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PREZISTA should be used in combination with low dose ritonavir as a pharmacokinetic enhancer.
The interaction profile of PREZISTA depends on whether ritonavir is used as pharmacokinetic enhancer. PREZISTA may therefore have different recommendations for concomitant medications depending on whether PREZISTA is boosted with ritonavir. The dosing recommendations for PREZISTA/rtv that are listed as follows.
PREZISTA should not be used in combination with other antiretrovirals that also require pharmacokinetic boosting with ritonavir.
Darunavir when used in combination ritonavir is an inhibitor of CYP3A, CYP2D6 and P-gp. Co-administration of PREZISTA/rtv and medicinal products primarily metabolized by CYP3A, CYP2D6, or transported by P-gp may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and adverse events. Co-administration of PREZISTA/rtv with drugs that have active metabolite(s), formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect.
Darunavir and ritonavir are metabolized by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lower plasma concentrations of darunavir and ritonavir. Co-administration with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.
Drug-drug interactions presented by drug class including drug name examples are presented as follows. This list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with PREZISTA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
Antiretroviral medicinal products: Integrase strand transfer inhibitors: Dolutegravir: PREZISTA/rtv (600/100 mg b.i.d.) did not have a clinically relevant effect on dolutegravir exposure. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir had no clinically significant effect on the pharmacokinetics of darunavir. PREZISTA/rtv co-administered with dolutegravir can be used without dose adjustment.
Elvitegravir: When PREZISTA/rtv (600/100 mg b.i.d.) is used in combination with elvitegravir, the dose of elvitegravir should be 150 mg once daily.
The pharmacokinetics and dosing recommendations for other doses of darunavir have not been established. Therefore, co-administration of PREZISTA/rtv in doses other than 600/100 mg b.i.d. and elvitegravir is not recommended.
Raltegravir: Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations. At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant.
PREZISTA co-administered with low dose ritonavir and raltegravir can be used without dose adjustments.
Nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs): Didanosine: PREZISTA/rtv (600/100 mg b.i.d.) did not significantly affect didanosine exposure. The combination of PREZISTA co-administered with low dose ritonavir and didanosine can be used without dose adjustments. It is recommended that didanosine be administered on an empty stomach. Didanosine should be administered 1 hour before or 2 hours after PREZISTA/rtv (which are administered with food).
Tenofovir disoproxil fumarate: The results of an interaction trial with tenofovir (tenofovir disoproxil fumarate 300 mg once daily [q.d.]) demonstrated that the systemic exposure of tenofovir was increased by 22% when co-administered with PREZISTA/rtv (300/100 mg b.i.d.). This finding is not considered to be clinically relevant. There was no change in the urinary excretion of tenofovir or darunavir during co-administration. Tenofovir did not have a significant influence on darunavir exposure. No dose adjustments of PREZISTA, ritonavir or tenofovir disoproxil fumarate are required when these drugs are co-administered.
Other NRTIs: Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine, and abacavir) that are primarily renally excreted, no drug interactions are expected for these medicinal compounds and PREZISTA/rtv.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Delavirdine: Co-administration of PREZISTA/rtv and delavirdine may increase darunavir and delavirdine concentrations (inhibition of CYP3A).
The appropriate doses of PREZISTA/rtv and delavirdine have not been established. The combination of PREZISTA/rtv and delavirdine is not recommended.
Etravirine: In an interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and etravirine, there was a 37% decrease in etravirine exposure in the presence of PREZISTA/rtv and no relevant change in exposure to darunavir. Therefore, PREZISTA/rtv can be co-administered with etravirine 200 mg b.i.d. without dose adjustments.
Efavirenz: An interaction trial between PREZISTA/rtv (300/100 mg b.i.d.) and efavirenz (600 mg q.d.) has been performed. In the presence of efavirenz, a decrease of 13% for darunavir exposure was observed. Exposure to efavirenz was increased by 21% when administered in combination with PREZISTA/rtv. Since this difference is considered not to be clinically relevant, the combination of PREZISTA/rtv and efavirenz can be used without dose adjustments.
