Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abatacept is a fusion protein consisting of the extracellular domain of human CTLA-4 linked to a modified Fc portion of human IgG1 and is likely to be eliminated via proteolytic catabolism throughout the body. Ritonavir is metabolized by CYP3A4.

Coadministration has been studied and is not recommended. Abemaciclib is metabolized by CYP3A4 and is a substrate of P-gp and BCRP. Clarithromycin (a strong CYP3A4 inhibitor) increased abemaciclib AUC by 3.4-fold and increased the AUC of abemaciclib with its three active metabolites by 2.2-fold. A similar effect is expected with ritonavir. Coadministration should be avoided if possible. If concurrent use is unavoidable, adjust the dose of abemaciclib to 50 mg once daily with close monitoring for signs of toxicity. If the treatment is well tolerated, consider increasing abemaciclib to 50 mg twice daily (for once daily ritonavir boosted regimens).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abiraterone is metabolized by CYP3A4 and SULT2A1. A 15% increase in abiraterone exposure has been reported in presence of ketoconazole (a strong CYP3A4 inhibitor) and a similar effect is expected with ritonavir used as a pharmacokinetic booster, but this is not considered to be clinically relevant.

Coadministration has not been studied. Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9, and to a lesser extent by CYP3A4 and CYP2B6. Ritonavir inhibits CYP3A but induces CYP2C19 and CYP2C9, the main enzymes contributing to abrocitinib metabolism, and could potentially decrease abrocitinib exposure. 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.

Coadministration has not been studied but should be avoided. Acalabrutinib is metabolized by CYP3A4. Itraconazole (a CYP3A4 inhibitor) increased acalabrutinib AUC and Cmax by 5.1- and 3.9-fold, respectively. A similar effect may occur with ritonavir. Increased acalabrutinib concentrations may result in increased toxicity, therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acamprosate is eliminated unchanged in the urine.

Coadministration has not been studied. Acenocoumarol is mainly metabolized by CYP2C9. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster and may decrease acenocoumarol concentrations. Monitor INR. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acetazolamide is primarily excreted unchanged via the kidneys, there is therefore little potential for interaction with ritonavir via modulation of, or competition for metabolic pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aclidinium bromide is rapidly and extensively hydrolyzed (non-enzymatic and enzymatic transformation by esterases and butylrylcholineesterases) to its pharmacologically inactive metabolites with only a minor role for CYP metabolism.

Coadministration has not been studied. Activated charcoal absorbs substances in the stomach and intestines and may decrease absorption of orally administered medicines. If coadministration is required, administration of activated charcoal and ritonavir should be separated by 4 hours. [Note: this interaction is not specific for ritonavir, but for any oral medication taken with activated charcoal.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Adalimumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Adrenaline is rapidly inactivated, mostly in the liver by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). There is therefore little potential for interaction with ritonavir via modulation of, or competition for metabolic or elimination pathways.

Coadministration 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 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.

Coadministration has not been studied but based on the metabolic data there is little potential for pharmacokinetic interactions. African potato was shown to inhibit CYP3A4 and P-gp in vitro and to activate PXR suggesting that inhibition may occur initially followed by induction of CYP3A4 and P-gp when used for extended periods. However, coadministration of African potato with lopinavir/ritonavir in healthy volunteers did not result in significant pharmacokinetic changes suggesting that boosting by ritonavir could offset the inducing effect of African potato. Similarly, no significant effect is expected on the pharmacokinetics of ritonavir.

Coadministration has not been studied. Agomelatine is metabolised predominantly by CYP1A2. Ritonavir used as a pharmacokinetic booster induces CYP1A2 and could potentially decrease agomelatine exposure. Monitor clinical effect and increase dosage if needed.

In vitro studies suggest that albendazole is predominantly metabolised by CYP450 enzymes, including CYP3A4. In a clinical study in 8 healthy volunteers, steady state ritonavir (200 mg twice daily) decreased albendazole and the active metabolite albendazole sulfoxide AUC (73% and 59% respectively) and Cmax (74% and 48% respectively). Co-administration may cause a reduction in the clinical effect of albendazole.

Coadministration has not been studied. Albuvirtide is a peptide which is eliminated by catabolism to its constituent amino acids. Based on data from studies with lopinavir/ritonavir, concentrations of ritonavir decrease but this is not expected to be clinically relevant. Coadministration of albuvirtide (320 mg once weekly intravenous) and oral lopinavir/ritonavir (400/100 mg twice daily) was evaluated in HIV-infected individuals. Albuvirtide exposure was not significantly affected by lopinavir/ritonavir. However, both lopinavir and ritonavir concentrations were lower in presence of albuvirtide compared with lopinavir/ritonavir alone (lopinavir AUC, Cmax and Ctrough decreased by 37%, 33% and 35%, respectively; ritonavir AUC, Cmax and Ctrough decreased by 38%, 39% and 28%, respectively). The mean lopinavir Ctrough in presence of albuvirtide (7.1 µg/ml) remained higher than the minimal lopinavir Ctrough previously associated with efficacy. Furthermore, a randomized, phase 3 study (TALENT study) showed that albuvirtide + lopinavir/ritonavir was non-inferior to the standard second-line regimen lopinavir/ritonavir + zidovudine/tenofovir disoproxil fumarate + lamivudine in HIV infected Chinese individuals suggesting that this interaction has no clinical consequences. In vitro human microsomal studies indicate that albuvirtide has no inducing properties on P450 enzymes. In addition, albuvirtide binds to <1% of serum albumin in the range of clinical concentrations, thus the observed decrease in lopinavir and ritonavir concentrations is unlikely to result from protein binding displacement. However, binding of the albuvirtide-albumin complex to the HIV protease inhibitor cannot be excluded.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alcuronium is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied. Alectinib is metabolised by CYP3A4 to an active metabolite (M4), which is also metabolised by CYP3A4. Alectinib does not inhibit CYP3A4 to a clinically relevant extent. Concentrations of alectinib and M4 may increase due to inhibition of CYP3A4 by ritonavir, although to a modest extent. Posaconazole (a strong CYP3A inhibitor) had only a minor effect on the combined exposure of alectinib and M4 (7% decrease in Cmax; 36% increase in AUC). Monitoring for alectinib toxicity should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alemtuzumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body. Ritonavir is metabolized by CYP3A4. CYP-mediated drug interactions are not expected with alemtuzumab. Note, use of alemtuzumab (marketed as Lemtrada) for the treatment of relapsing remitting multiple sclerosis is contraindicated in patients with HIV infection as it causes prolonged reductions of CD4+ lymphocyte counts.

If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product.

Coadministration is contraindicated as it may increase alfuzosin concentrations and lead to severe hypotension.

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 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. Almotriptan is partly eliminated unchanged in the urine and partly metabolized (mainly via monoamine oxidase-A and to a lesser extent by CYP3A4, CYP2D6 and flavin monooxygenase). Coadministration may increase almotriptan concentrations due to inhibition of CYP3A4. The American product label for almotriptan recommends using an initial almotriptan dose of 6.25 mg with a strong CYP3A4 inhibitor and not exceeding 12.5 mg within a 24 hour period. It also recommends to avoid use of almotriptan and a strong CYP3A4 inhibitor in patients with impaired renal or hepatic function.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Aloe vera is only a weak inhibitor of CYPs in vitro and therefore is unlikely to cause clinically significant interactions. It does not inhibit P-gp and there is no evidence to suggest it impacts UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alogliptin is primarily excreted unchanged in the urine and undergoes negligible CYP-mediated metabolism. Alogliptin was shown to have no inhibitory or inducing effect on CYPs at concentrations achieved with the recommended dose of 25 mg alogliptin.

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 vivo data indicate that ritonavir induces CYP1A2, and coadministration could potentially decrease alosetron exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alpelisib is primarily metabolized by enzymatic hydrolysis to an inactive metabolite, with a minor contribution from CYP3A4. Ritonavir is a strong inhibitor of CYP3A4 and may increase alpelisib concentrations. However, no clinically significant effect is expected as CYP3A4 represents a minor pathway in alpelisib metabolism. A PBPK model predicted coadministration of ritonavir (100 mg twice daily) to increase alpelisib AUC by 1.16-fold. No dose adjustment of alpelisib is necessary and standard dosing can be continued.

Alprazolam metabolism was inhibited following the introduction of ritonavir (2.5-fold increase in AUC), but at steady state no significant inhibitory effect was observed (12% decrease in AUC). Caution is warranted during the first few days of coadministration, before induction of alprazolam metabolism develops.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Following administration, ~80% of circulating alprostadil is rapidly metabolised in the lungs primarily by beta- and omega- oxidation and the resulting metabolites are mainly excreted in urine. Ritonavir is metabolized by CYP3A4. Alprostadil is unlikely to affect CYP enzymes.

Coadministration of ambrisentan (5 mg once daily) and ritonavir (100 mg once daily) did not significantly modify ambrisentan exposure when administered to HIV-negative subjects for 10 days (n=42). 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. 

Coadministration has not been studied. Aminophylline is a complex of theophylline and ethylenediamine and is given for its theophylline activity. Theophylline is mainly metabolized by CYP1A2. In vitro data indicate that ritonavir induces CYP1A2 and may decrease theophylline exposure. Monitor plasma concentrations and increase aminophylline dosage if needed.

Coadministration is contraindicated as it is likely to increase amiodarone concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and therefore might increase amitriptyline exposure, although to a moderate extent. No a priori dosage adjustment is recommended if ritonavir is dosed as a pharmacokinetic booster, however, careful monitoring of therapeutic and adverse effects is recommended with full dose ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amivantamab is a monoclonal IgG1 and is eliminated primarily via intracellular catabolism similarly to endogenous IgG. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4 and ritonavir is predicted to increase amlodipine exposure by ~2-fold based on drug-drug interactions studies with amlodipine and indinavir/ritonavir or paritaprevir/ritonavir. If coadministration is indicated, consider a dose reduction for amlodipine of 50%. Close monitoring is recommended.

