For many eligible patients with multiple co-morbidities, careful management of drug-drug interactions will be necessary.
Ritonavir is a strong inhibitor of CYP3A4, CYP2D6, p-glycoprotein (PGP) and some other transporter proteins (BRCP, OATP-C and MRP). The effect is almost immediate on starting and lasts for several days after stopping. The effect on other cytochrome enzymes (eg, CYP2C19 or 1A2) is less concerning due to a weaker inhibition and a more prolonged onset of action, so with a five-day course there is minimal clinical impact.
Potential drug interactions need to be carefully considered ideally by a clinician familiar with the patient and their comorbidities. A careful patient history should be taken to identify current medicines, natural or complementary therapies and recreational drug use (especially methamphetamine).
To assess the risk of interactions, the University of Liverpool’s COVID-19 interaction checker should be used and then the Ontario Science Brief should be consulted for specific advice on management of interactions.
Other useful pages that can be found on the Liverpool website include a flow chart "Assessing a patient for treatment with Paxlovid" and drug interaction tables "Interactions with selected WHO essential medicines and Paxlovid". The Medsafe data sheet and New Zealand Formulary are also reliable resources but may not be updated as quickly and frequently as the Liverpool and Ontario websites.
Interactions are generally displayed in a tiered manner:
- RED (Do not co-administer/avoid combination)
- ORANGE (Potential interaction; modify dose or monitor)
- GREEN (No interaction expected)
Red level interactions are simple to manage; nirmatrelvir/ritonavir cannot be used. This is either because a co-medication reduces nirmatrelvir to sub-therapeutic concentrations by CYP3A4 induction or because ritonavir will change the concentration of the co-medicine that cannot be easily withheld or safely adjusted. Another COVID-19 treatment should be considered instead. Examples of red level interactions include:
- CYP3A4 inducers: rifampicin, phenytoin, St John’s wort and carbamazepine
- CYP3A4 or 2D6 substrates (increased by ritonavir): amiodarone, clozapine, tacrolimus, cyclosporin, flecainide, rivaroxaban.
Orange level interactions may produce significant toxicity or impaired efficacy of either drug. Careful considerations need to be made and communicated clearly with the patient. The patient, prescriber and pharmacist should all be involved in the medicine management plan. These interactions can be managed in one of four ways:
- Withhold/pause the interacting medicine.
- Adjust the dose of the interacting medicine (usually not feasible – see below).
- Counsel patients to monitor for side effects and advise to call if they occur.
- Choose an alternative COVID-19 treatment.
Consider if the medicine can be withheld without causing any patient harm. A good example is simvastatin. Concentrations are markedly increased with ritonavir and put the patient at high risk of rhabdomyolysis. Simvastatin should be withheld and restarted two to three days after stopping Paxlovid (ie, stop simvastatin for a week).
Adjusting the dose of the interacting medicine is often not feasible unless the half-life is very short and it has a wide therapeutic window. Examples of medicines where dose adjustment is not usually feasible include amiodarone due to its long half-life and tacrolimus due its narrow therapeutic window. Amlodipine is a good example of a medicine that could be dose-reduced during therapy.
Some medicines could be continued with a small risk of increased adverse effects due to increased concentrations. An example is warfarin, which for many people with stable INR, a modest change in concentration, and therefore INR, would not be harmful. Advising patients to be vigilant to monitor for signs of bruising or bleeding and call if it occurs could be appropriate, as is monitoring INR if clinically indicated.
An alternative COVID-19 treatment may be the best option if there are RED interactions or unmanageable ORANGE interactions. See HealthPathways for currently available alternatives and how to access these for eligible patients.