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. 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Darunavir/cobicistat does not inhibit or induce these CYPs in the range of clinical concentrations. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acetazolamide is predominantly excreted unchanged via active renal tubular secretion. Darunavir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely as aciclovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Darunavir/cobicistat 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 the metabolism and clearance a clinically significant interaction is unlikely as adefovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Darunavir/cobicistat 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). Darunavir/cobicistat does not interfere with this metabolic pathway.

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/cobicistat.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely as agomelatine is metabolised predominantly via CYP1A2. Cobicistat is unlikely to inhibit or induce CYP1A2 at clinically relevant concentrations. 

Coadministration has not been studied. In vitro studies have shown that CYP3A4 and the flavine-containing monooxygenase system are involved in the formation of the active metabolite albendazole sulfoxide. Darunavir/cobicistat could potentially reduce albendazole sulfoxidation and thus lower the clinical effect of albendazole. The clinical significance of this interaction is unknown. 

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/cobicistat 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/cobicistat 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/cobicistat 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 it 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/cobicistat. The product labels for aliskiren recommend avoiding concomitant use with CYP3A4 and P-gp inhibitors.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Darunavir/cobicistat does not interfere with this metabolic pathway.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that alosetron is metabolized by CYPs 2C9, 3A4 and 1A2; however, in vivo data suggest that CYP1A2 plays a more prominent role. Darunavir/cobicistat does not inhibit or induce CYP1A2 in the range of clinically relevant concentrations.

Coadministration has not been studied. Alprazolam is mainly metabolized by CYP3A4. Coadministration of darunavir/cobicistat may increase alprazolam concentrations and may result in enhanced sedation. A decrease in alprazolam dose may be needed.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Amantadine is mainly eliminated in the kidney 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 the metabolism and clearance a clinically significant interaction is unlikely as amikacin is eliminated 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/cobicistat is unlikely to inhibit OATs and OCTs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 darunavir/cobicistat does not inhibit CYP1A2 at physiological concentrations.

Coadministration has not been studied.  Amiodarone is metabolized by CYP2C8 and 3A4 and exposure may increase due to CYP3A4 inhibition by darunavir/cobicistat causing potential cardiac arrhythmias. The European product label for darunavir/cobicistat contraindicates coadministration but the US product label for darunavir/cobicistat 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/cobicistat is unlikely to inhibit OCTs at clinically relevant concentrations.

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

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4. Darunavir/cobicistat could potentially increase amlodipine exposure. Caution is warranted and clinical monitoring of therapeutic and adverse effects is recommended. Amlodipine should be started at low doses with careful titration to response.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Amodiaquine is metabolized mainly by CYP2C8. In vitro data indicate that cobicistat does not inhibit CYP2C8 in the range of clinically relevant concentrations. 

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/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6 and coadministration with darunavir/cobicistat 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 mainly excreted in the urine by glomerular filtration and tubular secretion. Darunavir/cobicistat 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 via UGT1A4. Darunavir/cobicistat could potentially increase anastrozole concentrations (via inhibition of CYP3A4). Monitor anastrozole related side effects.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as 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/cobicistat 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/cobicistat, 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 but based on metabolism and clearance a clinically significant interaction is unlikely as apomorphine is metabolized by several pathways including glucuronidation, sulfation and to a lesser extent N-demethylation. 

Coadministration has not been studied. Aprepitant is mainly metabolized by CYP3A4 and is a moderate inhibitor of CYP3A4. Darunavir/cobicistat 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/cobicistat is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Darunavir/cobicistat 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. Artemisinins undergo rapid metabolism via several CYP450 (CYPs 3A4, 2A6, 2B6) and the active metabolite (dihydroartemisinin, which has greater potency than the parent drug) is further metabolism via UGTs 1A9 and 2B7. Darunavir/cobicistat could potentially increase plasma levels of artemisinins. Close monitoring for artemisinin toxicity 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/cobicistat does not interfere with this metabolic pathway. 

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (CYP1A2 (major) and CYP3A4, 2D6 (minor)). Darunavir/cobicistat could potentially increase asenapine exposure by inhibition of CYP3A4, although to a limited extent as CYP3A4 does not play a major role in asenapine metabolism. No a priori dosage adjustment is recommended.

