Symtuza (darunavir, cobicistat, 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 abacavir would be possible from a pharmacokinetic standpoint. 

Coadministration has not been studied. Acamprosate is eliminated unchanged in the urine both via glomerular filtration and active secretion (renal transporter unknown, possibly OATs or OCTs). A clinically significant interaction with darunavir/cobicistat is unlikely. Tenofovir alafenamide is unlikely to compete with acamprosate for renal transporters as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. However, acamprosate and emtricitabine may compete for tubular secretion, which could lead to increased concentrations of either drug. The clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Acetazolamide is predominantly excreted unchanged via active renal tubular secretion. Darunavir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations. In vitro studies have shown acetazolamide may competitively inhibit the renal transporters OAT1, OAT3 and OAT4. Emtricitabine is eliminated by other renal transporters. Inhibition of these renal transporters is unlikely to lead to significant increase in tenofovir as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. Emtricitabine and tenofovir alafenamide are unlikely to compete with aciclovir for renal transporters as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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 and is contraindicated. Symtuza, which contains tenofovir (derived from tenofovir alafenamide), should not be used concomitantly with adefovir dipivoxil.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Adrenaline is rapidly inactivated, mostly in the liver by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

Coadministration has not been studied. 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. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and its absorption may be decreased due to induction of intestinal P-gp by African potato. No effect on emtricitabine is expected. 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. Darunavir/cobicistat is unlikely to inhibit or induce CYP1A2 at clinically relevant concentrations. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Symtuza (darunavir, cobicistat, 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 albuvirtide would be possible from a pharmacokinetic standpoint. Based on data from studies with lopinavir/ritonavir, concentrations of darunavir/cobicistat may decrease but this is not expected to be clinically relevant. An interaction with emtricitabine and tenofovir alafenamide is unlikely as albuvirtide is a peptide which is eliminated by catabolism to its constituent amino acids.

Coadministration has not been studied but based on metabolism and clearance a clinically significant reaction is unlikely. 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. Alcuronium is predominantly eliminated unchanged via the kidneys. As there are no available data determining whether excretion is via active tubular secretion or glomerular filtration, there is some potential for competition with emtricitabine for active renal transport mechanisms, which may lead to increased levels of either emtricitabine or alcuronium. This mechanism of interaction is unlikely to be relevant for tenofovir alafenamide as this prodrug results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration is contraindicated as darunavir/cobicistat may increase alfuzosin concentrations via CYP3A4 inhibition which may lead to severe hypotension. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration of aliskiren with P-gp inhibitors (such as darunavir and cobicistat) is not recommended. Aliskiren is minimally metabolized and is mainly excreted unchanged in faeces. Aliskiren is transported by P-gp and shows a 5-6 fold increase in exposure with itraconazole 100 mg twice daily (a CYP3A4 and P-gp inhibitor), P-glycoprotein is therefore a major determinant of aliskiren bioavailability. A similar interaction is possible with darunavir/cobicistat. The aliskiren label recommends avoiding concomitant use with CYP3A4 and P-gp inhibitors. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

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, emtricitabine and tenofovir alafenamide do 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 by darunavir/cobicistat. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 via OCT2. Darunavir/cobicistat does not interact with this elimination pathway. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interfere with amantadine renal elimination as they are eliminated by different renal transporters.

Coadministration has not been studied. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, and 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/cobicistat. Start ambrisentan at 5 mg and closely monitor the patient for tolerability. Emtricitabine and tenofovir alafenamide do not interfere with these metabolic pathways.

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 with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to compete for renal elimination as they are eliminated by other renal transporters

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 and cobicistat do not inhibit CYP1A2 at physiological concentrations. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 SmPC for Symtuza contraindicates coadministration, but the US prescribing information advises caution and clinical monitoring.  [This interaction checker reflects the more cautious option.] Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and inhibitors of P-gp such as amiodarone are expected to increase the absorption of tenofovir alafenamide and thereby increase the systemic concentration. Emtricitabine does not interact with this metabolic pathway.

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. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to significantly impair amisulpride elimination.

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 they are only weak inhibitors of CYP2D6. No dosage adjustment is recommended a priori. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Darunavir, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir derived from tenofovir alafenamide are secreted by other renal transporters.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration has not been studied. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion; clearance is reduced by probenecid. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use ~60-80% is excreted in the urine within 6 hours. Based on metabolism and clearance a clinically significant interaction with darunavir/cobicistat is unlikely as darunavir/cobicistat is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations. No interaction is expected with tenofovir alafenamide as it results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. However, as emtricitabine is eliminated by renal tubular secretion, there is potential for competition with ampicillin for renal transporters, which could lead to increased levels of either drug when ampicillin is administered intravenously. When administered orally, there is little potential for significant interaction. 

