Coadministration of abacavir (600 mg once daily) and darunavir/ritonavir (900/100 mg once daily) decreased abacavir AUC, Cmax and Cmin by 27%, 22% and 38%, respectively (n=19). Based on the different elimination pathways (abacavir metabolism is not mediated by CYP450), no significant interactions are expected with darunavir/ritonavir. However, studies are required to relate the change in plasma abacavir exposure to the active intracellular carbovir triphosphate.

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 but based on metabolism and clearance a clinically significant interaction is unlikely. After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and by the microbial flora.

Coadministration has not been studied. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9 and darunavir/ritonavir could potentially decrease acenocoumarol concentrations. Monitor INR.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as aciclovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as acitretin undergoes isomerisation and glucuronidation.

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 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 as adefovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

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).

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 darunavir/ritonavir.

Coadministration has not been studied. Agomelatine is metabolised predominantly by CYP1A2 which is induced by ritonavir. Coadministration with darunavir/ritonavir could potentially decrease agomelatine exposure. Monitor clinical effect and increase dosage if needed.

Coadministration has not been studied. In vitro studies have demonstrated that CYP3A4 and the flavine-containing monooxygenase system are involved in formation of the active metabolite albendazole sulfoxide. Short term (2 doses) coadministration with ritonavir (200 mg) did not impact albendazole pharmacokinetics whereas long-term coadministration (8 days) decreased albendazole exposure likely due to ritonavir inducing effect. Darunavir/ritonavir is unlikely to significantly affect albendazole exposure when used for a short duration treatment but may reduce the clinical effect of albendazole when used for a long duration treatment.

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 darunavir/ritonavir may 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. Alcohol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. The chronic use of alcohol may induce CYP2E1 and to a lesser extent CYP3A4. No a priori clinically relevant drug-drug interaction is anticipated.

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. Darunavir/ritonavir is unlikely to inhibit OATs and OCTs at clinically relevant concentrations.

Coadministration has not been studied. 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 has not been studied. Alfentanil undergoes extensive CYP3A4 metabolism. Darunavir/ritonavir could potentially increase alfentanil exposure. Administer with caution due to the risk of prolonged or delayed respiratory depression. A dosage reduction of alfentanil may be required.

Coadministration is contraindicated as darunavir/ritonavir may increase alfuzosin concentrations which may 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 darunavir/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 but based on metabolism and clearance a clinically significant interaction is unlikely as allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase.

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. In vitro data indicate that alosetron is metabolized by CYPs 2C9 (30%), 3A4 (18%) and 1A2 (10%); however, in vivo data suggest that CYP1A2 plays a more prominent role. In vitro data indicate that ritonavir induces CYP1A2, therefore coadministration with darunavir/ritonavir could potentially decrease alosetron exposure.

Coadministration has not been studied. Alprazolam is mainly metabolized by CYP3A4. Interaction studies with ritonavir have shown inhibition of alprazolam metabolism following the introduction of ritonavir but no significant inhibitory effect at steady state. Based on these data, when combined with a boosted PI, consider starting alprazolam at a lower dosage and increase if needed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amantadine is mainly eliminated renally by glomerular filtration and active secretion. A bicarbonate dependent organic cation transporter has been identified as the major uptake transporter of amantadine in the renal proximal tubule.

Coadministration has not been studied. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Ambrisentan concentrations may increase due to inhibition of OATP1B1 by darunavir. Start ambrisentan at 5 mg and closely monitor the patient for tolerability.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amikacin is eliminated renally by glomerular filtration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amiloride is eliminated unchanged by the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Darunavir/ritonavir is unlikely to inhibit OATs and OCTs at clinically relevant concentrations.

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 and in vitro data indicate that ritonavir induces CYP1A2. Darunavir/ritonavir could potentially decrease theophylline concentrations. Monitor plasma concentrations and increase aminophylline dosage if needed.

Coadministration may increase amiodarone concentrations. The European SmPC contraindicates coadministration. The US prescribing information suggests caution and concentration monitoring of amiodarone. [This interaction checker reflects the more cautious option.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally (possibly via OCT). Darunavir/ritonavir is unlikely to inhibit OCTs at clinically relevant concentrations.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Darunavir/ritonavir could potentially increase amitriptyline exposure, although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4 and darunavir/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. Darunavir/ritonavir could potentially decrease amodiaquine exposure, although to a limited 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 as amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6 and coadministration could potentially increase amphetamine exposure, although to a limited 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 as amphotericin is not appreciably metabolized and is eliminated to a large extent in the bile.

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. Darunavir/ritonavir is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations.

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. Anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperature.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as antacids are unlikely to alter darunavir/ritonavir absorption.

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. Concentrations of apixaban are expected to increase due to potent CYP3A4 and P-gp inhibition by darunavir/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. Aprepitant is mainly metabolized by CYP3A4 and is a moderate inhibitor of CYP3A4. Coadministration could potentially increase aprepitant concentrations. A decrease in aprepitant dose may be needed.

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 darunavir/ritonavir is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Darunavir/ritonavir could potentially increase aripiprazole concentrations. Monitor adverse effects and decrease aripiprazole dosage if needed. The European product label for aripiprazole 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 but may increase plasma levels of artemisinins. Artemisinin and derivatives are rapidly metabolized via CYP3A4 to an active metabolite, dihydroartemisinin which has greater potency than the parent drugs. Inhibition of CYP3A4 would reduce dihydroartemisinin, but increase concentrations of the parent drug. Close monitoring for artemisinin toxicity is required.

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. Darunavir/ritonavir does not interfere with this metabolic pathway.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (mainly CYP1A2, with minor contributions from CYP3A4 and CYP2D6). As ritonavir induces CYP1A2 and UGT1A4, darunavir/ritonavir could potentially decrease asenapine exposure. Monitor the clinical effect and increase dosage if needed.

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 UGTs, major UGT1A6).

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 UGTs, major UGT1A6).

Coadministration is contraindicated as it may increase astemizole concentrations which may result in serious and/or life threatening reactions such as cardiac arrhythmias.

Note: this interaction was studied using a darunavir/ritonavir dose lower than that licensed. Coadministration of atazanavir (300 mg once daily) and darunavir/ritonavir (400/100 mg twice daily) had no significant effect on darunavir or atazanavir exposure. Darunavir Cmax, AUC and Cmin increased by 2%, 3% and 1%, respectively. Atazanavir Cmax decreased by 11%; AUC and Cmin increased by 8% and 52%, respectively (relative to atazanavir/ritonavir 300/100 mg once daily alone). No dosage adjustments are recommended when darunavir/ritonavir is coadministered with atazanavir.

Coadministration has not been studied and is not recommended. Appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics of atazanavir have not been established.