Coadministration has not been studied. Amodiaquine is metabolized mainly by CYP2C8 to N-desethylamodiaquine, an active metabolite but less potent than the parent compound. Ritonavir dosed as a pharmacokinetic booster is a weak inducer of CYP2C8. Ritonavir could potentially decrease amodiaquine exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion, and in vitro data indicate that it is a substrate of OAT3.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak CYP2D6 inhibitor and could potentially increase amphetamine exposure, although to a moderate extent. However, as dosing of recreational drugs can be variable, caution is advised.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ampicillin is predominantly eliminated unchanged via renal pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Anakinra is an IL-1 receptor antagonist which is predominantly cleared renally by glomerular filtration and subsequent tubular metabolism. Ritonavir is metabolized by CYP3A4. Patients requiring treatment with anakinra may have elevated levels of cytokines (e.g., TNF-alpha, IL-1, IL-6, IL-10, IFN) which have been shown to suppress expression/activity of CYP3A4, CYP2C19, CYP2C9 and CYP1A2. Anakinra, per se, has no inhibitory or inducing effects on cytochromes. Anakinra will normalize cytochrome activity (via inhibition of IL-1) but no significant effect on ritonavir is expected and no a priori dose adjustment is required.

Coadministration has not been studied. Anastrozole is mainly oxidized to hydroxyanastrozole by CYP3A4 (major) and glucuronidated by UGT1A4. The magnitude of the interaction is predicted to be of moderate intensity as ritonavir has an opposite effect on CYP3A4 (inhibition) and UGT1A4 (induction), which might result in a counterbalancing effect. No a priori dosage adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Thymoglobulins are cleared by the reticuloendothelial system.

Coadministration has not been studied but should be avoided. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4. Apalutamide concentrations may increase as ritonavir inhibits CYP3A4. In addition, ritonavir is metabolized by CYP3A4 and apalutamide is a strong inducer of CYP3A4. Coadministration of apalutamide with midazolam (a CYP3A4 substrate) decreased midazolam AUC by 92%. A significant decrease in ritonavir exposure is expected after coadministration with apalutamide, leading to loss of therapeutic effect and possible development of resistance.

Coadministration has not been studied. Concentrations of apixaban are expected to increase due to potent CYP3A4 and P-gp inhibition by ritonavir, thereby increasing the bleeding risk. The product labels for apixaban do not recommend the concomitant use with strong dual CYP3A4 and P-gp inhibitors, although the US label gives the option to use apixaban at a reduced dose if needed. Note, patients already receiving apixaban at a dose of 2.5 mg twice daily should avoid coadministration with strong dual CYP3A4 and P-gp inhibitors. Of interest, there are case reports of no adverse outcomes in HIV infected patients treated with a reduced dose of apixaban (2.5 mg twice daily) while on ritonavir or cobicistat boosted regimens which supports the option of dose reduction given in the US label.

Coadministration has not been studied. Apomorphine is metabolized by several pathways that include mainly glucuronidation and sulfation and to a lesser extent N-demethylation. Although protease inhibitors have the potential to induce glucuronidation, the clinical relevance of such an interaction is unknown considering the numerous pathways contributing to apomorphine metabolism. No a priori dosage adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Apremilast is metabolized by multiple pathways involving hydrolysis, glucuronidation and oxidation by CYP3A4. Coadministration of apremilast with ketoconazole (a strong CYP3A4 inhibitor) increased apremilast AUC by 36%. This effect is not considered to be clinically significant and does not warrant a dosage adjustment of apremilast. Similarly, ritonavir is unlikely to significantly alter apremilast exposure. Furthermore, apremilast has no inhibitory or inducing effects on CYPs or drug transporters. Note: severe diarrhoea, nausea and vomiting can occur within the first few weeks after initiating apremilast treatment. Patients should be instructed to contact their healthcare provider if they experience severe diarrhoea, nausea or vomiting as this could potentially alter the absorption of orally administered antiretroviral drugs.

Coadministration has not been studied. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYPs 1A2 and 2C19. Ritonavir is a strong inhibitor of CYP3A4 and could potentially increase aprepitant concentrations. The European product label for aprepitant advises caution with CYP3A4 inhibitors, whereas the American product label advises to avoid concomitant use of aprepitant and moderate to strong CYP3A4 inhibitors. If coadministration is necessary, reduced doses of aprepitant may be required to minimize side effects. 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 ritonavir exposure is unlikely to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Argatroban undergoes metabolism in the liver via hydroxylation and aromatization. In vitro studies indicate that CYP3A4 plays a role in argatroban metabolism, however, human drug-drug interactions studies suggest that metabolism via CYP3A4 is not a major elimination pathway in vivo. Erythromycin (a strong CYP3A4 inhibitor) had no effect on argatroban pharmacokinetics and pharmacodynamics and an interaction with ritonavir is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Ritonavir could potentially increase aripiprazole concentrations. Monitor adverse effects and decrease aripiprazole dosage if needed. The European SPC advises reducing the aripiprazole dose to approximately one-half of its prescribed dose when given with potent inhibitors of CYP3A4, such as HIV protease inhibitors.

Coadministration has not been studied. Asciminib is metabolised by several pathways, including CYP3A4, UGT2B7 and UGT2B17. Ritonavir is metabolized by CYP3A and is a strong inhibitor of CYP3A4 and induces UGTs. Coadministration of asciminib (40 mg single dose) with clarithromycin (a strong CYP3A4 inhibitor) increased asciminib AUC and Cmax by 36% and 19%, although no clinically significant effect on asciminib concentrations was observed when coadministered with itraconazole, which is also a strong CYP3A4 inhibitor. Ritonavir could possibly cause a less pronounced increase due to the inducing effect of ritonavir on UGTs. Increased asciminib exposure is unlikely to be significant for patients on asciminib doses of 40-80 mg daily. However, for patients on the higher dose of 200 mg twice daily, closely monitor for adverse reactions if coadministered with ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ascorbic acid is oxidised to dehydroascorbic acid where some is metabolised to oxalic acid and the inactive ascorbate-2-sulphate. Large doses are rapidly excreted in the urine when in excess of the requirements of the body. Ritonavir does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with vitamin C when given alone or in multivitamins. Ascorbic acid is oxidised to dehydroascorbic acid where some is metabolised to oxalic acid and the inactive ascorbate-2-sulphate. Large doses are rapidly excreted in the urine when in excess of the requirements of the body. Ritonavir does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Ashwagandha extracts had no effect on CYP enzymes in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Limited data suggest that asparaginase is likely to be eliminated by the reticuloendothelial system.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to salicylic acid and then further metabolized mainly by glucuronidation (by several UGT, major UGT1A6).

Coadministration is contraindicated as it is likely to increase astemizole concentrations and the risk of cardiac arrhythmias.

Atazanavir/ritonavir should not be used in combination with medicinal products containing additional ritonavir. Coadministration of Reyataz with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. (Note, the European product label, but not the US label, for atazanavir suggests to consider a dose increase of ritonavir to 200 mg once daily if coadministration of atazanavir/ritonavir is necessary.)

Coadministration of atazanavir with ritonavir in doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. (Note, the European product label, but not the US label, for atazanavir suggests to consider a dose increase of ritonavir to 200 mg once daily if coadministration of atazanavir/ritonavir is necessary.)

Atazanavir/cobicistat should not be administered concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4. If switching from ritonavir to cobicistat, caution is required during the first two weeks of treatment with cobicistat, particularly if doses of any coadministered medicinal products have been titrated or adjusted during use of ritonavir. Unlike ritonavir, cobicistat is not an inducer of CYPs 1A2, 2B6, 2C8, 2C9, 2C19 or UGT1A1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atenolol is mainly eliminated by the kidney, both by glomerular filtration and active secretion via the renal transporters OCT2 and MATE1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atezolizumab is eliminated through catabolism. Ritonavir is mainly metabolized by CYP3A4.

Coadministration has not been studied. Atogepant is metabolized primarily by CYP3A4 and is a substrate of OATP. Concentrations of atogepant are expected to increase significantly due to strong inhibition of CYP3A4 by ritonavir. Atogepant AUC increased by 5.5-fold with itraconazole (a strong CYP3A4 inhibitor) The European product label for atogepant recommends a dose reduction to 10 mg once daily with strong CYP3A4 inhibitors. For the treatment of episodic migraine, the American product label for atogepant recommends a dose reduction to 10 mg once daily with strong CYP3A4 inhibitors and recommends to avoid use with strong CYP3A4 inhibitors if treatment is for chronic migraine.

Coadministration has not been studied. Atomoxetine is metabolized by CYP2D6. Atomoxetine exposure could potentially increase, although to a limited extent, as ritonavir is a weak inhibitor of CYP2D6 when used as a pharmacokinetic booster. No a priori dosage adjustment is recommended.

Use with caution. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir, are used in combination with atorvastatin. Titrate atorvastatin dose and use the lowest possible dose with careful monitoring.

Coadministration may decrease atovaquone concentrations. Careful monitoring of serum levels or therapeutic effects is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely when atropine is used either systemically or as eye drops. Although metabolism of atropine is not fully elucidated, up to 50% is excreted unchanged via the kidneys. There is therefore little potential for clinically significant interactions with ritonavir via modulation of, or competition for metabolic pathways.

Coadministration is contraindicated. Avanafil is primarily metabolized by CYP3A4. Coadministration of avanafil (50 mg single dose) and ritonavir (600 mg twice daily) increased avanafil AUC and Cmax by 13-fold and 2.4-fold.