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 increase potential serious and/or life-threatening adverse reactions such as cardiac arrhythmias.

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.

Atazanavir/cobicistat should not be used in combination with medicinal products also containing cobicistat.

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. Atenolol is mainly eliminated by the kidney, both by glomerular filtration and active secretion via the renal transporters OCT2 and MATE1. Cobicistat is unlikely to inhibit OCTs at clinically relevant concentrations. However, cobicistat reversibly inhibits MATE1, and concentrations of atenolol may be increased when coadministered with darunavir/cobicistat. It is recommended to start atenolol at a lower dose and adjust dosage until the desired clinical effect is achieved.

Coadministration of darunavir/cobicistat (800/150 mg once daily) and atorvastatin (10 mg) increased atorvastatin AUC and Cmax by 290% and 319% due to inhibition of CYP3A4, OATP1B1 and BCRP by darunavir/cobicistat. However, atorvastatin did not affect darunavir/cobicistat exposure. When administration of atorvastatin and darunavir/cobicistat is required, it is recommended to initiate atorvastatin with the lowest dose, and titrate to desired response while monitoring for safety. A daily dose of 40 mg atorvastatin should not be exceeded with careful safety monitoring. (Note, the US product label for Prezcobix 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. A possible mechanism was suggested to be induction of glucuronidation by ritonavir. There is no evidence that cobicistat inhibits or induces UGTs and therefore a clinically significant drug-drug interaction with atovaquone and darunavir/cobicistat is not expected. 

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 the presence of darunavir/cobicistat.

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

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/cobicistat could potentially increase azithromycin exposure (inhibition of P-gp and MRP2), however no a priori dosage adjustment is recommended for azithromycin.

Coadministration has not been studied but a clinically significant interaction is unlikely. 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 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 ritonavir (100 mg twice daily) increased the AUC and Cmax of beclomethasone-17-monoproprionate by 108% and 67%, respectively. However, although statistically significant, the 2-fold increase in AUC of the active metabolite seen with ritonavir did not affect the adrenal function. Use the lowest possible corticosteroid dose with caution and monitor for corticosteroid side effects.

Coadministration has not been studied. Bedaquiline is metabolised by CYP3A4. Moderate to strong CYP3A4 inhibitors, such as cobicistat, may increase bedaquiline exposure, which could potentially increase the risk of adverse reactions. Given that bedaquiline has a prolonged terminal half-life and that the impact of prolonged CYP3A4 inhibition on bedaquiline exposure is unknown, the combination of bedaquiline and moderate or strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided. If coadministration is required, more frequent electrocardiogram monitoring and monitoring of transaminases is recommended. 

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 has not been studied and is contraindicated. Bepridil is metabolized by CYP2D6 (major) and 3A4. Darunavir/cobicistat could potentially increase bepridil exposure resulting in the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 ritonavir-boosted atazanavir 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/cobicistat 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/cobicistat) 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/cobicistat exposure and therefore coadministration should be avoided.

Coadministration has not been studied but based on the 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/cobicistat 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. However, coadministration with darunavir/cobicistat (800/150 mg once daily) and tenofovir alafenamide (25 mg once daily) increased tenofovir AUC and Cmax by 224% and 216%, 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 urine. Darunavir/cobicistat could potentially increase bisoprolol exposure, although to a limited extent. No a priori dosage adjustment is needed.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on darunavir/cobicistat 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 CYPs 3A4 and 2C19 and to a lesser extent by CYPs 1A2, 2D6 and 2C9. Darunavir/cobicistat 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.

Coadministration has not been studied and may increase bosentan concentrations but decrease concentrations of cobicistat and darunavir. The European product label for darunavir/cobicistat does not recommended coadministration as it may lead to decreased cobicistat concentrations and consequently those of darunavir being boosted, leading to loss of therapeutic effect and possible development of resistance. However, the US product label suggests the following dose modifications. For patients stable on darunavir/cobicistat, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. When starting darunavir/cobicistat in patients stable on bosentan, discontinue bosentan at least 36 h prior to starting cobicistat and resume bosentan at 62.5 mg once daily or every other day based on individual tolerability after at least 10 days following starting darunavir/cobicistat. To switch from ritonavir to cobicistat, maintain bosentan dose.

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/cobicistat 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//cobicistat. No a priori dosage adjustment is required.