Coadministration has not been studied and is not recommended. Appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics of atazanavir have not been established.

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

Note: this interaction was studied using a darunavir/ritonavir dose lower than that licensed. Coadministration increases atorvastatin concentrations. Coadministration of atorvastatin (10 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) resulted in atorvastatin exposure that was only 15% lower than that obtained with atorvastatin 40 mg once daily alone. When coadministered it is recommended to start with atorvastatin 10 mg once daily. A gradual dose increase may be tailored to the clinical response. A daily dose of 40 mg atorvastatin should not be exceeded with careful safety monitoring. (Note, the US product label for Prezista states not to exceed atorvastatin 20 mg/day.)

Coadministration has not been studied. Atovaquone is mainly eliminated unchanged in the faeces. Administration of a single dose of atovaquone/proguanil with lopinavir/ritonavir or atazanavir/ritonavir decreased atovaquone AUC by 70% or 40-50%, respectively; proguanil AUC was also decreased. A possible mechanism was suggested to be induction of glucuronidation by ritonavir and so darunavir/ritonavir could potentially decrease atovaquone and proguanil. The clinical relevance of this interaction is unknown due to the lack of data on the minimal effective atovaquone plasma concentration in the setting of malaria prophylaxis. Consider taking atovaquone with a high fat meal to increase its bioavailability and increase the dosage if required.

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.

Coadministration has not been studied and is contraindicated. Avanafil is primarily metabolized by CYP3A4. Coadministration with ritonavir (600 mg twice daily) increased avanafil AUC by 13-fold. Similarly, a large increase in avanafil exposure is predicted in presence of darunavir/ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azathioprine is metabolized to 6-mercaptopurine which is further inactivated by xanthine oxidase and thiopurine methyltransferase.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion and animal data suggest this may occur via P-glycoprotein and MRP2. Darunavir/ritonavir could potentially increase azithromycin exposure (inhibition of P-glycoprotein and MRP2), however, no a priori dosage adjustment is recommended for azithromycin.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as baclofen is primarily eliminated by glomerular filtration.

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 once daily darunavir/ritonavir has not been studied. Beclometasone is a pro-drug which is not metabolised by CYP450, but 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 darunavir/ritonavir (600/100 mg twice daily) and inhaled beclometasone diproprionate (160 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. Use the lowest possible corticosteroid dose with caution and monitor for corticosteroid side effects.

Coadministration 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 moderate or strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided. If 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 co-administered 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. Benazepril is rapidly hydrolyzed to its active metabolite benazeprilat which is eliminated predominantly renally.

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 as benserazide is hydrolysed to trihydroxybenzylhydrazine.

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 may increase bepridil concentrations. The European SmPC contraindicates coadministration. The US prescribing information suggests caution and concentration monitoring of bepridil. [This interaction checker reflects the more cautious option.]

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. Caution is needed when betamethasone is administered orally or intravenously at high doses or for a long duration as it may decrease darunavir/ritonavir exposure.

Coadministration has not been studied. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. Coadministration with a P-gp inhibitor (such as darunavir/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. Bexarotene could also potentially decrease darunavir/ritonavir exposure and therefore coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as half of bezafibrate dose is eliminated unchanged in the urine.

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 with darunavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration of bictegravir and darunavir/cobicistat increased bictegravir AUC by 74%. 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. A comparable increase in bictegravir exposure is anticipated when coadministered with darunavir/ritonavir. However, 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 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. Bisacodyl is converted to an active metabolite by intestinal and bacterial enzymes. Absorption from the gastrointestinal tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide.

Coadministration has not been studied. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the kidney. Darunavir/ritonavir could potentially increase bisoprolol exposure, although to a limited extent. No a priori dosage adjustment is required.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on darunavir/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. Bleomycin is inactivated by a cytosolic enzyme, bleomycin hydrolase, and two thirds of the administered drug is excreted unchanged in urine, probably by glomerular filtration.

Coadministration has not been studied. Bortezomib is mainly metabolized by CYP3A4 and CYP2C19 and to a lesser extent by CYPs 1A2, 2D6 and 2C9. Darunavir/ritonavir could potentially increase bortezomib concentrations. Monitor for bortezomib-related side effects. The US product label for bortezomib suggests considering a dose reduction of bortezomib when given with strong CYP3A4 inhibitors, such as ritonavir.

Coadministration has not been studied, but may increase bosentan concentrations. For patients stable on darunavir/ritonavir, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. When starting darunavir/ritonavir in patients stable on bosentan, discontinue bosentan at least 36 h prior to starting darunavir/ritonavir. Resume bosentan at 62.5 mg once daily or every other day based on individual tolerability after at least 10 days of darunavir/ritonavir therapy.

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. Darunavir/ritonavir could potentially increase bromazepam concentrations although to a limited extent. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased bromazepam AUC by ~9%. A similar effect may occur with darunavir/ritonavir. No a priori dosage adjustment is required.

Coadministration of darunavir/ritonavir 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 inhaled or intranasally administered fluticasone; this could also occur with other corticosteroids metabolised via the P450 3A pathway 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 have to be performed over a longer period.

Coadministration has not been studied. Bupivacaine is predominantly metabolized by CYP3A4. CYP3A4 inhibitors such as darunavir/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 of buprenorphine/naloxone and twice daily darunavir/ritonavir had no significant effect on buprenorphine or naloxone, but increased concentrations of norbuprenorphine. Coadministration with once daily darunavir/ritonavir produced no significant changes in the pharmacokinetics of buprenorphine or norbuprenorphine, but increased concentrations of the inactive buprenorphine-3-glucuronide. The clinical relevance of the increase in norbuprenorphine concentrations has not been established. Dose adjustment for buprenorphine may not be necessary but careful clinical monitoring for opiate toxicity is recommended.

Coadministration has not been studied. Bupropion is primarily metabolized by CYP2B6 and in vivo data indicate that ritonavir induces CYP2B6. Darunavir/ritonavir could potentially decrease bupropion concentrations. Titrate bupropion dose based on response, but the recommended dose of bupropion should not be exceeded.

Coadministration has not been studied. Buspirone is metabolized by CYP3A4 but does not inhibit CYP3A4. Darunavir/ritonavir could potentially increase buspirone concentrations. A low dose of buspirone used cautiously is recommended and adjust dosage based on the clinical response.

Coadministration has not been studied. Caffeine is mainly metabolized by CYP1A2. In vivo data indicate that ritonavir induces CYP1A2 and therefore boosted protease inhibitors 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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine and sweat.

Coadministration has not been studied. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4. Darunavir/ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction by ritonavir 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 as candesartan is mainly eliminated unchanged via urine and bile.