Coadministration has not been studied and should be avoided. Avapritinib is predominantly mediated by CYP3A4 and to a minor extent by CYP2C9. Ritonavir is a strong inhibitor of CYP3A4 and could significantly increase avapritinib exposure. Based on drug interaction studies with other strong CYP3A4 inhibitors, avapritinib exposure is expected to increase by 600% after multiple doses.

Coadministration has not been studied. Avatrombopag is mainly metabolized by CYP2C9 and CYP3A4. Ritonavir is a strong inhibitor of CYP3A4 and is expected to increase concentrations of avatrombopag. Coadministration of avatrombopag and itraconazole (a strong CYP3A4 inhibitor) increased avatrombopag exposure by 37%. A similar effect may occur with ritonavir. No a priori dose adjustment is needed for avatrombopag but monitor platelet counts and adjust the avatrombopag dose as necessary as indicated in the avatrombopag product label.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Avelumab is primarily metabolized through catabolic pathways and drug-drug interactions are not expected.

Coadministration has not been studied. Axitinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1. Ritonavir is a strong inhibitor of CYP3A4 and has some inducing effects on CYP1A2, CYP2C19 and UGT1A1. Given that CYP3A4 is the major pathway, ritonavir is expected to increase concentrations of axitinib. Increased axitinib exposure may increase the risk of exposure-related toxicity. Coadministration of ketoconazole (a strong CYP3A4 inhibitor) with axitinib increased axitinib AUC by 2-fold. A similar effect is expected with ritonavir. Use with caution. If coadministration is unavoidable, a 50% dose reduction of axitinib is recommended and monitor for toxicity.

Coadministration has not been studied. Ayahuasca preparations contain N,N-dimethyltryptamine (DMT, a psychedelic substance along with monoamine oxidase inhibitors (MAOI) which attenuates the breakdown of DMT. MAOI are substrate of MRP2 which is inhibited by ritonavir thereby potentially increasing DMT toxicity by slowing its breakdown. Given the narrow therapeutic index of DMT, caution is advised. Harma alkaloids found in ayahuasca preparations may cause weak/moderate inhibition of CYP3A4 which is unlikely to alter exposure of ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Urinary excretion is the primary route of elimination of azacitidine and/or its metabolites. Following cellular uptake, azacitidine is sequentially phosphorylated via phosphokinases activities to azacitidine triphosphate which is able to incorporate into DNA and RNA. Ritonavir is metabolised by CYP3A4. Azacitidine does not inhibit or induce CYP enzymes.

Coadministration has not been studied. Azilsartan is metabolized mainly by CYP2C9. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 and could potentially decrease azilsartan concentrations, however, the clinical relevance of this is unknown. No a priori dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Baricitinib is mainly eliminated renally through glomerular filtration and active secretion via OAT3, P-gp, BCRP and MATE2-K, with CYP3A4 metabolism representing less than 10% of its overall metabolism. Ritonavir is metabolized by CYP3A4 and is a strong inhibitor of CYP3A4. Baricitinib is not expected to have a clinically relevant effect on drugs metabolised by CYP enzymes. No effect on baricitinib is expected as it is mainly eliminated renally and CYP3A4 contributes to less than 10% of its overall metabolism. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) had no significant impact on baricitinib exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Basiliximab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration with bazedoxifene alone or coformulated with conjugated estrogens as hormone replacement therapy (HRT) has not been studied. Bazedoxifene is glucuronidated by UGT1A1/8/10 and conjugated estrogens are metabolized by CYP3A4, CYP1A2 and are glucuronidated. Coadministration could potentially decrease exposure of bazedoxifene and conjugated estrogens due to induction of CYP1A2 and glucuronidation. Monitor for signs of estrogen deficiency.

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 beclomethasone diproprionate (160 mg twice daily) increased the AUC and Cmax of beclomethasone-17-monoproprionate by 108% and 67%, respectively. However, coadministration of a boosted PI (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. Use the lowest possible corticosteroid dose with caution and monitor for corticosteroid side effects.

Coadministration with ritonavir alone has not been studied. In an interaction study of single-dose bedaquiline and multiple-dose lopinavir/ritonavir, bedaquiline AUC was increased by 22%. This increase is likely due to ritonavir and increases in bedaquiline exposure would be expected when coadministered with other ritonavir-boosted HIV protease inhibitors. The combination of bedaquiline and ritonavir should be avoided. If  the benefit of coadministration outweighs the risk and coadministration is necessary, clinical monitoring including frequent electrocardiogram assessment and monitoring of transaminases is recommended. There are no clinical data on the safety and efficacy of bedaquiline when coadministered with antiretroviral agents.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Belatacept is a protein that undergoes non-CYP mediated metabolism in the liver.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Belimumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied. Bempedoic acid is glucuronidated by UGT2B7 and also converted to an active metabolite by aldo-keto reductase. Ritonavir induces UGT2B7 and could potentially reduce bempedoic acid concentrations. However, the clinical relevance is unknown given that several pathways are involved in the elimination of bempedoic acid. Bempedoic acid does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Benazepril is rapidly hydrolyzed to its active metabolite benazeprilat which is eliminated predominantly renally.

Coadministration has not been studied. Bendamustine is metabolised by multiple routes including hydrolysis (main), glutathione conjugation and hepatic metabolism via CYP1A2 (to form the metabolites M3 and M4). Ritonavir is metabolized by CYP3A4. Bendamustine does not inhibit or induce CYP enzymes. However, ritonavir induces CY1A2 and has the potential to increase the formation of the metabolites but the clinical relevance is unknown as CYP1A2 plays a minor role in the overall metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%), although the exact pathway is not known. It is unlikely that CYP enzymes are involved in this process and no transporter interactions have been described. There is no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Available information on the metabolism of benzatropine is limited but no clinically significant interactions are expected. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Benznidazole undergoes non-CYP mediated metabolism and partly CYP mediated metabolism. Renal elimination of unchanged benznidazole appears to be minimal and there is little potential for an interaction via competition for renal elimination pathways.

Coadministration is contraindicated as it is likely to increase bepridil concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Beta-alanine is a non-essential amino acid and dietary supplements enter the same physiological processes as endogenous beta-alanine. Excess beta-alanine is excreted in the urine by the kidneys. Ritonavir is metabolized by CYP3A4. Beta-alanine is unlikely to affect CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Betahistine is metabolized by monoamine oxidase. Betahistine does not induce or inhibit CYP450 enzymes.

Coadministration has not been studied. Betamethasone is metabolized by CYP3A4 and coadministration may therefore lead to elevated corticosteroid levels, Cushing’s syndrome and adrenal axis suppression. A case of Cushing’s syndrome and adrenal suppression in a patient on atazanavir/ritonavir and dexamethasone 0.1% eye drops and betamethasone 0.1% eye ointment has been reported. Betamethasone is a moderate inducer of CYP3A4. Chronic or high doses of betamethasone may decrease 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.

Coadministration has not been studied but no clinically relevant drug interactions are expected with the topical use of betamethasone (for example, ointment, cream, lotion, emollient, foam).

Coadministration has not been studied. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. Coadministration with a P-gp inhibitor (such as 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. Of note, coadministration of betrixaban might need to be reconsidered in patients with concomitant renal impairment (creatinine clearance <60 ml/ml) as renal impairment per se does increase betrixaban exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely as bevacizumab is metabolized via proteolytic catabolism. 

Coadministration has not been studied and should be avoided. Bexarotene is mainly metabolized by CYP3A4 and induces CYP3A4 (after repeated administration and especially at doses greater than 300 mg/m2/day). Coadministration could potentially increase bexarotene concentrations and thus increase the risk of side effects. In addition, bexarotene could potentially decrease ritonavir exposure and therefore coadministration should be avoided.

Coadministration has not been studied. Bicalutamide is metabolized by CYP3A4 and UGT1A9. Ritonavir is metabolized by CYP3A4. Bicalutamide is a weak inhibitor of CYP3A4 but is unlikely to have a clinically significant effect on ritonavir. Inhibition of CYP3A4 by ritonavir may increase bicalutamide concentrations. No a priori dose reduction is required but use with caution and monitoring of side effects is recommended.

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration of ritonavir-boosted darunavir (or indinavir) would be possible from a pharmacokinetic standpoint. Coadministration of bictegravir and darunavir/cobicistat increased bictegravir AUC by 74%. A comparable increase in bictegravir exposure is anticipated when coadministered with darunavir/ritonavir. This increase is unlikely to be clinically significant; available dose exposure data, as well as data from phase 2 and phase 3 studies (48 weeks treatment), have shown a good safety profile with up to a 2.4-fold increase in bictegravir AUC. However, darunavir/ritonavir increases tenofovir alafenamide (the prodrug of tenofovir) due to inhibition of intestinal P-gp thereby increasing the systemic concentration. Coadministration of darunavir/ritonavir (800/100 mg once daily) and tenofovir alafenamide (10 mg once daily) increased tenofovir AUC and Cmax by 105% and 142%, respectively. The recommended dose of 10 mg tenofovir alafenamide with P-gp inhibitors is not possible with Biktarvy which is only available as a fixed dose combination containing 25 mg tenofovir alafenamide, but it should be noted that tenofovir alafenamide has been associated with a large clinical safety profile.

