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

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

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

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

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. Cobicistat could potentially reduce albendazole sulfoxidation and thus lower the clinical effect of albendazole. The clinical significance of this interaction is unknown.

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

Coadministration has not been studied 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 cobicistat, an inhibitor of P-gp. The product labels for aliskiren recommend avoiding concomitant use with CYP3A4 and P-gp inhibitors.

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

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

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.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase amitriptyline exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

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

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

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

Coadministration has not been studied and is not recommended. Concentrations of apixaban are expected to increase due to potent CYP3A4 and P-gp inhibition by cobicistat. Increased concentrations of apixaban increase the bleeding risk and the combination should be avoided if possible.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (CYP1A2 (major) and CYP3A4, 2D6 (minor)). 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. 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 salicylic acid and then further metabolized mainly by glucuronidation (by several UGT, major UGT1A6).

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

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 cobicistat. It is recommended to start atenolol at a lower dose and adjust dosage until the desired clinical effect is achieved.

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. 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 cobicistat concentrations and consequently lower darunavir or atazanavir exposure.

Coadministration has not been studied. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. Coadministration with a P-gp inhibitor (such as 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.

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and is not recommended in Biktarvy product label. However in specific clinical situations where an intensification of HIV treatment is needed, the coadministration of darunavir/cobicistat would be possible from a pharmacokinetic standpoint. Coadministration of bictegravir and darunavir/cobicistat increased bictegravir AUC by 74%. This increase is unlikely to be clinically significant; available dose exposure data, as well as data from phase 2 and phase 3 studies (48 weeks treatment), have shown a good safety profile with up to a 2.4 fold increase in bictegravir AUC. However, coadministration of cobicistat (150 mg once daily) and tenofovir alafenamide (8 mg once daily) increased tenofovir alafenamide Cmax and AUC by 183% and 165%. Cobicistat Cmax, AUC and Cmin increased by 6%, 9% and 11%, respectively. The recommended dose of 10 mg tenofovir alafenamide with P-gp inhibitors such as darunavir/cobicistat is not possible with Biktarvy which is only available as a fixed dose combination containing 25 mg tenofovir alafenamide, but it should be noted that tenofovir alafenamide has been associated with a large clinical safety profile.

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

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. Cobicistat could potentially increase bromazepam concentrations although to a moderate extent. No a priori dosage adjustment is required.

Coadministration of 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.

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 cobicistat.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Tetrahydrocannabinol (THC, the psychoactive component of cannabis) is metabolized mainly by CYP2C9 and to a lesser extent by CYP3A4. Cobicistat is a strong inhibitor of CYP3A4 and could increase THC, although to a modest extent. Patients should be aware of the potential for increased side effects.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase carvedilol, although to a moderate extent. No a priori dosage adjustment is required.

Coadministration has not been studied. Cat’s claw is a strong inhibitor of CYP3A4 in vitro and 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 cobicistat. Coadministration should be avoided.

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 cobicistat. The clinical significance of this interaction is unknown. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

Coadministration has not been studied. 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.

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. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase chlorpromazine although to a moderate extent. No a priori dosage adjustment is recommended.

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

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. 

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. The analgesic effect requires conversion of codeine to morphine via CYP2D6 and in vitro data suggest that cobicistat is a weak inhibitor of CYP2D6. Cobicistat could potentially reduce the analgesic efficacy. No a priori dosage adjustment is recommended but monitoring the analgesic effect may be considered.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although several constituents of Piper cubeba were shown to inhibit CYP3A4 in vitro, any additional effect on exposure of atazanavir or darunavir in the presence of cobicistat is unlikely.

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 atazanavir or darunavir 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 and therefore coadministration is not recommended.

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 cobicistat.

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.

When darunavir is coadministered with ritonavir, it should not be administered with cobicistat or fixed dosed combination products containing cobicistat.

Symtuza is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, Symtuza contains cobicistat, and must not be administered with other products containing cobicistat.

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

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and cobicistat may significantly increase dasatinib concentrations. If coadministration is unavoidable, close monitoring for toxicity is required and dasatinib dose reduction to 20-40 mg daily should be considered.

Coadministration has not been studied. Delamanid is primarily metabolised by albumin to DM-6705; metabolism of DM-6705 to other metabolites is thought to involve pathways mediated by CYP enzymes, including CYP3A4. Co-administration of delamanid with a strong inhibitor of CYP3A4 (lopinavir/ritonavir) increased DM-6705 exposure by 25-30%. QTc prolongation has been reported with delamanid (and is very closely correlated with the metabolite DM-6705). A similar increase would be expected with cobicistat and caution is advised. If coadministration is considered necessary, frequent monitoring of ECGs is recommended, throughout the full delamanid treatment period (for example, at least fortnightly for the first month and if the QTc interval remains within normal range to reduce this to monthly thereafter).

