Coadministration has not been studied and is not recommended. Ibrutinib is metabolised primarily by CYP3A4 and to a minor extent by CYP2D6. Concentrations are expected to increase significantly due to strong inhibition of CYP3A4 and CYP2D6 by nirmatrelvir/ritonavir. Ketoconazole (a strong CYP3A4 inhibitor) increased ibrutinib AUC by 24-fold. A similar effect is expected with nirmatrelvir/ritonavir and coadministration is not recommended. The decision to pause ibrutinib treatment should be made in conjunction with the patient’s oncologist. It may be dangerous to interrupt therapy in patients with high volume chronic lymphocytic leukaemia or mantle cell lymphoma due to disease flare and/or cytokine release. Consider an alternative COVID-19 therapy. If treatment with nirmatrelvir/ritonavir is necessary, consider pausing ibrutinib treatment and starting nirmatrelvir/ritonavir 12 hours after the last ibrutinib dose. Restart ibrutinib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Note: the European label for nirmatrelvir/ritonavir mentions that coadministration should be avoided but if the benefit is considered to outweigh the risk and ritonavir must be used, ibrutinib dose should be reduced to 140 mg with close monitoring for toxicity. Of interest, a PBPK modelling study predicted ritonavir (100 mg twice daily for 5 days) to increase ibrutinib Cmax and AUC by 33- and 53.88-fold and suggests that the interaction with nirmatrelvir/ritonavir can be overcome by administering ibrutinib at a reduced dose of 25 mg every 48 hours.