Genvoya (elvitegravir, 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 elvitegravir or 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. Acetazolamide is predominantly excreted unchanged via active renal tubular secretion. In vitro studies have shown acetazolamide may competitively inhibit renal transporters OAT1, OAT3 and OAT4. 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. Elvitegravir/cobicistat and emtricitabine do not interact with acetazolamide elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aciclovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Elvitegravir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations. In addition, emtricitabine and tenofovir alafenamide are unlikely to compete with acyclovir 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. 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.

Genvoya, which contains tenofovir (derived from tenofovir alafenamide), should not be used concomitantly with adefovir dipivoxil.

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.  This inducing effect is unlikely to cause a decrease in the exposure of elvitegravir and cobicistat, however, 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 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. Elvitegravir/cobicistat could possibly 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.

Genvoya (elvitegravir, 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 studies with lopinavir/ritonavir, concentrations of elvitegravir/cobicistat may decrease but this effect 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. Inhibition of metabolism by elvitegravir/cobicistat is unlikely to affect albuvirtide.

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 drug. 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-TF. Elvitegravir/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 is contraindicated as it may increase alfuzosin concentrations which may lead to severe hypotension.

Coadministration has not been studied and is not recommended. Aliskiren is minimally metabolized by CYP450, however, P-gp is a major determinant of aliskiren bioavailability. A 5-6 fold increase in exposure was observed with itraconazole 100 mg twice daily (a CYP3A4 and P-gp inhibitor) and a similar interaction is possible with Genvoya (due to inhibition of P-gp by cobicistat). The product labels for aliskiren recommend avoiding concomitant use with CYP3A4 and P-gp inhibitors. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied. Almotriptan is partly eliminated unchanged in the urine and partly metabolized mainly via monoamine oxidase-A, and to a lesser extent by CYP3A4, CYP2D6 and flavin monooxygenase. Coadministration may increase almotriptan concentrations due to inhibition of CYP3A4. The American product label for almotriptan recommends using an initial almotriptan dose of 6.25 mg with a strong CYP3A4 inhibitor and not exceeding 12.5 mg within a 24 hour period. It also recommends to avoid use of almotriptan and a strong CYP3A4 inhibitor in patients with impaired renal or hepatic function. 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 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. Elvitegravir/cobicistat is unlikely to inhibit OCT2; 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Coadministration of ritonavir (100 mg once daily) did not significantly modify ambrisentan exposure. Similarly, cobicistat is unlikely to inhibit OATP1B1 in the range of concentrations obtained when used as a pharmacokinetic enhancer. Elvitegravir, emtricitabine and tenofovir alafenamide do not interfere with ambrisentan metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amikacin is eliminated renally by glomerular filtration. Coadministration 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. Elvitegravir/cobicistat is unlikely to inhibit OCTs. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. 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 cobicistat does not inhibit CYP1A2 at physiological concentrations. Similarly, emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Amiodarone is metabolized by CYP3A4 and 2C8 and elvitegravir/cobicistat could potentially increase amiodarone concentrations by inhibition of CYP3A4. Coadministration is contraindicated in the European SPC, but the US Prescribing Information recommends caution and therapeutic concentration monitoring if amiodarone if available.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Elvitegravir/cobicistat could potentially increase amitriptyline exposure although to a moderate extent as cobicistat 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. Amlodipine is metabolized by CYP3A4. Elvitegravir/cobicistat is predicted to increase amlodipine exposure ~2-fold based on drug-drug interactions studies with amlodipine and indinavir/ritonavir or paritaprevir/ritonavir. If coadministration is indicated, consider a dose reduction for amlodipine of 50%. Close monitoring is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6. Elvitegravir/cobicistat could potentially increase amphetamine exposure although to a moderate 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; it is reduced by probenecid. About 20 to 40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60 to 80% is excreted in the urine within 6 hours. No interaction is expected with elvitegravir/cobicistat as it does not inhibit the renal transporters OATs and OCTs, or 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 with Genvoya has not been studied. Elvitegravir plasma concentrations are lower with antacids due to local complexation in the gastrointestinal tract and not to changes in gastric pH. The European SPC recommends to separate Genvoya and antacid administration by at least 4 hours, whereas the US Prescribing Information recommends at least 2 hours separation. Simultaneous administration of a magnesium/aluminium-containing antacid and elvitegravir/ritonavir decreased elvitegravir AUC, Cmax and Cmin by 45%, 47% and 41%, respectively. Separating the doses by 2 hours decreased elvitegravir exposure by 10-20%, whereas separating the doses by 4 hours did not affect elvitegravir exposure. Coadministration with antacids containing calcium carbonate has not been studied. Emtricitabine and tenofovir alafenamide do not interact with antacids.

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 elvitegravir/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. 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 elvitegravir/cobicistat is unlikely. No interaction is expected with emtricitabine or tenofovir alafenamide.

