Coadministration has not been studied. Abemaciclib is primarily metabolised by CYP3A4 and concentrations are expected to increase significantly due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Coadministration with strong CYP3A4 inhibitors is not recommended. The decision to pause or dose-adjust abemaciclib should be made in conjunction with the patient’s oncologist. Cyclin-dependent kinase inhibitors may be paused in the context of acute infection. Restart abemaciclib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Alternatively, if coadministration is necessary, consider a dose reduction to 50 mg once daily with close monitoring for toxicity.

Coadministration has not been studied and is not recommended. Acalabrutinib is metabolised by CYP3A4 and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Itraconazole (a strong CYP3A4 inhibitor) increased acalabrutinib AUC by 5-fold. A similar effect is expected with nirmatrelvir/ritonavir and coadministration is not recommended. When short course treatment with strong inhibitors (such as nirmatrelvir/ritonavir) is required, the product label for acalabrutinib advises to stop temporarily acalabrutinib treatment. Restart acalabrutinib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Of interest, a PBPK modelling study predicted ritonavir (100 mg twice daily for 5 days) to increase acalabrutinib Cmax and AUC by 3.85- and 6.54-fold and suggests that the interaction with nirmatrelvir/ritonavir can be overcome by administering acalabrutinib at a reduced dose of 25 mg twice daily.

Coadministration has not been studied. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. Ritonavir also induces CYP1A2 and CYP2C19. Nirmatrelvir/ritonavir could potentially decrease acenocoumarol concentrations. Monitor INR as clinically indicated especially in the immediate post-nirmatrelvir/ritonavir period. Of interest, INR was measured in 29 patients treated with nirmatrelvir/ritonavir and warfarin (metabolized by CYP1A2, CYP3A4 and CYP2C9). Median INR before administration of nirmatrelvir/ritonavir was 2.4 (IQR, 1.1-3.7) but decreased to 1.95 (IQR 1.5-2.3) after nirmatrelvir/ritonavir was commenced, with approximately half of the patients experiencing subtherapeutic INR values (target INR 2-3). When compared to pre-nirmatrelvir/ritonavir INR, no statistically significant differences in INR were observed during coadministration of nirmatrelvir/ritonavir, however, INR showed a median decrease of 0.5 (P = 0.026) after completion of nirmatrelvir/ritonavir treatment.

Coadministration with nirmatrelvir/ritonavir has not been studied. Afatinib is mainly eliminated unchanged in the faeces and is a substrate of P-glycoprotein and BCRP. Administration of ritonavir (200 mg twice daily for 3 days) 1 hour before afatinib (20 mg single dose) increased afatinib AUC and Cmax by 48% and 39%. However, coadministration of ritonavir simultaneously or 6 hours after afatinib (40 mg) resulted in minimal increase in afatinib AUC and Cmax (19% and 4% for simultaneous administration; 11% and 5% for the staggered administration). The European product label for afatinib recommends to administer strong P-gp inhibitors (such as nirmatrelvir/ritonavir) 6 hours apart from afatinib. The US product label includes a recommendation to decrease afatinib daily dose by 10 mg if not tolerated for patients who require a therapy with a P-gp inhibitor. The previous afatinib dose should be resumed after discontinuation of the P-gp inhibitor as tolerated.

Coadministration has not been studied. Alfentanil undergoes extensive CYP3A4 metabolism. Nirmatrelvir/ritonavir could potentially increase alfentanil exposure and thereby increase the risk of prolonged or delayed respiratory depression. Coadministration should ideally be done in a setting which allows clinical monitoring. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect takes several days to resolve. Alfentanil should be used with caution up to 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration with alfuzosin with potent CYP3A4 inhibitors, such as ritonavir, is contraindicated. Coadministration may increase alfuzosin concentrations due to inhibition of CYP3A4 by nirmatrelvir/ritonavir which may result in severe hypotension. Given the short duration of nirmatrelvir/ritonavir treatment, alfuzosin should be stopped. Given the mechanism-based inhibition of nirmatrelvir/ritonavir, alfuzosin treatment would have to be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration has not been studied and is not recommended. Aliskiren is minimally metabolized by CYP450, however, P-gp is a major determinant of aliskiren bioavailability. A 5-6-fold increase in exposure was observed with itraconazole 100 mg twice daily (a CYP3A4 and P-gp inhibitor) and a similar interaction is possible with nirmatrelvir/ritonavir (due to inhibition of P-gp by ritonavir). The product labels for aliskiren recommend avoiding concomitant use with CYP3A4 and P-gp inhibitors.

Coadministration has not been studied. In vitro data indicate that alosetron is metabolized by CYPs 2C9 (30%), 3A4 (18%) and 1A2 (10%); however, in vivo data suggest that CYP1A2 plays a more prominent role. In vitro data indicate that ritonavir induces CYP1A2, therefore coadministration with nirmatrelvir/ritonavir could potentially decrease alosetron exposure. Monitor therapeutic effect and increase the dose if needed.

Coadministration with nirmatrelvir/ritonavir has not been studied. Alprazolam is mainly metabolized by CYP3A4. Interaction studies with ritonavir have shown inhibition of alprazolam metabolism following the introduction of ritonavir but no significant inhibitory effect at steady state. Based on these data, when combined with nirmatrelvir/ritonavir, consider a lower dose of alprazolam used cautiously and monitor for adverse effects. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration with nirmatrelvir/ritonavir has not been studied. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Ambrisentan concentrations may increase due to inhibition of OATP1B1 by ritonavir. Given the short duration of nirmatrelvir/ritonavir treatment, a clinically significant interaction is unlikely and no dose adjustment is required. Coadministration of ambrisentan (5 mg once daily) and ritonavir (100 mg once daily for 10 days) had no clinically relevant effect on ambrisentan (Cmax increased by 7%; AUC decreased by 5%) or ritonavir (Cmax decreased by 2%; AUC decreased by 3%).

Coadministration has not been studied and is contraindicated. Amiodarone is metabolised by CYP3A4 and concentrations may be increased due to inhibition of CYP3A4 by nirmatrelvir/ritonavir thereby increasing the risk of arrhythmias or other serious adverse reactions. Note, amiodarone has a long elimination half-life and the risk of drug-drug interactions may not be overcome even by stopping amiodarone administration. Consider an alternative COVID-19 treatment.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Nirmatrelvir/ritonavir could potentially increase amitriptyline exposure, although to a moderate extent given that ritonavir is a weak inhibitor of CYP2D6 at a dose of 100 mg. The potential limited increase in amitriptyline exposure is not expected to increase the risk of QT interval prolongation. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4. Nirmatrelvir/ritonavir is predicted to increase amlodipine exposure by ~2-fold based on drug-drug interactions studies with amlodipine and indinavir/ritonavir or paritaprevir/ritonavir leading to the recommendation to reduce amlodipine dosage by 50% or to take the dose every other day. However, a dose adjustment can be optional in the case of amlodipine given that patients can be advised to monitor for symptoms of hypotension and to temporarily pause the antihypertensive drug if needed. If the dose is adjusted, the usual dose of amlodipine should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as the inhibitory effect of ritonavir is expected to last up to 3 days after completing nirmatrelvir/ritonavir.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6 and coadministration could potentially increase amphetamine exposure (caution as non-linear pharmacokinetics). Furthermore, dosing of recreational drugs can be variable, thus the use of amphetamine should be avoided while the patient is treated with nirmatrelvir/ritonavir and for 3 days after the last dose of nirmatrelvir/ritonavir. Ensure the patient is aware of signs of possible amphetamine toxicity.

