin) or a very long half-life of the comedication (for example, amiodarone), potentially resulting in inadequate exposure to nirmatrelvir or toxic drug levels, respectively. An alternative COVID-19 treatment would be considered in such situations.
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