Coadministration has not been studied. 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. A pharmacokinetic interaction is unlikely with elvitegravir and vitamin C itself as elvitegravir/cobicistat does not interfere with this metabolic pathway. However, vitamin C can be found in multivitamins preparations which may also contain minerals. As the effect of cationic complexation with elvitegravir cannot be excluded, it is recommended to separate the administration of elvitegravir/cobicistat and multivitamin preparations by at least 4 hours. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (CYP1A2 (major) and CYP3A4, 2D6 (minor). Elvitegravir/cobicistat could potentially increase asenapine exposure by inhibition of CYP3A4, although to a moderate extent as CYP3A4 does not play a major role in asenapine metabolism. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. No a priori dosage adjustment is recommended.

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 form salicylic acid which is further glucuronidated by several UGTs (major UGT1A6). Coadministration is unlikely to be of concern for nephrotoxicity as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF.

Genvoya (elvitegravir, 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 atazanavir would be possible from a pharmacokinetic standpoint. A small study reported virological suppression in four treatment-experienced patients receiving Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) and atazanavir (300 mg once daily). Coadministration of Genvoya and atazanavir may result in a similar virological effect. Further studies evaluating the safety, efficacy, and pharmacokinetics of this combination are warranted, given the lack of information currently available.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and coadministration with other antiretroviral agents is not recommended in the Genvoya product labels. Atazanavir/cobicistat should not be administered with other products containing cobicistat. Coadministration would be possible with unboosted atazanavir in clinical situations requiring treatment intensification. 

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and coadministration with other antiretroviral agents is not recommended in the Genvoya product labels. Atazanavir/ritonavir should not be used in combination with medicinal products containing cobicistat due to similar effects of cobicistat and ritonavir on CYP3A. Coadministration would be possible with unboosted atazanavir in clinical situations requiring treatment intensification. 

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 elvitegravir/cobicistat. Emtricitabine and tenofovir alafenamide 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.

Concentrations of atorvastatin are increased when coadministered with Genvoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide). Atorvastatin is metabolized by CYP3A4. Coadministration of atorvastatin (10 mg single dose) and elvitegravir/cobicistat (150/150 mg once daily, administered with emtricitabine and tenofovir alafenamide as Genvoya) was studied in 16 subjects. Elvitegravir Cmax, AUC and Cmin decreased by 9%, 8% and 12%, respectively. Atorvastatin Cmax and AUC increased by 132% and 160%. If the use of atorvastatin is considered necessary, start with the lowest dose of atorvastatin and titrate carefully while monitoring for safety. A daily dose of 40 mg atorvastatin should not be exceeded with careful safety monitoring. (Note, American treatment guidelines recommend a maximum daily dose of 20 mg for atorvastatin.) Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Avanafil is primarily metabolized by CYP3A4 and coadministration with strong CYP3A4 inhibitors is contraindicated in the product labels for avanafil. Coadministration with ritonavir (600 mg twice daily) increased avanafil exposure by 13-fold. Similarly, a large increase in avanafil exposure is predicted in the presence of elvitegravir/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. Azithromycin is mainly eliminated via biliary excretion and animal data suggest this may occur via P-glycoprotein and MRP2. Elvitegravir/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 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 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. 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. Bepridil is metabolized by CYP2D6 (major) and 3A4. Elvitegravir/cobicistat could potentially increase bepridil concentrations. Caution is warranted and 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. Betahistine is metabolized by monoamine oxidase. Betahistine does not induce or inhibit CYP450 enzymes.

Coadministration has not been studied. Betamethasone is metabolized by CYP3A4 and coadministration may therefore lead to elevated corticosteroid levels, Cushing’s syndrome and adrenal axis suppression. A case of Cushing’s syndrome and adrenal suppression in a patient on ritonavir-boosted atazanavir and dexamethasone 0.1% eye drops and betamethasone 0.1% eye ointment has been reported. Betamethasone is a moderate inducer of CYP3A4. Caution is needed when betamethasone is administered orally or intravenously at high doses or for a long duration as it may decrease elvitegravir/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 cobicistat) is expected to increase betrixaban exposure. The US product label for betrixaban recommends for patients receiving or starting a strong P-gp inhibitor to reduce betrixaban dose and use an initial dose of 80 mg followed by 40 mg once daily.  Furthermore, patients should be monitored closely and any signs or symptoms of blood loss should be evaluated promptly. Of note, coadministration of betrixaban might need to be reconsidered in patients with concomitant renal impairment (creatinine clearance <60 ml/ml) as renal impairment per se does increase betrixaban exposure.

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

Coadministration has not been studied and should be avoided. Bexarotene is mainly metabolized by CYP3A4 and induces CYP3A4 (after repeated administration and especially at doses greater than 300 mg/m2/day). Elvitegravir/cobicistat could potentially increase bexarotene concentrations and thus increase the risk of side effects. In addition, bexarotene could potentially decrease elvitegravir exposure and therefore coadministration should be avoided. No significant interaction are expected with emtricitabine and tenofovir alafenamide.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) and Biktarvy (bictegravir, 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. In addition, both products contain emtricitabine and tenofovir alafenamide and must not be administered with other products containing emtricitabine and tenofovir alafenamide. Furthermore, coadministering two integrase inhibitors (i.e., bictegravir and elvitegravir) is unlikely to be of clinical benefit.