Coadministration has not been studied. Bilastine is mainly excreted unchanged and is a substrate of P-gp and OATP1A2. Ritonavir is metabolized by CYP3A4. Bilastine is unlikely to affect CYP3A4. However, ritonavir is a strong P-gp inhibitor and a weak OATP1B1 inhibitor and is expected to increase bilastine concentrations. No a priori dose modification is recommended but close monitoring for signs and symptoms of increased bilastine exposure is recommended. Coadministration of bilastine and P-gp inhibitors should be avoided in subjects with moderate or severe renal impairment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bimekizumab is an IgG1 monoclonal antibody and is likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied. Binimetinib is primarily metabolised by UGT1A1 and the active metabolite M3 is metabolised by CYP1A2 and CYP2C19. Ritonavir is mainly metabolized by CYP3A4. Binimetinib is unlikely to affect CYP3A4. However, ritonavir induces glucuronidation, CYP1A2 and CYP2C19 and has the potential to decrease exposure of binimetinib. Use with caution.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Following absorption, vitamin B7 is stored in the liver, kidney and pancreas.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Following absorption, vitamin B7 is stored in the liver, kidney and pancreas.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although limited human data suggest biperiden undergoes hydroxylation in the liver, there are no known or documented interactions with other drugs that have an effect on metabolism or transport.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bismuth subsalicylate is largely hydrolysed in the stomach to form salicylic acid, which is rapidly absorbed, and insoluble bismuth salts, which are excreted unchanged in faeces. Ritonavir is metabolized by CYP3A4. Bismuth subsalicylate is unlikely to affect CYP3A4.

Coadministration has not been studied. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Coadministration could potentially increase bisoprolol concentrations, although to a moderate extent. Pharmacokinetic studies between ritonavir and drugs that prolong the PR interval, including beta blockers, have not been performed. An additive effect of ritonavir and these drugs cannot be excluded. Note, PR interval monitoring may be warranted in patients with underlying block or those with atrioventricular nodal blocking agents.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on ritonavir is expected as black cohosh had no significant effect on the pharmacokinetics of midazolam (a CYP3A4 substrate) or digoxin (a P-gp substrate).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An indirect effect of blinatumomab on CYPs may occur due to transient release of cytokines during the first days of therapy which can inhibit CYP450 metabolism, however, this is unlikely to be clinically relevant. The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Coadministration may increase bosentan concentrations. Coadministration with lopinavir/ritonavir increased bosentan trough concentrations by ~48-fold and ~5-fold on days 4 and 10, respectively. Bosentan did not affect lopinavir and ritonavir AUC or Cmax to a clinically relevant extent. The US Prescribing Information suggests for patients who have been receiving ritonavir for at least 10 days, to start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. In patients on bosentan, it suggests to discontinue bosentan at least 36 hours prior to initiation of ritonavir and after at least 10 days of ritonavir, to resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Coadministration has not been studied but should be avoided. Bosutinib is metabolized by CYP3A4. Ketoconazole (a strong CYP3A4 inhibitor) increased bosutinib AUC by 8.6-fold. A similar effect may occur with ritonavir. Use an alternative antiretroviral drug with no inhibitory or inducing effects.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Branched chain amino acids (BCAAs) mainly undergo intracellular catabolism in skeletal muscle. Excess BCAAs and BCAA-derived metabolic products are excreted in the urine by the kidneys. Ritonavir is metabolized by CYP3A4. BCAAs are unlikely to affect CYP3A4.

Coadministration has not been studied but should be used with caution. 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 and does not interact with ritonavir. However, MMAE is a substrate of CYP3A4 and P-gp, therefore 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%. Patients receiving ritonavir concomitantly with brentuximab vedotin should be closely monitored for adverse reactions of brentuximab vedotin. If neutropenia develops, refer to the dosing recommendations for neutropenia in the product label for brentuximab vedotin.

Coadministration has not been studied. Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6. Ritonavir is metabolized by CYP3A4 and is a strong inhibitor of CYP3A4. Ketoconazole (a strong CYP3A4 inhibitor) increase brexpiprazole AUC by 97% and similar effect may occur with 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.

Coadministration has not been studied. Brigatinib is metabolised by CYP2C8 and CYP3A4. Ritonavir is a strong inhibitor of CYP3A4 and is expected to increase brigatinib concentrations. Coadministration of brigatinib (90 mg single dose) and itraconazole, a strong CYP3A4 inhibitor (200 mg twice daily) increased brigatinib exposure by 101%. A similar effect is expected with ritonavir and coadministration is not recommended. If coadministration is necessary, reduce the dose of brigatinib by 50% and monitor for toxicity.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brimonidine is metabolized mainly by aldehyde oxidase.

Coadministration has not been studied. Brincidofovir is a prodrug converted to cidofovir which is eliminated renally via glomerular filtration and active renal secretion by OAT1 and OAT3. Ritonavir does not interfere with this pathway. However, brincidofovir is a substrate of OATP1B1 and concentrations may increase due to inhibition of OATP1B1 by ritonavir. If concomitant use with brincidofovir is necessary, increase the monitoring for adverse reactions associated with brincidofovir (i.e. elevations in transaminases and bilirubin, diarrhea, or other gastro-intestinal adverse events) and postpone the dosing of ritonavir for at least 3 hours after brincidofovir administration.

Coadministration has not been studied. Brinzolamide is mainly metabolised by CYP3A4, and to a lesser extent by CYPs 2A6, 2C8 and 2C9. Ritonavir is metabolized by CYP3A4. Brinzolamide does not inhibit or induce CYP3A4. However, ritonavir is a strong CYP3A4 inhibitor and may increase brinzolamide concentrations. Caution is advised, and a dose reduction could be considered at higher doses. Monitor for increased side effects such as blurred vision or eye irritation and consider intraocular pressure checks during the first week of coadministration.

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. 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 ritonavir. No a priori dosage adjustment is required.

Coadministration has not been studied. Bromocriptine is metabolised by CYP3A4. Ritonavir is metabolized by CYP3A4. Bromocriptine is unlikely to affect CYP3A4 at clinically relevant concentrations. However, ritonavir is a strong inhibitor of CYP3A4 and may increase bromocriptine concentrations. Erythromycin (a strong CYP3A4 inhibitor) increased bromocriptine AUC by 3.7-fold and a similar effect may occur with ritonavir. Use with caution. A decrease in bromocriptine dose may be needed.

Coadministration is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and fluticasone; this could also occur with other corticosteroids metabolised by CYP3A e.g., budesonide. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may be required over a longer period.

Coadministration has not been studied. Bulevirtide is catabolized by peptidases and elimination occurs through binding to NTCP (a bile salt liver transporter serving as HDV/HBV entry receptor). Coadministration with NTCP inhibitors (e.g. ritonavir) is not recommended as it may alter bulevirtide elimination. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bumetanide is hepatically metabolized and approximately 50-80% of bumetanide is excreted in the urine by OAT1 and OAT3, mainly as unchanged drug (~50%). Ritonavir is metabolized by CYP3A4. and is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied. Bupivacaine is predominantly metabolized by CYP3A4. CYP3A4 inhibitors such as ritonavir may increase levels of bupivacaine. A clinical study with bupivacaine and itraconazole, a CYP3A4 inhibitor, reported a 20-25% increase in steady state concentration of bupivacaine when administered with itraconazole, compared to placebo.

Coadministration with ritonavir (100 mg twice daily) increased concentrations of buprenorphine 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. When used in boosted regimens with buprenorphine, the SPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

Coadministration is expected to decrease bupropion levels. Coadministration with ritonavir (100 mg twice daily) decreased bupropion AUC and Cmin by 22% and 21%. There was no significant interaction with bupropion after short-term administration of ritonavir (200 mg twice daily for 2 days). Reductions in bupropion concentrations may have onset several days after initiation of ritonavir. However, because ritonavir both induces and inhibits CYP2B6, the recommended dose of bupropion should not be exceeded. Patients receiving ritonavir and bupropion concurrently should be monitored for adequate clinical response to bupropion.

Coadministration has not been studied. Buspirone is metabolized by CYP3A4 but does not inhibit CYP3A4. Ritonavir could potentially increase buspirone concentrations due to inhibition of CYP3A4. A low dose of buspirone used cautiously is recommended with careful monitoring of therapeutic and adverse effects. Adjust dosage based on the clinical response.

Coadministration has not been studied. Busulfan is metabolised through conjugation with glutathione (spontaneous and GST-mediated) and then by hepatic oxidation (likely CYP3A4-mediated). Ritonavir is metabolized by CYP3A4. Busulfan is unlikely to affect CYP3A4. However, ritonavir is a strong inhibitor of CYP3A4 and may increase busulfan concentrations. Itraconazole (a strong CYP3A4 inhibitor) decreased busulfan clearance by approximately 20%. A similar effect may occur with ritonavir which may increase the risk and severity of myelosuppression. Patients should be monitored for signs of toxicity.

Coadministration has not been studied and should be used with caution. Cabazitaxel is metabolized by CYP3A4. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) increased cabazitaxel exposure by 25% and a similar effect is expected with ritonavir. Thus, coadministration should be avoided but if coadministration is required, consider a dose reduction of cabazitaxel of up to 25% and monitor for cabazitaxel toxicity.

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 ritonavir is expected to increase cabergoline exposure. Consider a reduction in cabergoline dose if the patient presents with adverse drug effects. No effect on ritonavir is expected as cabergoline does not inhibit or induce drug metabolizing enzymes. 

Coadministration has not been studied but a clinically significant interaction is unlikely when cabergoline is administered as a single dose to suppress lactation. Cabergoline is extensively metabolized by the liver, predominantly via hydrolysis (non-CYP mediated metabolism), and is a substrate of P-gp. Cabergoline exposure was shown to increased 2.6- to 4-fold in the presence of the strong P-gp inhibitors itraconazole or clarithromycin. Although ritonavir inhibits P-gp, no dose adjustment of cabergoline is required when cabergoline is administered as a single dose to suppress lactation. No effect on ritonavir is expected as cabergoline does not inhibit or induce drug metabolizing 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 by UGT1A9. Induction of UGTs by ritonavir is unlikely to cause a clinically relevant decrease in cabotegravir exposure based on drug-drug interaction studies with rifabutin, another moderate inducer. Note, cabotegravir used as PrEP is not expected to be coadministered with antiretrovirals except in the case of breakthrough infection when an antiretroviral treatment should be initiated. Residual concentrations of cabotegravir may remain in the systemic circulation for prolonged periods (up to 12 months or longer) but are not expected to affect the exposure of antiretroviral drugs initiated after discontinuation of Apretude.