Coadministration has not been studied. Amphetamine mixed salts contain both levoamphetamine and dextroamphetamine. Amphetamine mixed salts are metabolized by CYP2D6 to some extent, but a large proportion is excreted unchanged. Nirmatrelvir/ritonavir is metabolized by CYP3A and inhibits CYP3A. Coadministration could potentially increase amphetamine mixed salts exposure (caution as non-linear pharmacokinetics). The amphetamine mixed salts product label advises caution with ritonavir. The European product label for Paxlovid recommends careful monitoring of adverse effect when nirmatrelvir/ritonavir is coadministered with amphetamine and its derivatives. Alternatively, consider pausing amphetamine mixed salts and restarting 3 days after completing nirmatrelvir/ritonavir treatment.

Coadministration of nirmatrelvir/ritonavir with apalutamide, a strong CYP3A4 inducer, is contraindicated as it may cause large decreases in nirmatrelvir/ritonavir concentrations which may in turn significantly decrease the nirmatrelvir/ritonavir therapeutic effect. Due to the persisting inducing effect upon discontinuation of a strong inducer, consider an alternative COVID-19 treatment.

Coadministration has not been studied. Apixaban is a substrate of P-gp and is metabolized by CYP3A4. Concentrations of apixaban are expected to increase due to CYP3A4 and P-gp inhibition by ritonavir. The product labels for apixaban do not recommend the concomitant use with strong dual CYP3A4 and P-gp inhibitors, although the US label for apixaban gives the option to use apixaban at a reduced dose (i.e., 2.5 mg) if needed. Of interest, no adverse outcomes were reported in six HIV infected patients treated with a reduced dose of apixaban (2.5 mg twice daily) while on ritonavir boosted regimens suggesting that a reduced dose of apixaban could be used with nirmatrelvir/ritonavir. If nirmatrelvir/ritonavir treatment is needed, consider adjusting apixaban dosage according to risk, indication and current dose. For treatment of atrial fibrillation with standard apixaban dose (i.e., 5 mg twice daily), reduce apixaban to 2.5 mg twice daily. For treatment of atrial fibrillation with low dose apixaban (i.e., 2.5 mg twice daily), continue low dose on a case-by-case basis. For patients at high risk of venous/arterial thromboembolism (VTE/ATE), consider switching from apixaban to low molecular weight heparin (LMWH); patients with a lower risk of VTE/ATE could be switched to aspirin on a case-by-case basis. The usual apixaban treatment should be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration has not been studied. Aprepitant is mainly metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C19. Nirmatrelvir/ritonavir is metabolized by CYP3A. Aprepitant shows an initial inhibitory effect on CYP3A4 followed by a weak inducing effect from day 8 which is clinically insignificant by two weeks. Any transient change in nirmatrelvir/ritonavir exposure is unlikely to be clinically significant. However, nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4 and may increase aprepitant concentrations. The European product label for aprepitant advises caution with CYP3A4 inhibitors, whereas the American product label advises that administration of moderate or strong CYP3A4 inhibitors should be avoided. If coadministration is necessary, closely monitor patients for aprepitant toxicity. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Nirmatrelvir/ritonavir could potentially increase aripiprazole concentrations. Monitor adverse effects and decrease aripiprazole dosage if needed. The European product label advises reducing the aripiprazole dose to approximately one-half of its prescribed dose when given with potent inhibitors of CYP3A4, such as ritonavir. The decision to modify the dosage should be done in consultation with a specialist in mental health medicine. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied but a significant effect on artesunate/dihydroartemisinin is not anticipated. Artesunate is rapidly converted to dihydroartemisinin (DHA), an active metabolite which has greater potency than the parent drug and which is further metabolised via UGTs 1A9 and 2B7. At steady-state, ritonavir (100 mg twice daily) increased artesunate exposure by 27% and decreased DHA exposure by 38% due to induction of UGTs. However, nirmatrelvir/ritonavir is expected to minimally decrease DHA exposure given the maximal inducing effect of ritonavir is not reached with the short duration of nirmatrelvir/ritonavir treatment.

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification. Patients should be informed about the potential occurrence of adverse effects (i.e. gastro-intestinal due to the higher dose of ritonavir).

Coadministration with nirmatrelvir/ritonavir has not been studied. If atazanavir is prescribed alone for the treatment of HIV then coadministration with nirmatrelvir/ritonavir is possible with no dose adjustment required. Although coadministration with ritonavir increased atazanavir AUC and Cmax by 86% and 11-fold, as a result of CYP3A4 inhibition, atazanavir is licensed to be administered with or without ritonavir and no significant interaction is expected when combining atazanavir with nirmatrelvir/ritonavir for 5 days.

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification. Patients should be informed about the potential occurrence of adverse effects.

Coadministration has not been studied. Atorvastatin is metabolized by CYP3A4 and concentrations are expected to increase due to inhibition of CYP3A4 by nirmatrelvir/ritonavir. Coadministration is not recommended unless specifically required for patient management. Given the short duration of nirmatrelvir/ritonavir treatment, atorvastatin should be stopped. The pragmatic approach to stop temporarily atorvastatin (or any other statin) is acceptable considering that it will not negatively affect the therapeutic effect but can minimize the risk for adverse events related to a drug interaction. if it is decided to pause atorvastatin during nirmatrelvir/ritonavir treatment, atorvastatin should be restarted 3 days after the last dose of nirmatrelvir/ritonavir as CYP3A4 inhibition by ritonavir takes several days to resolve. If coadministration is necessary, reduce atorvastatin to 10 mg daily and resume the usual dose 3 days after completing nirmatrelvir/ritonavir.

Coadministration has not been studied but a significant effect on atovaquone is not anticipated. Atovaquone is mainly eliminated unchanged in the faeces, with some possible metabolism by UGTs. Coadministration with ritonavir-boosted HIV protease inhibitors at steady-state has been reported to decrease atovaquone AUC by 70% (lopinavir/ritonavir) or by 40-50% (atazanavir/ritonavir) due to induction of UGTs. However, nirmatrelvir/ritonavir is expected to minimally decrease atovaquone exposure given the maximal inducing effect of ritonavir is not reached with the short duration of nirmatrelvir/ritonavir treatment. Furthermore, the clinical relevance of the interaction even with long-term use of ritonavir is unclear due to the lack of data on the minimal effective atovaquone plasma concentration in the setting of malaria prophylaxis. Atovaquone/proguanil could be taken with a high fat meal to increase its bioavailability.