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. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Elvitegravir/cobicistat could potentially increase bisoprolol exposure, although to a moderate extent. No a priori dosage adjustment is required. Emtricitabine and tenofovir derived from tenofovir alafenamide 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 elvitegravir, 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 may increase bosentan concentrations. The European SPC suggests to consider alternative endothelin receptor antagonists. The US Prescribing Information for Genvoya suggests the following dose modifications. For patients on stable Genvoya, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. When starting elvitegravir/cobicistat in patients stable on bosentan, discontinue bosentan at least 36 hours prior to initiation of Genvoya. After at least 10 days following the initiation of Genvoya, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

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. Elvitegravir/cobicistat could potentially increase bromazepam concentrations although to a moderate extent. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased bromazepam AUC by ~9%. A similar effect may occur with elvitegravir/cobicistat. No a priori dosage adjustment is required. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

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

Coadministration with Genvoya has not been studied. Coadministration of elvitegravir/cobicistat to subjects stable on buprenorphine/naloxone increased buprenorphine AUC, Cmax and Cmin by 35%, 12% and 66%, respectively. Norbuprenorphine AUC, Cmax and Cmin increased by 42%, 24% and 57%. Naloxone AUC and Cmax both decreased by 28% and there was no effect on the AUC, Cmin and Cmax of elvitegravir or cobicistat. No dose adjustment of buprenorphine/naloxone is required. Patients should be closely monitored for sedation and cognitive effects. Based on metabolism and clearance pathways, no interaction is expected between buprenorphine and emtricitabine or tenofovir alafenamide.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolized by CYP2B6. Cobicistat is not expected to be a clinically relevant inducer. In human hepatocyte study, messenger RNA for CYP2B6 was largely unaffected by cobicistat at concentrations up to 30 µM. Note: the US Prescribing Information suggests that concentrations of bupropion may be increased when coadministered with Genvoya and recommends careful dose titration and monitoring for antidepressant response. 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. Elvitegravir/cobicistat could potentially increase buspirone concentrations. A dose reduction of buspirone may be necessary, a clinical monitoring is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid, an active metabolite of folinic acid. In theory, calcium could chelate with elvitegravir and potentially decrease the amount of elvitegravir available to bind to the active site of the HIV integrase. However, given that the extent of chelation is dependent on the amount of calcium, this risk is predicted to be low when administering calcium folinate in small doses at frequent intervals. Since calcium is distributed rapidly, separating the intake of elvitegravir from the IV administration of calcium folinate by 2 hours should eliminate any risk of chelation. No interaction is expected with cobicistat, emtricitabine or tenofovir alafenamide.

Coadministration has not been studied. As with other HIV integrase inhibitors, elvitegravir may be subject to chelation by high concentrations of divalent cations which may result in reduced elvitegravir concentrations. Therefore administration should be staggered by at least 4 hours from mineral supplements containing calcium, zinc or iron. Emtricitabine and tenofovir alafenamide do not interact with calcium.

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 elvitegravir, 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. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19. Coadministration is expected to significantly increase cannabidiol exposure (inhibition of CYP3A4 by 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. In vitro and in vivo data indicate that elvitegravir is a modest inducer of CYP2C9. Elvitegravir/cobicistat could potentially decrease THC exposure although to a moderate extent. 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. Elvitegravir/cobicistat does not interfere with these metabolic pathways. However, nucleoside/tide analogues such as emtricitabine and tenofovir alafenamide 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. 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. In addition, elvitegravir/cobicistat is unlikely to interfere with capreomycin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Elvitegravir/cobicistat and tenofovir alafenamide do not inhibit OAT1 and therefore are unlikely to interact with captopril. Emtricitabine is unlikely to interfere with captopril elimination as emtricitabine is eliminated by different transporters.

Coadministration with Genvoya has not been studied but could potentially increase carbamazepine concentrations and significantly reduce elvitegravir/cobicistat concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration is contraindicated. Alternative anticonvulsants should be considered.

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. Carboplatin is excreted primarily by renal glomerular filtration and therefore there is little potential for a pharmacokinetic interaction. Elvitegravir/cobicistat and emtricitabine do not interfere with carboplatin elimination pathway. 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 additionally metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Elvitegravir/cobicistat could potentially increase carvedilol, although to a moderate extent as cobicistat is a weak inhibitor of CYP2D6. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. No a priori dosage adjustment is required.

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 elvitegravir and cobicistat. Coadministration should be avoided. No effect on emtricitabine or tenofovir alafenamide is expected.

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 elvitegravir is a modest inducer of CYP2C9. A dose adjustment is unlikely to be required for celecoxib when coadministered with elvitegravir/cobicistat. 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. In vitro data indicate that cetirizine inhibits OCT2. Emtricitabine and tenofovir derived from tenofovir alafenamide are not transported by OCT2 and no pharmacokinetic interaction is expected with elvitegravir/cobicistat.