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 darunavir + 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 darunavir/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. Darunavir/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. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Darunavir/cobicistat is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations.

Coadministration has not been studied, based on metabolism and clearance a clinically significant interaction is unlikely as captopril is largely excreted in the urine (40-50% as unchanged drug, the rest as disulfide and other metabolites).

Coadministration with twice daily darunavir/ritonavir had no significant effect on darunavir exposure, but increased carbamazepine AUC by 45%. No a priori dose modification of darunavir/ritonavir or carbamazepine is recommended when initiating therapy, but patients should be monitored for potential carbamazepine related adverse events. Carbamazepine concentrations should be monitored; the carbamazepine dose may need to be reduced by 25% to 50% to achieve the desired clinical response. Limited data from a small number of patients showed TDM evaluations for carbamazepine and oxcarbazepine were within the therapeutic ranges and TDM results of darunavir were comparable with control values.

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. Carbimazole is a pro-drug which undergoes rapid and virtually complete metabolism to the active metabolite, thiamazole (also known as methimazole). Despite this potential hepatic metabolism very few data exist on carbimazole drug interactions and a marked interaction is not expected.

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. In vitro studies have shown that carboplatin does not significantly inhibit cytochrome P450 metabolic enzymes.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additionally metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Darunavir/ritonavir could potentially increase carvedilol concentrations via CYP2D6 inhibition or decrease carvedilol concentrations via induction of glucuronidation. The net effect on carvedilol concentrations is difficult to predict but likely to be moderate in magnitude. No a priori dosage adjustment is required.

Coadministration has not been studied. Caspofungin undergoes spontaneous chemical degradation and metabolism via a non CYP-mediated pathway. In vitro data indicate that caspofungin is a substrate of the hepatic transporter OATP1B1 and that darunavir and ritonavir are inhibitors of OATP1B1. Darunavir/ritonavir could potentially increase caspofungin exposure. No a priori dosage adjustment is recommended for caspofungin but monitor side effects.

Coadministration has not been studied. 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. Similar increases would be expected for other CYP3A4 substrates, such as darunavir. Coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged renally (by glomerular filtration and tubular secretion via OAT1 and MATE1. Ritonavir is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations. In vitro data indicate that ritonavir inhibits MATE1 but is unlikely to cause a clinically relevant drug interaction with cefalexin due to its large therapeutic index.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Darunavir/ritonavir is unlikely to inhibit the renal transporters OATs at clinically relevant concentrations.

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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolized by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OATs participate to the renal elimination of cefotaxime. Darunavir/cobicistat is unlikely to inhibit the renal transporters OATs at clinically relevant concentrations.

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. Celecoxib is primarily metabolized by CYP2C9 and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. A dose adjustment is unlikely to be required for celecoxib when coadministered with darunavir/ritonavir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. The effect of cetirizine on ECG was studied in 10 HIV+ subjects receiving PIs (details not given) and no patient had significant ECG changes during cetirizine administration.

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, but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorambucil is almost completely metabolized (little is known about chlorambucil metabolism in humans, most probably non-CYP mediated) and has extremely low urinary excretion. In vitro studies have shown that chlorambucil does not inhibit cytochrome P450 metabolic enzymes.

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 darunavir/ritonavir. 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 has not been studied. Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. When combined with darunavir/ritonavir, the activity of chlordiazepoxide may be increased.

Coadministration has not been studied. Chloroquine is metabolised by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). Darunavir/ritonavir could potentially increase chloroquine exposure by inhibition of CYPs 3A4 and 2D6 although to a moderate extent due to the multiple elimination pathways. No dosage adjustment is recommended for chloroquine but monitor toxicity.

Coadministration has not been studied. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Darunavir/ritonavir could potentially increase chlorphenamine exposure although to a limited extent as ritonavir is a weak inhibitor of CYP2D6. No a priori dosage adjustment is required.

Coadministration has not been studied. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Darunavir/ritonavir could potentially increase chlorpromazine exposure although to a limited extent. No a priori dosage adjustment is recommended but monitor side effects.

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

Coadministration has not been studied. Ciclesonide can be administered with darunavir/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 darunavir/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 has not been studied. Coadministration may increase ciclosporin concentrations. Therapeutic concentration monitoring of ciclosporin is recommended when coadministered.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cilazapril is mainly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on results with ranitidine (no effect on darunavir AUC, Cmax or Cmin), darunavir/ritonavir can be coadministered with H2 receptor antagonists without dose adjustments.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolized and partially cleared through the bile and intestine.

Coadministration is contraindicated as it may increase cisapride concentrations which may result in 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. Cisatracurium undergoes mainly (80% of overall elimination) spontaneous degradation in plasma and tissues at physiological pH and temperature (Hofmann elimination).

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%). Darunavir/ritonavir could potentially increase citalopram concentrations although to a moderate extent. No a priori dosage adjustment is recommended.

Note: this interaction was studied using a darunavir/ritonavir dose lower than that licensed. Coadministration of clarithromycin (500 mg twice daily) and darunavir/ritonavir (400/100 mg twice daily) increased clarithromycin AUC (57%), Cmax (26%) and Cmin (174%); darunavir AUC, Cmax and Cmin were unchanged. Caution is warranted and clinical monitoring is recommended. No adjustment to the licensed doses of darunavir or clarithromycin is required for patients with normal renal function. The US Prescribing Information recommends dose reduction of clarithromycin for patients with impaired renal function (CLcr 30-60 mL/min, dose reduce clarithromycin by 50%; CLcr less than 30 mL/min, dose reduce clarithromycin by 75%).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolized (likely by a non-CYP mediated pathway) and excreted in the urine by glomerular filtration.

Coadministration has not been studied. Clindamycin is metabolized by CYP3A4 and coadministration may increase clindamycin concentrations due to inhibition of CYP3A. A decrease in clindamycin dose may be needed.

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 darunavir + 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 darunavir + 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolyzed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

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. Darunavir/ritonavir may increase clomifene exposure, although to a limited extent, via CYP2D6 inhibition. 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. Darunavir/ritonavir could potentially increase clomipramine concentrations. Use with caution as clomipramine has been shown to prolong the QT interval and has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Monitor adverse effects. If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied but may increase clonazepam concentrations and a decrease in dose may be necessary. Use with caution and perform therapeutic drug monitoring for clonazepam.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in form of the unchanged parent drug (40-60% of the dose).

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 has not been studied. Clorazepate is rapidly converted to nordiazepam which is then metabolized to oxazepam by CYP3A4. Darunavir/ritonavir could potentially increase nordiazepam exposure which could prolong sedation. Clinical and/or concentration monitoring is recommended and a dosage reduction may be required.