Nevirapine: The results of an interaction trial with PREZISTA/rtv (400/100 mg b.i.d.) and nevirapine (200 mg b.i.d.) demonstrated that darunavir exposure was not affected when administered concomitantly with nevirapine. Exposure to nevirapine increased by 27% (compared to historical controls) when administered in combination with PREZISTA/rtv. Since this difference is not considered to be clinically relevant, the combination of PREZISTA/rtv and nevirapine can be used without dose adjustments.
Rilpivirine: In an interaction trial between PREZISTA/rtv (800/100 mg q.d.) and rilpivirine (150 mg q.d.), no clinically relevant effect on darunavir exposure was observed. Exposure to rilpivirine increased by 130% (2.3-fold) when administered in combination with PREZISTA/rtv. Since this difference is not considered to be clinically relevant, the combination of PREZISTA/rtv and rilpivirine can be used without dose adjustments.
HIV protease inhibitors (PIs): Ritonavir: The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg PREZISTA was given orally in combination with ritonavir at 100 mg b.i.d. Therefore, PREZISTA should only be used in combination with a pharmacokinetic enhancer such as low dose ritonavir (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Lopinavir/ritonavir: Results of interaction trials with PREZISTA with or without ritonavir and lopinavir/ritonavir (1200 mg darunavir b.i.d. with or without 100 mg ritonavir b.i.d. and lopinavir/ritonavir 400/100 mg b.i.d. or 533/133.3 mg b.i.d.) demonstrated a decrease in the exposure (AUC) of darunavir by 40%. The appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer PREZISTA/rtv with lopinavir/ritonavir.
Saquinavir: In an interaction trial between PREZISTA (400 mg b.i.d.), saquinavir (1000 mg b.i.d.) and ritonavir (100 mg b.i.d.), darunavir exposure was decreased by 26% in the presence of saquinavir/rtv; saquinavir exposure was not affected by the presence of PREZISTA/rtv. It is not recommended to combine saquinavir and PREZISTA, with or without low dose ritonavir.
Atazanavir: An interaction trial between PREZISTA/rtv (400/100 mg b.i.d.) and atazanavir (300 mg q.d.) demonstrated that systemic exposure to darunavir and atazanavir was not significantly affected when co-administered.
Atazanavir can be co-administered with PREZISTA/rtv.
Indinavir: In an interaction trial between PREZISTA/rtv (400/100 mg b.i.d.) and indinavir (800 mg b.i.d.), darunavir exposure was increased by 24% in the presence of indinavir/rtv; indinavir exposure was increased by 23% in the presence of PREZISTA/rtv.
When used in combination with PREZISTA/rtv, dose adjustment of indinavir from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in case of intolerance.
Other HIV PIs: The co-administration of PREZISTA/rtv and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir have not been studied.
Therefore, such co-administration is not recommended.
CCR5 antagonist: When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily. An interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and maraviroc (150 mg b.i.d.) demonstrated that in the presence of PREZISTA/rtv the exposure of maraviroc was increased by 305%. There was no apparent effect of maraviroc on darunavir/ritonavir exposure.
Other medicinal products: Acid reducing agents: Antacids: e.g. Aluminium/magnesium hydroxide, calcium carbonate: No interaction is expected between antacids and PREZISTA/rtv.
PREZISTA/rtv and antacids can be used concomitantly without dose adjustments.
H2-receptor antagonists: e.g. Cimetidine, famotidine, nizatidine, ranitidine: Co-administration of ranitidine (150 mg b.i.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not affect the exposure to darunavir.
PREZISTA/rtv can be co-administered with H2-receptor antagonists without dose adjustments.
Proton pump inhibitors: e.g. Esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole: Co-administration of omeprazole (20 mg q.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not affect the exposure to darunavir. PREZISTA/rtv and proton pump inhibitors can be co-administered without dose adjustment.
Alpha 1-adrenoreceptor antagonist: Alfuzosin: Exposure to alfuzosin may be increased when co-administered with PREZISTA/rtv.