Coadministration has not been studied. Anastrozole is mainly oxidized to hydroxyanastrozole by CYP3A4 (major) and glucuronidated via UGT1A4. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway, but 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. Antacids are unlikely to alter absorption of darunavir, cobicistat, emtricitabine or tenofovir alafenamide.

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. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. No interaction is expected with emtricitabine or tenofovir alafenamide.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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

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. Less than 0.1% of a total injected dose is recovered in urine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid which is further glucuronidated by several UGTs (major UGT1A6). In addition, coadministration with an NSAID is unlikely to be of concern for nephrotoxicity as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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). Darunavir, cobicistat, emtricitabine and tenofovir alafenamide do not interact with these pathways. Coadministration is unlikely to be of concern for nephrotoxicity as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration is contraindicated. Astemizole is metabolized by CYPs 2D6, 2J2 and 3A4. Darunavir/cobicistat may increase astemizole concentrations which may increase potential serious and/or life-threatening adverse reactions such as cardiac arrhythmias. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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, appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics have not been established.

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

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, atazanavir/ritonavir should not be used in combination with medicinal products containing cobicistat due to similar effects of cobicistat and ritonavir on CYP3A.

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. Emtricitabine and tenofovir do not interfere with atenolol renal elimination. It is recommended to start atenolol at a lower dose and adjust dosage until the desired clinical effect is achieved.

Coadministration with Symtuza has not been studied. 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 Symtuza 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 Symtuza states not to exceed atorvastatin 20 mg/day.) Emtricitabine and tenofovir alafenamide do not interact atorvastatin metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Atovaquone is mainly eliminated unchanged in the faeces. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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

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. Emtricitabine and tenofovir alafenamide do not interact with this pathway.

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, emtricitabine and tenofovir alafenamide do 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. Emtricitabine and tenofovir alafenamide are not expected to interfere with this metabolic pathway.

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. A similar interaction may occur with darunavir/cobicistat. Use the lowest possible corticosteroid dose with caution and monitor for corticosteroid side effects. Emtricitabine and tenofovir alafenamide do not interact with beclometasone metabolism.

Coadministration has not been studied. There are no data on the safety and efficacy of bedaquiline when coadministered with antiretroviral agents. Bedaquiline is metabolised by CYP3A4. Moderate to strong CYP3A4 inhibitors, such as darunavir/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. Based on metabolism and clearance a clinically significant interaction with emtricitabine or tenofovir alafenamide is unlikely. Bedaquiline is mainly eliminated in faeces.

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. Bendroflumethiazide is also excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically relevant drug interaction is unlikely in the range of observed clinical concentrations with emtricitabine and tenofovir derived from tenofovir alafenamide. 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 CYP3A4. Darunavir/cobicistat could potentially increase bepridil exposure resulting in the potential for serious and/or life threatening reactions such as cardiac arrhythmias. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 with darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with betamethasone metabolism.

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. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely. [Note, the US product label for Symtuza states no interaction expected and no dose adjustment required.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant 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 the risk of side effects. In addition, bexarotene could potentially decrease darunavir/cobicistat exposure and therefore coadministration should be avoided. No significant interaction are expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as half of bezafibrate dose is eliminated unchanged in the urine. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1 but a clinically relevant drug interaction with tenofovir derived from tenofovir alafenamide is unlikely in the observed range of clinical concentrations. Darunavir/cobicistat and emtricitabine do not interfere with this elimination pathway.

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, both products contain emtricitabine and tenofovir alafenamide and must not be administered with other products containing emtricitabine and tenofovir alafenamide.

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. Emtricitabine and tenofovir are not expected to significantly interfere with bisoprolol elimination.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on darunavir, cobicistat, emtricitabine or tenofovir alafenamide 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. Emtricitabine and tenofovir alafenamide do not interact with this pathway.

Coadministration has not been studied and is not recommended. Bosentan is metabolized by CYP3A4 and CYP2C9. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway, but coadministration may increase bosentan concentrations and decrease concentrations of cobicistat/darunavir. The European SmPC for Symtuza 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 who have been receiving Symtuza for ten days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. When starting Symtuza in patients stable on bosentan, discontinue bosentan at least 36 h prior to starting Symtuza. After ten days, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. To switch from darunavir/ritonavir to Symtuza, 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied and 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 (such as darunavir/cobicistat) 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. Renal excretion of unchanged bupivacaine is thought to account for approximately 1% of a dose therefore there is little potential for interaction with emtricitabine and tenofovir derived from tenofovir alafenamide.