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

Coadministration has not been studied. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4. Coadministration of chloramphenicol may potentially increase levels of elvitegravir. The clinical significance of this interaction is unknown. Elvitegravir/cobicistat, emtricitabine and tenofovir alafenamide are unlikely to affect chloramphenicol metabolism which undergoes glucuronidation via UGT2B7. Ocular use: although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

Coadministration has not been studied. Chloroquine undergoes CYP mediated metabolism by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). Elvitegravir/cobicistat could potentially increase chloroquine exposure by inhibition of CYPs 3A4 and 2D6, but to a moderate extent due to the multiple elimination pathways. 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. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. In vitro data indicate that cobicistat is a weak inhibitor of CYP2D6 and could potentially increase chlorphenamine concentrations although to a moderate extent. No a priori dosage adjustment is required. Since only 22% of a chlorphenamine dose is excreted unchanged in the urine, emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interact with chlorphenamine.

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. Elvitegravir/cobicistat could potentially increase chlorpromazine although to a moderate extent (cobicistat 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. Ciclesonide can be administered with elvitegravir/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 elvitegravir/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 but may increase ciclosporin concentrations. Therapeutic concentration monitoring of ciclosporin is recommended when coadministered. In addition, 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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cidofovir is eliminated renally via glomerular filtration and active renal secretion by OAT1, OAT3. Elvitegravir/cobicistat is unlikely to inhibit OATs. In addition, 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 with Genvoya has not been studied but is not expected to alter elvitegravir concentrations. No dose adjustment is needed when Genvoya is combined with H2 receptor antagonists. Administration of famotidine 12 h apart from elvitegravir/cobicistat had no effect on the AUC and Cmax of elvitegravir or cobicistat. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 at concentrations much higher than the observed clinical concentrations. No interaction is expected with tenofovir derived from tenofovir alafenamide or emtricitabine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged through the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolized and partially cleared through the bile and intestine. Elvitegravir/cobicistat, emtricitabine and tenofovir derived from tenofovir alafenamide do not interfere with this 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.

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. Elvitegravir/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 slow their elimination. Close monitoring of renal function is recommended.

Coadministration has not been studied. Citalopram is metabolized by CYP2C19 (38%), 2D6 (31%) and 3A4 (31%). Elvitegravir/cobicistat could potentially increase citalopram concentrations although to a moderate 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. Elvitegravir/cobicistat could potentially increase clarithromycin concentrations. Furthermore, clarithromycin is a strong inhibitor of CYP3A4 and thus could potentially increase elvitegravir/cobicistat exposure. No dose adjustment is necessary for patients with normal renal function or mild renal impairment (creatinine clearance 60-90 ml/min). The US Prescribing Information advises for patients with creatinine clearance 50-60 ml/min, the dose of clarithromycin should be reduced by 50%, whereas the European SPC advises a 50% dose reduction for patients with creatinine clearance 30-60 ml/min.

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 elvitegravir/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 elvitegravir/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 cobicistat. Topical clobetasol can be used with caution. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

Coadministration has not been studied. In vitro studies have suggested that transformation of clomifene to its active metabolite is likely to be mediated via CYP2D6. In vitro data indicate that cobicistat is a weak inhibitor of CYP2D6 and could potentially interact with clomifene, although the clinical significance is unknown. 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 CYP3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolized by CYP2D6. Elvitegravir/cobicistat could potentially increase clomipramine concentration, thereby increasing the risk of QTc prolongation. Coadministration is not 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 pharmacokinetic 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). Elvitegravir/cobicistat does not interfere with clonidine elimination. Clonidine is a weak inhibitor of OCT2 but 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.

Coadministration has not been studied. Clorazepate is rapidly converted to nordiazepam which is then metabolized to oxazepam by CYP3A4. Elvitegravir/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. The analgesic effect requires conversion of codeine to morphine via CYP2D6 and in vitro data suggest that cobicistat is a weak inhibitor of CYP2D6. Elvitegravir/cobicistat could potentially reduce the analgesic efficacy. No a priori dosage adjustment is recommended but monitoring the analgesic effect may be considered. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but is expected to increase colchicine concentrations. Genvoya is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. For treatment of gout-flares, use 0.6 mg (one tablet) of colchicine, followed by 0.3 mg (half tablet) 1 hour later. The treatment course should be repeated no earlier than 3 days. For the prophylaxis of gout-flares, if the original regimen was 0.6 mg twice a day, adjust the treatment 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 the treatment of familial Mediterranean fever, use a maximal daily dosage of 0.6 mg (may be given as 0.3 mg twice a day).

Coadministration has not been studied. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of vitamin D and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on vitamin D clearance. As an inhibitor of CYP3A, 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, though no effect of antiretroviral therapy on the response to vitamin D supplementation was found in a PK modelling study. No interaction is expected with elvitegravir and vitamin D given as a single agent (i.e. not with calcium or in a multivitamin preparation) or as an injection. However, colecalciferol can be found in multivitamins preparations which may also contain minerals. As the effect of cationic complexation with elvitegravir cannot be excluded, it is recommended to separate the administration of elvitegravir/cobicistat and multivitamin preparations by at least 4 hours. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied. Although several constituents of Piper cubeba were shown to inhibit CYP3A4 in vitro, any additional effect on exposure of elvitegravir in the presence of cobicistat is unlikely. 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. However, since the clinical relevance of this effect has not been evaluated, Descovy should be dosed according to the concomitant antiretroviral agent and not based on a potential effect of Piper cubeba on P-gp substrates. No effect on emtricitabine exposure is expected.