Concomitant use of PREZISTA/rtv with alfuzosin is contraindicated.
Anti-anginal/Antiarrhythmics: Ranolazine: Exposure to ranolazine may be increased (CYP3A inhibition) when co-administered with PREZISTA/rtv. Concomitant use of PREZISTA/rtv with ranolazine is contraindicated.
Ivabradine: Concomitant use of PREZISTA/rtv with ivabradine is contraindicated.
Amiodarone, bepridil, disopyramide, dronedarone, flecainide, mexiletine, propafenone, systemic lidocaine, and quinidine: Exposure to these antiarrhythmics may be increased when co-administered with PREZISTA/rtv.
Caution is warranted and therapeutic drug monitoring of antiarrhytmics is recommended when available.
Concomitant use of PREZISTA/rtv with dronedarone is contraindicated.
Digoxin: An interaction trial with PREZISTA/rtv (600/100 mg b.i.d.) and a single dose of digoxin (0.4 mg) showed an increase of digoxin AUClast of 77% (ratio of Least Square Means (LSM) was 1.77 with a 90% CI of 0.90 to 3.50). It is recommended that the lowest dose of digoxin should initially be prescribed and digoxin dose should be titrated to obtain the desired clinical effect when co-administered with PREZISTA/rtv. Serum digoxin concentrations should be monitored to assist in the titration.
Antibacterial: Clarithromycin: An interaction trial between PREZISTA/rtv (400/100 mg b.i.d.) and clarithromycin (500 mg b.i.d.) showed an increase in exposure to clarithromycin by 57%, while exposure to darunavir was not affected. PREZISTA/rtv and clarithromycin can be used without dose adjustment in patients with normal renal function. For patients with renal impairment, a dose reduction of clarithromycin should be considered. Consult the prescribing information for clarithromycin for the recommended dosage.
Anticoagulants: Direct Oral Anticoagulants (DOACs): apixaban, dabigatran, edoxaban, rivaroxaban: DOACs are primarily metabolized by CYP3A4 and/or transported by P-gp. Co-administration with PREZISTA/rtv may result in increased plasma concentrations of the DOAC, which may lead to an increased bleeding risk.
Co-administration of a DOAC affected by both P-gp and CYP3A4, including apixaban and rivaroxaban, is not recommended with PREZISTA/rtv.
The results of a drug-drug interaction study between darunavir 800 mg, ritonavir 100 mg and dabigatran etexilate 150 mg in healthy participants showed a 1.7-fold increase in dabigatran plasma AUC after single dosing of darunavir and ritonavir, and a 1.2-fold increase in dabigatran plasma AUC after repeated dosing of darunavir and ritonavir. The study demonstrated a 1.6-fold increase in dabigatran plasma Cmax after single dosing of darunavir and ritonavir, and a 1.2-fold increase in dabigatran plasma Cmax after repeated dosing of darunavir and ritonavir.
Clinical monitoring and/or dose adjustment is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran and edoxaban, is co-administered with PREZISTA/rtv.
The results of a drug-drug interaction study between darunavir/cobicistat 800/150 mg and 538 dabigatran etexilate 150 mg in healthy participants showed a 2.6-fold increase in dabigatran plasma AUC after single dosing of darunavir/cobicistat, and a 1.9-fold increase in dabigatran plasma AUC after repeated dosing of darunavir/cobicistat. The study demonstrated a 2.6-fold increase in dabigatran plasma Cmax after single dosing of darunavir/cobicistat and a 2.0-fold increase in dabigatran plasma Cmax after repeated dosing of darunavir/cobicistat.
Clinical monitoring is required when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with PREZISTA/cobi. A dose reduction of the DOAC may be needed.
Warfarin: Warfarin concentrations may be affected when co-administered with PREZISTA/rtv. It is recommended that the international normalized ratio (INR) is monitored when warfarin is combined with PREZISTA/rtv.