Coadministration has not been studied. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolized by CYP2B6. Darunavir/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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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

Coadministration has not been studied but a clinically significant pharmacokinetic 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, cobicistat, emtricitabine or tenofovir alafenamide. Canagliflozin is a weak P-gp inhibitor but is unlikely to affect tenofovir alafenamide concentrations to a significant extent. Although an increased risk for bone fractures has been reported with canagliflozin (particularly in patients with a history of, or at high risk of, cardiovascular disease), coadministration with tenofovir alafenamide is unlikely to be problematic in terms of additive bone toxicity as tenofovir alafenamide results in 90% lower systemic exposure of tenofovir compared to tenofovir-DF.

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. Emtricitabine and tenofovir alafenamide do not interfere with cannabidiol elimination.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Capecitabine is activated by sequential enzyme reactions to fluorouracil. Dihydropyrimidine dehydrogenase plays a role in fluorouracil metabolism. Darunavir/cobicistat do not interfere with these metabolic pathways. However, nucleoside/tide analogues such as tenofovir alafenamide and emtricitabine may compete for these metabolic pathways. The clinical relevance of this interaction is unknown.

Coadministration has not been studied. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Based on metabolism and clearance a clinically significant interaction with darunavir/cobicistat is unlikely as darunavir/cobicistat is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations. As capreomycin may potentially compete with emtricitabine for renal elimination transport mechanisms, levels of either drug may increase. Renal function should be monitored as clinically appropriate. Note, coadministration with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. 

Coadministration has not been studied, based on metabolism and clearance a clinically significant interaction is unlikely as captopril is largely excreted in the urine by OAT1 (40-50% as unchanged drug, the rest as disulfide and other metabolites). Darunavir and cobicistat do not interact with this elimination pathway. Emtricitabine and tenofovir alafenamide are unlikely to compete with captopril for renal transporters as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration with Symtuz has not been assessed in pharmacokinetic studies and is contraindicated. Coadministration could potentially increase carbamazepine concentrations and significantly reduce darunavir/cobicistat and tenofovir alafenamide plasma concentrations which may result in loss of therapeutic effect and development of resistance. Coadministration of carbamazepine (titrated from 100 mg to 300 mg twice a day) with emtricitabine/tenofovir alafenamide (200/25 mg once daily) decreased tenofovir alafenamide AUC and Cmax by 55% and 57%, respectively. Emtricitabine does not interact with this metabolic pathway. 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. Emtricitabine and tenofovir alafenamide do not interact with carbimazole metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carboplatin is excreted primarily by renal glomerular filtration and therefore there is little potential for a pharmacokinetic interaction with emtricitabine and tenofovir alafenamide. In vitro studies have shown that carboplatin does not significantly inhibit cytochrome P450 metabolic enzymes. Coadministration with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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 darunavir/cobicistat is a weak inhibitor of CYP2D6. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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/cobicistat. 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. Darunavir/cobicistat is unlikely to inhibit the renal transporters OATs and OCTs at clinically relevant concentrations. In vitro data indicate that darunavir/cobicistat inhibits MATE1 but is unlikely to cause a clinically relevant drug interaction with cefalexin due to its large therapeutic index. Emtricitabine and tenofovir alafenamide are unlikely to compete with cephalexin for renal transporters as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. OAT3 does not play a major role in tenofovir and emtricitabine renal elimination.

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. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interact with this elimination pathway.

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 OAT3 participates in the renal elimination of cefotaxime. Darunavir/cobicistat is unlikely to inhibit the renal transporters OATs at clinically relevant concentrations. Emtricitabine and tenofovir derived from tenofovir alafenamide are eliminated by other renal transporters.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftazidime is predominantly eliminated unchanged via renal glomerular filtration. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interact with this elimination pathway.

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. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interact with this elimination pathway.

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 are unlikely to induce or inhibit CYP2C9 in the range of clinical concentrations. In addition, coadministration with an NSAID is unlikely to be of concern for nephrotoxicity as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. In vitro data indicate that cetirizine inhibits OCT2. Emtricitabine and tenofovir derived from tenofovir alafenamide are not transported by OCT2 and therefore no pharmacokinetic interaction is expected.