Coadministration of darunavir/cobicistat 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 strong inhibitors of CYP3A4 and fluticasone; this could also occur with other corticosteroids metabolised by CYP3A e.g. budesonide. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). 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/cobicistat 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 has not been studied. Based on theoretical considerations, darunavir/cobicistat may increase buprenorphine and/or norbuprenorphine plasma concentrations. Dose adjustment for buprenorphine may not be necessary when coadministered with darunavir/cobicistat, but careful clinical monitoring for signs of opiate toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolized by CYP2B6. Cobicistat is not expected to be a clinically relevant inducer. In human hepatocyte study, messenger RNA for CYP2B6 was largely unaffected by cobicistat at concentrations up to 30 µM. 

Coadministration has not been studied. Buspirone is metabolized by CYP3A4 but does not inhibit CYP3A4. Darunavir/cobicistat 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 but based on the metabolism and clearance a clinically significant interaction is unlikely. Caffeine is mainly metabolized by CYP1A2. In vitro data indicate that darunavir/cobicistat does not inhibit CYP1A2 in the range of clinically relevant concentrations.

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4 which are not affected by darunavir or cobicistat.

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 is expected to significantly increase cannabidiol exposure (inhibition of CYP3A4 by darunavir/cobicistat) which may result in a greater risk of adverse reactions. Consider a dose reduction of cannabidiol. Advise patients to be aware of adverse reactions to cannabidiol. 

Coadministration has not been studied. Tetrahydrocannabinol (THC, the psychoactive component of cannabis) is metabolized mainly by CYP2C9 and to a lesser extent by CYP3A4. Darunavir/cobicistat could potentially modestly increase THC. The patient should be made aware of potential increased side effects.

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/cobicistat 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 has not been studied and is contraindicated. Coadministration could potentially increase carbamazepine concentrations and significantly reduce darunavir/cobicistat concentrations which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered. 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 with darunavir/cobicistat 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 additional metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Darunavir/cobicistat could potentially increase carvedilol although to a limited extent as cobicistat is a weak inhibitor of CYP2D6. No a priori dosage adjustment is needed.

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. Darunavir/cobicistat could potentially increase caspofungin exposure (inhibition of OATP1B1) although to a limited extent. 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. Cobicistat is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations. In vitro data indicate that cobicistat 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/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 as cefixime is renally excreted predominantly by glomerular filtration.

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 as ceftazidime is excreted predominantly by 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 predominantly 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 vitro data indicate that darunavir/cobicistat is unlikely to induce or inhibit CYP2C9 in the range of clinical concentrations. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Darunavir/cobicistat is unlikely to inhibit OATs and OCTs at clinically relevant concentrations. 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/cobicistat. 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/cobicistat, the activity of chlordiazepoxide may be increased.

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

Coadministration has not been studied. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. In vitro data indicate that cobicistat is a weak inhibitor of CYP2D6. Darunavir/cobicistat could potentially increase chlorphenamine concentrations 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. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Darunavir/cobicistat could potentially increase chlorpromazine although to a limited extent (cobicistat is a weak inhibitor of CYP2D6). 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 chlortalidone is mainly excreted unchanged in the urine and faeces.

Coadministration has not been studied. Ciclesonide can be administered with darunavir/cobicistat 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/cobicistat 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 the metabolism and clearance a clinically significant interaction is unlikely as cidofovir is eliminated renally via glomerular filtration and active renal secretion by OAT1 and OAT3. Darunavir/cobicistat 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 cilazapril is mainly eliminated unchanged by the kidneys.

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

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 increase potential serious and/or life-threatening adverse 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 cobicistat is a moderate inhibitor of MATE1. Cobicistat 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 CYP2C19 (38%), 2D6 (31%) and 3A4 (31%). Darunavir/cobicistat could potentially increase citalopram concentrations although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Clarithromycin is metabolized by CYP3A4. Concentrations of clarithromycin may be increased upon co-administration of darunavir/cobicistat. In addition, clarithromycin may increase darunavir/cobicistat plasma concentrations. The European SPC for darunavir/cobicistat recommends dose reduction of clarithromycin for patients with impaired renal function (CLcr 30-60 ml/min, clarithromycin dose reduction by 50%, CLcr less than 30 ml/min, clarithromycin dose reduction by 75%). The US prescribing information for darunavir/cobicistat recommends to use an alternative antibiotic.