Anticonvulsants: Phenobarbital and phenytoin: Phenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with these medicines, as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Carbamazepine: An interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and carbamazepine (200 mg b.i.d.) showed that the exposure to darunavir, co-administered with ritonavir, was unaffected by carbamazepine. Ritonavir exposure (AUC12h) was decreased by 49%. For carbamazepine, AUC12h was increased by 45%. No dose adjustment for PREZISTA/rtv is recommended. If there is a need to combine PREZISTA/rtv and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of PREZISTA/rtv.
Clonazepam: Co-administration of PREZISTA/rtv with clonazepam may increase concentrations of clonazepam. Clinical monitoring is recommended when co-administering PREZISTA/rtv with clonazepam.
Antidepressants: Paroxetine and sertraline: In an interaction trial between paroxetine (20 mg q.d.) or sertraline (50 mg q.d.) and PREZISTA/rtv (400/100 mg b.i.d.), the exposure to darunavir was not affected by the presence of sertraline or paroxetine. Exposure to sertraline and paroxetine, was decreased by 49% and 39%, respectively, in the presence of PREZISTA/rtv. If SSRIs are co-administered with PREZISTA/rtv, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/rtv should be monitored for an antidepressant response.
Amitriptyline, desipramine, imipramine, nortriptyline, and trazodone: Concomitant use of PREZISTA/rtv and these antidepressants may increase concentrations of the antidepressant (inhibition of CYP2D6 and/or CYP3A).
Clinical monitoring is recommended when co-administering PREZISTA/rtv with these antidepressants and a dose adjustment of the antidepressant may be needed.
Antiemetics: Domperidone: Use with caution: monitor for domperidone adverse reactions.
Antifungals: Itraconazole, isavuconazole ketoconazole, posaconazole, and voriconazole: Itraconazole, isavoconazole, ketoconazole, posaconazole, and voriconazole are moderate to potent inhibitors of CYP3A and/or some are substrates of CYP3A. Concomitant systemic use of these antifungals with PREZISTA/rtv may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of some of these antifungals may be increased by PREZISTA/rtv. This was confirmed in an interaction trial where the concomitant administration of ketoconazole (200 mg b.i.d.) with PREZISTA/rtv (400/100 mg b.i.d.) increased exposure of ketoconazole and darunavir by 212% and 42%, respectively.
Plasma concentrations of voriconazole may be decreased in the presence of PREZISTA/rtv. Voriconazole should not be administered to patients receiving PREZISTA/rtv unless an assessment of the benefit/risk ratio justifies the use of voriconazole. Clinical monitoring is recommended when co-administering PREZISTA/rtv with posaconazole or isavuconazole. When co-administration is required the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
Clotrimazole and fluconazole: Co-administration of PREZISTA/rtv with these antifungals may increase concentrations of darunavir, ritonavir, and/or the antifungal. Clinical monitoring is recommended when co-administering PREZISTA/rtv with these antifungals.
Anti-gout: Colchicine: Concomitant use of colchicine and PREZISTA/rtv may increase the exposure to colchicine. The following dose adjustments are recommended for colchicine. For the treatment of gout-flares in patients on PREZISTA/rtv, the recommended dose of colchicine is 0.6 mg, followed by 0.3 mg 1 hour later. Treatment course to be repeated no earlier than 3 days. For the prophylaxis of gout-flares in patients on PREZISTA/rtv, the recommended dose of colchicine is 0.3 mg q.d. or q.o.d. For the treatment of familial Mediterranean fever in patients on PREZISTA/rtv, the maximum dose of colchicine is 0.6 mg q.d. (may be given as 0.3 mg b.i.d.). Co-administration of PREZISTA/rtv with colchicine in patients with renal or hepatic impairment is contraindicated.
Antihistamines: Astemizole, terfenadine: Exposure to these antihistamines may be increased when co-administered with PREZISTA/rtv. Concomitant use of PREZISTA/rtv with astemizole and terfenadine is contraindicated.