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. Coadministration of chloramphenicol may potentially increase levels of darunavir and 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. Chloramphenicol is predominantly metabolised via UDP-glucuronyltransferases, in particular UGT2B7. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

Coadministration has not been studied. Compounds that inhibit certain hepatic microsomal enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. When combined with darunavir/cobicistat, the activity of chlordiazepoxide may be increased. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Emtricitabine and tenofovir alafenamide are not expected to cause a clinically relevant drug-drug interaction.

Coadministration has not been studied. Only 22% of a chlorphenamine dose is excreted unchanged in the urine, as chlorphenamine is predominantly metabolized in the liver via CYP2D6. In vitro data indicate that darunavir/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. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interact with chlorphenamine renal excretion.

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 (as they are weak inhibitors of CYP2D6). No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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/emtricitabine/tenofovir alafenamide 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. Emtricitabine and tenofovir alafenamide do not interfere with ciclesonide metabolism.

Coadministration has not been studied. Ciclosporin is metabolized by CYP3A4 and is a potent P-gp inhibitor. Coadministration with darunavir/cobicistat may increase ciclosporin concentrations. Therapeutic concentration monitoring of ciclosporin is recommended when coadministered. Ciclosporin is a potent P-gp inhibitor and coadministration is expected to increase plasma concentrations of tenofovir alafenamide. Of note: ciclosporin can impair renal function but this is unlikely to be problematic as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. Emtricitabine does not interact with this metabolic pathway

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. Emtricitabine does not interact with this metabolic pathway. Tenofovir alafenamide is unlikely to compete with cidofovir for renal transporters or to be of concern when coadministered with nephrotoxic agents such as cidofovir as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. 

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. Cimetidine is unlikely to alter darunavir/cobicistat absorption. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 at concentrations much higher than the observed clinical concentrations. No interaction is expected with emtricitabine or tenofovir derived from tenofovir alafenamide.

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. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

Coadministration is contraindicated as it may increase cisapride concentrations which may increase potential serious and/or life-threatening adverse reactions such as cardiac arrhythmias. Cisapride is metabolized by CYP3A4. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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). Darunavir, cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this elimination pathway.

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. In addition, cisplatin and emtricitabine could potentially compete for MATE1 which could further slow their elimination. Close monitoring of renal function is recommended.

Coadministration has not been studied. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Darunavir/cobicistat could potentially increase citalopram concentrations although to a limited extent. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Clarithromycin is metabolized by CYP3A4. Darunavir/cobicistat may increase concentrations of clarithromycin; clarithromycin may increase concentrations of darunavir/cobicistat. The European SmPC for Symtuza advises caution if clarithromycin is coadministered and recommends consulting the clarithromycin SmPC for dosing in patients with renal impairment. The US prescribing information for Symtuza recommends to use an alternative antibiotic. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and inhibitors of P-gp such as clarithromycin are expected to increase the absorption of tenofovir alafenamide and thereby increase the systemic concentration. Emtricitabine does not interact with these metabolic pathways.

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. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

Coadministration has not been studied. Clindamycin is metabolized by CYP3A4 and coadministration may increase clindamycin concentrations due to inhibition of CYP3A by darunavir/cobicistat. A decrease in clindamycin dose may be needed. Emtricitabine and tenofovir alafenamide are unlikely to interfere with this pathway.

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. Emtricitabine and tenofovir alafenamide do not interfere with these metabolic pathways.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by darunavir/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 glycosuria 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Darunavir/cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

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. Tenofovir alafenamide is unlikely to compete with the elimination of clofibrate as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF and emtricitabine is eliminated by other renal transporters.

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 may increase clomifene exposure although to a limited extent via CYP2D6 inhibition. No a priori dosage adjustment is needed. Renal excretion of clomifene is thought to account for approximately 8% of an oral dose therefore there is little potential for an interaction with emtricitabine and tenofovir derived from tenofovir alafenamide.

Coadministration has not been studied. Clomipramine is metabolized by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolized by CYP2D6. Darunavir/cobicistat could potentially increase clomipramine concentrations. Use with caution as clomipramine has been shown to prolong the QT interval and has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Monitor adverse effects. If coadministration is necessary, clinical monitoring including ECG assessment is recommended. Emtricitabine and tenofovir alafenamide do not interact with clomipramine's metabolic pathway.