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. Ketoconazole (a strong CYP3A4 inhibitor) was shown to increase clobazam exposure by 54%. A similar effect is expected with darunavir/cobicistat. Consider starting on the recommended dose, but with close monitoring for side effects associated with clobazam and decrease dose if necessary. Clobazam is unlikely to significantly impact darunavir/cobicistat.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by cobicistat. 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/cobicistat 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/cobicistat might increase clomifene exposure although to a limited extent via CYP2D6 inhibition. No a priori dosage adjustment is needed.

Coadministration has not been studied. Clomipramine is metabolized by CYP3A4, 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/cobicistat could potentially increase clomipramine concentration. 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/cobicistat 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/cobicistat 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/cobicistat 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/cobicistat 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. The analgesic effect requires conversion of codeine to morphine via CYP2D6 and in vitro data suggest that cobicistat is a weak inhibitor of CYP2D6. Darunavir/cobicistat could potentially reduce the analgesic efficacy. No a priori dosage adjustment is recommended but monitor the analgesic effect.

Coadministration is expected to increase colchicine concentrations. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with darunavir/cobicistat is required. The US product label for darunavir/cobicistat gives the following dose modifications. 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. 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. 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). Note, coadministration is contraindicated in patients with renal or hepatic impairment. 

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/cobicistat 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 cobicistat 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 theory, darunavir/cobicistat 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 cobicistat. 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. Cytarabine is metabolized by cytidine deaminase. Darunavir/cobicistat does not interfere with this metabolic pathway.

Coadministration of dabigatran (150 mg) and darunavir/cobicistat (800/150 mg single dose and multiple doses once daily) was studied in 14 subjects. Single dose administration increased dabigatran AUC and Cmax by 164% and 164%, whereas dabigatran AUC and Cmax increased by 88% and 99% with darunavir/cobicistat once daily. The effect of separating dosing was studied using cobicistat alone. Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before cobicistat alone (150 mg once daily) was studied in HIV negative subjects. Simultaneous administration increased dabigatran AUC by 127% (n=16). Separating the dosing by 2 h did not overcome the interaction (dabigatran AUC increased by 110%, n=18). This pharmacokinetic interaction (due to inhibition of intestinal P-gp by cobicistat) resulted in a more pronounced anticoagulant response as indicated by measurements of the thrombin times. A population/PBPK/PD analysis indicates that in presence of cobicistat, the dabigatran dose should be reduced to 110 mg twice daily in individuals with normal renal function and to 75 mg twice daily in individuals with moderate renal impairment, and that coadministration should be avoided in case of severe renal impairment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dacarbazine undergoes activation to MTIC primarily via CYP1A2 and to a lesser extent by CYP2E1, with CYP1A1 having a role in extrahepatic metabolism. Darunavir/cobicistat does not inhibit or induce these cytochromes at clinically relevant concentrations. 

Coadministration with darunavir/cobicistat has not been studied. 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 is required with daclatasvir 60 mg once daily and darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily). Similarly, no dose adjustment is required with darunavir/cobicistat.

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 a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via 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 which is not affected by darunavir or cobicistat.

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 cobicistat), but the US product label recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

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

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

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and darunavir/cobicistat may significantly increase exposure to 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 cobicistat 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 with darunavir/cobicistat has not been studied. Coadministration of desipramine (50 mg single dose) and cobicistat (150 mg once daily) increased desipramine to a limited extent (Cmax and AUC by 24% and 65%, n=8). A similar effect may be expected with darunavir/cobicistat. 

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 with darunavir/cobicistat is predicted to increase the conversion to the active metabolite etonogestrel due to inhibition of CYP3A4. Since no data are available to make recommendations on the use of darunavir/cobicistat with combined contraceptives, alternative forms of contraception 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 possible 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/cobicistat.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dexmedetomidine undergoes extensive hepatic metabolism biotransformation through direct glucuronidation (mainly via UGT1A4, 2B10) and cytochrome P450 (mainly CYP2A6). There is no evidence that darunavir/cobicistat inhibits or induces these metabolic enzymes.