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. Darunavir/ritonavir is unlikely to inhibit OATs and OCTs at clinically relevant concentrations.

Coadministration has not been studied. Clozapine is metabolized by CYPs 1A2, 2C19, 3A4, and to a lesser extent by CYPs 2C9 and 2D6. Darunavir/ritonavir could potentially increase clozapine exposure. Monitor patient closely for toxicity.

Coadministration has not been studied. Cocaine is metabolized by several pathways, with metabolism to norcocaine by CYP3A4 being less than 10% of the overall metabolic clearance. Darunavir/ritonavir could potentially increase concentrations of the parent compound. The clinical relevance is unknown as cocaine is metabolized by other non-CYP mediated pathways. Ensure the patient is aware of signs/symptoms of cocaine toxicity.

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.

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-gp. The interaction with darunavir/ritonavir has not been studied, but coadministration is expected to increase colchicine concentrations. Ritonavir (100 mg twice daily) significantly increased colchicine Cmax (2.7-fold) and AUC (3.5-fold) when given with a single dose of colchicine (0.6 mg). Patients with renal or hepatic impairment should not be coadministered colchicine. 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. 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 darunavir/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 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, any additional effect on exposure of darunavir in the presence of ritonavir is unlikely.

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. 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, darunavir/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 darunavir/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 as cytarabine is metabolized by cytidine deaminase.

Coadministration of dabigatran (150 mg) and darunavir/ritonavir (800/100 mg single dose and multiple doses once daily) was studied. Single dose administration increased dabigatran AUC and Cmax by 72% and 64% when administered as single dose, whereas dabigatran AUC and Cmax increased by 18% and 22% with darunavir/ritonavir once daily. The effect of separating dosing was studied using ritonavir alone. 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 darunavir/ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment. Coadministration with darunavir/ritonavir is contraindicated in the European product label for darunavir/ritonavir.

Coadministration has not been studied. Dacarbazine undergoes activation to MTIC primarily via CYP1A2 and to a lesser extent by CYP2E1, with CYP1A1 having a role in extrahepatic metabolism. In vitro data indicate that ritonavir induces CYP1A2. Darunavir/ritonavir may increase the conversion to MTIC and thereby increase the efficacy and toxicity of dacarbazine. Monitor side effects.

Coadministration of daclatasvir and darunavir/ritonavir (800/100 mg once daily) decreased darunavir AUC, Cmax and Cmin by 10%, 3% and 2%; daclatasvir AUC increased by 41% and Cmax decreased by 23%. No dose adjustment of daclatasvir 60 mg once daily or darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily) is required.

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. Dalteparin is excreted largely unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Darunavir/ritonavir may affect dapagliflozin due to UGT induction by ritonavir 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. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Clinically significant interactions are unlikely, but cannot be excluded.

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 product label for darifenacin contraindicates its use with potent CYP3A4 inhibitors (such as ritonavir), but the US product label recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) should not be administered with other products containing darunavir.

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 darunavir/ritonavir has not been studied with respect to safety, efficacy and pharmacokinetics.

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and darunavir 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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. A clinical study showed that protease inhibitors indinavir, saquinavir or ritonavir did not significantly affect liposomal daunorubicin pharmacokinetics.

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 darunavir/ritonavir 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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Denosumab is not eliminated via hepatic metabolism but follows the immunoglobulin clearance pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desflurane is almost exclusively eliminated unchanged by the lungs.

Coadministration has not been studied. Desipramine is metabolized by CYP2D6. Darunavir/ritonavir could potentially increase desipramine concentrations, although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration with a desogestrel-containing combined oral contraceptive (COC) has not been studied. Desogestrel is a prodrug that 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 the conversion to the active metabolite etonogestrel and, based on studies with norethisterone used as a POP, the contraceptive efficacy of a desogestrel POP is unlikely to be compromised by darunavir/ritonavir.

Coadministration has not been studied. Dexmedetomidine undergoes extensive hepatic biotransformation through direct glucuronidation (mainly via UGT1A4, 2B10) and cytochrome P450 (mainly 2A6). Study data indicate that ritonavir decreases exposure of lamotrigine, a UGT1A4 probe substrate. Darunavir/ritonavir could potentially decrease dexmedetomidine concentrations. No a priori dosage adjustment is recommended but monitor clinical effect.

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 has not been studied. Diamorphine is rapidly metabolized by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). As ritonavir induces glucuronidation, darunavir/ritonavir could potentially decrease the analgesic effect although to a moderate extent as induction of glucuronidation may increase the formation of the active metabolite. No a priori dosage adjustment is recommended but monitor the analgesic effect and signs of opiate withdrawal.

Coadministration has not been studied. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4). Darunavir/ritonavir could potentially increase diazepam exposure by inhibition of CYP3A4. This could prolong sedation and a dosage reduction may be required.

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, however 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. Darunavir/ritonavir is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations.

Coadministration of darunavir/ritonavir (600/100 mg twice daily) and digoxin (0.4 mg single dose) increased digoxin AUC and Cmax by 61% and 29%, respectively (n=8). Start with the lowest dose of digoxin and monitor digoxin concentrations.

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. Darunavir/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 may increase dihydroergotamine concentrations which may result in 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 has not been studied. Diltiazem is metabolized by CYP3A4 and CYP2D6. Darunavir/ritonavir could potentially increase diltiazem exposure. Caution is warranted and clinical monitoring of therapeutic and adverse effects is recommended. Diltiazem should be started at low doses with careful titration to response.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. Darunavir/ritonavir could potentially increase diphenhydramine concentrations although to a limited 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. Coadministration could potentially decrease dipyridamole exposure due to induction of glucuronidation, thereby reducing the antiplatelet effect.

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

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Disulfiram is reduced to diethyldithiocarbamic acid, is conjugated with glucuronic acid, oxidised to sulphate, methylated and decomposed to diethylamine and carbon disulphide.

Coadministration with darunavir/ritonavir has not been studied. Coadministration with ritonavir may increase concentrations of docetaxel and increase the risk of severe toxicities. There have been several case reports of severe haematological and cutaneous toxicity when coadministered with ritonavir, a potent CYP3A inhibitor. Ideally avoid coadministration with boosted protease inhibitors or consider using an alternative taxane.

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

Coadministration has not been studied. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolized by CYP2D6 (10-20%) and CYP3A4 (<1%). Coadministration could potentially increase dolasetron concentrations although this is unlikely to be clinically meaningful since CYP-mediated metabolism is minor and dolasetron has a wide therapeutic margin.

Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of dolutegravir. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and dolutegravir (30 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 11%, 22% and 38%, respectively. Coadministration with darunavir/ritonavir and etravirine had no significant effect on dolutegravir exposure (AUC, Cmax and Ctrough decreased by 25%, 12% and 37%, respectively). There was no effect on darunavir or ritonavir exposure. No dose adjustment is necessary.