Coadministration with nirmatrelvir/ritonavir has not been studied but is contraindicated. Coadministration of ritonavir (600 mg twice daily) and avanafil (50 mg single dose) increased avanafil AUC and Cmax by 13-fold and 2-fold, and prolonged the half-life of avanafil to 9 hours. Coadministration with avanafil and nirmatrelvir/ritonavir is contraindicated in the European product label for Paxlovid. Given the short duration of nirmatrelvir/ritonavir treatment, avanafil should be stopped. Given the mechanism-based inhibition of CYP3A4 by nirmatrelvir/ritonavir, avanafil would have to be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration with nirmatrelvir/ritonavir has not been studied. In vitro data indicate that beclometasone is a pro-drug which is hydrolysed via esterase enzymes to the highly active metabolite beclometasone -17-monopropionate. This active metabolite is subsequently converted to inactive metabolites via CYP3A4/5. Coadministration of ritonavir (100 mg twice daily) and inhaled beclometasone dipropionate (160 mg twice daily) increased the AUC and Cmax of beclomethasone-17-monoproprionate by 108% and 67%, respectively. However, coadministration of a ritonavir-boosted HIV protease inhibitor (darunavir/ritonavir, 600/100 mg twice daily) decreased the AUC and Cmax of the active metabolite by 11% and 19%, respectively. No significant effect on adrenal function was seen with either ritonavir or darunavir/ritonavir. Although statistically significant, the 2-fold increase in AUC of the active metabolite seen with ritonavir is unlikely to be of clinical significance. Given the short duration of nirmatrelvir/ritonavir treatment this is unlikely to be clinically significant. No a priori dose change required.

Coadministration has not been studied. Bedaquiline is metabolised by CYP3A4 and mainly eliminated in faeces. Inhibition of CYP3A4 by ritonavir is expected to increase bedaquiline exposure. If coadministration is necessary, clinical monitoring including ECG assessment and monitoring of transaminases is recommended. Consider delaying the next due dose of bedaquiline if it falls during nirmatrelvir/ritonavir treatment until after nirmatrelvir/ritonavir treatment has been completed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendamustine is metabolised by multiple routes including hydrolysis, glutathione conjugation and hepatic metabolism via CYP1A2. Nirmatrelvir/ritonavir is metabolized by CYP3A4 and induces CYP1A2. However, induction of CYP1A2 by ritonavir is unlikely to cause a clinically relevant decrease in bendamustine exposure given induction does not reach maximal effect due to the short duration of nirmatrelvir/ritonavir treatment.

Coadministration has not been studied. Bepridil and nirmatrelvir/ritonavir should not be coadministered as bepridil concentrations may increase which has the potential to produce serious and/or life-threatening adverse events. Coadministration would warrant caution and therapeutic drug monitoring when available. Note: bepridil has a long elimination half-life and the risk of drug-drug interactions may not be overcome even by stopping bepridil administration. Consider an alternative COVID-19 treatment.

Coadministration has not been studied. Betamethasone is metabolized by CYP3A4 and coadministration may therefore lead to elevated corticosteroid levels. The US product label for Paxlovid does not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression. However, given the short duration of nirmatrelvir/ritonavir treatment, this risk is considered to be low. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration has not been studied. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. Coadministration with a P-gp inhibitor (such as nirmatrelvir/ritonavir) is expected to increase betrixaban exposure. The US product label for betrixaban recommends for patients receiving or starting a strong P-gp inhibitor to reduce betrixaban dose and use an initial dose of 80 mg followed by 40 mg once daily. Furthermore, patients should be monitored closely and any signs or symptoms of blood loss should be evaluated promptly. Coadministration of betrixaban might need to be reconsidered in patients with concomitant renal impairment (creatinine clearance less than 60 ml/ml) as renal impairment increases betrixaban exposure. The management of this interaction should also take into account the indication of the anticoagulation and whether or not betrixaban can be stopped during the course of nirmatrelvir/ritonavir treatment (consult a cardiologist/haematologist about the risks of stopping the anticoagulant). 

Coadministration with Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) has not been studied. Concentrations of bictegravir may increase due to inhibition of CYP3A4 by nirmatrelvir/ritonavir but this is unlikely to be clinically significant as clinical data have shown a good safety profile with up to a 2.4-fold increase in bictegravir AUC. No interaction with emtricitabine is expected. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and ritonavir, a P-gp inhibitor, is expected to increase the absorption of tenofovir alafenamide, thereby increasing the systemic concentration of tenofovir. However, this increase is not problematic as tenofovir alafenamide has a good safety profile.

Coadministration with nirmatrelvir/ritonavir has not been studied and is not recommended. Coadministration of nirmatrelvir/ritonavir for 5 days may result in significant increases bosentan trough concentrations. Coadministration with lopinavir/ritonavir (also containing ritonavir 100 mg twice daily) increased bosentan trough concentrations by ~48-fold and ~5-fold on days 4 and 10, respectively. The US product label for Paxlovid advises to discontinue bosentan at least 36 hours prior to initiation of nirmatrelvir/ritonavir.

Coadministration has not been studied. Brentuximab vedotin is an antibody-drug conjugate comprising a monoclonal antibody and monomethyl auristatin E (MMAE), a potent chemotherapeutic agent. The monoclonal antibody undergoes elimination via intracellular catabolism. MMAE is a substrate of CYP3A4 (and possibly CYP2D6) and P-gp. Nirmatrelvir/ritonavir is metabolized by CYP3A. Brentuximab vedotin and MMAE are unlikely to have a clinically significant effect on drugs metabolized by CYP enzymes. However, strong inhibition of CYP3A4 and P-gp by nirmatrelvir/ritonavir may increase concentrations of MMAE and the incidence of neutropenia. Coadministration of brentuximab vedotin and ketoconazole (a strong inhibitor of CYP3A4 and P-gp) increased MMAE AUC by 34%. Depending on the indication, brentuximab vedotin is administered on day 1 and 15 of each 28-day cycle or every 3 weeks. Therefore, if possible, consider delaying brentuximab vedotin treatment until the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir has mostly disappeared (i.e., 3 days after last dose of nirmatrelvir/ritonavir). The decision to delay brentuximab vedotin should be made in conjunction with the patient’s oncologist.

Coadministration has not been studied. Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6 and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Ketoconazole (a strong CYP3A4 inhibitor) increase brexpiprazole AUC by 97% and similar effect may occur with nirmatrelvir/ritonavir. Product labels for brexpiprazole advise a dose reduction of 50% with strong CYP3A4 inhibitors. A dosing modification to a quarter of the recommended dose is required for known CYP2D6 poor metabolisers while taking strong inhibitors. Monitor for toxicity, such as confusion, restlessness and sedation. The decision to modify the dosage should be done in consultation with a specialist in mental health medicine. The usual dose of brexpiprazole should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as the inhibitory effect of ritonavir is expected to last up to 3 days after completing nirmatrelvir/ritonavir.