Coadministration has not been studied. Cyanocobalamin undergoes enterohepatic recycling and is excreted almost entirely in the urine. No interaction is expected with elvitegravir and vitamin B12 when given as a single agent (i.e. not in a multivitamin preparation) or as an injection. However, vitamin B12 can be found in multivitamins preparations which may also contain minerals. As the effect of cationic complexation with elvitegravir cannot be excluded, it is recommended to separate the administration of elvitegravir/cobicistat and multivitamin preparations by at least 4 hours. Significant interactions are not expected with cobicistat, emtricitabine and tenofovir alafenamide.

Coadministration has not been studied. Cyclophosphamide is metabolized by two pathways. Activation (major pathway) to 4-hydroxycyclophosphamide is catalyzed by CYPs 2B6 (major), 2C9 and 3A4. Inactivation (minor, 10%) to the neurotoxic chloroacetaldehyde metabolite is performed mainly by CYP3A4. In theory, elvitegravir/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. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.

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

Coadministration with cobicistat with elvitegravir/emtricitabine/tenofovir alafenamide has not been studied. Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before cobicistat alone (150 mg once daily administered at steady-state) was studied in HIV negative subjects. Simultaneous administration increased dabigatran AUC by 127% (n=16). Separating the dosing by 2 h did not overcome the interaction (dabigatran AUC increased by 110%, n=18). This pharmacokinetic interaction (due to inhibition of intestinal P-gp by cobicistat) resulted in a more pronounced anticoagulant response as indicated by measurements of the thrombin times. A population/PBPK/PD analysis indicates that in presence of cobicistat, the dabigatran dose should be reduced to 110 mg twice daily in individuals with normal renal function and to 75 mg twice daily in individuals with moderate renal impairment, and that coadministration should be avoided in case of severe renal impairment.

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

Coadministration has not been studied. Darifenacin is metabolized by CYP3A4 and CYP2D6 and coadministration is likely to increase concentrations. A 5-fold increase in darifenacin exposure was seen with ketoconazole (a strong inhibitor of CYP3A4) and the magnitude of the interaction could be even more pronounced in poor metabolizer individuals The European Summary of Product Characteristics for darifenacin contraindicates its use with potent CYP3A4 inhibitors (such as cobicistat), but the US Prescribing Information recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and coadministration with other antiretroviral agents is not recommended in the Genvoya product labels. Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) contain cobicistat and should not be administered with other products containing cobicistat. Coadministration would be possible with unboosted darunavir (Prezista) in clinical situations requiring treatment intensification. 

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.

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

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

Coadministration has not been studied. 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 elvitegravir/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 pharmacokinetic interaction is unlikely. Denosumab is not eliminated via hepatic metabolism but follows the immunoglobulin clearance pathway. (Note, caution is required if given with calcium supplements as elvitegravir may be subject to chelation by high concentrations of divalent cations which may result in reduced elvitegravir concentrations.)

Coadministration with Genvoya has not been studied. Coadministration of desipramine (50 mg single dose) and cobicistat alone (150 mg once daily) caused a limited increase in desipramine Cmax and AUC by 24% and 65% (n=8). Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. No a priori dosage adjustment is required. Note, the product label for Genvoya is more cautious in its recommendation and suggests careful dose titration of desipramine with monitoring for antidepressant response and adverse effects.

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 possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration is predicted to increase etonogestrel due to inhibition of CYP3A4 and to moderately decrease ethinylestradiol. The European SPC for Genvoya states a hormonal contraceptive should contain at least 30 µg ethinylestradiol. Contraceptive efficacy is likely to be maintained if Genvoya is used with a desogestrel COC which contains at least 30 µg ethinylestradiol.

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

Coadministration has not been studied. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4. Elvitegravir/cobicistat could potentially increase diazepam exposure by inhibition of CYP3A4. Coadministration of Genvoya with diazepam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. 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. In vitro data indicate that elvitegravir is a modest inducer of CYP2C9 however a dose adjustment is unlikely to be required for diclofenac when co-administered with elvitegravir/cobicistat. 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 with Genvoya has not been studied. Coadministration of digoxin (0.5 mg single dose) and cobicistat alone (150 mg once daily) increased digoxin Cmax by 41% and increased AUC by 8%. Start with the lowest dose of digoxin and monitor digoxin concentrations. Digoxin is unlikely to interact with emtricitabine and tenofovir derived from tenofovir alafenamide as it is eliminated via different renal transporters (OATP4C1 and P-glycoprotein).

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

Coadministration has not been studied. Diltiazem is metabolized by CYP3A4 and CYP2D6. Elvitegravir/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 and could potentially increase diphenhydramine concentrations, although to a moderate extent. 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. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. There is no evidence that cobicistat inhibits or induces these UGTs.

Coadministration has not been studied but may increase disopyramide exposure and thereby the risk of cardiac arrhythmias. Coadministration is not recommended. Disopyramide is metabolized by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. In vitro data suggest that disopyramide weakly inhibits the renal transporter OCT2 in rats. Emtricitabine and tenofovir derived from tenofovir alafenamide are not transported by OCT2 and therefore are unlikely to be affected by disopyramide.