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 darunavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration of darunavir/ritonavir and dolutegravir decreased dolutegravir AUC, Cmax and Ctrough by 22%, 11% and 38%, respectively; there was no effect on darunavir or ritonavir. Coadministration of abacavir (600 mg once daily) and darunavir/ritonavir (900/100 mg once daily) decreased abacavir AUC, Cmax and Cmin by 27%, 22% and 38%, respectively (n=19). No interaction is expected with lamivudine.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. Coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended in the US Prescribing Information for Dovato. However, the European product label for Dovato advises that no dose adjustment is necessary with darunavir/ritonavir. Coadministration of darunavir/ritonavir and dolutegravir decreased dolutegravir AUC, Cmax and Ctrough by 22%, 11% and 38%, respectively; there was no effect on darunavir or 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. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with darunavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and dolutegravir (30 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 11%, 22% and 38%, respectively. Coadministration of rilpivirine (150 mg once daily) and darunavir/ritonavir (800/100 mg once daily) was studied in 14 subjects. Rilpivirine Cmax increased by 79% and AUC and Cmin increased by 2.3- and 2.78-fold, respectively. Darunavir Cmax, AUC and Cmin decreased by 10%, 11% and 11%, respectively. [Note: this interaction study has been performed with a dose higher than the licensed dose for rilpivirine assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the licensed dose of rilpivirine 25 mg once daily.]

Coadministration has not been studied and is contraindicated with potent CYP3A4 inhibitors, such as ritonavir. Domperidone is mainly metabolized by CYP3A4. Darunavir/ritonavir could potentially increase domperidone exposure and increase the risk of cardiac adverse effects (QT interval prolongation).

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.

Coadministration has not been studied. 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.

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 darunavir 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 (300 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) increased darunavir Cmax (16%), AUC (21%) and Cmin (24%). Tenofovir Cmax, AUC and Cmin increased by 24%, 22% and 37%, respectively. No adjustments to the licensed doses are required. A higher risk of renal impairment has been reported in patients receiving tenofovir-DF and a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function and for tenofovir-associated adverse reactions 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 darunavir/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 darunavir/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. Darunavir/ritonavir could potentially increase doxepin and nordoxepin concentrations although to a limited 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. Doxorubicin is mainly eliminated in the bile and does not undergo CYP-mediated metabolism. (Some product labels suggest doxorubicin is a substrate of CYP3A4, however, there are no strong data supporting the role of CYP3A4 in doxorubicin metabolism.) Doxorubicin is a substrate of P-glycoprotein, however, coadministration with protease inhibitors did not modify significantly doxorubicin exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No significant metabolism of doxycycline occurs, it is cleared intact by renal and biliary mechanisms.

Coadministration has not been studied. Droloxifene is mainly glucuronidated and coadministration with darunavir/ritonavir could potentially decrease droloxifene exposure due to induction of glucuronidation. Monitor droloxifene therapeutic effect.

Coadministration has not been studied. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. In vitro and 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 darunavir/ritonavir could potentially decrease dronabinol concentrations (induction of CYP2C9) or increase dronabinol concentrations (inhibition of CYP3A4). No a priori dosage adjustment is recommended.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolised in part by CYP3A4. Coadministration is predicted to increase drospirenone exposure and clinical monitoring is recommended due to the potential for hyperkalaemia. 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 drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone exposure and clinical monitoring is recommended due to the potential risk for hyperkalaemia. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In contrast, exposure of estrogens/estradiol administered as part of HRT may decrease. Monitor for signs of hormone deficiency. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.  

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is presumed to be degraded by general protein catabolism pathways. Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. However, interaction studies did not result in any clinically relevant effects and no dose adjustment of comedications is recommended.

Coadministration has not been studied. Duloxetine is metabolized by CYP2D6 and CYP1A2. In vitro data indicate that ritonavir induces CYP1A2 but inhibits CYP2D6. The net clinical effect of this interaction is difficult to predict, but is expected to be of weak intensity. No a priori dosage adjustment is required.

Coadministration has not been studied. Dutasteride is mainly metabolized by CYP3A4. Darunavir/ritonavir could potentially increase dutasteride concentrations. A reduction of dutasteride dosing frequency can be considered if side effects are noted.

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration is predicted to increase dydrogesterone exposure due to inhibition of CYP3A4. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In contrast, exposure of estrogens/estradiol administered as part of HRT may decrease. Monitor for signs of hormone deficiency. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Studies using a cocktail of probe drugs showed Echinacea inhibited CYP1A2 and intestinal CYP3A activity, and induced hepatic CYP3A activity. However, coadministration of Echinacea and lopinavir/ritonavir showed no clinically significant effect of Echinacea on lopinavir or ritonavir concentrations (most likely due to the potent CYP3A inhibition by ritonavir). Based on these data, Echinacea is unlikely to alter darunavir/ritonavir exposure.

Coadministration has not been studied. MDMA is metabolized mainly by CYP2D6. Darunavir/ritonavir could potentially increase MDMA concentrations. Ensure the patient is aware of signs/symptoms of MDMA toxicity.

Coadministration has not been studied. Edoxaban is a substrate for P-gp and coadministration is expected to increase edoxaban concentrations due to P-gp inhibition. The European product label for edoxaban states to consider a dose reduction of edoxaban from 60 mg to 30 mg with strong P-gp inhibitors, however, the US product label recommends no dose modification.

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir at a dose lower than that licensed (300/100 mg twice daily) decreased darunavir Cmax (15%), AUC (13%) and Cmin (31%). Efavirenz Cmax, AUC and Cmin increased by 15%, 21% and 17%, respectively. The clinical significance has not been established. Coadministration of efavirenz and once daily darunavir/ritonavir (900/100 mg once daily) decreased darunavir AUC (14%), Cmax (8%) and Ctrough (57%). Ritonavir AUC and Ctrough were significantly reduced, but there was no significant effect on efavirenz AUC, Cmax or Ctrough. The combination should be used with caution. Clinical monitoring for CNS toxicity associated with increased efavirenz exposure may be indicated.

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

Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as darunavir is contraindicated as it may significantly increase grazoprevir plasma concentrations. Coadministration of darunavir/ritonavir increased grazoprevir AUC by 7.5-fold and elbasvir AUC by 66%. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration has not been studied. Eltrombopag is metabolised by cleavage conjugation (UGTs 1A1 and 1A3) and oxidation (CYPs 1A2 and 2C8). Coadministration of eltrombopag (100 mg single dose) with lopinavir/ritonavir decreased eltrombopag AUC by 17%. Similarly, darunavir/ritonavir could potentially decrease eltrombopag exposure. Caution should be used when coadministering these drugs and platelet count monitoring is recommended.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and coadministration with other antiretroviral agents is not recommended in the Genvoya product labels. When darunavir is coadministered with ritonavir, it should not be administered with cobicistat or fixed dosed combination products containing cobicistat. Coadministration would be possible with unboosted darunavir (Prezista) in clinical situations requiring treatment intensification. 