Coadministration has not been studied but may increase clonazepam concentrations and a decrease in dose may be necessary. Clonazepam is metabolized by CYP3A4. Darunavir/cobicistat is a CYP3A4 inhibitor, but emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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). Clonidine is a weak inhibitor of OCT2. Darunavir/cobicistat does not interact with this elimination pathway. Clonidine is unlikely to interact with emtricitabine and tenofovir derived from tenofovir alafenamide which are eliminated by different renal transporters.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. As total renal elimination is approximately 35% of a dose, there is little potential for significant interactions with emtricitabine or tenofovir (derived from tenofovir alafenamide) via competition for renal transporters.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Codeine undergoes predominantly direct glucuronidation. Codeine is also a substrate of CYP2D6 (major) and CYP3A4. The analgesic effect requires conversion of codeine to morphine via CYP2D6 and in vitro data suggest that darunavir/cobicistat is a weak inhibitor of CYP2D6. Darunavir/cobicistat could potentially reduce the analgesic efficacy. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. 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 Symtuza is required. The US product label for Symtuza 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 and/or hepatic impairment due to potential for serious and/or life-threatening reactions. 

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. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied. Piperine, a component of Piper cubeba, inhibits intestinal P-gp. Tenofovir alafenamide is a substrate of P-gp and absorption of tenofovir alafenamide could potentially increase. The clinical relevance of this effect has not been evaluated. No effect on emtricitabine exposure is expected. 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. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway. 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 darunavir/cobicistat. A dose adjustment of cyproterone may be required. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

Coadministration with Symtuza has not been studied. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely, however, dabigatran concentrations are increased by cobicistat. 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. Note, the European SmPC for Symtuza states that coadministration may increase dabigatran concentrations and does not recommend coadministration, whereas the US prescribing information expects no effect on dabigatran concentrations and states that no dose adjustment is necessary.

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 and cobicistat does not inhibit or induce these cytochromes at clinically relevant concentrations. Emtricitabine and tenofovir are unlikely to compete for active renal transport as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration with Symtuza 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9 which is not affected by darunavir, cobicistat, emtricitabine or tenofovir alafenamide.

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 with darunavir/cobicistat are unlikely, but cannot be excluded. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

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 darunavir/cobicistat), but the US product label recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

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.

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

Coadministration has not been studied. Dasatinib is metabolized by CYP3A4. Darunavir/cobicistat may significantly increase exposure to dasatinib concentrations through CYP3A4 inhibition, resulting in the potential for increased adverse events usually associated with dasatinib. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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.

Coadministration has not been studied. Delamanid is primarily metabolised by albumin to DM-6705; metabolism of DM-6705 to other metabolites is thought to involve pathways mediated by CYP enzymes, including CYP3A4. Co-administration of delamanid with a strong inhibitor of CYP3A4 (lopinavir/ritonavir) increased DM-6705 exposure by 25-30%. QTc prolongation has been reported with delamanid (and is very closely correlated with the metabolite DM-6705). A similar increase would be expected with darunavir/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). No interaction is expected with emtricitabine or tenofovir alafenamide.

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 Symtuza has not been studied. Desipramine is metabolized by CYP2D6. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. 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. Emtricitabine and tenofovir alafenamide do not interact with these metabolic pathways.

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. Darunavir/cobicistat 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 or cobicistat. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 or cobicistat inhibit or induce these metabolic enzymes, and emtricitabine and tenofovir do not interact with this metabolic pathway.

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 with darunavir/cobicistat could markedly increase the exposure of dextropropoxyphene. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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 darunavir/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. Clinical monitoring is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. In addition, coadministration with an NSAID is unlikely to be of concern for nephrotoxicity as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. No interaction is expected with emtricitabine and a clinically significant interaction is not expected with tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration has not been studied but based on metabolism and clearance, 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 Symtuza. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration with dihydroergotamine 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. Dihydroergotamine is metabolized by CYP3A4.

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. Darunavir, cobicistat, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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 darunavir/cobicistat inhibits or induces these UGTs. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir derived from tenofovir alafenamide do not interact with these metabolic pathways.

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 has not been studied but darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide are not expected to interfere with docetaxel metabolism.

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. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely as dofetilide is mainly excreted unchanged in urine.

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 of darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Symtuza (darunavir, cobicistat, 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 dolutegravir 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 dolutegravir (50 mg once daily) with emtricitabine/tenofovir alafenamide (200/10 mg, once daily) increased tenofovir AUC and Cmax by 25% and 10% (n=10). No significant effects were observed on dolutegravir pharmacokinetics relative to historical controls.

Triumeq (dolutegravir, abacavir, lamivudine) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are both indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, as Triumeq contains lamivudine it should not be taken with medicinal products containing emtricitabine due to the risk for intracellular interactions between cytidine analogues, such as lamivudine and emtricitabine.