Coadministration has not been studied. Bromazepam undergoes oxidative biotransformation. Drug-drug interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may play a role. Bromazepam does not inhibit CYP3A4. Nirmatrelvir/ritonavir could potentially increase bromazepam concentrations, although to a moderate extent. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased bromazepam AUC by ~9%. A similar effect may occur with nirmatrelvir/ritonavir. Given the short duration of nirmatrelvir/ritonavir treatment, a dose adjustment is unlikely to be necessary. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Nirmatrelvir/ritonavir is metabolized by CYP3A and strongly inhibits CYP3A4. Budesonide is metabolized by CYP3A4 and concentrations are expected to increase due to CYP3A4 inhibition by nirmatrelvir/ritonavir. However, unlike with other strong CYP3A4 inhibitors, this is unlikely to be clinically relevant due to the short duration of nirmatrelvir/ritonavir treatment. The risk of Cushing syndrome is also considered to be low for inhaled budesonide used in COVID-19 treatment (2 weeks). However, prescribers should be aware of and to look out for signs of systemic corticosteroid side effects. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration has not been studied. Nirmatrelvir/ritonavir is metabolized by CYP3A and strongly inhibits CYP3A4. Budesonide is metabolized by CYP3A4 and concentrations are expected to increase due to CYP3A4 inhibition by nirmatrelvir/ritonavir. However, this is unlikely to be clinically relevant due to the short duration of nirmatrelvir/ritonavir treatment. Product labels for Paxlovid do not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression, but given the short duration of nirmatrelvir/ritonavir treatment, this risk is considered to be low. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration with nirmatrelvir/ritonavir has not been studied. Buprenorphine is mainly metabolized by CYP3A4 to form the active metabolite norbuprenorphine, but is also glucuronidated by UGT2B7 and UGT1A1. Coadministration with ritonavir (100 mg twice daily) increased exposure of buprenorphine (~57%) and its active metabolite, but this did not lead to clinically significant pharmacodynamic changes in a population of opioid tolerant patients. Dose adjustment of either drug may therefore not be necessary, but should be guided by clinical monitoring. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Bupropion is primarily metabolized by CYP2B6 and in vivo data indicate that ritonavir induces CYP2B6 in a dose dependent manner. Nirmatrelvir /ritonavir could potentially decrease bupropion concentrations, although to a limited extent with a ritonavir dose of 100 mg. However, given that induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment, no a priori dosage adjustment is recommended.

Coadministration has not been studied. Buspirone is metabolized by CYP3A4. Nirmatrelvir/ritonavir strongly inhibits CYP3A4. Coadministration with itraconazole (200 mg for 4 days), another strong CYP3A4 inhibitor, increased buspirone AUC by 19-fold and requires a significant reduction in buspirone dose (i.e., 2.5 mg once daily). A similar interaction is expected with nirmatrelvir/ritonavir. Pause buspirone and restart 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Alternatively, use buspirone at a low dose such as 2.5mg once daily.

Coadministration has not been studied but is not recommended. Cabazitaxel is metabolised by CYP3A4. Nirmatrelvir/ritonavir is metabolized by CYP3A. Cabazitaxel does not inhibit or induce CYPs. However, nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4 and may increase cabazitaxel concentrations. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) increased cabazitaxel exposure by 25%. A similar effect is expected with nirmatrelvir/ritonavir. If possible, consider delaying cabazitaxel treatment until the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir has mostly disappeared (i.e., 3 days after last dose of nirmatrelvir/ritonavir). The decision to delay cabazitaxel should be made in conjunction with the patient’s oncologist.

Coadministration has not been studied. Cabergoline is extensively metabolized by the liver, predominantly via hydrolysis (non-CYP mediated metabolism), and is a substrate of P-gp. Cabergoline exposure increased by 2.6- to 4-fold in the presence of the strong P-gp inhibitors itraconazole or clarithromycin. Similarly, coadministration with nirmatrelvir/ritonavir is expected to increase cabergoline exposure. No a priori dose adjustment is needed however inform the patient about potential adverse effects (nausea, vomiting, stomach upset, constipation, dizziness, lightheadedness, or tiredness). Nirmatrelvir/ritonavir is metabolized by CYP3A and inhibits CYP3A. Cabergoline neither induces nor inhibits CYP enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cabotegravir is mainly metabolized by UGT1A1 and to a lesser extent UGT1A9. Induction of UGTs by ritonavir is unlikely to cause a clinically relevant decrease in cabotegravir exposure given induction does not reach maximal effect due to the short duration of nirmatrelvir/ritonavir treatment. Cabotegravir is not expected to alter concentrations of other antiviral products.

Coadministration has not been studied. Cabotegravir is mainly metabolized by UGT1A1 and to a lesser extent by UGT1A9. Induction of UGTs by ritonavir is unlikely to cause a clinically relevant decrease of cabotegravir exposure given induction does not reach maximal effect due to the short duration of nirmatrelvir/ritonavir treatment. Rilpivirine is primarily metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir however this increase is not clinically relevant. No dose adjustment of rilpivirine is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4. Nirmatrelvir/ritonavir could potentially decrease canagliflozin exposure due to induction of UGTs by ritonavir. However, given that induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment, no a priori dosage adjustment is recommended.

Coadministration is contraindicated as it may lead to a loss of virological response and possible resistance. Coadministration of carbamazepine (300 mg twice daily for 16 doses) and nirmatrelvir/ritonavir (300/100 mg twice daily for 16 doses) decreased nirmatrelvir Cmax and AUC by 43% and 55%. In addition, inhibition of CYP3A4 by ritonavir may increase concentrations of carbamazepine as it is metabolised by CYP3A4 and UGT2B7. Use an alternative COVID-19 treatment.

Coadministration has not been studied. Carbidopa is partly metabolized and partly eliminated unchanged (30% of the total urinary excretion). In the presence of a peripheral dopa-decarboxylase inhibitor (such as carbidopa) levodopa is metabolised mainly to 3-O-methyldopa by catechol-O-methyltransferase. Nirmatrelvir/ritonavir is metabolized by CYP3A and inhibits CYP3A. Enhanced levodopa effects including severe diskinesias were described in a case report after initiation of an antiretroviral regimen containing indinavir to an individual who was previously stable on levodopa/carbidopa therapy. When reintroduced alone, indinavir monotherapy induced the abnormal movements, which resolved on discontinuation. Based on this isolated case, the risk of an interaction with ritonavir is unclear.

Coadministration has not been studied and is not recommended. Metabolism of cariprazine and its major active metabolites is mediated mainly by CYP3A4 with a minor contribution of CYP2D6, and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Cariprazine and its metabolites have very long elimination half-lives and changes in dose may not be fully reflected in plasma for several weeks. The European product label for cariprazine contraindicates coadministration with strong CYP3A4 inhibitors, whereas the American product label advises dose modification if a strong CYP3A4 inhibitor is initiated while on a stable dose of cariprazine. Refer to the product label for cariprazine for more information. Consider an alternative COVID-19 treatment.

Coadministration has not been studied but is not recommended. Ceritinib is metabolised by CYP3A4 and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Coadministration of ceritinib (450 mg single dose) with ketoconazole, a strong CYP3A/P-gp inhibitor (200 mg twice daily for 14 days) increased ceritinib AUC and Cmax by 2.9-fold and 1.2-fold. A similar effect is expected with nirmatrelvir/ritonavir and coadministration is not recommended. The decision to pause or dose-adjust ceritinib should be made in conjunction with the patient’s oncologist. If it is decided to pause ceritinib treatment, start nirmatrelvir/ritonavir 24 hours after the last dose of ceritinib due to the long elimination half-life of ceritinib. Restart ceritinib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition by ritonavir takes several days to resolve. Alternatively, if coadministration is necessary, consider reducing ceritinib dose by 33% (dose rounded to the nearest multiple of the 150 mg dosage strength) and monitor for toxicity.