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV 1 infection and coadministration with other antiretroviral agents is not recommended in the Stribild product labels. When darunavir is coadministered with ritonavir, it should not be administered with cobicistat or fixed dosed combination products containing cobicistat. Coadministration would be possible with unboosted darunavir (Prezista) in clinical situations requiring treatment intensification. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is metabolised by UGTs and is a substrate of P-gp, BCRP, OAT3 and OATP1B1/1B3. Although darunavir/ritonavir inhibits P-gp and OATP, data with verapamil (a P-gp inhibitor) and rifampicin (an OATP1B1/1B3 inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as emtricitabine is primarily renally excreted. Darunavir/ritonavir is unlikely to inhibit OCTs at clinically relevant concentrations.

Coadministration of darunavir/ritonavir (800/100 mg once daily) with emtricitabine/tenofovir alafenamide (200/10 mg, once daily) increased tenofovir AUC and Cmax by 105% and 142% (n=10). No significant effects were observed on darunavir pharmacokinetics relative to historical controls. The recommended dose of Descovy for HIV-1 treatment is 200/10 mg once daily (where available).

Coadministration with emtricitabine/tenofovir-DF has not been studied. Based on metabolism and clearance a clinically significant interaction is unlikely with emtricitabine as it is primarily renally excreted and darunavir/ritonavir is unlikely to inhibit OCTs at clinically relevant concentrations. Coadministration of tenofovir-DF (300 mg once daily) and darunavir/ritonavir (300/100 mg twice daily, a dose lower than that licensed) increased darunavir Cmax (16%), AUC (21%) and Cmin (24%). Tenofovir Cmax, AUC and Cmin increased by 24%, 22% and 37%, respectively. No adjustments to the licensed doses are required. A higher risk of renal impairment has been reported in patients receiving tenofovir-DF and a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function and for tenofovir-associated adverse reactions is required in these patients.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is eliminated renally, possibly via OATs. Darunavir/ritonavir is unlikely to inhibit the renal transporters OATs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as enflurane is predominantly metabolized by CYP2E1. There is no evidence that darunavir/ritonavir inhibits or induces this metabolic enzyme.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enoxaparin does not undergo cytochrome metabolism but is desulphated and depolymerised in the liver, and is excreted predominantly renally.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Entecavir is eliminated renally via glomerular filtration and active renal secretion by both organic anion and cation transporters. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ephedrine is predominantly eliminated unchanged via the kidneys via the renal transporter OCT2. Darunavir/ritonavir is unlikely to inhibit OCTs at clinically relevant concentrations.

Coadministration has not been studied. Epirubicin is glucuronidated by UGT2B7. Darunavir/ritonavir could potentially reduce epirubicin concentrations (induction of UGT2B7 by ritonavir) and thus decrease the efficacy.

Coadministration has not been studied and is contraindicated. Eplerenone is metabolized by CYP3A4 and coadministration is expected to substantially increase eplerenone exposure due to inhibition of CYP3A4 and thereby increase the risk of hyperkalaemia. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, increased eplerenone AUC by 441%. There is a case report of a patient on fosamprenavir/ritonavir developing severe hyperkalaemia when eplerenone was initiated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Epoprostenol is rapidly hydrolyzed in the blood.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as eprosartan is largely excreted in bile and urine as unchanged drug.

Coadministration is contraindicated as it may increase ergometrine concentrations which may result in serious and/or life threatening reactions such as acute ergot toxicity.

Coadministration is contraindicated as it may increase ergotamine concentrations which may result in serious and/or life threatening reactions such as acute ergot toxicity.

Coadministration has not been studied. Erlotinib is mainly metabolized by CYP3A4 and coadministration could potentially increase erlotinib concentrations. Ketoconazole (a strong CYP3A4 inhibitor) increased erlotinib AUC by 86%. As erlotinib is dosed at/near the maximum tolerated dose (MTD), any increase in erlotinib exposure may lead to toxicity. Coadministration of a potent CYP3A4 inhibitor should be avoided, but if this is not possible, use with caution and close monitoring for erlotinib mediated toxicity is necessary. The erlotinib dose should be reduced in 50 mg increments if toxicity is observed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor role.

Coadministration has not been studied but may increase erythromycin concentrations. Use with caution and monitor erythromycin related side adverse effects, especially cardiac adverse events. Erythromycin has a possible risk of QTc prolongation and/or TdP on the CredibleMeds.org website. If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Darunavir/ritonavir could potentially increase escitalopram concentrations although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Eslicarbazepine is partly eliminated unchanged renally and partly glucuronidated by UGT2B4. Eslicarbazepine is a weak/moderate inducer of CYP3A4. Coadministration could potentially reduce darunavir + ritonavir concentrations, leading to loss of therapeutic effect and possible development of resistance. Consider use of other anticonvulsants. If coadministration is necessary, closely monitor virological response and monitor darunavir + ritonavir plasma concentrations (when possible).

Coadministration has not been studied but based on results with omeprazole (no effect on darunavir AUC, Cmax or Cmin), darunavir/ritonavir can be coadministered with proton pump inhibitors without dose adjustments.

Coadministration has not been studied. Estazolam is metabolized to its major metabolite 4-hydroxyestazolam via CYP3A4. Darunavir/ritonavir could potentially increase estazolam exposure. This could prolong sedation and a dosage reduction may be required.

Coadministration with estradiol as hormone replacement therapy (HRT) has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Coadministration could potentially decrease estradiol exposure due to induction of CYP1A2 and glucuronidation (rather than increase it due to inhibition of CYP3A4). Monitor for signs of estrogen deficiency.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Estramustine phosphate undergoes rapid dephosphorylation to estramustine which is then oxidized by 17beta-hydroxysteroid dehydrogenases to estromustine. Estramustine and estromustine are subsequently hydrolyzed to estradiol and estrone, respectively. Estradiol is then hydroxylated by CYPs 1A1, 1A2 and 3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).

Coadministration of an oral contraceptive (ethinylestradiol/norethindrone 0.035/1.0 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) decreased ethinylestradiol AUC (44%), Cmax (32%) and Cmin (62%). Norethindrone AUC, Cmax and Cmin decreased by 14%, 10% and 30%, respectively. Alternative or additional contraceptive measures are recommended. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency. Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethionamide is extensively metabolized in the liver, animal studies suggest involvement of flavin-containing monooxygenases. Ethionamide does not affect metabolism mediated by CYP450 enzymes in vitro.