Antimalarial: Artemether/lumefantrine: An interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and artemether/lumefantrine (80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours) showed an increase in exposure to lumefantrine by 2.75-fold, while exposure to darunavir was not affected. The exposure to artemether and its active metabolite, dihydroartemisinin, decreased by 16% and 18%, respectively. The combination of PREZISTA/rtv and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
Antimycobacterials: Rifampin and rifapentine: Co-administration of PREZISTA/rtv with rifampin and rifapentine may decrease darunavir concentrations (induction of CYP3A), which may result in loss of therapeutic effect of PREZISTA.
Co-administration of PREZISTA/rtv with rifampin is contraindicated.
Co-administration of PREZISTA/rtv with rifapentine is not recommended.
Rifabutin: Rifabutin is a substrate of CYP450 enzymes. In an interaction trial, an increase of systemic exposure to darunavir by 57% was observed, when PREZISTA/rtv (600/100 mg b.i.d.) was administered with rifabutin (150 mg once every other day [q.o.d.]). Based on the safety profile of PREZISTA/rtv, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for PREZISTA/rtv. The interaction trial showed a comparable systemic exposure for rifabutin between treatment at 300 mg q.d. alone and at 150 mg q.o.d. in combination with PREZISTA/rtv (600/100 mg b.i.d.) with an increase in exposure to the active metabolite 25-O-desacetylrifabutin.
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg q.o.d.) and increased monitoring for rifabutin-related adverse events is warranted in patients receiving the combination.
Antineoplastics: Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine: The plasma concentrations of these antineoplastics are expected to increase with co-administration of PREZISTA/rtv (inhibition of CYP3A), resulting in the potential for adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with PREZISTA/rtv.
Concomitant use of everolimus or irinotecan and PREZISTA/rtv is not recommended.
Antiplatelets: Clopidogrel: Co-administration of PREZISTA/rtv with clopidogrel is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel. Co-administration of PREZISTA/rtv with clopidogrel is not recommended.
Prasugrel: PREZISTA/rtv is not expected to have a clinically relevant effect on plasma concentrations of the active metabolite of prasugrel.
Antipsychotics/neuroleptics: Lurasidone: Concomitant use of lurasidone and PREZISTA/rtv may increase the exposure to lurasidone (inhibition of CYP3A4). Concomitant use of PREZISTA/rtv with lurasidone is contraindicated.
Pimozide: Concomitant use of pimozide and PREZISTA/rtv may increase the exposure to pimozide (inhibition of CYP3A and CYP2D6). Concomitant use of PREZISTA/rtv with pimozide is contraindicated.
Perphenazine: Co-administration of PREZISTA/rtv and perphenazine may increase concentrations of the neuroleptic (inhibition of CYP3A or CYP2D6). Clinical monitoring is recommended when co-administering PREZISTA/rtv with perphenazine and a lower dose of the neuroleptic should be considered.
Risperidone, thioridazine: Concomitant use of risperidone or thioridazine and PREZISTA/rtv may increase the exposure to these antipsychotics (inhibition CYP2D6 and/or P-gp). Decrease of risperidone or thioridazine dose may be needed when co-administered with PREZISTA/rtv.
Quetiapine: Concomitant use of quetiapine and PREZISTA/rtv may increase the exposure to quetiapine (inhibition of CYP3A). The quetiapine dose should be substantially reduced when co-administered with PREZISTA. For details, refer to the quetiapine prescribing information.
β-Blockers: Carvedilol, metoprolol, timolol: Co-administration of PREZISTA/rtv and beta-blockers may increase concentrations of the beta-blocker (inhibition of CYP2D6). Clinical monitoring is recommended when co-administering PREZISTA/rtv with beta-blockers and a lower dose of the beta-blocker should be considered.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil: The exposure to calcium channel blockers may increase when PREZISTA/rtv are used concomitantly (inhibition of CYP2D6 and/or CYP3A).
Caution is warranted and careful clinical monitoring is recommended.
Contraceptives: Ethinylestradiol and norethindrone: The results of an interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and ethinylestradiol and norethindrone demonstrated that at steady-state systemic exposures to ethinylestradiol and norethindrone are decreased by 44% and 14%, respectively.
Ethinylestradiol and drospirenone: The effect of PREZISTA/rtv on drospirenone exposure is not known.