Coadministration has not been studied and is not recommended. Dofetilide is metabolized to a small degree by CYP3A4 and therefore elvitegravir/cobicistat could potentially increase dofetilide exposure and thereby increase the risk of cardiac arrhythmias. No interaction is expected with emtricitabine or tenofovir alafenamide.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, coadministering two integrase inhibitors (i.e., dolutegravir and elvitegravir) is unlikely to be of clinical benefit.

Triumeq (dolutegravir, abacavir, lamivudine) and Genvoya (elvitegravir, 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. In addition, Triumeq 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. Furthermore, coadministering two integrase inhibitors (i.e., elvitegravir and dolutegravir) is unlikely to be of clinical benefit.

Dovato (dolutegravir/lamivudine) and Genvoya (elvitegravir, 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. In addition, 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. Furthermore, coadministering two integrase inhibitors (i.e., elvitegravir and dolutegravir) is unlikely to be of clinical benefit.

Juluca (dolutegravir/rilpivirine) and Genvoya (elvitegravir, 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, coadministering two integrase inhibitors (i.e., elvitegravir and dolutegravir) is unlikely to be of clinical benefit.

Genvoya (elvitegravir, 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 is a strong inhibitor of CYP3A4 and is expected to increase doravirine exposure by ~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. Emtricitabine and tenofovir alafenamide do not interact with doravirine.

Genvoya (elvitegravir, 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, Delstrigo contains lamivudine and tenofovir-DF and should not be administered products containing emtricitabine or tenofovir alafenamide.

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 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, 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 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.

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. Elvitegravir/cobicistat could potentially increase doxepin and nordoxepin concentrations although to a moderate extent as cobicistat 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. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. In vitro data indicate that elvitegravir is a modest inducer of CYP2C9. Elvitegravir/cobicistat could potentially decrease dronabinol exposure although to a moderate extent. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolised in part by CYP3A4. Coadministration is predicted to increase drospirenone due to inhibition of CYP3A4 and to moderately decrease ethinylestradiol. Clinical monitoring is recommended due to the potential for hyperkalaemia. The European SPC for Genvoya states a hormonal contraceptive should contain at least 30 µg ethinylestradiol. 

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone exposure and clinical monitoring is recommended due to the potential for hyperkalaemia. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In 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 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. Elvitegravir/cobicistat could potentially increase duloxetine concentration although to a moderate extent as cobicistat 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 and elvitegravir/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 dutasteride metabolism.

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration is predicted to increase dydrogesterone exposure due to inhibition of CYP3A4. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In 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. Edoxaban is a substrate for P-gp and coadministration is expected to increase edoxaban concentrations due to P-gp inhibition by cobicistat. The European product label for edoxaban states to consider a dose reduction of edoxaban from 60 mg to 30 mg with strong P-gp inhibitors, however, the US product label recommends no dose modification.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Genvoya should not be used in conjunction with non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products. When switching patients who are CYP2B6 poor metabolisers from an efavirenz containing regimen to Genvoya, there is a potential for lower elvitegravir exposure due to prolonged CYP3A induction by efavirenz. Monitoring of viral load is recommended for these patients during the first month after switching treatment to Genvoya.

Coadministration has not been studied. Eflornithine 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 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. Elvitegravir/cobicistat is unlikely to interfere with eflornithine elimination. As <1% of topically applied eflornithine is systemically absorbed, no clinically significant interactions are expected with topical preparations.

Coadministration is not recommended as it may substantially increase grazoprevir exposure. Coadministration with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide has not been studied. However, coadministration with elvitegravir/cobicistat/emtricitabine/tenofovir-DF increased grazoprevir exposure by ~5.4-fold. A similar increase would be expected with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.

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

Coadministration has not been studied. Empagliflozin is mainly glucuronidated by UGTs 1A3, 1A8, 1A9 and 2B7. It is a substrate of P-gp and BCRP, and also a substrate of the renal transporter OAT3 and the hepatic transporters OATP1B1 and OATP1B3. Although cobicistat inhibits P-gp, BCRP and OATP1B1/3, data with verapamil (a P-gp inhibitor) and rifampicin (an OATP1B1/1B3 inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely. Although an increased risk for bone fractures and decreased bone mineral density has been reported for other sodium glucose cotransporter 2 inhibitors, coadministration with tenofovir alfenamide 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 disoproxil.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, it must not be administered with additional emtricitabine.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, it must not be administered with other products containing emtricitabine and tenofovir alafenamide.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Furthermore, Genvoya contains tenofovir alafenamide and emtricitabine and should not be administered with tenofovir-DF or additional emtricitabine (both components of Truvada).

Coadministration has not been studied. Entecavir is eliminated renally via glomerular filtration and active renal secretion by both organic anions and cations transporters. Elvitegravir/cobicistat is unlikely to inhibit OATs and OCTs 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 possibly via the renal transporter OCT2. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interact as they are not transported by OCTs. Furthermore, elvitegravir/cobicistat is unlikely to inhibit OATs and OCTs.