Coadministration 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. Since no data are available to make recommendations on the use of atazanavir/cobicistat or darunavir/cobicistat with combined oral contraceptives, alternative forms of contraception should be used.

Coadministration with a desogestrel-containing progestogen-only pill (POP) has not been studied. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and 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 cobicistat with atazanavir or daruanvir.

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. Cobicistat could potentially increase dihydrocodeine exposure by inhibition of CYP3A4 and CYP2D6. No a priori dose adjustment is required, but monitoring for analgesic effect and for signs of opiate toxicity may be required as clinically indicated.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. In vitro data indicate that cobicistat is a weak inhibitor of CYP2D6 and coadministration could potentially increase diphenhydramine concentrations, although to a moderate extent. No a priori dosage adjustment is recommended.

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

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

Juluca is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration of darunavir/cobicistat or atazanavir/cobicistat with Juluca would be possible from a pharmacokinetic standpoint.

Coadministration has not been studied. Doravirine is metabolized by CYP3A4. Cobicistat is a strong inhibitor of CYP3A4 and is expected to increase doravirine exposure by a~ 3.5-fold based on the drug interaction study with ritonavir. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure. 

Delstrigo (doravirine, lamivudine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral agents is not recommended in Delstrigo product labels. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with cobicistat would be possible from a pharmacokinetic standpoint. Coadministration with ritonavir increased doravirine AUC by 3.5 fold and Cmin by 2.9 fold. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure. Boosted PIs were shown to increase tenofovir-DF. There are currently inadequate data to determine whether tenofovir-DF plus cobicistat is associated with a greater risk of renal adverse reactions than tenofovir-DF without cobicistat. The European SPC for tenofovir-DF advises close renal monitoring of patients receiving tenofovir-DF with a cobicistat-boosted protease inhibitor. The US Prescribing Information for cobicistat does not recommend coadministration of cobicistat and tenofovir-DF in combination with concomitant or recent use of a nephrotoxic agent. Note, cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine and should not be initiated in patients with creatinine clearance less than 70 ml/min if tenofovir-DF requires dose adjustment based on creatinine clearance. 

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

Coadministration has not been studied. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase doxepin and nordoxepin concentrations although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent CYP3A4. Cobicistat could potentially increase dronabinol exposure via CYP3A4 inhibition, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolised in part by CYP3A4. Coadministration is predicted to increase exposure of drospirenone and ethinylestradiol. Since no data are available to make recommendations on the use of atazanavir/cobicistat or darunavir/cobicistat with combined contraceptives, alternative forms of contraception should be used.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone exposure. 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. The use of an estrogen alone or in combination with a progestogen should be used at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely 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. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase duloxetine concentration although to a moderate extent. No a priori dosage adjustment is recommended.

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

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration is predicted to increase dydrogesterone exposure due to inhibition of CYP3A4. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. The use of estrogen alone or in combination with a progestogen should be used at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary.

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

Coadministration has not been studied and  is not recommended as it may substantially increase grazoprevir exposure. Coadministration has only been studied with cobicistat in combination with elvitegravir/emtricitabine/tenofovir-DF which increased grazoprevir exposure by ~5.4-fold. A similar increase could be expected with other cobicistat-containing regimens.

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.

Coadministration of cobicistat (150 mg once daily) and tenofovir alafenamide (8 mg once daily) increased tenofovir alafenamide Cmax and AUC by 183% and 165%. Cobicistat Cmax, AUC and Cmin increased by 6%, 9% and 11%, respectively. When administered with atazanavir/cobicistat or darunavir/cobicistat, the recommended dose of Descovy is 200/10 mg once daily (where available).

Coadministration with emtricitabine/tenofovir-DF has not been studied. Based on metabolism and clearance a pharmacokinetic interaction with emtricitabine is unlikely. Coadministration with tenofovir-DF increased tenofovir AUC and Cmax by 23% and 55%, but this increase is not considered to be clinically relevant and no dose adjustment of tenofovir is required. Note, cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. Emtricitabine/tenofovir-DF should only be used in individuals with creatinine clearance (CrCl) less than 80 mL/min if the potential benefits are considered to outweigh the potential risks and should not be initiated in patients with creatinine clearance less than 60 ml/min. The European SPC for emtricitabine/tenofovir-DF advises close renal monitoring of patients receiving tenofovir-DF with a cobicistat-boosted protease inhibitor and in HIV-1 infected patients with renal risk factors, the co-administration of tenofovir-DF with a boosted protease inhibitor should be carefully evaluated.

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%.

