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 taking into consideration the planned duration of nirmatrelvir/ritonavir treatment. 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. Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9, and to a lesser extent by CYP3A4 and CYP2B6. Nirmatrelvir/ritonavir inhibits CYP3A but induces CYP2C19 and CYP2C9, the main enzymes contributing to abrocitinib metabolism. When used for an extended treatment duration (10 days or longer), nirmatrelvir/ritonavir could potentially decrease abrocitinib exposure due to induction of CYP2C19 and CYP2C9. The product label for abrocitinib does not recommend coadministration with moderate or strong inducers of both CYP2C19 and CYP2C9 and therefore coadministration should be avoided. Consider an alternative COVID-19 treatment.

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 is required, the product label for acalabrutinib advises to stop temporarily acalabrutinib treatment. Depending on the duration of nirmatrelvir/ritonavir treatment, the decision to pause acalabrutinib should be made in conjunction with the patient’s oncologist. 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 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 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. A clinically significant interaction is unlikely and no dose adjustment is required when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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 in the British and American product labels for Paxlovid (5 day administration), whereas the European product label for Paxlovid (5 day administration) advises that coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it. 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. 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 (5 day administration) 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. Note, the European product label for Paxlovid (5 day administration) recommends to reduce the apixaban dose by 50% for apixaban doses of 5 mg or 10 mg twice daily and to avoid coadministration in patients already taking apixaban 2.5 mg twice daily.

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. Artemether is rapidly metabolized by CYP3A4 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, a ritonavir-boosted HIV protease inhibitor (lopinavir/ritonavir) has been shown to reduce artemether and DHA exposures by 40% due to induction of UGTs. A similar interaction may occur when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). Use with caution as the reduction in DHA exposure may result in the potential loss of antimalarial efficacy.

Coadministration has not been studied. 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. A similar interaction may occur when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). Use with caution as the reduction in DHA exposure may result in the potential loss of antimalarial efficacy.

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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 when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer).

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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. When nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer), pause atorvastatin during nirmatrelvir/ritonavir treatment if possible. 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. Note, the British and American product labels for Paxlovid (5 day administration) advise that atorvastatin does not need to be held prior to or after completing Paxlovid, whereas the European product label for Paxlovid (5 day administration) advises to use the lowest possible dose of atorvastatin.

Coadministration has not been studied. 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. A similar interaction may occur when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). The clinical relevance of the interaction 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 (5 day administration). Given the relatively 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. No clinically significant interaction is expected when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer) and 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.

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. In addition, chronic or high doses of betamethasone may decrease nirmatrelvir/ritonavir plasma concentrations due to CYP3A4 induction with the possible loss of therapeutic effect and development of resistance. However, this risk is expected to be lower when using lower doses of betamethasone. Furthermore, the risk of Cushing’s syndrome is less likely to occur when using betamethasone at a low dose or for a short treatment duration as compared to higher doses and long treatment duration. The US product label for Paxlovid (5 day administration) does not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression. However, 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. Therefore, the risk of developing a Cushing’s syndrome is expected to be low when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer. However, prescribers should be aware of and to look out for signs of systemic corticosteroid side effects.

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 American product label for Paxlovid (5 days administration) advises to discontinue bosentan at least 36 hours prior to initiation of nirmatrelvir/ritonavir, whereas the European product label for Paxlovid (5 day administration) advises to avoid concomitant use. If nirmatrelvir/ritonavir is planned to be administered for longer than 10 days, bosentan can be resumed at 62.5 mg once daily or every other day based on individual tolerability after at least 10 days of nirmatrelvir/ritonavir therapy.

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 taking into consideration the planned duration of nirmatrelvir/ritonavir treatment.

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. No a priori dosage adjustment is required. 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. The European product label for Paxlovid (5 day administration) does not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression. However, the British and American product labels for Paxlovid (5 day administration) advise that the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is low. However, the risk of developing a Cushing syndrome is also considered to be low for inhaled budesonide used in COVID-19 treatment (2 weeks) with an extended treatment duration (10 days or longer) of nirmatrelvir/ritonavir. 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. The European product label for Paxlovid (5 day administration) does not recommend coadministration due to the risk of Cushing’s syndrome and adrenal axis suppression. However, the British and American product labels for Paxlovid (5 day administration) advise that the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is 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. Therefore, the risk of developing a Cushing’s syndrome is expected to be low when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). However, prescribers should be aware of and to look out for signs of systemic corticosteroid side effects.

Coadministration is not recommended. Bulevirtide is catabolized by peptidases and elimination occurs through binding to NTCP. Coadministration with NTCP inhibitors (e.g. ritonavir) is not recommended as it may alter bulevirtide elimination. Use an alternative COVID-19 treatment.

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. When used for an extended treatment duration (10 days or longer), nirmatrelvir /ritonavir could potentially decrease bupropion concentrations, although to a limited extent with a ritonavir dose of 100 mg. Monitor for an adequate response to bupropion.

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 taking into consideration the planned duration of nirmatrelvir/ritonavir treatment.

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 with nirmatrelvir/ritonavir for an extended treatment duration (10 days or longer) has not been studied but 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 Paxlovid (5 day administration) contraindicates coadministration with strong CYP3A4 inhibitors, whereas the British and American product labels advise dose modification of cariprazine. Refer to the product labels 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 taking into consideration the planned duration of nirmatrelvir/ritonavir treatment. 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. 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 British and American product labels for Paxlovid (5 day administration) state that the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is low, but also advise that alternative corticosteroids (e.g., beclomethasone, prednisone, prednisolone) should be considered. 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. Therefore, the risk of developing a Cushing’s syndrome is expected to be low when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). However, prescribers should be aware of and to look out for signs of systemic corticosteroid side effects.