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 based on drug-drug interaction studies with rifabutin, another moderate inducer. Cabotegravir is not expected to alter concentrations of other antiretroviral products. 

Cabenuva (cabotegravir LA, rilpivirine LA) is indicated for use as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with ritonavir would be possible from a pharmacokinetic standpoint. Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for a prolonged period after discontinuation of intramuscular cabotegravir/rilpivirine but are not expected to affect exposure of antiretroviral drugs.

Coadministration has not been studied but should be used with caution. Cabozantinib is metabolized by CYP3A4. Ketoconazole (a strong CYP3A4 inhibitor) increased cabozantinib AUC by 38%. A similar effect may occur with ritonavir. Avoid concomitant use with strong inhibitors if possible. If a strong CYP3A4 inhibitor must be used, reduce the cabozantinib daily dose by 20 mg. Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Caffeine is mainly metabolised by CYP1A2. Ritonavir is metabolized by CYP3A4. Caffeine is unlikely to affect CYP3A4. In vivo data indicate that ritonavir induces CYP1A2 and could potentially decrease caffeine concentrations. However, no a priori dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcitonin is primarily metabolized via proteolysis in the kidney. Ritonavir does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4. Ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction as rifampicin (a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4) decreased canagliflozin AUC by 51% which may result in reduced efficacy. If coadministration is deemed necessary, increasing canagliflozin to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR ≥60 mL/min/1.73m2 or CrCl ≥60 mL/min, and require additional glycaemic control. Other glucose-lowering therapies should be considered for patients with an eGFR 45 mL/min/1.73m2 to <60 mL/min/1.73m2 or CrCl 45 mL/min to <60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycaemic control.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Canakinumab is an IL-1 beta monoclonal antibody and is eliminated via intracellular catabolism. Ritonavir is metabolized by CYP3A4. Patients requiring treatment with anakinra may have elevated levels of cytokines (e.g., TNF-alpha, IL-1, IL-6, IL-10, IFN) which have been shown to suppress expression/activity of CYP3A4, CYP2C19, CYP2C9 and CYP1A2. Canakinumab, per se, has no inhibitory or inducing effects on cytochromes. Canakinumab will normalize cytochrome activity (via inhibition of IL-1) but no significant effect on ritonavir is expected and no a priori dose adjustment is required.

Coadministration has not been studied. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19. Coadministration may increase cannabidiol concentrations due to strong inhibition of CYP3A4 by ritonavir and decrease cannabidiol concentrations due to induction of CYP2C19 by ritonavir. The net effect of these interactions is unknown. Monitor effect and occurrence of side effects and adjust cannabidiol dosage accordingly.

Coadministration has not been studied. Tetrahydrocannabinol (THC, the psychoactive component of cannabis) is metabolized mainly by CYP2C9 and to a lesser extent by CYP3A4. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 and a strong inhibitor of CYP3A4. The net clinical effect of this interaction is difficult to predict as ritonavir could potentially decrease THC exposure (induction of CYP2C9) or increase THC exposure (inhibition of CYP3A4).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Capecitabine is activated by sequential enzyme reactions to fluorouracil. Ritonavir does not interfere with this metabolic pathway.

Coadministration has not been studied. Capmatinib is primarily metabolized by CYP3A4. Ritonavir is metabolized by CYP3A and is a strong inhibitor of CYP3A4. Coadministration of capmatinib (400 mg single dose) and itraconazole, a strong CYP3A4 inhibitor, (200 mg once daily), increased capmatinib exposure by 42% with no change to Cmax. A similar effect is expected with ritonavir. Given the modest increase in capmatinib exposure and its toxicity profile, no a priori dose adjustment of capmatinib is necessary, however, monitor as toxicity of capmatinib may be increased. If treatment-toxicities occur, a dose reduction should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Capreomycin is predominantly excreted via the kidneys as unchanged drug.

Use with caution. Ritonavir used as a pharmacokinetic booster may increase carbamazepine concentrations and a decrease in dose may be necessary. Careful monitoring of adverse effects and therapeutic concentration monitoring of carbamazepine is recommended. Two cases reported increased carbamazepine concentrations in patients receiving ritonavir (400 mg twice daily).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbidopa is partly metabolized and partly eliminated unchanged (30% of the total urinary excretion).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbocisteine is metabolized in the liver via acetylation, decarboxylation and sulfoxidation with up to 60% excreted unchanged in the urine. The likelihood of a clinically significant drug interaction is low and no studies have been performed. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carboplatin is excreted primarily by renal glomerular filtration and therefore there is little potential for a pharmacokinetic interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carfilzomib is rapidly metabolized, mainly by peptidase cleavage and epoxide hydrolysis with CYP-mediated metabolism representing a minor pathway. Ritonavir is metabolized by CYP3A4 and is a strong inhibitor of CYP3A4. Carfilzomib is not expected to have a clinically relevant effect on drugs metabolised by CYPs and is unlikely to be affected by inhibitors and inducers of CYPs and P-gp.

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 from CYP2D6. Ritonavir is metabolized by CYP3A4. Cariprazine is unlikely to affect CYP3A4. However, ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor and is expected to increase cariprazine concentrations. 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 cariprazine product labels for more information.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. The net effect on carvedilol concentrations is difficult to predict but likely to be moderate in magnitude. Pharmacokinetic studies between ritonavir and drugs that prolong the PR interval (including beta blockers) have not been performed. An additive effect of ritonavir and these drugs cannot be excluded. Note, PR interval monitoring may be warranted in patients with underlying block or those with atrioventricular nodal blocking agents.

Cat’s claw is a strong inhibitor of CYP3A4 in vitro but has also been shown to induce CYP3A4 activity in vitro. Increased concentrations of atazanavir, saquinavir and ritonavir were reported in a patient receiving Cat’s claw. Coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cedazuridine is eliminated renally and converted to its epimer (which is then renally excreted). Ritonavir is metabolised by CYP3A4. Cedazuridine does not inhibit or induce CYP enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 50% of the absorbed dose is excreted unchanged in the urine; there is no evidence of metabolism of cefixime in vivo. In vitro studies have shown that cefixime does not inhibit/induce major cytochrome P450 metabolic enzymes, and would not be expected to cause clinically significant interactions with other drugs, which are metabolized by CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftazidime is predominantly eliminated unchanged via renal glomerular filtration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftriaxone is eliminated mainly as unchanged drug; approximately 60% of the dose being excreted in the urine, almost exclusively by glomerular filtration, and the remainder via the biliary and intestinal tracts.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefuroxime is not metabolised and is excreted predominantly by renal glomerular filtration, with no significant active renal tubular secretion. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolized by CYP2C9 and in vivo data indicate that ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster. A dose adjustment is unlikely to be required for celecoxib when coadministered with ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cemiplimab is primarily metabolised through catabolic pathways and drug-drug interactions are not expected. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied and is not recommended. Cenobamate is primarily glucuronidated by UGT2B7 and to a lesser extent by UGT2B4. CYP3A4 contributes to cenobamate metabolism but to a minor extent. Cenobamate is a dose-dependent inducer of CYP3A4 and was shown to reduce exposure of midazolam (a CYP3A4 substrate) by 72% at a dose of 200 mg daily and by 27% at a dose of 100 mg daily. Cenobamate is dose-titrated until the 200 mg maintenance dose is reached. Cenobamate at a daily dose of 200 mg or greater may significantly decrease ritonavir plasma concentrations due to CYP3A4 induction.

Coadministration has not been studied. Ceritinib is metabolized by CYP3A4. Ritonavir is a strong inhibitor of CYP3A4. 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 ritonavir and therefore coadministration is not recommended. However, 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Certolizumab pegol is an antibody Fab’ fragment conjugated with polyethylene glycol (PEG). The Fab’ fragment is expected to be degraded to peptides and amino acids by proteolysis; the PEG moiety is mainly excreted in urine without further metabolism. Ritonavir is metabolized by CYP3A4.

Coadministration with ritonavir dosed as a pharmacokinetic booster has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Furthermore, no significant electrocardiographic changes were observed when cetirizine was coadministered to 10 HIV+ subjects receiving PIs (details not given).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetuximab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration has not been studied. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4. Coadministration of chloramphenicol may potentially increase levels of ritonavir via this mechanism, increasing the risk of adverse events. The clinical significance of this interaction is unknown Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

Coadministration with a chlormadinone-containing combined oral contraceptive (COC) has not been studied. Chlormadinone undergoes extensive hepatic metabolism by hydroxylation (likely CYP mediated). Coadministration is predicted to increase exposure of chlormadinone. When used in a combined pill, the estrogen component is reduced. Given the lack of clinical data on the contraceptive efficacy, caution is recommended and additional contraceptives measures should be used.

Coadministration has not been studied. Chloroquine undergoes CYP mediated metabolism by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). Ritonavir could potentially increase chloroquine exposure by inhibition of CYPs 3A4 and 2D6. No dosage adjustment is recommended for chloroquine but monitor toxicity.

Coadministration has not been studied. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase chlorphenamine exposure, although to a moderate extent. No a priori dosage adjustment is required.

Coadministration has not been studied. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase chlorpromazine exposure, although to a moderate extent. No a priori dosage adjustment is recommended but monitor side effects.