When PREZISTA/rtv is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential of hyperkalemia.
No data are available to make recommendations on the use of PREZISTA/rtv with other hormonal contraceptives. Therefore, additional or alternative (non-hormonal) methods of contraception are recommended.
Corticosteroids: Corticosteroids primarily metabolized by CYP3A (betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone). Concomitant use of corticosteroids and PREZISTA/rtv may increase plasma concentrations of these corticosteroids. Concomitant use may increase the risk for development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Clinical monitoring is recommended when co-administering PREZISTA/rtv with corticosteroids. Alternatives should be considered, particularly for long term use.
For co-administration of cutaneously-administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for conditions or uses that augment its systemic absorption.
Systemic dexamethasone: Systemic dexamethasone induces CYP3A and thereby may decrease darunavir exposure. This may result in loss of therapeutic effect.
Therefore, this combination should be used with caution.
Endothelin receptor antagonist: Bosentan: Concomitant use of bosentan and PREZISTA/rtv may increase plasma concentrations of bosentan. In patients who have been receiving PREZISTA/rtv for at least 10 days, start bosentan at 62.5 mg q.d. or q.o.d. based upon individual tolerability. For patients on bosentan and initiating PREZISTA/rtv, discontinue the use of bosentan at least 36 hours prior to initiation of PREZISTA/rtv. After at least 10 days following the initiation of PREZISTA/rtv, resume bosentan at 62.5 mg q.d. or q.o.d. based upon individual tolerability.
Ergot alkaloids: e.g., Ergotamine, ergonovine, dihydroergotamine, and methylergonovine: Exposure to the ergot alkaloids may be increased when co-administered with PREZISTA/rtv. Concomitant use of PREZISTA/rtv with ergot alkaloids is contraindicated.
Gastrointestinal motility agent: Cisapride: Exposure to cisapride may be increased when co-administered with PREZISTA/rtv. Concomitant use of PREZISTA/rtv with cisapride is contraindicated.
Hepatitis C virus (HCV) direct-acting antivirals: Boceprevir: In an interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and boceprevir (800 mg three times daily), darunavir exposure was reduced by 44% and boceprevir exposure was reduced by 32%.
It is not recommended to co-administer PREZISTA/rtv with boceprevir.
Elbasvir/Grazoprevir: Concomitant use of elbasvir/grazoprevir and PREZISTA/rtv may increase the exposure to grazoprevir (inhibition of CYP3A).
Concomitant use of PREZISTA/rtv with elbasvir/grazoprevir is contraindicated.
Glecaprevir/Pibrentasvir: Concomitant use of glecaprevir/pibrentasvir and PREZISTA/rtv may increase the exposure to glecaprevir and pibrentasvir (inhibition of P-gp, BCRP and/or OATP1B1/3).
Co-administration of PREZISTA/rtv with glecaprevir/pibrentasvir is not recommended.
Herbal product: St. John's wort: Co-administration of PREZISTA/rtv with products containing St. John's wort (Hypericum perforatum) may cause significant decreases in darunavir concentrations (induction of CYP3A), which may result in loss of therapeutic effect to PREZISTA. Co-administration of PREZISTA/rtv with products containing St. John's wort (Hypericum perforatum) is contraindicated.
HMG-CoA reductase inhibitors: Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, which are highly dependent on CYP3A metabolism, are therefore expected to have markedly increased plasma concentrations when co-administered with PREZISTA/rtv. Increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis. Concomitant use of PREZISTA/rtv with lovastatin and simvastatin is contraindicated. The results of an interaction trial with atorvastatin show that atorvastatin (10 mg q.d.) in combination with PREZISTA/rtv (300/100 mg b.i.d.) provides an exposure to atorvastatin, which is only 15% lower than that obtained with atorvastatin (40 mg q.d.) alone. When administration of atorvastatin and PREZISTA/rtv is desired, it is recommended to start with an atorvastatin dose of 10 mg q.d. A gradual dose increase of atorvastatin may be tailored to the clinical response. PREZISTA/rtv (600/100 mg b.i.d.) increased exposure to a single dose of pravastatin (40 mg) by approximately 80%, but only in a subset of subjects. When administration of pravastatin and PREZISTA/rtv is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effects while monitoring safety. An interaction study evaluating PREZISTA/rtv (600/100 mg b.i.d.) in combination with rosuvastatin (10 mg q.d.) resulted in an increase in rosuvastatin exposure. When administration of rosuvastatin and Prezista/rtv is desired, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
Other lipid modifying agents: Lomitapide: PREZISTA/rtv is expected to increase the exposure of lomitapide when co-administered. Co-administration is contraindicated.