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. An alternative COVID treatment will need to be considered if therapeutic drug monitoring cannot be put in place. 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. 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 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. 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, 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. Therefore, the risk of developing a Cushing’s syndrome is expected to be low when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer. However, prescribers should be aware of and to look out for signs of systemic corticosteroid side effects.

Coadministration has not been studied. Clonazepam is metabolized by CYP3A4. Inhibition of CYP3A4 by ritonavir may increase clonazepam concentrations and increase the risk of extreme sedation and respiratory depression. A dose decrease of clonazepam may be needed when coadministered with Paxlovid and careful monitoring of therapeutic and adverse effects is recommended.

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) may tolerate a reduced effect for a short duration 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 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.

Coadministration with nirmatrelvir/ritonavir has not been studied but is likely to reduce the effect of clopidogrel. 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 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.

Coadministration has not been studied and is contraindicated in the European product label for Paxlovid (5 day administration). 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 is contraindicated in the European product label for Paxlovid (5 day administration), whereas the British and American product labels for Paxlovid (5 day administration) advise a dose decrease of clorazepate may be needed and recommend careful monitoring of therapeutic and adverse effects. Given the mechanism-based inhibition of nirmatrelvir/ritonavir, if it is decided to pause or reduce the dose of clorazepate during nirmatrelvir/ritonavir treatment, the previous dose of clorazepate should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as CYP3A4 inhibition takes several days to resolve upon discontinuation of nirmatrelvir/ritonavir.

Coadministration has not been studied. 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 British and American product labels for Paxlovid (5 day administration) advise if coadministration is necessary to consider reducing the clozapine dose and to monitor for adverse reactions. Whereas, the European product label for Paxlovid (5 day administration) advises that given the risk of increase in clozapine exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.

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 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). Ritonavir has a mixed inhibitory/inducing effect on P-gp. The magnitude of the interaction is expected to be attenuated when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer) as the inducing effect on P-gp (which reaches maximal effect over time) will attenuate the inhibitory effect on P-gp. Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before ritonavir alone (100 mg once daily administered at steady state) was studied in HIV negative subjects. Simultaneous administration did not significantly change dabigatran PK. Administration 2 hours before ritonavir decreased dabigatran AUC by 29% and Cmax by 27% (n=16). These results suggest that dabigatran can be administered simultaneously with ritonavir in patients with no renal impairment. Data with verapamil (a P-gp inhibitor) and dabigatran suggest caution is needed in patients with mild or moderate renal impairment as the dabigatran dose might need to be reduced in presence of a P-gp inhibitor such as nirmatrelvir/ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment.

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 and the European label for Paxlovid (5 day administration) advises coadministration should not be used unless a multidisciplinary consultation can be obtained to safely guide it. However, the British and American product labels for darifenacin and Paxlovid (5 day administration) recommend that the daily dose of darifenacin should not exceed 7.5mg when coadministered with Paxlovid (refer to the darifenacin labels for more information).

Coadministration has not been studied. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment with no dosage modification when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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 when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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 when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer). 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 taking into consideration the planned duration of nirmatrelvir/ritonavir treatment. 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. 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. However, when nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer), ritonavir may induce glucuronidation and decrease deferasirox exposure, leading to a potential decrease in deferasirox efficacy. Patient serum concentrations should be monitored and a deferasirox dose increase may be required to maintain therapeutic effect. The American product label for deferasirox advises to consider increasing the initial dose of deferasirox by 50%.

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.

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, though it may increase the risk of irregular bleeding. However, it should be noted that the Paxlovid product labels (5 day administration) 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 this risk is considered to be low with an extended treatment duration (10 days or longer) of nirmatrelvir/ritonavir. 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 (5 day administration) 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 and is contraindicated in the European product label for Paxlovid (5 days administration). Diazepam is metabolized to nordiazepam (by CYP3A4 and CYP2C19) 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 is contraindicated in the European product label for Paxlovid (5 day administration), whereas the British and American product labels for Paxlovid (5 day administration) advise a dose decrease of diazepam may be needed and recommend careful monitoring of therapeutic and adverse effects. Given the mechanism-based inhibition of nirmatrelvir/ritonavir, if it is decided to pause or reduce the dose of diazepam during nirmatrelvir/ritonavir treatment, the previous dose of diazepam should be resumed 3 days after the last dose of nirmatrelvir/ritonavir as CYP3A4 inhibition takes several days to resolve upon discontinuation of nirmatrelvir/ritonavir.

Coadministration has not been studied but is expected to increase digoxin concentrations due to P-gp inhibition by ritonavir. Caution should be exercised when co-administering nirmatrelvir/ritonavir with digoxin. A dose reduction in digoxin may be needed with appropriate monitoring of serum digoxin levels.

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. 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. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. When used for an extended treatment duration (10 days or longer), nirmatrelvir/ritonavir could potentially decrease dipyridamole exposure due to induction of glucuronidation and potentially reduce the antiplatelet effect. Monitor therapeutic effect.

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 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. 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. In vitro data indicate that ritonavir induces CYP1A2 and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. When nirmatrelvir/ritonavir is used for an extended treatment duration (10 days or longer), ritonavir may inhibit CYP2D6 but induce CYP1A2 and CYP2C9. The net effect on doxylamine concentrations is not known. No a priori dosage adjustment is recommended but monitor for therapeutic effect and toxicity.

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, though it may increase the risk of irregular bleeding. However, it should be noted that the Paxlovid product labels (5 day administration) 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.