Coadministration has not been studied. Ciclesonide can be administered with ritonavir without dose adjustment, but with close monitoring. There is a risk of steroid side effects occurring, particularly if a high dose is used, or in case of prolonged administration, or if used with another medicine containing corticosteroids. These side effects are also more likely during periods of physiological stress. 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. Ciclesonide is mainly absorbed by the lungs, has a high protein binding and a high clearance resulting in a lower potential to cause systemic effects compared to some other inhaled corticosteroids. Hence, any interaction with ritonavir would not require any dosage/therapy adjustments, particularly if ciclesonide is administered at lower or medium clinical doses, but close monitoring for Cushing’s syndrome signs is required when using a higher dose or with prolonged administration. 

Coadministration may increase ciclosporin concentrations. Therapeutic concentration monitoring is recommended for ciclosporin.

Based on interaction studies with lopinavir/ritonavir and atazanavir/ritonavir, concurrent administration of a proton pump inhibitor (omeprazole) or a H2-receptor antagonist (ranitidine) does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure of about 6-18%.

Coadministration has not been studied. Cinacalcet is metabolized by multiple CYP enzymes, mainly CYP3A4, CYP2D6 and CYP1A2. Ritonavir is mainly metabolized by CYP3A4. Cinacalcet does not inhibit or induce CYP3A4. However, concentrations of cinacalcet may increase due to inhibition of CYP3A4 by ritonavir. Use with caution and a dose adjustment of cinacalcet may be required. Monitoring of iPTH serum phosphorus and serum calcium is recommended when starting or discontinuing a strong CYP3A4 inhibitor.

Coadministration is contraindicated as it is likely to increase cisapride concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied. Cisplatin is eliminated renally via OCT2 and MATE1 and in vitro data indicate that ritonavir is a moderate inhibitor of MATE1. Ritonavir could potentially slow down cisplatin renal elimination and thus increase the risk of nephrotoxicity. Close monitoring of renal function is recommended.

Coadministration has not been studied. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Ritonavir could potentially increase citalopram concentrations, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration of ritonavir (200 mg twice daily) with clarithromycin (500 mg twice daily) increased ritonavir AUC (12%), Cmax (15%) and Cmin (14%). Clarithromycin AUC and Cmax increased by 77% and 31%, respectively, whilst Cmin increased 2.8-fold; 14-OH clarithromycin metabolite AUC, Cmax and Cmin all decreased by 99-100%. No dose adjustment for patients with normal renal function is necessary. For patients with creatinine clearance 30-60 ml/min reduce clarithromycin dose by 50%. For patients with creatinine clearance less than 30 ml/min reduce clarithromycin dose by 75%.

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. CYP3A4 inhibition by 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. Monitor for side effects and clinical effect. Clobazam is unlikely to significantly impact ritonavir.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by ritonavir. Topical clobetasol can be used with caution. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion.

Coadministration has not been studied. In vitro studies have suggested that transformation of clomifene to its active metabolite is likely to be mediated via CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak CYP2D6 inhibitor and could increase clomifene exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

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. Monitor adverse effects.

Use with caution. Coadministration may increase clonazepam concentrations and a decrease in dose may be necessary. Therapeutic concentration monitoring of clonazepam is recommended.

Coadministration of clopidogrel and boosted regimens has been evaluated in clinical studies. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. In HIV-positive subjects, the presence of a pharmacoenhancer (ritonavir n=8; cobicistat n=1) decreased the AUC and Cmax of clopidogrel’s active metabolite both by 69% when compared to values obtained in HIV-negative subjects (n=12). In HIV-negative subjects (n=12), coadministration of clopidogrel and ritonavir (100 mg twice daily) decreased the AUC and Cmax of clopidogrel’s active metabolite by 51% and 48%. 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 or cobicistat. Consistently, the study in HIV-negative subjects showed that the average inhibition of platelet aggregation was decreased from 51% (clopidogrel alone) to 31% (clopidogrel + ritonavir). Of interest, the study with HIV-infected patients showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. The differential impact on clopidogrel and prasugrel pharmacodynamics effect is in line with clinical observations. Early thrombosis of a coronary stent was reported in a patient treated with darunavir/ritonavir concomitantly with clopidogrel while subsequent replacement of clopidogrel by prasugrel did not lead to novel stent thrombosis episodes. Taken together these data suggest that given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered.

Coadministration may increase clorazepate concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir used as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir used as a pharmacokinetic enhancer.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion.

Coadministration may increase clozapine concentrations thereby increasing the risk of serious haematologic abnormalities, or other serious adverse effects. Coadministration is contraindicated in the European SPC, but the US prescribing information does not mention the interaction. The charts reflect a cautious option based on the use of ritonavir as a pharmacokinetic enhancer.

Coadministration has not been studied but should be avoided. Cobimetinib is metabolised by CYP3A4 and UGT2B7. Cobimetinib concentrations are expected to increase due to strong inhibition of CYP3A4 by ritonavir. Itraconazole (a strong CYP3A4 inhibitor) increased cobimetinib AUC by 6.7-fold. A similar effect is expected with ritonavir and therefore coadministration is not recommended.

Coadministration has not been studied. Codeine is a substrate of CYP2D6 (major) and CYP3A4. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose, ritonavir does not appear to markedly inhibit CYP2D6. While no a priori dose adjustment is required, the analgesic effect requires conversion of codeine to morphine via CYP2D6 and ritonavir could potentially reduce the analgesic efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The major route of elimination for coenzyme Q10 is by biliary and faecal excretion; only a small fraction is eliminated in the urine. Ritonavir is metabolised by CYP3A4. Coenzyme Q10 is unlikely to have a clinically significant effect on substrates of CYP3A4, UGTs and P-gp.

Coadministration of ritonavir (100 mg twice daily for 5 days) and colchicine (0.6 mg single dose) significantly increased colchicine Cmax and AUC by 2.7-fold and 3.5-fold, respectively. Coadministration is contraindicated in patients with renal or hepatic impairment. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. When coadministered for treatment of gout flares, the recommended dosage is 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. The dose is to be repeated no earlier than 3 days. When coadministered for prophylaxis of gout flares, if the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day; if the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. When coadministered for treatment of familial Mediterranean fever (FMF) do not exceed a maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Coadministration has not been studied. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of vitamin D and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on vitamin D clearance. Inhibition of CYP3A by ritonavir is not expected to reduce the effect of vitamin D, but the consequence of CYP3A inhibition on the clinical effect of vitamin D is not known. However, no effect of antiretroviral therapy on the response to vitamin D supplementation was found in a PK modelling study.

Coadministration has not been studied. No interaction is expected with vitamin D when given with calcium or in a multivitamin preparation. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of vitamin D and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on vitamin D clearance. Inhibition of CYP3A by ritonavir is not expected to reduce the effect of vitamin D, but the consequence of CYP3A inhibition on the clinical effect of vitamin D is not known. However, no effect of antiretroviral therapy on the response to vitamin D supplementation was found in a PK modelling study

Coadministration has not been studied. Colesevelam is not absorbed from the gastrointestinal tract, is not metabolised and does not affect CYP enzymes. Ritonavir is metabolised by CYP3A4. However, given that colesevelam can reduce the gastrointestinal absorption of some drugs, colesevelam should be administered at least four hours before or after ritonavir to minimize the risk of reduced absorption.

Coadministration has not been studied. Colestyramine may delay or reduce the absorption of drugs. Administration of other drugs should be at least 1 hour before or 4-6 hours after colestyramine. [Note: this interaction is not specific for ritonavir, but for any medication taken with colestyramine.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Collagen hydrolysate is digested and absorbed as essential amino acids for use in essential physiological processes. Ritonavir is metabolized by CYP3A4. Collagen hydrolysate is unlikely to affect CYP3A4.

Coadministration with conjugated estrogens as hormone replacement therapy (HRT) has not been studied. Conjugated estrogens are metabolized by CYP3A4, CYP1A2 and are glucuronidated. Coadministration could potentially decrease exposure of conjugated estrogens due to induction of CYP1A2 and glucuronidation (rather than increase it due to inhibition of CYP3A4). Monitor for signs of estrogen deficiency. In contrast, exposure of progestogens administered as part of HRT may increase. The clinical relevance of this is unknown but increased progestogen concentrations may be associated with a higher incidence of side effects. Note, use of conjugated estrogens as part of gender affirming treatment should be avoided as they are associated with high thromboembolic risk.

Coadministration has not been studied. Copanlisib is metabolised by CYP3A (~90%) and CYP1A1 (~10%). Ritonavir is metabolized by CYP3A4. Copanlisib does not inhibit or induce CYP3A4. However, ritonavir is a strong inhibitor of CYP3A4 and may increase copanlisib concentrations. Coadministration of copanlisib (60 mg i.v. infusion) and a strong CYP3A4 inhibitor (itraconazole, 200 mg once daily for 10 days) increased copanlisib AUC by 53% with no effect on Cmax (3% increase). A similar effect can be expected with ritonavir. The American product label for copanlisib states that if coadministration with strong CYP3A inhibitors cannot be avoided, to reduce the copanlisib dose from 60 mg to 45 mg.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Creatine monohydrate is not degraded during normal digestion and nearly 99% of orally ingested creatine monohydrate is either taken up by muscle or excreted in urine. Ritonavir is metabolized by CYP3A4. Creatine is unlikely to affect CYP3A4.