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). There is no evidence that darunavir/cobicistat inhibits or induces UGT2B7, UGT1A1. However, morphine and morphine-6-glucuronide are substrates of P-gp and coadministration may potentiate the effects of opiate in the CNS due to inhibition of P-gp at the blood-brain barrier by cobicistat. Monitor for signs of opiate toxicity.

Coadministration has not been studied. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4). Darunavir/cobicistat 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 (catalyzes the major route of diclofenac oxidative metabolism). There is no evidence that darunavir/cobicistat inhibits or induces UGT2B7 or CYP2C9. 

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

Coadministration has not been studied but based on metabolism and clearance, darunavir/cobicistat is predicted to increase digoxin plasma concentrations (P-gp inhibition). It is recommended that the lowest possible dose of digoxin should initially be given to patients on darunavir/cobicistat. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.

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/cobicistat could potentially increase dihydrocodeine exposure by inhibition of CYP3A4 and CYP2D6. 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 of dihydroergotamine and darunavir/cobicistat is contraindicated due to potential for serious and/or life threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

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/cobicistat 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. In vitro data indicate that cobicistat is a weak inhibitor of CYP2D6. Darunavir/cobicistat could potentially increase diphenhydramine concentrations 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. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. There is no evidence that cobicistat inhibits or induces these UGTs.

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/cobicistat has not been studied but 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 potent CYP3A inhibitors. Ideally avoid coadministration 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/cobicistat 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.

Coadministration of dolutegravir (50 mg once daily) and darunavir/cobicistat (800/150 mg once daily) decreased dolutegravir Cmax, AUC, and C24 by 11%, 16% and 19%, respectively (n=9). Darunavir Cmax, AUC, and C24 decreased 21%, 13% and 18%, respectively, and cobicistat Cmax, AUC and C24h decreased by 14%, 12% and 2%, respectively. Dolutegravir and darunavir/cobicistat can be administered without dose adjustments.

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/cobicistat would be possible from a pharmacokinetic standpoint. Coadministration of dolutegravir (50 mg once daily) and darunavir/cobicistat (800/150 mg once daily) decreased dolutegravir Cmax, AUC, and C24 by 11%, 16% and 19%, respectively (n=9). Darunavir Cmax, AUC, and C24 decreased 21%, 13% and 18%, respectively, and cobicistat Cmax, AUC and C24h decreased by 14%, 12% and 2%, respectively. No interaction is expected with abacavir or lamivudine.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with darunavir/cobicistat would be possible from a pharmacokinetic standpoint. Coadministration of dolutegravir (50 mg once daily) and darunavir/cobicistat (800/150 mg once daily) decreased dolutegravir Cmax, AUC, and C24 by 11%, 16% and 19%, respectively (n=9). Darunavir Cmax, AUC, and C24 decreased 21%, 13% and 18%, respectively, and cobicistat Cmax, AUC and C24h decreased by 14%, 12% and 2%, respectively. 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 Juluca would be possible from a pharmacokinetic standpoint. Coadministration of dolutegravir (50 mg once daily) and darunavir/cobicistat (800/150 mg once daily) decreased dolutegravir Cmax, AUC, and C24 by 11%, 16% and 19%, respectively (n=9). Darunavir Cmax, AUC, and C24 decreased 21%, 13% and 18%, respectively, and cobicistat Cmax, AUC and C24h decreased by 14%, 12% and 2%, respectively. Coadministration of rilpivirine and darunavir/cobicistat is expected to increase plasma concentration of rilpivirine, but the expected increase in rilpivirine concentrations is not considered clinically relevant.

Coadministration has not been studied and is contraindicated with potent CYP3A4 inhibitors. Domperidone is mainly metabolized by CYP3A4. Darunavir/cobicistat 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. There is little potential for dopamine to affect the disposition of darunavir/cobicistat, or to be affected if co-administered with darunavir/cobicistat.

Coadministration has not been studied. Doravirine is metabolized by CYP3A4. Cobicistat is a strong inhibitor of CYP3A4 and is expected to increase doravirine exposure by a~ 3.5-fold based on the drug interaction study with ritonavir. 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/cobicistat 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 and a similar increase may occur with cobicistat. 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. Boosted PIs were shown to increase tenofovir-DF and there are currently inadequate data to determine whether tenofovir-DF plus cobicistat is associated with a greater risk of renal adverse reactions than tenofovir-DF without cobicistat. The European SPC for tenofovir-DF advises close renal monitoring of patients receiving tenofovir-DF with a cobicistat-boosted protease inhibitor. The US Prescribing Information for cobicistat does not recommend coadministration of cobicistat and tenofovir-DF in combination with concomitant or recent use of a nephrotoxic agent. Note, cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine and should not be initiated in patients with creatinine clearance less than 70 ml/min if tenofovir-DF requires dose adjustment based on creatinine clearance.