Coadministration has not been studied. Chlordiazepoxide is extensively metabolized by hepatic microsomal enzymes. Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. When combined with nirmatrelvir/ritonavir, the activity of chlordiazepoxide may be increased. Use with caution, consider dose reduction and monitor for adverse effects. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Ciclesonide can be administered with nirmatrelvir/ritonavir without dose adjustment. Ciclesonide is a pro-drug activated by esterases in the lungs to des-ciclesonide which then undergoes CYP3A4-mediated metabolism. Coadministration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 7 days) with orally inhaled ciclesonide (320 µg once daily) did not alter ciclesonide but resulted in a 3.5-fold increase in the AUC and a 2-fold increase in the Cmax of des-ciclesonide. However, given that ciclesonide is mainly absorbed by the lungs, it is characterized by a lower potential to cause systemic effects compared to some other inhaled corticosteroids. The US product label for Paxlovid does not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression. However, given the short duration of nirmatrelvir/ritonavir treatment, this risk is considered to be low. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration with nirmatrelvir/ritonavir has not been studied. Ciclosporin is metabolized by CYP3A4 and plasma concentrations of ciclosporin are expected to increase due to inhibition of CYP3A4 by nirmatrelvir/ritonavir. This could increase or prolong its therapeutic and adverse events. Coadministration with a ritonavir-boosted HIV protease inhibitor has been reported to increase ciclosporin concentrations and profoundly prolong half-life. If coadministered, it is stressed that management of this interaction is challenging and would require dosage adjustment and therapeutic drug monitoring of ciclosporin which may not be possible given the short duration of nirmatrelvir/ritonavir treatment. An alternative COVID treatment will need to be considered. However, if frequent therapeutic drug monitoring for ciclosporin is available, an empiric dose reduction of ciclosporin has been suggested (reduce total daily dose by 80% and consider administering once daily) and to start nirmatrelvir/ritonavir 12 hours after the last dose of ciclosporin. Continue at reduced dose during treatment with nirmatrelvir/ritonavir (days 1-5). Ciclosporin concentrations should be assessed on day 6 or 7 and repeated every 2-4 days. If concentrations are supratherapeutic, the current ciclosporin dose should be reduced. If concentrations are therapeutic, the current ciclosporin dose should be continued. If concentrations are subtherapeutic, increase the ciclosporin daily dose and consider resumption of twice daily dosing. In all cases, repeat ciclosporin concentration monitoring after 2-4 days and continue to dose adjust accordingly.

Coadministration has not been studied. Cilostazol is extensively metabolised by CYP3A4 and CYP2C19 and to a lesser extent CYP1A2. Nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4 and is expected to increase the pharmacological activity of cilostazol. Product labels for cilostazol recommend a dose reduction to 50 mg twice daily in patients receiving strong CYP3A4 inhibitors. The usual dose of cilostazol should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as the inhibitory effect of ritonavir is expected to last up to 3 days after completing nirmatrelvir/ritonavir.

Coadministration has not been studied and is contraindicated. Cisapride is metabolized by CYP3A4. Nirmatrelvir/ritonavir may increase cisapride concentrations which may result in serious and/or life-threatening reactions such as cardiac arrhythmias. Coadministration should be avoided. Pause cisapride and restart 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Nirmatrelvir /ritonavir could potentially increase citalopram concentrations although to a limited extent. The potential limited increase in citalopram exposure is not expected to increase the risk of QT interval prolongation. No a priori dosage adjustment is recommended.

Coadministration with nirmatrelvir/ritonavir has not been studied. Coadministration with ritonavir increased clarithromycin AUC and Cmax by 77% and 31%; AUC and Cmax of 14-OH clarithromycin decreased by 100% and 99%. Due to the large therapeutic window of clarithromycin no dose reduction should be necessary in patients with normal renal function. Clarithromycin doses greater than 1 g per day should not be coadministered with ritonavir dosed as a pharmacokinetic enhancer. Product labels recommend a dose reduction of clarithromycin for patients with impaired renal function (Clcr 30-60 mL/min, dose reduce clarithromycin by 50%; CLcr less than 30 mL/min, dose reduce clarithromycin by 75%). After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Clobazam is metabolised by CYP3A4 (major) and CYP2B6 and CYP2C19 (minor) to the active metabolite N-desmethylclobazam, which is metabolised by CYP2C19. Inhibition of CYP3A4 by nirmatrelvir/ritonavir may increase clobazam exposure and prolong the duration of its effect, whereas induction of CYP2C19 by ritonavir may decrease N-desmethylclobazam. The net effect of these interactions is unknown, however, given that induction reaches maximal effect after several days, any impact on enzyme induction as a result of nirmatrelvir/ritonavir is unlikely to be significant due to the short duration of therapy. Use with caution, consider dose reduction and monitor for adverse effects. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by nirmatrelvir/ritonavir. Coadministration with strong inhibitors is generally not recommended due to the risk of Cushing’s syndrome and adrenal axis suppression. However, given the short duration of nirmatrelvir/ritonavir treatment, this risk is considered to be low. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration has not been studied. Clomipramine is metabolized by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolized by CYP2D6. Coadministration could potentially increase clomipramine concentrations, although to a moderate extent which is not expected to significantly increase the risk of QT interval prolongation related to clomipramine. Patients should be advised of the potential for increased drowsiness. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration has not been studied and is contraindicated in the European product label for nirmatrelvir/ritonavir, but the American product label advises a dose decrease for clonazepam may necessary and recommends clinical monitoring. Clonazepam is metabolized by CYP3A4. Inhibition of CYP3A4 by ritonavir may increase clonazepam concentrations and increase the risk of extreme sedation and respiratory depression. Consider an alternative COVID-19 treatment.

Coadministration with nirmatrelvir/ritonavir has not been studied but is likely to reduce the effect of clopidogrel. Coadministration should be avoided in patients at very high-risk of thrombosis, e.g. at least within 6 weeks of coronary stenting. However, other conditions (e.g. clopidogrel used as an alternative to aspirin in intolerant patients or when used outside the critical period post coronary stenting associated with a higher risk of coronary artery stent thrombosis) may tolerate a reduced effect for the short duration of nirmatrelvir/ritonavir treatment and it may be possible to maintain some patients on clopidogrel during treatment with nirmatrelvir/ritonavir. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Coadministration of clopidogrel and ritonavir-boosted HIV protease inhibitors has been evaluated in clinical studies and showed that ritonavir decreased the AUC and Cmax of clopidogrel’s active metabolite. Importantly, the decrease in clopidogrel’s active metabolite lead to insufficient inhibition of platelet aggregation in 44% of the patients treated with clopidogrel and ritonavir. The inhibition of platelet aggregation has been shown to be unaltered when prasugrel was coadministered with ritonavir; therefore, prasugrel could be used with nirmatrelvir/ritonavir. The management of this interaction requires to take into account whether or not a transient loss of clopidogrel efficacy during the short duration of nirmatrelvir/ritonavir treatment is acceptable. The initial period (at least 6 weeks) post coronary stenting represents a high-risk situation which does typically warrant a transition to prasugrel or, if this is not possible, an alternative COVID-19 treatment should be considered. However, a transient loss in efficacy (and therefore maintaining clopidogrel treatment) may be acceptable for other clinical situations.