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

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

Coadministration with estradiol as hormone replacement therapy (HRT) has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Contrary to ritonavir, cobicistat does not induce CYP1A2 and glucuronidation and therefore coadministration is predicted to increase estradiol exposure due to inhibition of CYP3A4. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones in unknown. The use of estradiol alone or in combination with a progestogen should be used at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for individual women. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary.

Coadministration 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 cobicistat could potentially increase etonogestrel exposure and therefore is not expected to impair the contraceptive efficacy of etonogestrel when administered as an 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. Cobicistat is predicted to increase both etonogestrel and ethinylestradiol, therefore maintaining the contraceptive efficacy of the etonogestrel CVR.

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 atazanavir or darunavir in the presence of cobicistat is unlikely.

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

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

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

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

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

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

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.

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 cobicistat. Note, the European SPC suggests that fluconazole concentrations may be increased with cobicistat and recommends clinical monitoring.

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.

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

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase levels of fluphenazine although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Concomitant use of 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 inhaled or nasal corticosteroids may be considered, particularly for long term use. Systemic corticosteroid effects have been reported in patients receiving strong inhibitors of CYP3A4 and inhaled or intranasally administered fluticasone propionate. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Coadministration has not been studied. Fluvastatin is partially metabolised by CYP2C9 and is a substrate of OATP1B1 and there is a potential for a moderate increase in fluvastatin exposure when coadministered with atazanavir/cobicistat or darunavir/cobicistat. Start fluvastatin at the lowest recommended dose and titrate as clinically indicated.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Cobicistat is a weak inhibitor of CYP2D6 and could potentially increase fluvoxamine concentrations although to a moderate extent. No a priori dosage adjustment is recommended.

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

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 cobicistat could be decreased via induction of CYP3A4 and/or P-gp. Patients should be advised against the use of garlic supplements.

Coadministration with a gestodene-containing combined oral contraceptive (COC) has not been studied. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Coadministration is predicted to increase exposure of gestodene and ethinylestradiol. Since no data are available to make recommendations on the use of atazanavir/cobicistat or darunavir/cobicistat with combined contraceptives, alternative forms of contraception should 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 atazanavir or darunavir in the presence of cobicistat is unlikely.

Coadministration with cobicistat and atazanavir or darunavir has not been studied. Coadministration with cobicistat-boosted HIV integrase inhibitors was allowed in clinical studies, however, cobicistat-boosted HIV protease inhibitors are not recommended (see individual HIV protease inhibitors for recommendations). Coadministration of glecaprevir/pibrentasvir and cobicistat (with elvitegravir/emtricitabine/tenofovir alafenamide) increased glecaprevir Cmax, AUC and Cmin by 2.50-fold, 3.05-fold and 4.58-fold, respectively, However these increases were deemed to be within safety limits.

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.

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

Coadministration has not been studied. Griseofulvin is a liver microsomal enzyme inducer and may lower plasma levels (and therefore reduce the efficacy) of concomitantly administered medicinal products that are metabolized by cytochrome P450 3A4, such as cobicistat.

Coadministration has not been studied. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGT2B7>1A4, 1A9), carbonyl reduction, and oxidative metabolism (CYP3A4, CYP2D6). Cobicistat could potentially increase haloperidol exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyurea undergoes metabolism via non-CYP mediated metabolism and is not a substrate of P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Inhibition of metabolism by cobicistat is unlikely to affect ibalizumab, a monoclonal antibody binding to the CD4 receptor, which is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies. Dose modifications of ibalizumab are not required when administered with any other antiretroviral.

Ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Iloprost is extensively metabolized via beta oxidation of the carboxyl side chain with only a minor role for CYP metabolism.

Coadministration has not been studied. Imipramine is metabolized by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolized by CYP2D6. Cobicistat could potentially increase imipramine concentrations. Careful dose titration of imipramine with monitoring for antidepressant response and adverse effects are recommended. Consider dose reduction if needed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Indacaterol is eliminated partly unchanged (33%) and partly metabolized by CYP3A4 and UGT1A1, and is a weak substrate of P-gp. Coadministration with ritonavir increased indacaterol exposure up to two-fold and a similar effect may occur with cobicistat. However, this increase does not raise any safety concerns given the safety experience of indacaterol at doses up to twice the maximum recommended therapeutic dose in clinical studies of up to one year and dose adjustment is not required.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although alantolactone, a component of Inula racemosa, moderately inhibits CYP3A4 in vitro, any additional effect on exposure of atazanavir or darunavir in the presence of cobicistat is unlikely.

Coadministration has not been studied. Ivermectin is predominantly metabolised by CYP3A4. There is potential for cobicistat to increase levels of ivermectin via inhibition of CYP3A4, however the clinical relevance of this interaction is low given that ivermectin is administered as a single dose.