Coadministration has not been studied but may increase ethosuximide concentrations. Use with caution and perform therapeutic drug monitoring for ethosuximide.

Coadministration has not been studied. Etidocaine is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by darunavir/ritonavir. Use with caution.

Coadministration of darunavir/ritonavir (600/100 mg twice daily) and an etonogestrel-containing progestogen-only implant (68 mg) was studied in 30 HIV-positive women. When compared to a control group of HIV-negative women not receiving ART (n=20), etonogestrel was 156% and 120% higher in the darunavir/ritonavir group at Weeks 24 and 48, respectively. Although etonogestrel concentrations were higher in the darunavir/ritonavir group, no implant-related serious adverse events were observed and these pharmacokinetic findings are not considered clinically significant. These results suggest an etonogestrel implant represents a suitable contraceptive option for women receiving darunavir/ritonavir-based antiretroviral regimens.

Coadministration with the etonogestrel as a combined vaginal ring (CVR) has not been studied. Etonogestrel is metabolized by CYP3A4 and is coformulated in the CVR with ethinylestradiol which is released at a dose of 0.015 mg/day. Darunavir/ritonavir is predicted to increase etonogestrel but to reduce ethinylestradiol concentrations. Since no dosage adjustment of ethinylestradiol is possible with the CVR, alternative forms of contraception should be used.

Coadministration has not been studied. Etoposide is partly metabolized by CYP3A4 to reactive catechol metabolites. Conversion to reactive metabolites can also be mediated by prostaglandin synthase or myeloperoxidase. Furthermore, etoposide is partly glucuronidated by UGT1A1. Ketoconazole (a strong CYP3A4 inhibitor) increased etoposide exposure by 20%. The net effect of this interaction is difficult to predict as darunavir/ritonavir could potentially increase (inhibition of CYP3A4) or decrease (induction of UGT1A1) etoposide exposure. Close monitoring of etoposide induced toxicity is recommended. Reduce dose if clinically necessary or consider selection of an alternate non-CYP inhibiting antiretroviral regimen.

Etravirine and darunavir/ritonavir can be coadministered without any dose adjustments. Etravirine exposures from Phase 3 trials with darunavir/ritonavir as part of the background regimen were determined to be safe and effective. Coadministration decreased etravirine Cmax, AUC and Cmin by 32%, 37% and 49%, respectively; darunavir Cmax, AUC and Cmin increased by 11%, 15% and 2%, respectively. When etravirine was added to raltegravir/darunavir/ritonavir, raltegravir AUC, Cmax and Cmin increased by 29%, 21% and 54%, respectively and darunavir AUC, Cmax and Cmin increased by 14%, 6%, and 29%, respectively.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Eucalyptus is only a weak inhibitor of CYP3A4 and any additional effect on exposure of darunavir in the presence of ritonavir is unlikely.

Coadministration of has not been studied but should be avoided. Everolimus is metabolized by CYP3A4. Coadministration with ketoconazole (a potent inhibitor of CYP3A4) increased everolimus exposure by 15-fold. Similarly, a large increase in everolimus exposure is predicted in presence of darunavir/ritonavir. Coadministration is not recommended as there are currently insufficient data to allow dosing recommendations with potent CYP3A4 inhibitors.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Evolocumab 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. Exemestane is metabolised by CYP3A4 but coadministration with ketoconazole (a potent CYP3A4 inhibitor) showed no clinically significant effects and no effect is expected due to inhibition of CYP3A4 by darunavir/ritonavir. No a priori dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as exenatide is primarily eliminated by glomerular filtration. However, as exenatide slows gastric emptying it is advisable to take darunavir/ritonavir at least 1 hour before an exenatide injection. [Note: this interaction is not specific for darunavir/ritonavir, but for any medication taken with exenatide.]

Coadministration has not been studied. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Ezetimibe is a substrate of OATP1B1. Ritonavir induces UGTs but darunavir inhibits OATP1B1. These opposite effects might limit the magnitude of the interaction. No a priori dosage adjustment is needed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famciclovir is converted to penciclovir by aldehyde oxidase. Penciclovir is secreted in the urine possibly by OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied but based on results with ranitidine (no effect on darunavir AUC, Cmax or Cmin), darunavir/ritonavir can be coadministered with H2 receptor antagonists without dose adjustments.

Coadministration has not been studied. Felodipine is metabolized by CYP3A4. Darunavir/ritonavir could potentially increase felodipine concentrations. Caution is warranted and clinical monitoring of therapeutic and adverse effects is recommended.

Coadministration with darunavir/ritonavir has not been studied. Data from an interaction study with fenofibrate (145 mg single dose) and lopinavir/ritonavir (400/100 mg twice daily) or ritonavir alone (100 mg twice daily) suggest that an interaction is unlikely to occur in patients taking ritonavir-boosted regimens. Fenofibrate AUC and Cmax decreased by 14% and 3% with lopinavir/ritonavir and by 11% and 1% with ritonavir alone.

Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration may increase fentanyl concentrations due to inhibition of CYP3A4, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of a CYP3A4 inhibitor could decrease fentanyl concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When discontinuing CYP3A4 inhibitors in fentanyl-treated patients, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur. Note, the use of fentanyl in a non-therapeutic setting (i.e., as a recreational drug) should be avoided with darunavir as fentanyl exposure is expected to significantly increase and serious, life-threatening, or fatal respiratory depression may occur. Patients should be aware that recreational use could be potentially fatal.

Coadministration has not been studied. Fesoterodine is rapidly hydrolysed to its active metabolite which is subsequently metabolized by CYP2D6 and CYP3A4. Concentrations of the active metabolite of fesoterodine are likely to increase due to inhibition of CYP3A4. The maximum daily dose of fesoterodine should not exceed 4 mg when used concomitantly with potent CYP3A4 inhibitors such as ritonavir.

Coadministration has not been studied. Fexofenadine does not undergo CYP mediated metabolism but is a substrate of P-gp/OATP. Darunavir/ritonavir could potentially increase fexofenadine exposure by inhibition of P-gp. However, due to the large therapeutic index of fexofenadine, no dosage adjustment is recommended.

Coadministration has not been studied. Finasteride is metabolised by CYP3A4 and coadministration may increase finasteride concentrations. However, any increase is unlikely to be of clinical significance due to finasteride’s wide margin of safety and no a priori dose alteration is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. There are no clinical data, but fish oils inhibited CYP3A-mediated metabolism of saquinavir in rat liver microsomes and simultaneous coadministration with saquinavir in rats increased saquinavir exposure by ~3-fold. Separating the doses by 2 h overcame the interaction.

