Christchurch Medicines Information Service

Drug Interactions with nirmatrelvir-ritonavir (Paxlovid®)

- April 4, 2022

This page was last updated: 12 August 2022 at 4:45pm

Ritonavir increases (boosts) the concentration of nirmatrelvir by inhibiting its clearance by CYP3A enzymes. This also increases the concentration of other drugs metabolised by CYP3A. The tables below provide guidance on adjusting doses of patients’ medicines when treating COVID-19 infection with a 5 day course of nirmatrelvir-ritonavir. There are 4 ways to minimise the risk of adverse effects:

1. Withhold the affected medicine while taking nirmatrelvir-ritonavir (for 5 days).
2. Reduce the dose (amount or frequency) of the affected medicine while taking nirmatrelvir-ritonavir (for 5 days) and monitor.
3. Continue the affected medicine while taking nirmatrelvir-ritonavir, caution the patient and monitor for adverse effects.
4. Use remdesivir (or molnupiravir) instead of nirmatrelvir-ritonavir.

There is no one right approach, dosing decisions need to be individualised and closer monitoring will be indicated for some patients and some medicines not listed below.

Where dose changes are needed, we recommend withholding or reducing the dose of a medicine while taking nirmatrelvir-ritonavir (5 days) and then resuming the usual dose. This is simple for the patient to remember. It is important that patients resume their usual medicines after finishing the course of nirmatrelvir-ritonavir. Some guidelines recommend withholding for longer based on the predicted duration of the inhibitory effects of ritonavir on the CYP3A enzymes. 5 days is sufficient to avoid adverse effects in most circumstances; however, one week is another valid option.

Dose reduction is usually by halving the dose, this is not a precise correction but is sufficient to avoid adverse effects in many cases. To reduce the dose by half, either take every second dose (e.g. if twice daily then take once daily, or if once daily then take every second day) or the dose amount can be halved (e.g. halve the tablet, if not controlled release). Whichever is the easiest or most practical for the patient.

If in doubt discuss the patient with others involved in their care and/or seek advice.

Most drug-drug interactions can be safely managed using the following strategies:

Withhold for the duration of nirmatrelvir-ritonavir
α-blockers	doxazosin, prazosin, terazosin
Benzodiazepines	clonazepam, diazepam, midazolam, triazolam
Calcium channel blockers	amlodipine, felodipine, nifedipine
Statins	atorvastatin, simvastatin
Fibrates	bezafibrate
Urate lowering agents	colchicine

Halve the dose for the duration of nirmatrelvir-ritonavir
Anticoagulants (oral)	dabigatran etexilate, rivaroxaban, warfarin Monitor INR or TCT and for signs of bleeding and bruising (see below).
Calcium channel blockers	diltiazem, verapamil Monitor for bradycardia and hypotension.
Carbamazepine	Also induces CYP3A which will decrease nirmatrelvir concentrations.
Opioids	fentanyl, oxycodone, pethidine Consider morphine as a safer alternative. Otherwise, the opioid dose can be halved with close monitoring and further dose titration.

We recommend to continue (not withhold) anticoagulant medicines, as COVID-19 infection increases the risk of venous thromboembolism. For high-risk patients additional monitoring may be needed to manage risk.

• For dabigatran, the change in thrombin clotting time (TCT) can be used to monitor patients. A TCT prior to starting or immediately after starting and 3 days later can be used.
• For rivaroxaban, the change in INR can be used to monitor patients. An INR prior to starting or immediately after starting and 3 days later can be used.
• For warfarin, monitor INR every 2 or 3 days.
• INR and TCT test results are rapidly available after testing. Dabigatran and rivaroxaban concentrations can be measured but the result is not available quickly enough for acute decision making.

Seek specific advice
Antiarrhythmics	amiodarone, flecainide Discuss with the patient’s cardiologist. Amiodarone has a long half-life and could be withheld or continued depending on the clinical scenario.
Cytotoxic agents	Concomitant use is high risk for many cytotoxic agents. Contact the treating oncologist BEFORE starting nirmatrelvir-ritonavir.
Immunosuppressants	tacrolimus, ciclosporin Contact the transplant team (or treating specialist for other conditions) BEFORE starting nirmatrelvir-ritonavir.
Phenytoin	Nirmatrelvir may be ineffective, discuss with infectious diseases.
Rifampicin	Nirmatrelvir may be ineffective, discuss with infectious diseases.

 

Examples of medicines that can be continued at the same dose
Antiplatelets	aspirin, clopidogrel Reduced effectiveness of clopidogrel (a prodrug) is likely.
Benzodiazepines	lorazepam, oxazepam, temazepam Metabolised by pathways other than CYP3A.
Finasteride	Adverse effects not significantly increased.
Fludrocortisone	Potential for fluid retention.
Hormonal contraceptives	Consider an additional non-hormonal method of contraception. Contraceptive effectiveness is expected to be maintained.
Loratadine	Potential for sedation.
Low molecular weight heparin	enoxaparin
Morphine, methadone	Metabolised by pathways other than CYP3A.
Pravastatin	Metabolised by pathways other than CYP3A.

 

General

• Don’t change the dose regimen of nirmatrelvir-ritonavir.
• CYP3A inhibition by ritonavir resolves within 3 days of stopping.
• The lists in the tables are not exhaustive. The examples presented have been raised in questions to the medicines information service.
• Patient information for nirmatrelvir-ritonavir is available from MyMedicines

If this guidance is insufficient to manage interactions for your patient, please contact the Medicines Information Service 03 364 0900.

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