Coadministration with nirmatrelvir/ritonavir has not been studied but is likely to reduce the effect of clopidogrel. Avoid in patients at very high-risk of thrombosis, e.g. at least within 6 weeks of coronary stenting. Other conditions may tolerate reduced effect for the short duration of nirmatrelvir/ritonavir treatment. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Coadministration of clopidogrel and ritonavir-boosted HIV protease inhibitors has been evaluated in clinical studies and showed that ritonavir decreased the AUC and Cmax of clopidogrel’s active metabolite. Importantly, the decrease in clopidogrel’s active metabolite lead to insufficient inhibition of platelet aggregation in 44% of the patients treated with clopidogrel and ritonavir. The inhibition of platelet aggregation has been shown to be unaltered when prasugrel was coadministered with ritonavir; therefore, prasugrel could be used with nirmatrelvir/ritonavir. The management of this interaction requires to take into account whether or not a transient loss of clopidogrel efficacy during the short duration of nirmatrelvir/ritonavir treatment is acceptable. The initial period (at least 6 weeks) post coronary stenting represents a high-risk situation which does typically warrant a transition to prasugrel or, if this is not possible, an alternative COVID-19 treatment should be considered. A transient loss in efficacy (and therefore maintaining clopidogrel treatment) may be acceptable for other clinical situations.

Coadministration has not been studied and should be avoided. Clorazepate is rapidly converted to nordiazepam which is then metabolized to oxazepam by CYP3A4. Nirmatrelvir/ritonavir could potentially increase nordiazepam exposure. This could increase the risk of extreme sedation and respiratory depression and this effect could be prolonged due to the very long half-life of the active metabolite. Coadministration should be avoided. Given the mechanism-based inhibition of nirmatrelvir/ritonavir, if it is decided to pause clorazepate during nirmatrelvir/ritonavir treatment, clorazepate should be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration has not been studied and is contraindicated in the European product label for Paxlovid due to the potential for serious and/or life-threatening adverse effects (i.e., serious haematological abnormalities). Clozapine is metabolized by CYPs 1A2, 2C19, 3A4, and to a lesser extent by CYPs 2C9 and 2D6. Nirmatrelvir/ritonavir could potentially increase clozapine exposure. The American product label for Paxlovid advises if coadministration is necessary to consider reducing the clozapine dose and to monitor for adverse reactions. Consider an alternative COVID-19 treatment.

Coadministration with nirmatrelvir/ritonavir has not been studied. Colchicine is a CYP3A4 and P-gp substrate. Coadministration of ritonavir (100 mg twice daily for 5 days) and colchicine (0.6 mg single dose) increased colchicine Cmax and AUC by 2.7-fold and 3.5-fold, respectively. In addition, there is the potential effect of inflammation to increase colchicine exposure so extreme caution is necessary. Unless there is a compelling reason to administer (with dose reduction) coadministration is not recommended. Note, coadministration of colchicine and P-gp inhibitors or strong CYP3A4 inhibitors is contraindicated in patients with renal or hepatic impairment.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Colesevelam is not metabolised and does not interfere with P450 enzymes. Nirmatrelvir/ritonavir undergoes CYP3A4 metabolism. However, given that colesevelam can reduce the gastrointestinal absorption of some drugs, colesevelam should be administered at least four hours before or after nirmatrelvir/ritonavir to minimize the risk of reduced absorption.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Colestyramine is not absorbed systemically. Nirmatrelvir/ritonavir undergoes CYP3A4 metabolism. However, given that colestyramine can reduce the gastrointestinal absorption of some drugs, nirmatrelvir/ritonavir should be administered at least 1 hour before or 4-6 hours after colestyramine to minimize the risk of reduced absorption.

Coadministration of dabigatran (75 mg single dose) and nirmatrelvir/ritonavir (300/100 mg twice daily for three doses) increased dabigatran Cmax and AUC by 133% and 94% (n=24). If nirmatrelvir/ritonavir treatment is needed, consider adjusting dabigatran dosage according to risk, indication and current dose. For treatment of atrial fibrillation with standard dabigatran dose (i.e., 150 mg twice daily), reduce dabigatran to 110 mg twice daily in patients with normal renal function and to 75 mg twice daily in patients with moderate renal impairment. For treatment of atrial fibrillation with low dose dabigatran (i.e., 110 mg twice daily), continue low dose on a case-by-case basis. For patients at high risk of venous/arterial thromboembolism (VTE/ATE), consider switching from dabigatran to low molecular weight heparin (LMWH); patients with a lower risk of VTE/ATE could be switched to aspirin on a case-by-case basis. The usual dabigatran treatment should be resumed 3 days after the last dose of nirmatrelvir/ritonavir. [These dosing recommendations are based on the interaction between dabigatran and darunavir/cobicistat as this is of a similar magnitude to ritonavir given for a short duration (i.e., only an inhibitory effect on P-gp with short duration ritonavir administration vs a mixed inhibitory/inducing effect with long-term ritonavir use)].

Coadministration has not been studied. Darifenacin is metabolized by CYP3A4 and CYP2D6. Nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4 and is expected to increase darifenacin concentrations. A 5-fold increase in darifenacin exposure was seen with ketoconazole (a strong inhibitor of CYP3A4) and the magnitude of the interaction could be even more pronounced in CYP2D6 poor metabolizer individuals. The European product label for darifenacin contraindicates its use with potent CYP3A4 inhibitors, but the American product labels for darifenacin and Paxlovid recommend that the daily dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification. Patients should be informed about the potential occurrence of adverse effects (i.e. gastro-intestinal due to the higher dose of ritonavir).

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification. No interaction is expected with emtricitabine. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and ritonavir, a P-gp inhibitor, is expected to increase the absorption of tenofovir alafenamide, thereby increasing the systemic concentration of tenofovir. However, this increase is not problematic as tenofovir alafenamide has a good safety profile.

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification. Patients should be informed about the potential occurrence of adverse effects.

Coadministration has not been studied and is not recommended. Dasatinib is metabolised by CYP3A4 and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Ketoconazole (a strong CYP3A4 inhibitor) increased dasatinib AUC by 5-fold. A similar effect is expected with nirmatrelvir/ritonavir and coadministration with strong CYP3A4 inhibitors is not recommended. Nirmatrelvir/ritonavir and dasatinib should not be coadministered in patients with accelerated or blast phase chronic myelogenous leukaemia (CML). For this particular indication, maintain dasatinib treatment and use an alternative COVID-19 therapy. In chronic phase CML, the decision to pause or dose adjust dasatinib should be made in conjunction with the patient’s oncologist. Restart dasatinib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Alternatively, if coadministration is necessary, consider reducing dasatinib dose to 40 mg (in patients taking dasatinib 140 mg once daily) and to 20 mg (in patients taking dasatinib 100 or 70 mg once daily) with close monitoring for toxicity.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent by UGT1A3; CYP-mediated metabolism appears to be minor (~8%). Nirmatrelvir/ritonavir is metabolized by CYP3A. Deferasirox is a weak inducer of CYP3A4 and was shown to reduce midazolam exposure by 17%, although it is unlikely to significantly decrease nirmatrelvir/ritonavir concentrations. Although ritonavir may induce glucuronidation, given that induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment, no effect on deferasirox is anticipated.