Dovato (dolutegravir, lamivudine) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are both indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, Dovato contains lamivudine and should not be taken with medicinal products containing emtricitabine due to the risk for intracellular interactions between cytidine analogues, such as lamivudine and emtricitabine.

Juluca (dolutegravir/rilpivirine) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are both indicated for use as complete regimens for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration would be possible from a pharmacokinetic standpoint as no clinically relevant drug-drug interactions are expected. 

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). Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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, emtricitabine or tenofovir, or to be affected if coadministered with Symtuza.

Symtuza (darunavir, cobicistat, 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 doravirine would be possible from a pharmacokinetic standpoint. Doravirine is metabolized by CYP3A4. Cobicistat (a component of Symtuza) 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-to 4-fold increase in exposure. No interaction is expected with doravirine and emtricitabine or tenofovir alafenamide.

Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) and Delstrigo (doravirine, lamivudine, tenofovir-DF) are both indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, Symtuza contains emtricitabine and tenofovir alafenamide and must not be administered with products containing lamivudine and tenofovir-DF.

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 Symtuza, 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 Symtuza.

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 it is a weak inhibitor of CYP2D6. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway

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. Doxycycline is excreted in the urine and faeces as unchanged active substance, with 40-60% of an administered dose being accounted for in the urine. Darunavir and cobicistat do not interfere with these elimination pathways, and there is little potential for a clinically significant interaction with emtricitabine and tenofovir (derived from tenofovir alafenamide) via competition for renal elimination transport 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 darunavir/cobicistat inhibits or induces UGTs. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. Darunavir/cobicistat could potentially increase dronabinol exposure (via CYP3A4 inhibition) although to a limited extent. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. Coadministration is predicted to increase drospirenone exposure due to inhibition of CYP34A by darunavir and cobicistat. 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 hyperkalaemia.

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 it is a weak inhibitor of CYP2D6. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. Coadministration is predicted to increase dydrogesterone exposure due to inhibition of CYP3A4 by darunavir/cobicistat. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Ecstasy (MDMA) is metabolized mainly by CYP2D6. Darunavir/cobicistat could potentially increase MDMA concentrations although to a limited extent as they are weak inhibitors 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Edoxaban is minimally metabolised by hydrolysis (mediated by carboxylesterase 1), conjugation, or oxidation by CYP3A4/5 (<10%) and is eliminated primarily as unchanged drug in urine. Edoxaban is a substrate for P-gp and coadministration is expected to increase edoxaban concentrations due to P-gp inhibition by darunavir/cobicistat. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely. 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 labels for edoxaban and Symtuza recommend no dose modification. [This interaction checker reflects the more cautious option.]

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, efavirenz 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. Eflornithine is predominantly eliminated unchanged via the kidneys. Based on metabolism and clearance a clinically significant interaction with darunavir/cobicistat is unlikely. As there are no available data determining whether excretion is via active tubular secretion or glomerular filtration, there is potential for competition with emtricitabine for active renal transport mechanisms, which may lead to increased levels of either drug. This mechanism of interaction is unlikely to be problematic for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration of elbasvir/grazoprevir and OATP1B inhibitors such as darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are both indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, both products contain cobicistat, emtricitabine and tenofovir alafenamide and must not be administered with other products containing cobicistat, emtricitabine and tenofovir alafenamide.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) and Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) are both indicated for use as complete regimens for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, Symtuza contains cobicistat, emtricitabine and tenofovir alafenamide and must not be administered with other products containing cobicistat and emtricitabine, or with tenofovir-DF.

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 (an OATP1B1/1B3 inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely. An increased risk for bone fractures and decreased bone mineral density has been reported for other sodium glucose cotransporter 2 inhibitors, but coadministration with tenofovir alafenamide is unlikely to be problematic in terms of additive bone toxicity as tenofovir alafenamide results in 90% lower systemic exposure of tenofovir compared to tenofovir-DF. Emtricitabine does not interact with this metabolic pathway.

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, Symtuza contains emtricitabine and must not be administered with other products containing emtricitabine.

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, Symtuza contains emtricitabine and tenofovir alafenamide and must not be administered with other products containing emtricitabine and tenofovir alafenamide.

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, Symtuza contains emtricitabine and tenofovir alafenamide must not be administered with other products containing emtricitabine, or with tenofovir-DF.

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. No interaction is expected with emtricitabine or tenofovir alafenamide.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide are unlikely to significantly interact with entecavir.

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. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interact as they are not transported by OCTs.

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. Emtricitabine and tenofovir alafenamide do not interfere with this pathway.