Coadministration has not been studied but should be avoided. Crizotinib is mainly metabolized by CYP3A4. Ritonavir is a strong inhibitor of CYP3A4 and is expected to increase crizotinib concentrations. Coadministration with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUC and Cmax by 3.2-fold and 1.4-fold, respectively. A similar effect is expected with ritonavir and therefore coadministration is not recommended.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although several constituents of Piper cubeba were shown to inhibit CYP3A4 in vitro, a clinically relevant effect on ritonavir exposure is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cyanocobalamin undergoes enterohepatic recycling and is excreted almost entirely in the urine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with cyanocobalamin when given alone or in multivitamins. Cyanocobalamin undergoes enterohepatic recycling and is excreted almost entirely in the urine.

Coadministration has not been studied. The metabolism of cyclizine has not been fully described but may involve CYP2D6. Ritonavir is mainly metabolized by CYP3A4. Ritonavir is a weak inhibitor of CYP2D6 when used as a pharmacokinetic booster and could potentially increase cyclizine exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Cyclophosphamide is metabolized by two pathways. Activation (major pathway) to 4-hydroxycyclophosphamide is catalyzed by CYPs 2B6 (major), 2C9 and 3A4. Inactivation (minor, 10%) to the neurotoxic chloroacetaldehyde metabolite is performed mainly by CYP3A4. In vivo data indicate that ritonavir induces CYP2B6. In theory, ritonavir could potentially reduce the risk of neurotoxicity and increase the amount of drug available for the activation pathway which may increase the efficacy and the toxicity of cyclophosphamide (i.e., myelosuppression, nausea, vomiting). Careful monitoring of cyclophosphamide related side effects is recommended. Adjust dose if clinically necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly excreted renally via glomerular filtration.

Coadministration has not been studied. Cyproterone acetate is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. A dose adjustment of cyproterone may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cytisine is primarily excreted renally as unchanged drug. There are no reports of CYP or transporter involvement and significant pharmacokinetic interactions are unlikely. Ritonavir is metabolised by CYP3A4.

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 (possibly due to mixed induction and inhibition of P-gp by ritonavir as dabigatran is a substrate of P-gp). 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 when used once daily as a pharmacokinetic enhancer in patients with no renal impairment, though no data are available when ritonavir is used twice daily as a pharmacokinetic enhancer. 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 ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment.

Coadministration has not been studied but is not recommended. Dabrafenib is metabolized by CYP3A4 and CYP2C8 and the active metabolites are metabolized by CYP3A4. Ritonavir is metabolized by CYP3A4 and is a strong inhibitor of CYP3A4 and therefore may increase dabrafenib concentrations. Coadministration of ketoconazole (another strong CYP3A4 inhibitor) and dabrafenib increased dabrafenib AUC and Cmax by 71% and 33%, respectively. The AUC of hydroxyl-dabrafenib and desmethyl-dabrafenib increased by 82% and 68%, respectively; Cmax of hydroxyl-dabrafenib and desmethyl-dabrafenib increased by 27% and 72%, respectively. In addition, dabrafenib is a strong inducer of CYP3A4 and may decrease ritonavir concentrations and may impact the boosting effect.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dacomitinib is metabolised by CYP2D6 (~26%) to O-desmethyl dacomitinib, an active metabolite with similar activity to dacomitinib, whilst CYP3A4 (~6%) contributes to the formation of other minor metabolites. Ritonavir is a strong inhibitor of CYP3A4 and may increase dacomitinib concentrations. However, this is unlikely to be clinically significant as CYP3A4 contributes to dacomitinib metabolism only to a small degree.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dactinomycin is minimally metabolized.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Ritonavir may affect dapagliflozin due to UGT induction but a clinically relevant effect is not expected as coadministration of dapagliflozin with rifampicin (an inducer of several UGT enzymes) decreased dapagliflozin systemic exposure by 22% but had no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ritonavir is metabolized by CYP3A4. Dapivirine is metabolized mainly by CYP3A4 and to a lesser extent by glucuronidation. However, the risk of drug-drug interactions is low with the dapivirine vaginal ring due to its low systemic exposure. Furthermore, dapivirine concentrations in vaginal fluid exceed the in vitro HIV IC99 by 1000-fold.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Daptomycin is eliminated renally.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Daratumumab, is an IgG1 monoclonal antibody and is likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Ritonavir is metabolized by CYP3A4.

Coadministration has not been studied but is contraindicated. Daridorexant is mainly metabolised by CYP3A4. Ritonavir is metabolized by CYP3A4. Daridorexant is a weak inhibitor of CYP3A4 but is unlikely to have a clinically significant effect on ritonavir. However, ritonavir is a strong CYP3A4 inhibitor and is expected to significantly increase daridorexant concentrations. Coadministration of daridorexant (25 mg) and the moderate CYP3A4 inhibitor diltiazem (240 mg once daily) increased daridorexant AUC and Cmax by 2.4- and 1.4-fold, respectively. No clinical study was conducted with a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors is contraindicated in the European product label for daridorexant, whereas the American product label recommends to avoid coadministration.

Coadministration has not been studied. Darifenacin is metabolized by CYP3A4 and CYP2D6 and coadministration is likely to increase 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 poor metabolizer individuals. The European Summary of Product Characteristics for darifenacin contraindicates its use with potent CYP3A4 inhibitors (such as ritonavir), but the US Prescribing Information recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

Coadministration has not been studied. Darolutamide is primarily metabolised by CYP3A4, and to a lesser extent by UGT1A9 and UGT1A1, and is a substrate of P-gp. Ritonavir is metabolized by CYP3A4. Darolutamide is a weak inducer of CYP3A4 but is unlikely to have a clinically significant effect on ritonavir. Inhibition of CYP3A4 and P-gp by ritonavir may increase darolutamide concentrations. No a priori dose adjustment is required but monitor for adverse effects.

Darunavir should be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer. Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.

Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, adding an extra dose of ritonavir has not been studied with respect to safety, efficacy and pharmacokinetics.

Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) should not be administered concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4.

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and ritonavir may significantly increase dasatinib concentrations. If coadministration is unavoidable, close monitoring for toxicity is required. The US product information for dasatinib recommends a dose reduction to 20 mg daily (for patients taking dasatinib 100 mg) and to 40 mg (for patients taking dasatinib 140 mg) in presence of strong inhibitors of CYP3A4.

A clinical study reported that ritonavir had no effect on daunorubicin (liposomal) pharmacokinetics. An in vitro study has shown that daunorubicin was able to inhibit metabolism mediated by CYP3A4, but was unlikely to cause clinically significant drug interactions via this mechanism. There is therefore little potential for pharmacokinetic interaction. Damage to the myocardium is one of the major risks of daunorubicin treatment and may include dose-independent supraventricular arrhythmias (sinus tachycardia, premature ventricular contractions, AV-block) and/or non-specific ECG abnormalities. Caution is required if prescribing ritonavir with medicines known to prolong the PR interval.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The primary route of decitabine metabolism is likely by cytidine deaminase. Decitabine is a prodrug and is activated intracellularly through sequential phosphorylation via phosphokinases activities to the active triphosphate. Ritonavir is metabolised by CYP3A4. Decitabine does not inhibit or induce CYP enzymes.

Coadministration has not been studied but should be avoided. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent by UGT1A3; CYP-mediated metabolism appears to be minor (~8%). Ritonavir is metabolized by CYP3A4. Deferasirox is a weak inducer of CYP3A4 and was shown to reduce midazolam exposure by 17%, although it is unlikely to significantly decrease ritonavir concentrations. However, ritonavir induces UGT and may decrease deferasirox concentrations leading to a possible decrease in efficacy. Avoid concomitant use of UGT inducers with deferasirox. If coadministration with ritonavir is unavoidable, the American product label advises to consider increasing the deferasirox dose by 50%, and to monitor serum ferritin levels and clinical responses for further dose modification.

Coadministration has not been studied. Deflazacort is immediately metabolised by plasma esterases to the active metabolite (21-desdeflazacort) which is then metabolised mainly by CYP3A4 to several inactive metabolites which are excreted in the urine (~70%) and faeces (~30%). Ritonavir is metabolized by CYP3A4. Deflazacort and 21-desdeflazacort do not inhibit or induce CYP3A4. However, ritonavir is a strong inhibitor of CYP3A4 and may increase exposure of 21-desdeflazacort. Coadministration of deflazacort and clarithromycin (a strong CYP3A4 inhibitor), increased total exposure of 21-desdeflazacort by about 3-fold. The European product label for deflazacort recommends coadministration with CYP3A inhibitors should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects. The US product label suggests a dose reduction to one third of the normal recommended deflazacort dosage with moderate/strong CYP3A4 inhibitors.

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. Co-administration of delamanid with a strong inhibitor of CYP3A4 (lopinavir/ritonavir) increased DM-6705 exposure by 25-30%. QTc prolongation has been reported with delamanid (and is very closely correlated with the metabolite DM-6705). A similar increase would be expected with ritonavir when used to boost other protease inhibitors and caution is advised. If coadministration is considered necessary, frequent monitoring of ECGs is recommended, throughout the full delamanid treatment period (for example, at least fortnightly for the first month and if the QTc interval remains within normal range to reduce this to monthly thereafter).

Coadministration of ritonavir (100 mg twice daily) and desipramine (50 mg single dose) increased desipramine AUC by 26%. No a priori dosage adjustment is recommended when ritonavir is used as a pharmacokinetic booster.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desloratadine is metabolized to the active metabolite 3-hydroxydesloratadine, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of the active metabolite have not been identified, but no clinically relevant interactions have been observed with inhibitors of CYP enzymes. Ritonavir is metabolized by CYP3A4. Desloratadine does not inhibit CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desmopressin undergoes no significant hepatic metabolism and is not a substrate for CYP enzymes. Ritonavir is metabolized by CYP3A4. Desmopressin does not inhibit CYP enzymes and no metabolic drug interactions are expected.