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

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

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

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

Coadministration has not been studied. Erlotinib is mainly metabolized by CYP3A4 and coadministration could potentially increase erlotinib concentrations. Ketoconazole (a strong CYP3A4 inhibitor) increased erlotinib AUC by 86%. As erlotinib is dosed at/near the maximum tolerated dose (MTD), any increase in erlotinib exposure may lead to toxicity. Coadministration of a potent CYP3A4 inhibitor should be avoided, but if this is not possible, use with caution and close monitoring for erlotinib mediated toxicity is necessary. The erlotinib dose should be reduced in 50 mg increments if toxicity is observed. No interaction is expected with emtricitabine and tenofovir alafenamide.

Coadministration has not been studied but may increase erythromycin concentrations via inhibition of CYP3A4 by elvitegravir/cobicistat. Use with caution and monitor erythromycin related side adverse effects, especially cardiac adverse events (QT interval prolongation). Emtricitabine and tenofovir alafenamide are unlikely in interfere with erythromycin metabolism.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Elvitegravir/cobicistat could potentially increase escitalopram concentrations although to a moderate 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 elvitegravir/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 is not expected to alter elvitegravir concentrations. No dose adjustment is needed when Genvoya is combined with proton pump inhibitors. When omeprazole was administered 2 h prior to elvitegravir/cobicistat, elvitegravir AUC and Cmax increased by 10% and 16% but those of cobicistat decreased by 8% and 10%. Separating omeprazole and elvitegravir/cobicistat by 12 h had no effect (<10% change) on the AUC or Cmax of elvitegravir or cobicistat. Emtricitabine and tenofovir alafenamide do not interact with esomeprazole.

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

Coadministration with Genvoya has not been studied. Coadministration of an oral contraceptive containing norgestimate (0.180/0.215 mg once daily) and ethinylestradiol (0.025 mg once daily) with Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir-DF) had no effect on AUC, Cmin and Cmax of elvitegravir. Ethinylestradiol AUC, Cmin and Cmax decreased by 25%, 44% and 6%, respectively. Norgestimate AUC, Cmin and Cmax increased by 126%, 167% and 108%, respectively. The European SPC for Genvoya states a hormonal contraceptive should contain at least 30 µg ethinylestradiol and norgestimate as the progestogen. Coadministration of Genvoya with oral contraceptives containing progestogens other than norgestimate has not been studied. Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

Coadministration has not been studied but may increase ethosuximide concentrations as ethosuximide is mainly oxidized by CYP3A4. Use with caution and perform therapeutic drug monitoring for ethosuximide. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Etidocaine is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by elvitegravir/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 AUC, Cmax and Cmin by 52%, 61% and 34%, respectively) suggesting that lopinavir/ritonavir may not impair the efficacy of etonogestrel implants. Similarly, coadministration with Genvoya could potentially increase etonogestrel exposure and therefore is not expected to impair the contraceptive efficacy of etonogestrel when administered as implant.

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

Coadministration has not been studied. Etoposide is partly metabolized by CYP3A4 to reactive catechol metabolites. Conversion to reactive metabolites can also be mediated by prostaglandin synthase or myeloperoxidase. Furthermore, etoposide is partly glucuronidated by UGT1A1. Ketoconazole (a strong CYP3A4 inhibitor) increased etoposide exposure by 20%. Elvitegravir/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.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Genvoya should not be used in conjunction with non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products.

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 elvitegravir in the presence of cobicistat is unlikely. There is no evidence to suggest that eucalyptus impacts UGTs or P-gp.

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

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

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Exemestane is metabolised by CYP3A4 but coadministration with ketoconazole (a potent CYP3A4 inhibitor) showed no clinically significant effects and no effect is expected due to inhibition of CYP3A4 by cobicistat. No a priori dose adjustment is required. 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 as exenatide is cleared mainly by glomerular filtration. However, as exenatide slows gastric emptying it is advisable to take Genvoya at least 1 hour before an exenatide injection. [Note: this interaction is not specific for Genvoya, but for any medication taken with exenatide.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famciclovir is converted to penciclovir by aldehyde oxidase. Penciclovir is secreted in the urine possibly by OAT1. Elvitegravir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations. In addition, no significant interactions were observed when emtricitabine (200 mg single dose) and famciclovir (500 mg single dose) was studied in 12 HIV-negative subjects (there was no change in AUC or Cmax 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 with Genvoya has not been studied. Coadministration of famotidine (40 mg once daily given 12 hours after elvitegravir) and elvitegravir/cobicistat (150/150 mg once daily) increased elvitegravir Cmax, AUC and Cmin by 2%, 3% and 18% respectively (n=10). When the same doses were given simultaneously, there was no change in elvitegravir Cmax, but AUC and Cmin increased by 3% and 7% (n=16). No dose adjustment is needed when Genvoya is combined with H2 receptor antagonists. Emtricitabine and tenofovir alafenamide do not interact with famotidine.

Coadministration has not been studied. Felodipine is metabolized by CYP3A4. Elvitegravir/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. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration may increase fentanyl concentrations due to inhibition of CYP3A4, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway. 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 Genvoya as fentanyl exposure is expected to significantly increase and serious, life-threatening, or fatal respiratory depression may occur. Patients should be aware that recreational use could be potentially fatal.