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 by darunavir/cobicistat and thereby increase the risk of hyperkalaemia. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, increased eplerenone AUC by 441%. No interaction is expected with emtricitabine or tenofovir alafenamide. 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 darunavir/cobicistat may increase ergometrine concentrations via CYP3A4 inhibition, which may result in serious and/or life threatening reactions such as acute ergot toxicity. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration with ergotamine and 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. Ergotamine is metabolized by CYP3A4.

Coadministration has not been studied. Erlotinib is mainly metabolized by CYP3A4 and darunavir/cobicistat 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. No interaction is expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor role. Probenecid, an anion transport inhibitor, was found to decrease the renal clearance of ertapenem with ertapenem half-life only increasing slightly from 4.0 to 4.8 hours. Darunavir/cobicistat do not interact with this elimination pathway and there is little potential for a clinically significant interaction with emtricitabine and tenofovir (derived from tenofovir alafenamide) via competition for renal elimination transport mechanisms.

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. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Eslicarbazepine was shown to have no clinically significant effect on digoxin (a P-glycoprotein substrate) therefore no significant effect is expected on tenofovir alafenamide. No interaction is expected with emtricitabine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is mainly metabolized by CYP2C19 (major) and CYP3A4 (minor) and is unlikely to alter absorption of darunavir, cobicistat, emtricitabine or tenofovir alafenamide.

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. Clinical monitoring is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interact with these metabolic pathways

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%). Darunavir, cobicistat, emtricitabine and tenofovir alafenamide do not interact with these pathways.

Ethinylestradiol is mainly metabolized by hydroxylation. 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. No dosing recommendations can be made. Alternative reliable barrier methods of contraception are recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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. Darunavir, cobicistat, emtricitabine and tenofovir alafenamide do not interact with these pathways.

Coadministration has not been studied. Ethosuximide is mainly oxidized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by darunavir/cobicistat is a CYP3A4 inhibitor. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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. Renal excretion of unchanged bupivacaine is less than 10% therefore there is little potential for interaction with emtricitabine and tenofovir alafenamide.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway

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. Emtricitabine and tenofovir alafenamide do not interact with these metabolic pathways.

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. Emtricitabine and tenofovir alafenamide do not interact with etoposide metabolism.

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, boosting of darunavir with cobicistat is not recommended in the presence of etravirine due to the marked decrease in cobicistat exposure and in darunavir Cmin.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interfere with this pathway

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. Emtricitabine and tenofovir alafenamide do not interfere with this pathway.

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 Symtuza at least 1 hour before an exenatide injection. [Note: this interaction is not specific for Symtuza, 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 could increase ezetimibe to a limited extent due to inhibition of OATP1B1. No a priori dosage adjustment is needed. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. No significant interactions were observed when emtricitabine (200 mg single dose) and famciclovir (500 mg single dose) was studied in 12 HIV-negative subjects as there was no change in the AUC or Cmax values for emtricitabine or famciclovir. Tenofovir alafenamide is unlikely to compete with famciclovir for renal transporters as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is eliminated by renal excretion via OAT3 (65-70%) and by metabolic routes (30-35%). Famotidine is unlikely to alter absorption of darunavir, cobicistat, emtricitabine or tenofovir alafenamide.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. In vitro data suggest that fenofibric acid inhibits OAT3 but this is unlikely to impact emtricitabine or tenofovir derived from tenofovir alafenamide as they are eliminated by other renal transporters. Darunavir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations.

Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration may increase fentanyl concentrations due to inhibition of CYP3A4 by darunavir/cobicistat, 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/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

Coadministration has not been studied. Fexofenadine does not undergo CYP-mediated metabolism. It is mainly eliminated unchanged in the faeces and is a substrate of P-gp. Darunavir/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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Finasteride is metabolised by CYP3A4 and coadministration with darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Based on metabolism and clearance a clinically significant interaction with emtricitabine and tenofovir alafenamide is unlikely.

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 such as darunavir/cobicistat is contraindicated due to increased flibanserin concentrations which can cause severe hypotension and syncope. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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). Emtricitabine and tenofovir alafenamide are unlikely to compete with flucloxacillin for renal transporters as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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 SmPC for Symtuza says coadministration may result in increased concentrations of fluconazole, darunavir, cobicistat, and tenofovir alafenamide. Caution is warranted and clinical monitoring is recommended.