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/cobicistat, 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/cobicistat.

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/cobicistat could potentially increase doxepin and nordoxepin concentrations although to a limited extent as cobicistat is a weak inhibitor of CYP2D6. 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Droloxifene is mainly glucuronidated. There is no evidence that cobicistat inhibits or induces UGTs. 

Coadministration has not been studied. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent 3A4. Darunavir/cobicistat could potentially increase dronabinol exposure (via CYP3A4 inhibition) although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration of multiple doses of darunavir/cobicistat (800/150 mg once daily) and a single dose of a combined oral contraceptive (COC) containing drospirenone/ethinylestradiol was evaluated in a drug-drug interaction study. Coadministration increased drospirenone AUC by 1.6 fold, however, ethinylestradiol AUC decreased by 30%. Clinical monitoring is recommended due to the potential risk for hyperkalaemia. The efficacy of hormonal contraceptives may be impaired. Alternative reliable barrier methods of contraception are recommended.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone exposure. 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 in unknown. In addition, exposure of estrogens/estradiol administered as part of HRT may also increase. The use of estradiol/estrogens alone or in combination with a progestogen should be at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. Clinical monitoring is recommended due to the potential risk for hyperkaliemia.

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. Darunavir/cobicistat could potentially increase duloxetine concentration although to a limited extent as cobicistat is a weak inhibitor of CYP2D6. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Dutasteride is mainly metabolized by CYP3A4. Darunavir/cobicistat 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 in unknown. In addition, exposure of estrogens/estradiol administered as part of HRT may also increase. The use of estradiol/estrogens alone or in combination with a progestogen should be at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. 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/cobicistat exposure.

Coadministration has not been studied. MDMA is metabolized mainly by CYP2D6. Darunavir/cobicistat could potentially increase MDMA concentrations although to a limited extent as cobicistat is a weak inhibitor of CYP2D6. However, as dosing of recreational drugs can be variable, caution is advised. 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 by cobicistat. 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.

Coadministration has not been studied and is not recommended because it is expected to decrease darunavir/cobicistat exposure which may result in loss of therapeutic effect and development of resistance to darunavir. 

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.

Coadministration of elbasvir/grazoprevir and 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%. A similar interaction may occur with darunavir/cobicistat. 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 but, based on metabolism and clearance, a clinically significant interaction is unlikely. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1, UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Darunavir/cobicistat is unlikely to inhibit CYP1A2 or CYP2C8 at clinically relevant concentrations and there is no evidence that it inhibits or induces UGTs. 

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. Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) contain cobicistat and should not be administered with other 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. Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) contain cobicistat and should not be administered with other 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/cobicistat inhibits P-gp and OATP, data with verapamil (a P-gp inhibitor) and rifampicin (a 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/cobicistat is unlikely to inhibit OCTs at clinically relevant concentrations.

Coadministration with emtricitabine/tenofovir alafenamide has not been studied. Coadministration with darunavir/cobicistat (800/150 mg once daily) and tenofovir alafenamide alone (25 mg once daily) increased tenofovir AUC and Cmax by 224% and 216%, respectively. No significant effects were observed on darunavir pharmacokinetics with either darunavir/ritonavir or darunavir/cobicistat. The recommended dose of Descovy for HIV-1 treatment is 200/10 mg once daily (where available).

Coadministration 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/cobicistat is unlikely to inhibit OCTs at clinically relevant concentrations. However, darunavir/cobicistat is expected to increase tenofovir plasma concentrations (inhibition of P-gp). Darunavir/cobicistat and tenofovir disoproxil fumarate can be used without dose adjustments, but monitoring of renal function may be indicated when darunavir/cobicistat is given in combination with tenofovir disoproxil fumarate, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents. 