Coadministration has not been studied. Delamanid is primarily metabolised by albumin to DM-6705; metabolism of DM-6705 to other metabolites is thought to involve pathways mediated by CYP enzymes, including CYP3A4. Coadministration of delamanid and a ritonavir-boosted HIV protease inhibitor (lopinavir/ritonavir 400/100 mg twice daily for 14 days) increased the exposure of delamanid metabolite DM-6705 by 30%. Due to the risk of QTc prolongation associated with DM-6705, if coadministration is necessary, ECG monitoring is recommended. Consider delaying the next due dose of delamanid if it falls during nirmatrelvir/ritonavir treatment until after nirmatrelvir/ritonavir treatment has been completed.

Coadministration with nirmatrelvir/ritonavir has not been studied. Desipramine is metabolized by CYP2D6. Nirmatrelvir/ritonavir could potentially increase desipramine concentrations, although to a limited extent, as ritonavir is a weak inhibitor of CYP2D6 at a dose of 100 mg. Coadministration of ritonavir (100 mg twice daily) and desipramine (50 mg single dose) increased desipramine AUC by 26%. This pharmacokinetic change is not expected to increase the risk of QT interval prolongation. No a priori dosage adjustment is recommended.

Coadministration with a desogestrel-containing combined oral contraceptive (COC) has not been studied. Desogestrel is a prodrug that is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration may increase etonogestrel exposure. When used in a combined pill, the estrogen component is expected to be reduced. This is unlikely to impair contraceptive efficacy, particularly considering the short duration of nirmatrelvir/ritonavir treatment, though it may increase the risk of irregular bleeding. However, it should be noted that the Paxlovid product labels state patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with nirmatrelvir/ritonavir, and until one menstrual cycle after stopping nirmatrelvir/ritonavir.

Coadministration has not been studied. Nirmatrelvir/ritonavir is metabolized by CYP3A4 and strongly inhibits CYP3A4. Dexamethasone is a substrate of CYP3A4 and concentrations are expected to increase due to inhibition of CYP3A4 which may increase the risk for Cushing’s syndrome and adrenal suppression. Model-based predictions with voriconazole (a strong CYP3A4 inhibitor) suggest an increase of 2.44-fold and 2.60-fold for dexamethasone Cmax and AUC. A similar effect is expected with nirmatrelvir/ritonavir. The dose of dexamethasone should be reduced by 50% and the usual dose resumed 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition by ritonavir takes several days to resolve. Dexamethasone is a dose-dependent inducer of CYP3A4 and is a moderate CYP3A4 inducer at doses above 16 mg and may decrease nirmatrelvir/ritonavir concentrations, although to a limited extent. Drug-drug interactions studies with efavirenz (a moderate inducer) and darunavir (an HIV protease inhibitor) reduced darunavir AUC by 10% when darunavir was administered with twice daily ritonavir. Efavirenz had a more pronounced effect on darunavir when administered with ritonavir 100 mg once daily suggesting that twice daily ritonavir may be sufficient to counteract moderate induction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nirmatrelvir/ritonavir is metabolized by CYP3A4 and strongly inhibits CYP3A4. Dexamethasone is a weak CYP3A4 inducer at a low dose but is unlikely to have a clinically significant effect on nirmatrelvir/ritonavir. Product labels for dexamethasone do not recommend coadministration of strong CYP3A4 inhibitors with dexamethasone due to the risk of Cushing’s syndrome, but based on the low dose of dexamethasone used in COVID-19 treatment and given the short duration of nirmatrelvir/ritonavir treatment, this risk is considered to be low. A retrospective review of published case reports of individuals developing a Cushing’s syndrome while treated concurrently with a boosted HIV protease inhibitor and inhaled corticosteroids indicated that this adverse effect tended to occur after several months (and more rarely 2 weeks) of concurrent administration of these drugs.

Coadministration has not been studied. Dexamfetamine is metabolized by CYP2D6 to some extent, whereas a large part is excreted unchanged. Nirmatrelvir/ritonavir is metabolized by CYP3A and inhibits CYP3A. Coadministration could potentially increase dexamfetamine exposure (caution as non-linear pharmacokinetics). The European product label for Paxlovid recommends careful monitoring of adverse effect when nirmatrelvir/ritonavir is coadministered with amphetamine and its derivatives. Alternatively, consider pausing dexamfetamine and restarting 3 days after completing nirmatrelvir/ritonavir treatment.

Coadministration has not been studied. Diamorphine is rapidly metabolized by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). As ritonavir induces glucuronidation, nirmatrelvir/ritonavir could potentially decrease the analgesic effect although to a moderate extent as induction of glucuronidation may increase the formation of the active metabolite. Morphine (and its metabolites) are substrates of P-gp and coadministration with nirmatrelvir/ritonavir may potentiate the effects of opiate in the CNS (via inhibition of P-gp by ritonavir at the blood-brain barrier). Monitor for signs of opiate toxicity.

Coadministration has not been studied and is contraindicated in the European product label for Paxlovid. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4). Nirmatrelvir/ritonavir could potentially increase diazepam exposure by inhibition of CYP3A4. This could increase the risk of extreme sedation and respiratory depression and this effect could be prolonged due to the very long half-life of the active metabolite. Coadministration should be avoided. Given the mechanism-based inhibition of nirmatrelvir/ritonavir, if it is decided to pause diazepam during nirmatrelvir/ritonavir treatment, diazepam should be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration has not been studied but is expected to increase digoxin concentrations due to P-gp inhibition by ritonavir. The management of this drug interaction would require to individualize the digoxin dosage or dosing schedule based on the treatment indication, the patient’s renal function (digoxin has an elimination half-life of 36 hours in patients with normal renal function but is longer in patients with impaired renal function), and the plasma digoxin concentration. Thus, coadministration of digoxin and nirmatrelvir/ritonavir would require evaluation of the risk/benefit if sufficient information on how to adapt the dosage or dosing schedule are not available.

Coadministration is contraindicated as it may increase dihydroergotamine concentrations which may result in serious and/or life-threatening reactions such as acute ergot toxicity. Dihydroergotamine should be paused during nirmatrelvir/ritonavir treatment and for at least 3 days after the last dose of nirmatrelvir/ritonavir. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect takes several days to resolve.

Coadministration has not been studied. Diltiazem is metabolized by CYP3A4 and CYP2D6, and is a moderate inhibitor of CYP3A4. Coadministration may increase diltiazem concentrations and a dose reduction of 50% or taking the dose every other day could be considered. However, a dose adjustment could be optional given that patients can be advised to monitor for symptoms of hypotension, flushing and oedema and, if necessary, to temporarily pause the antihypertensive drug. If the dose is adjusted, the usual dose of diltiazem should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as the inhibitory effect of ritonavir is expected to last up to 3 days after completing nirmatrelvir/ritonavir.

Coadministration has not been studied and is not recommended. Disopyramide is metabolized by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Coadministration may increase disopyramide exposure and thereby the risk of cardiac arrhythmias. Consider an alternative COVID-19 treatment.