Coadministration has not been studied. Flucytosine is metabolised to 5-flurouracil which is further metabolised by dihydropyrimidine dehydrogenase. This enzyme is also involved in the catabolic pathway of pyrimidine analogs and competition could potentially increase haematological toxicity. This mechanism of interaction is unlikely to be problematic for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF but could be relevant for emtricitabine. Monitor haematological parameters and consider dose reduction if required. Based on metabolism and clearance a clinically significant interaction with darunavir and cobicistat is unlikely.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. Emtricitabine and tenofovir alafenamide do not interfere with flunisolide metabolism.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide are unlikely to interact with topical fluocinolone.

Coadministration has not been studied. Fluorouracil is metabolised via the same mechanisms as endogenous uracil, including via dihydropyrimidine dehydrogenase. Darunavir/cobicistat do not interfere with this metabolic pathway and an interaction is unlikely with tenofovir alafenamide as it results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. However, emtricitabine may compete for this metabolic pathway. The clinical relevance of this interaction is unknown. 

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. Emtricitabine and tenofovir do not interact with this metabolic pathway.

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 (they are weak inhibitors of CYP2D6). No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway

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. Clinical monitoring is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration 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 (such as darunavir/cobicistat) 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. beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. Emtricitabine and tenofovir alafenamide are unlikely to interact with fluticasone.

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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Darunavir and/cobicistat could potentially increase fluvoxamine concentrations although to a limited extent as it is a weak inhibitor of CYP2D6. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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, emtricitabine and tenofovir alafenamide do 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, emtricitabine and tenofovir alafenamide do 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, emtricitabine or tenofovir alafenamide inhibit 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 with darunavir and cobicistat is low. Emtricitabine and tenofovir alafenamide do not interact with formoterol metabolism.

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 with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3 but this is unlikely to significantly impact tenofovir concentration as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. Emtricitabine is unlikely to interact as it is eliminated by different renal transporters.

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. Emtricitabine and tenofovir alafenamide are unlikely to compete with ganciclovir for renal transporters as emtricitabine is eliminated by different renal transporters and tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Coadministration has not been studied and it is difficult to predict interactions with garlic. Garlic has been shown to inhibit CYPs 2C9, 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%. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and its absorption could decrease due to induction of intestinal P-gp by garlic. Patients should be advised against the use of garlic supplements.

Coadministration has not been studied. Gefitinib is metabolized by CYP3A4 and CYP2D6 and coadministration could potentially increase gefitinib concentrations via CYP inhibition by darunavir/cobicistat. 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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, emtricitabine and tenofovir alafenamide do 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 darunavir/cobicistat inhibits or induces UGT2B7. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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. No interaction is expected with darunavir/cobicistat and emtricitabine. There is little potential for interaction with tenofovir alafenamide via competition for active renal transport mechanisms. Coadministration with nephrotoxic agents is unlikely to be of concern for tenofovir alafenamide which results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

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. Darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with these metabolic pathways.

Coadministration with darunavir/cobicistat/emtricitabine/tenofovir alafenamide 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. Emtricitabine and tenofovir alafenamide do not undergo CYP3A4 metabolism. No effect on absorption of tenofovir alafenamide is expected as gingerols are unlikely to cause clinically significant inhibition of P-gp.

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. No interaction is expected with emtricitabine and tenofovir alafenamide.

Coadministration with Symtuza has not been studied and is not recommended as it may substantially increase glecaprevir exposure. Medicinal products that inhibit OATP1B1/3 (e.g. darunavir/cobicistat 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. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Glibenclamide is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9. Darunavir/cobicistat could potentially increase glibenclamide concentrations. Monitor clinical effect and reduce glibenclamide dosage if needed. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C19. In vitro data indicate that cobicistat does not inhibit or induce these CYPs in the range of clinically relevant concentrations. Darunavir, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is mainly metabolized by CYP2C9. In vitro data indicate that cobicistat does not inhibit or induce CYP2C9 in the range of clinically relevant concentrations. Darunavir, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glipizide is mainly metabolized by CYP2C9. In vitro data indicate that cobicistat does not inhibit or induce CYP2C9 in the range of clinically relevant concentrations. Darunavir, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glyceryl trinitrate is metabolised by aldehyde dehydrogenase-2. Glyceryl trinitrate is not known to induce or inhibit CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glycopyrronium bromide is mainly eliminated renally (active secretion via organic cation transporter) and is also partly hydroxylated via multiple CYPs. Inhibition or induction of its metabolism is unlikely to result in a significant change in exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Goldenseal has been shown to inhibit CYP3A4 in vitro, however, no significant effect of golden seal root on indinavir pharmacokinetics was observed in a study in HIV-negative subjects. Interactions with other drugs metabolized by CYP3A4 such as darunavir/cobicistat are unlikely. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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