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/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. Enflurane is predominantly metabolized by CYP2E1. There is no evidence that darunavir/cobicistat 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 anions and cations transporters. Darunavir/cobicistat 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/cobicistat is unlikely to inhibit OCTs at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Epirubicin is glucuronidated by UGT2B7. There is no evidence that cobicistat inhibits or induces UGT2B7.

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 of ergotamine and darunavir/cobicistat is contraindicated due to potential for serious and/or life threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

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 component. Probenecid was found to decrease the renal clearance of ertapenem with ertapenem half-life only increasing slightly from 4.0 to 4.8 hours.

Coadministration has not been studied but may increase erythromycin concentrations due to inhibition of CYP3A4 by darunavir/cobicistat. Consider alternative antibiotics or 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 CYP2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Darunavir/cobicistat 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/cobicistat 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/cobicistat plasma concentrations (when possible).

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

Coadministration has not been studied. Estazolam is metabolized to its major metabolite 4-hydroxyestazolam via CYP3A4. Darunavir/cobicistat 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. Contrary to ritonavir, cobicistat does not induce CYP1A2 and glucuronidation and therefore coadministration is predicted to increase estradiol 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 in unknown. The use of estradiol alone or in combination with a progestogen should be used at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. Postmenopausal women should be reevaluated 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. 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 CYP1A1, 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 multiple doses of darunavir/cobicistat (800/150 mg once daily) and a single dose of drospirenone/ethinylestradiol was evaluated in a drug-drug interaction study. Coadministration increased drospirenone AUC by 1.6 fold whereas ethinylestradiol AUC was decreased by 30%. The efficacy of hormonal contraceptives may be impaired. Alternative reliable barrier methods of contraception are recommended. 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/cobicistat. Use with caution.

Coadministration with an etonogestrel-containing progestogen-only implant has not been studied. Etonogestrel is metabolized by CYP3A4. Coadministration of lopinavir/ritonavir and etonogestrel implants increased etonogestrel exposure (52%, 61%, and 34% increases in AUC, Cmax, and Cmin, respectively) suggesting that lopinavir/ritonavir may not impair the efficacy of etonogestrel implants. Similarly, coadministration with darunavir/cobicistat could potentially increase etonogestrel exposure and therefore is not expected to impair the contraceptive efficacy of etonogestrel when administered as implant.

Coadministration with etonogestrel as a combined vaginal ring (CVR) has not been studied. Etonogestrel is metabolized by CYP3A4 and is coformulated with ethinylestradiol in the CVR which is released at a dose of 0.015 mg/day. Darunavir/cobicistat is predicted to increase etonogestrel but to reduce ethinylestradiol concentrations. Since no 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%. Darunavir/cobicistat could similarly increase 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.

Coadministration is not recommended. Coadministration of etravirine and darunavir/cobicistat decreased cobicistat AUC, Cmax and Cmin by 30%, 14% and 66%, respectively. Darunavir AUC and Cmax were not changed significantly but Cmin was decreased by 56%. On the other hand, darunavir/cobicistat had no significant effects on etravirine exposure. Boosting of darunavir with cobicistat is not recommended in presence of etravirine due to the marked decrease in cobicistat exposure and in darunavir Cmin. However, boosting of darunavir with ritonavir may constitute an option if darunavir has to be coadministered with etravirine.

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 cobicistat is unlikely.

Coadministration of these drugs 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/cobicistat. 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 cobicistat. No a priori dose adjustment is required.

Coadministration with exenatide has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as exenatide is eliminated via glomerular filtration. However, as exenatide slows gastric emptying it is advisable to take darunavir/cobicistat at least 1 hour before an exenatide injection. [Note: this interaction is not specific for darunavir/cobicistat, 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. Darunavir/cobicistat does not inhibit or induce UGTs but darunavir could increase ezetimibe to a limited extent due to inhibition of OATP1B1. No a priori dosage adjustment is needed.

Coadministration has not been studied but based on the 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/cobicistat 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 famotidine is unlikely to alter darunavir/cobicistat absorption.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolyzed to an active metabolite, fenofibric acid.

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 darunavir/cobicistat.

Coadministration has not been studied. Fexofenadine does not undergo CYP-mediated metabolism but is a substrate of P-gp. Cobicistat inhibits P-gp during intestinal absorption and could potentially increase the exposure of fexofenadine. However, due to the large therapeutic index of fexofenadine, no a priori 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.