Coadministration has not been studied. Disulfiram is converted to an active metabolite by mainly by CYP3A4, with UGTs also involved in its metabolism. Nirmatrelvir/ritonavir is metabolized by CYP3A. Nirmatrelvir/ritonavir is a strong inhibitor of CYP3A4. Ritonavir may induce glucuronidation, but induction reaches maximal effect after several days. When given for 5 days nirmatrelvir/ritonavir may inhibit the conversion of disulfiram to its active metabolite, leading to a lack of disulfiram-associated inhibition of alcohol dehydrogenase activity. Monitor for clinical effect as it is unlikely to be effective in deterring alcohol use. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect takes several days to resolve.

Coadministration has not been studied and is not recommended. Dofetilide is metabolized to a small degree by CYP3A4 and therefore nirmatrelvir/ritonavir could potentially increase dofetilide exposure and thereby increase the risk of cardiac arrhythmias. Consider an alternative COVID-19 treatment.

Coadministration has not been studied and is contraindicated with potent CYP3A4 inhibitors, such as ritonavir. Domperidone is mainly metabolized by CYP3A4. Nirmatrelvir/ritonavir could potentially increase domperidone exposure and increase the risk of cardiac adverse effects. Coadministration should be avoided. Pause domperidone and restart 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. After stopping nirmatrelvir/ritonavir, the CYP3A4 inhibitory effect of nirmatrelvir/ritonavir is predicted to mostly disappear after 3 days.

Coadministration with nirmatrelvir/ritonavir has not been studied. Doravirine is metabolized by CYP3A4 and coadministration may increase doravirine concentrations due to inhibition of CYP3A4 by nirmatrelvir/ritonavir. Coadministration with ritonavir (100 mg twice daily) increased doravirine AUC by 3.5-fold and Cmin by 2.9-fold. However, no dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure.

Coadministration with nirmatrelvir/ritonavir has not been studied. Doravirine is metabolized by CYP3A4 and coadministration may increase doravirine concentrations due to inhibition of CYP3A4 by nirmatrelvir/ritonavir r. Coadministration with ritonavir (100 mg twice daily) increased doravirine AUC by 3.5-fold and Cmin by 2.9-fold. However, no dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure. No interaction is expected with lamivudine. Tenofovir-DF (the prodrug of tenofovir) is a substrate of P-gp and ritonavir, a P-gp inhibitor, is expected to increase the absorption of tenofovir-DF, thereby increasing the systemic concentration of tenofovir. However, this increase is unlikely to be significant given the short duration of nirmatrelvir/ritonavir treatment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxylamine is metabolised primarily by CYP2D6, CYP1A2 and CYP2C9. Nirmatrelvir/ritonavir is metabolized by CYP3A. Doxylamine is unlikely to affect nirmatrelvir/ritonavir metabolism. Ritonavir is a weak inhibitor of CYP2D6 at a dose of 100 mg and could potentially increase doxylamine concentrations although to a limited extent. Although in vitro data indicate that ritonavir induces CYP1A2 and in vivo data indicate that ritonavir is a weak inducer of CYP2C9, this is unlikely to be clinically significant given that induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment. No a priori dosage adjustment is recommended.

Coadministration has not been studied but is contraindicated as it can cause serious adverse effects. Dronedarone is primarily metabolized by CYP3A4. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) increased dronedarone exposure by 17-fold. A similar effect is expected with nirmatrelvir/ritonavir. Use an alternative COVID-19 treatment.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolised in part by CYP3A4. Coadministration is predicted to increase drospirenone exposure. When used in a combined pill, the estrogen component is expected to be reduced. This is unlikely to impair contraceptive efficacy, particularly considering the short duration of nirmatrelvir/ritonavir treatment, though it may increase the risk of irregular bleeding. However, it should be noted that the Paxlovid product labels state patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with nirmatrelvir/ritonavir, and until one menstrual cycle after stopping nirmatrelvir/ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Durvalumab is a monoclonal IgG1k antibody; elimination is similar to endogenous IgG and occurs primarily via intracellular catabolism. Nirmatrelvir/ritonavir is metabolized by CYP3A.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nirmatrelvir/ritonavir is metabolized by CYP3A. Echinacea has a selective effect on CYP3A4 activity (inhibition of intestinal CYP3A4 and induction of hepatic CYP3A4) and its effect on the net exposure of a CYP3A4 substrate will depend on the extraction of the drug at the intestinal and hepatic sites. Coadministration of Echinacea and a ritonavir-boosted HIV protease inhibitor (lopinavir/ritonavir) showed no clinically significant effect of Echinacea on lopinavir or ritonavir concentrations (most likely due to the potent CYP3A inhibition by ritonavir). Based on these data, Echinacea is unlikely to alter nirmatrelvir/ritonavir exposure.

Coadministration has not been studied. Edoxaban is a substrate for P-gp, coadministration is expected to increase edoxaban concentrations due to P-gp inhibition by ritonavir. If nirmatrelvir/ritonavir treatment is needed, consider adjusting edoxaban dosage according to risk, indication and current dose. For treatment of atrial fibrillation with standard edoxaban dose (i.e., 60 mg once daily), reduce edoxaban to 30 mg once daily. For treatment of atrial fibrillation with low dose edoxaban (i.e., 30 mg once daily), continue low dose on a case-by-case basis. For patients at high risk of venous/arterial thromboembolism (VTE/ATE), consider switching from edoxaban to low molecular weight heparin (LMWH); patients with a lower risk of VTE/ATE could be switched to aspirin on a case-by-case basis. The usual edoxaban treatment should be resumed 3 days after the last dose of nirmatrelvir/ritonavir.

Coadministration has not been studied. Efavirenz is mainly metabolised by and is a moderate inducer of CYP3A4. Nirmatrelvir/ritonavir is not expected to significantly alter efavirenz pharmacokinetics. Available studies with ritonavir-boosted HIV protease inhibitors indicate that efavirenz can reduce ritonavir exposure, particularly when ritonavir is given once daily. However, twice daily administration of ritonavir is able to counteract efavirenz inducing effect. Thus, nirmatrelvir given with ritonavir 100 mg twice daily is not expected to be significantly reduced by efavirenz.

Coadministration of elbasvir/grazoprevir with ritonavir is contraindicated. Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as ritonavir, may increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Consider pausing elbasvir/grazoprevir during and up to 3 days after the completion of nirmatrelvir/ritonavir treatment. However, the risk/benefit of prescribing nirmatrelvir/ritonavir should be carefully evaluated in patients with suboptimal adherence to elbasvir/grazoprevir as further treatment interruption could potentially lead to HCV treatment failure.

Coadministration has not been studied but use of eletriptan is contraindicated within at least 72 hours of nirmatrelvir/ritonavir. Eletriptan is metabolized by CYP3A4 and is unlikely to cause clinically important drug interactions mediated by CYP enzymes. Nirmatrelvir/ritonavir is metabolized by CYP3A and inhibits CYP3A. Coadministration is expected to increase eletriptan concentrations. Coadministration of eletriptan within at least 72 hours of nirmatrelvir/ritonavir is contraindicated in the American product label for Paxlovid due to potential for serious adverse reactions including cardiovascular and cerebrovascular events. However, if deemed clinically appropriate to do so, wait at least 12 hours after the last eletriptan dose before starting nirmatrelvir/ritonavir. Given inhibition of CYP3A4 by nirmatrelvir/ritonavir take several days to resolve, resume eletriptan treatment 3 days after the last dose of nirmatrelvir/ritonavir.