Coadministration has not been studied but may increase flecainide concentrations which could increase or prolong its therapeutic effect and adverse reactions. Use with caution and monitor flecainide concentrations, if available.

Coadministration has not been studied. Flibanserin is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19. Coadministration of flibanserin with moderate or strong inhibitors of CYP3A4 is contraindicated due to increased flibanserin concentrations which can cause severe hypotension and syncope.

Coadministration has not been studied. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations. Flucloxacillin is thought to be a weak inducer of CYP3A4 particularly at higher doses (>2-3 g daily). A modest reduction in darunavir/ritonavir concentrations may be observed but this is unlikely to be clinically relevant unless flucloxacillin is prescribed at higher doses for a prolonged course (> 10-14 days).

Coadministration has not been studied. Fluconazole is a moderate inhibitor of CYP3A4, however, drug interactions studies with other protease inhibitors showed no clinically significant interactions with fluconazole.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-flurouracil which is further metabolised by dihydropyrimidine dehydrogenase.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludarabine phosphate is rapidly hydrolyzed (non-CYP mediated) to 2F-ara-A, the principal metabolite, which is then eliminated renally.

Coadministration has not been studied. Concomitant administration of darunavir/ritonavir and corticosteroids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Fludrocortisone is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir. Use alternative treatments.

Coadministration has not been studied. Flunisolide undergoes CYP3A4-mediated metabolism and coadministration may increase flunisolide concentrations. Flunisolide has properties (low binding affinity to glucocorticoid receptors, low lipophilicity and short elimination half-life) associated with a lower propensity to cause a Cushing syndrome. If coadministered with darunavir/ritonavir, it is recommended to use the lowest possible flunisolide dose with monitoring for corticosteroid side effects.

Coadministration has not been studied. Flunitrazepam is metabolized mainly via CYP3A4 and CYP2C19. Darunavir/ritonavir could potentially increase flunitrazepam exposure which could result in increased sedation or respiratory sedation. A dosage reduction may be required.

Coadministration has not been studied but may increase fluocinolone concentrations. Careful monitoring of corticoid side effects is recommended. Note, the extent of percutaneous absorption is determined by many factors such as the degree of inflammation or alteration of the skin, the duration, frequency and surface of application and the use of occlusive dressings.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluorouracil is metabolised via the same mechanisms as endogenous uracil, including via dihydropyrimidine dehydrogenase. There is therefore little potential for an interaction with darunavir and ritonavir via modulation of, or competition for metabolic pathways.

Coadministration has not been studied. Fluoxetine is metabolized by CYPs 2D6 and 2C9 and to a lesser extent by CYPs 2C19 and 3A4 to form norfluoxetine. Darunavir/ritonavir could potentially increase fluoxetine concentrations although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Darunavir/ritonavir could potentially increase levels of fluphenazine, although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. The metabolism of flurazepam is most likely CYP-mediated. Darunavir/ritonavir could potentially increase flurazepam exposure which could result in increased sedation or respiratory sedation. A dosage reduction may be required.

Coadministration of darunavir/ritonavir 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 inhaled or intranasally administered fluticasone; this could also occur with other corticosteroids metabolised via the P450 3A pathway 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 have to be performed over a longer period.

Coadministration has not been studied. Fluvastatin is partially metabolised by CYP2C9 and is a substrate of OATP1B1. There is potential for a moderate increase in fluvastatin exposure when coadministered with darunavir/ritonavir as ritonavir induces CYP2C9 but darunavir inhibits OATP1B1 and these opposite effects might limit the magnitude of the interaction. No a priori dosage adjustment is needed.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Darunavir/ritonavir could potentially increase fluvoxamine concentrations although to a limited 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. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely when folic acid is administered in a multivitamin preparation. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is eliminated predominantly renally.

Coadministration has not been studied. Formestane undergoes reductive metabolism by hepatic hydroxysteroid dehydrogenase and glucuronidation. Coadministration with darunavir/ritonavir could potentially decrease formestane exposure due to induction of glucuronidation. Monitor formestane therapeutic effect.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation being another pathway. As multiple CYP450 and UGT enzymes catalyze the transformation the potential for a pharmacokinetic interaction is low.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as foscarnet is cleared mainly by glomerular filtration.

Coadministration has not been studied. Fosinopril is hydrolysed by esterases in the GI mucosa and liver and is transported by MRP2. Darunavir + ritonavir may increase fosinopril exposure due to inhibition of MRP2 by ritonavir. The clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally. Darunavir/ritonavir is unlikely to inhibit the renal transporters OATs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as gabapentin is cleared mainly by glomerular filtration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ganciclovir is primarily eliminated by the kidney and in vitro data suggest that it is a substrate of the renal transporter OAT1. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied in pharmacokinetic trials. Concentrations of ritonavir-boosted darunavir could be decreased via induction of CYP3A4 and/or P-gp. Subtherapeutic trough concentrations of darunavir and ritonavir have been reported in two subjects taking darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily) with significant garlic consumption. Garlic supplements have been shown to decrease unboosted saquinavir AUC by 50% in a clinical trial and there is a case report of treatment failure due to garlic cloves (six garlic cloves three times weekly) decreasing ritonavir-boosted atazanavir trough concentrations by ~70%. Patients should be advised against the use of garlic supplements.

Coadministration has not been studied. Gefitinib is metabolized by CYP3A4 and CYP2D6 and coadministration could potentially increase gefitinib concentrations. Itraconazole (a strong CYP3A4 inhibitor) increased gefitinib exposure by 80%. A similar effect is expected with darunavir/ritonavir. If coadministration is necessary, close monitoring of gefitinib induced toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemcitabine is metabolized in the liver by cytidine deaminase to an inactive metabolite.

Coadministration has not been studied. Gemfibrozil is metabolised mainly by UGT2B7. As ritonavir induces glucuronidation, darunavir/ritonavir could potentially decrease gemfibrozil exposure, although to a limited extent. No a priori dosage adjustment is required.

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

Coadministration with a gestodene-containing combined oral contraceptive (COC) has not been studied. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Coadministration is predicted to increase gestodene exposure. 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. A case was reported of a patient experiencing a near fatal reaction from a small dose of GHB while on saquinavir and ritonavir (400 mg twice daily). Darunavir/ritonavir may increase gamma-hydroxybutyrate concentrations. Ensure the patient is aware of signs/symptoms of GHB toxicity.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although gingerols moderately inhibit CYP3A4 in vitro, any additional effect on exposure of darunavir in the presence of ritonavir is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Coadministration is unlikely to affect concentrations of darunavir when boosted with ritonavir.