Coadministration has not been studied. Flecainide is metabolized mainly via CYP2D6, with a proportion of the parent drug also eliminated unchanged renally. Darunavir/cobicistat could potentially increase flecainide concentrations. Caution is warranted and clinical monitoring is recommended upon coadministration of these agents.

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/cobicistat 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/cobicistat 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 protease inhibitors showed no clinically significant interactions with fluconazole. Similarly, no significant interaction is expected with darunavir/cobicistat. Note, the European product label for darunavir/cobicistat suggests that fluconazole concentrations may be increased with darunavir/cobicistat and recommends clinical monitoring.

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 to 2F-ara-A, the principal metabolite (non CYP mediated metabolism) which is then eliminated renally.

Coadministration has not been studied. Concomitant administration of darunavir/cobicistat 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 cobicistat. 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/cobicistat, 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/cobicistat 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/cobicistat via modulation of, or competition for metabolic pathways.

Coadministration has not been studied. Fluoxetine is metabolized by CYP2D6 and CYP2C9 and to a lesser extent by CYPs 2C19 and 3A4 to form norfluoxetine. Darunavir/cobicistat 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/cobicistat could potentially increase levels of fluphenazine via inhibition of CYP2D6 metabolism although to a limited extent (cobicistat is a weak inhibitor of CYP2D6). No a priori dosage adjustment is recommended.

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

Coadministration of darunavir/cobicistat is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Alternative inhaled or nasal corticosteroids may be considered, particularly for long term use. Systemic corticosteroid effects have been reported in patients receiving strong inhibitors of CYP3A4 and inhaled or intranasally administered fluticasone propionate. 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. beclomethasone). 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 therefore there is a potential for moderate increase in fluvastatin exposure when co-administered with darunavir/cobicistat. Start fluvastatin with the lowest recommended dose and titrate up to the desired clinical effect while monitoring for safety.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Darunavir/cobicistat could potentially increase fluvoxamine concentrations although to a limited extent as cobicistat is a weak inhibitor of CYP2D6. 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. Darunavir/cobicistat does not interfere with this metabolic pathway.

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

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Formestane undergoes reductive metabolism by hepatic hydroxysteroid dehydrogenase and glucuronidation. There is no evidence that darunavir/cobicistat inhibits or induce UGTs. 

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Fosinopril is hydrolysed by esterases in the GI mucosa and liver. Fosinopril does not inhibit or induce CYP450 enzymes.

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 (via OATs). 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 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/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied and it is difficult to predict interactions with garlic. Garlic has been shown to inhibit CYP2C9, 2C19, 3A4 in vitro but there are inconsistencies in the literature regarding the ability of garlic to modulate CYP activity in vivo (probably arising due to variations in the amount of garlic components used in different studies). 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%. Caution should be used when using 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/cobicistat. 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. Darunavir/cobicistat does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7. There is no evidence that cobicistat inhibits or induces UGT2B7. 

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

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 exposure of gestodene. 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 darunavir/cobicistat has not been studied. Coadministration of cobicistat (150 mg once daily) and gamma-hydroxybutyric acid (GHB, 25 mg/kg single oral dose) had no substantial effect on the pharmacokinetics of GHB (AUC and Cmax both decreased by 5%; n=10). Furthermore, coadministration of cobicistat did not cause significant changes in subjective effects, blood pressure, heart rate and oxygen saturation. No drug-related adverse events necessitating subject withdrawal or medical intervention were observed during the study. This clinical trial suggests that coadministration of GHB is possible with cobicistat-containing regimens as no significant changes in GHB pharmacokinetics or pharmacodynamics were observed. Note, caution is needed with pharmacokinetic boosters in the context of chemsex when substances additional to GHB may be used.

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 cobicistat 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 cobicistat.

Coadministration with darunavir/cobicistat has not been studied and is not recommended as it may substantially increase glecaprevir exposure. Medicinal products that inhibit OATP1B1/3 (e.g. darunavir) increase systemic concentrations of glecaprevir. Coadministration of darunavir/ritonavir (800/100 mg) increased glecaprevir AUC, Cmax and Cmin by 4.97-fold, 3.09-fold and 8.24-fold, respectively. A similar interaction may occur with darunavir/cobicistat.