Coadministration with a desogestrel-containing combined oral contraceptive (COC) has not been studied. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration is predicted to increase etonogestrel due to induction of CYP2C9 and inhibition of CYP3A4. When used in a combined pill, the estrogen component is reduced. Given the lack of clinical data on the contraceptive efficacy, caution is recommended and additional contraceptives measures should be used.

Coadministration with a desogestrel-containing progestogen-only pill (POP) has not been studied. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration is predicted to increase etonogestrel and, based on studies with norethisterone used as a POP, the contraceptive efficacy of a desogestrel POP is unlikely to be compromised by ritonavir.

Coadministration has not been studied. Dexamethasone is metabolized by CYP3A4. Ritonavir may increase dexamethasone concentrations due to inhibition of CYP3A4. A dose reduction of dexamethasone may be necessary with monitoring for symptoms of Cushing’s syndrome. Dexamethasone is a dose-dependent inducer of CYP3A4 and is a moderate CYP3A4 inducer at doses above 16 mg. Chronic or high doses of dexamethasone may decrease ritonavir plasma concentrations due to CYP3A induction with the possible loss of therapeutic effect and development of resistance. Use with caution. Adrenal axis suppression and Cushing's syndrome was reported in a woman receiving atazanavir/ritonavir, tenofovir and emtricitabine with dexamethasone 0.1% eye drops six times daily. Elevated levels of dexamethasone were measured at presentation (1.4-1.7 nmol/L) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/L). The clinical time-course strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular dexamethasone.

Coadministration has not been studied. Dexamethasone is metabolized by CYP3A4. Ritonavir may increase dexamethasone concentrations due to inhibition of CYP3A4. A dose reduction of dexamethasone may be necessary with monitoring for symptoms of Cushing’s syndrome. Adrenal axis suppression and Cushing's syndrome was reported in a woman receiving atazanavir/ritonavir, tenofovir and emtricitabine with dexamethasone 0.1% eye drops six times daily. Elevated levels of dexamethasone were measured at presentation (1.4-1.7 nmol/L) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/L). The clinical time-course strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular dexamethasone. Use with caution. Dexamethasone is a weak CYP3A4 inducer at a low dose and is unlikely to have a clinically significant effect on ritonavir. Note, it is expected that the risk of Cushing’s syndrome is less likely to occur when using dexamethasone at a low dose and for a short treatment duration as compared to higher doses and long treatment duration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dexketoprofen is mainly excreted as glucuronide conjugates; CYP2C8/9 plays a minor role in metabolism. Ritonavir is metabolized by CYP3A4. Dexketoprofen is unlikely to affect CYP3A4. Inhibition or induction of UGTs and CYPs by ritonavir is unlikely to have a significant impact on dexketoprofen exposure as it is likely multiple UGTs are involved in the metabolism of dexketoprofen and CYP2C8 represents a minor metabolic pathway.

Based on interaction studies with lopinavir/ritonavir and atazanavir/ritonavir, concurrent administration of a proton pump inhibitor (omeprazole) or a H2-receptor antagonist(ranitidine) does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure of about 6-18%.

Coadministration has not been studied. Dextromethorphan is metabolized by CYP2D6. Ritonavir is metabolized by CYP3A4. Dextromethorphan does not inhibit or induce CYP3A4. However, dextromethorphan concentrations are expected to increase as ritonavir inhibits CYP2D6 at a dose of 100 mg. Coadministration of darunavir/ritonavir or lopinavir/ritonavir increased dextromethorphan AUC by 1.23-fold and 2.7-fold, respectively. If coadministration is necessary, use with caution and a dose reduction of dextromethorphan may be required based on clinical response.

Coadministration has not been studied and is not recommended. Dextropropoxyphene has been withdrawn from most European and North American countries due to the risk of arrhythmias and fatalities. As it is metabolized mainly by CYP3A4, coadministration could markedly increase the exposure of dextropropoxyphene.

Coadministration may increase diazepam concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir dosed as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir dosed as a pharmacokinetic enhancer.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidized by CYP2C9. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster. A dose adjustment is unlikely to be required for diclofenac.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diethylcarbamazine is mainly excreted unchanged in the urine. 

Coadministration increases digoxin concentrations. If patients are already on ritonavir, start with the lowest dose of digoxin and monitor digoxin concentrations. Patients starting ritonavir whilst already on digoxin, should have their digoxin dose halved and their digoxin concentrations monitored. The impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-adrenergic blockers) has not been evaluated. Clinical monitoring is recommended.

Coadministration has not been studied. Dihydrocodeine is converted to dihydromorphine (active metabolite) via CYP2D6, to dihydrocodeine-6-glucuronide via UGT2B7 (major pathway) and to nordihydrocodeine via CYP3A4. The analgesic effect appears to be primarily due to the parent compound. Ritonavir could potentially increase dihydrocodeine exposure (inhibition of CYP3A4 and CYP2D6) and increase the conversion to dihydrocodeine-6-glucuronide (induction of UGT2B7). The net clinical effect of this interaction is difficult to predict. No a priori dose adjustment is required, but monitoring for analgesic effect and for signs of opiate toxicity may be required as clinically indicated.

Coadministration is contraindicated as it is likely to increase dihydroergotamine concentrations and the potential for serious and/or life threatening reactions such as acute ergot toxicity.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diloxanide furoate is largely hydrolysed under the combined action of bacterial and gut esterases and consequently glucuronidated. No clinically-significant drug interactions are known, and significant interactions with antiretrovirals are unlikely.

Coadministration may increase diltiazem concentrations and a decrease in dose may be necessary. Caution is warranted and careful monitoring of therapeutic and adverse effects is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dimethyl fumarate is metabolized by esterases before entering the blood stream. Further metabolism occurs though the TCA cycle. Ritonavir is metabolised by CYP3A4. Dimethyl fumarate is unlikely to have a clinically significant effect on substrates of CYPs, UGTs and P-gp.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase diphenhydramine concentrations, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Ritonavir used as a pharmacokinetic booster induces glucuronidation and may potentially decrease dipyridamole exposure, thereby reducing the antiplatelet effect.

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

Coadministration is not recommended with ritonavir ORAL SOLUTION as it contains alcohol (43% v/v). Ritonavir capsules have a lower alcohol content of 12% (w/w). Ritonavir tablets do not contain alcohol.

Coadministration has not been studied and is not recommended. Dofetilide is metabolized to a small degree by CYP3A4 and therefore ritonavir could potentially increase dofetilide exposure and thereby increase the risk of cardiac arrhythmias.

Coadministration with ritonavir alone has not been studied. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No dosage adjustment is necessary.

Dolutegravir/lamivudine/tenofovir-DF is indicated for use as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with a protease inhibitor boosted with ritonavir would be possible from a pharmacokinetic standpoint, but with close monitoring for tenofovir-associated adverse events. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No interaction is expected with lamivudine. Coadministration of tenofovir-DF and ritonavir (100 mg twice daily with lopinavir, darunavir or saquinavir) had no significant effect on ritonavir concentrations. However, a higher risk of renal impairment has been reported in patients receiving tenofovir-DF in combination with a ritonavir boosted protease inhibitor. Close monitoring of renal function is required in these patients.

Triumeq (dolutegravir, abacavir, lamivudine) is indicated for use as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with ritonavir would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No interaction is expected with abacavir or lamivudine.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with ritonavir would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No interaction is expected with lamivudine.

Juluca (dolutegravir/rilpivirine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with ritonavir-boosted PIs would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. Coadministration has not been studied but may increase rilpivirine concentrations, however, no dose adjustment is required. Rilpivirine is not expected to affect the plasma concentrations of ritonavir.

Coadministration has not been studied. Donepezil is metabolized by CYP3A4 and CYP2D6 (minor). A 30% increase in donepezil exposure has been reported in presence of ketoconazole, a strong CYP3A4 inhibitor. A similar effect is expected with ritonavir. No a priori dose modification is required but monitoring for increased side effects is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dopamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase to inactive compounds. About 25% of a dose of dopamine is metabolised to norepinephrine within the adrenergic nerve terminals. There is little potential for dopamine to affect disposition of antiretrovirals, or to be affected if co-administered with antiretrovirals.

Coadministration with ritonavir increased doravirine AUC by ~3.5 fold and Cmin by ~2.9 fold. 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 of doravirine (50 mg single dose; half the recommended approved dose) with ritonavir (100 mg twice daily) increased doravirine AUC, Cmax and C24 by 254%, 31% and 191%, respectively (n=8).

Delstrigo (doravirine, lamivudine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with a protease inhibitor boosted with ritonavir would be possible from a pharmacokinetic standpoint, but with close monitoring for tenofovir-associated adverse events. Coadministration with ritonavir increased doravirine AUC by 3.5-fold and Cmin by 2.9-fold. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3- to 4-fold increase in exposure. Coadministration of tenofovir-DF and ritonavir (100 mg twice daily with lopinavir, darunavir or saquinavir) had no significant effect on ritonavir concentrations. However, a higher risk of renal impairment has been reported in patients receiving tenofovir-DF in combination with a ritonavir boosted protease inhibitor. Close monitoring of renal function is required in these patients. 

Coadministration has not been studied. Doxazosin is metabolized mainly by CYP3A4 and coadministration may increase doxazosin exposure which can result in hypotension. For patients already taking ritonavir, start doxazosin at the lowest dose (i.e., 1 mg daily) and increase dose slowly based on tolerance until an effective dose is reached. For patients already taking doxazosin, monitor blood pressure and reduce doxazosin dose as needed if hypotension occurs on starting ritonavir.

Coadministration has not been studied. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Ritonavir could potentially increase doxepin exposure although to a moderate extent. No a priori dose adjustment is required.