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

Coadministration has not been studied. Fexofenadine does not undergo CYP-mediated metabolism but is a substrate of P-gp and OATP. 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 fexofenadine metabolic pathway.

Coadministration has not been studied. Flecainide is metabolized mainly via CYP2D6, with a proportion of the parent drug also eliminated unchanged renally (approximately 30%). Elvitegravir/cobicistat could potentially increase flecainide concentrations. Caution is warranted and clinical monitoring is recommended.

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

Coadministration has not been studied. Fluconazole is a moderate inhibitor of CYP3A4 however drug interactions studies with protease inhibitors showed no clinically significant interactions with fluconazole. Similarly, no significant interaction is expected with elvitegravir/cobicistat. Note, the European SPC suggests that fluconazole concentrations may be increased with cobicistat and recommends clinical monitoring. Emtricitabine and tenofovir derived from tenofovir alafenamide are unlikely to interact as fluconazole is mainly eliminated by glomerular filtration.

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. Elvitegravir/cobicistat is unlikely to interact with this metabolic pathway.

Coadministration has not been studied. Concomitant administration of 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 are unlikely to interact with fludrocortisone.

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 elvitegravir/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. Fluorouracil is metabolised via the same mechanisms as endogenous uracil, including via dihydropyrimidine dehydrogenase. Elvitegravir/cobicistat does 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 2C9 and to a lesser extent by 2C19 and 3A4 to form norfluoxetine. Elvitegravir/cobicistat could potentially increase fluoxetine concentrations although to a moderate extent. No a priori dosage adjustment is recommended. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase concentrations of fluphenazine, although to a moderate extent and 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. Elvitegravir/cobicistat could potentially increase flurazepam 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. Concomitant use of elvitegravir/cobicistat and glucocorticoids metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Alternative corticosteroids should be considered, particularly for long term use. Systemic corticosteroid effects have been reported in patients receiving strong inhibitors of CYP3A4 and inhaled or intranasally administered fluticasone propionate. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. 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. Plasma concentration of fluvastatin could possibly increase when coadministered with elvitegravir/cobicistat possibly via inhibition of BCRP and OATP1B1. In the absence of pharmacokinetic data but in light of a case report of rhabdomyolysis noted in a patient using elvitegravir/cobicistat and pravastatin (not fluvastatin)/fenofibrate, it is recommended to start with the lowest 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. Elvitegravir/cobicistat could potentially increase fluvoxamine concentrations although to a moderate extent (cobicistat 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.

Coadministration has not been studied. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases. A pharmacokinetic interaction is unlikely with folic acid itself. However, folic acid may be administered in a multivitamin preparation which may also contain polyvalent cations. As the effect of cationic complexation cannot be excluded, it is recommended to separate the administration of elvitegravir/cobicistat and multivitamin preparations by at least 4 hours. Significant interactions are not expected with emtricitabine and tenofovir alafenamide.

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 the metabolism and clearance a clinically significant interaction is unlikely as foscarnet is cleared mainly by glomerular filtration. Elvitegravir/cobicistat and emtricitabine do not interfere with foscarnet elimination. 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. Dose Descovy according to the concomitant antiretroviral.

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 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. Elvitegravir/cobicistat is unlikely to inhibit OATs at clinically relevant concentrations. In addition, 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. 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%. Similarly, concentrations of elvitegravir and cobicistat could be decreased via induction of CYP3A4 and/or P-gp. In addition, 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. No effect on emtricitabine is expected as its metabolism is not CYP-mediated. Patients should be advised against the use of garlic supplements.

Coadministration has not been studied. Gefitinib is metabolized by CYP3A4 and 2D6 and coadministration could potentially increase gefitinib concentrations. Itraconazole (a strong CYP3A4 inhibitor) increased gefitinib exposure by 80%. A similar effect is expected with elvitegravir/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. Gentamicin is eliminated unchanged predominantly via glomerular filtration. No interaction is expected with elvitegravir/cobicistat or 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. Coadministration is predicted to increase gestodene exposure due to inhibition of CYP3A4 and to moderately decrease ethinylestradiol. The European SPC for Genvoya states a hormonal contraceptive should contain at least 30 µg ethinylestradiol. 

Coadministration with elvitegravir/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 elvitegravir in the presence of cobicistat is unlikely. No effect on absorption of tenofovir alafenamide is expected as gingerols are unlikely to cause clinically significant inhibition of P-gp. No effect on emtricitabine is expected.

Coadministration of glecaprevir/pibrentasvir (300/120 mg once daily) and elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide increased glecaprevir Cmax, AUC and Cmin by 2.50-fold, 3.05-fold and 4.58-fold, respectively; pibrentasvir Cmax, AUC and Cmin increased by 24%, 57% and 89% (n=24). However these increases were deemed to be within safety limits and no dose adjustment is required. There were no clinically significant changes in the pharmacokinetics of elvitegravir, cobicistat, emtricitabine or tenofovir.

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 are unlikely.