Immunosuppressants: Cyclosporin, everolimus, sirolimus, tacrolimus: Exposure to these immunosuppressants may be increased when co-administered with PREZISTA/rtv. Therapeutic drug monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/rtv. Concomitant use of everolimus and PREZISTA/rtv is not recommended.
Inhaled beta-agonist: Salmeterol: Concomitant use of salmeterol and PREZISTA/rtv is not recommended. The combination may result in increased risk of cardiovascular adverse events with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic analgesics/treatment of opioid dependence: Buprenorphine/naloxone: The results of an interaction trial with PREZISTA/rtv and buprenorphine/naloxone demonstrated that buprenorphine exposure was not affected when administered with PREZISTA/rtv. Exposure of the active metabolite, norbuprenorphine, increased by 46%. No dose adjustment for buprenorphine was required. Careful clinical monitoring is recommended if PREZISTA/rtv and buprenorphine are co-administered.
Fentanyl, oxycodone, tramadol: Co-administration of PREZISTA/rtv with fentanyl, oxycodone or tramadol may increase concentrations of the analgesic. Clinical monitoring is recommended when co-administering PREZISTA/rtv with these analgesics.
Methadone: An interaction trial investigating the effect of PREZISTA/rtv (600/100 mg b.i.d.) on a stable methadone maintenance therapy showed an AUC decrease of 16% for R-methadone. Based on pharmacokinetic and clinical findings, no adjustment of methadone dosage is required when initiating co-administration of PREZISTA/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted in some patients.
Opioid Antagonist: Naloxegol: Co-administration of PREZISTA/rtv with naloxegol is contraindicated.
PDE-5 inhibitors.
Treatment of erectile dysfunction: Avanafil, sildenafil, tadalafil, vardenafil: In an interaction trial a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with PREZISTA/rtv (400/100 mg b.i.d.). Concomitant use of PDE-5 inhibitors for the treatment of erectile dysfunction with PREZISTA/rtv should be done with caution. If concomitant use of PREZISTA/rtv with sildenafil, vardenafil, or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours or tadalafil at a single dose not exceeding 10 mg dose in 72 hours is recommended. Co-administration of PREZISTA/rtv and avanafil is not recommended.
Treatment of pulmonary arterial hypertension: Sildenafil, tadalafil: A safe and effective dose of sildenafil when combined with PREZISTA/rtv for the treatment of pulmonary arterial hypertension has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of PREZISTA/rtv with sildenafil when used for pulmonary arterial hypertension is contraindicated. For the treatment of pulmonary arterial hypertension with tadalafil co-administered with PREZISTA/rtv, a dose adjustment for tadalafil is warranted. In patients who have been receiving PREZISTA/rtv for at least 1 week, start tadalafil at 20 mg q.d., and increase to 40 mg q.d. based upon individual tolerability.
For patients on tadalafil and initiating PREZISTA/rtv, discontinue the use of tadalafil at least 24 hours prior to initiating PREZISTA/rtv and avoid the use of tadalafil during the initiation of PREZISTA/rtv. After at least 1 week following the initiation of PREZISTA/rtv, resume tadalafil at 20 mg q.d. and increase to 40 mg q.d. based upon individual tolerability.
Pharmacokinetic enhancer: PREZISTA should be used in combination with a pharmacokinetic enhancer such as low dose ritonavir. PREZISTA should not be used in combination with other antiretrovirals that also require pharmacokinetic boosting with ritonavir.
Platelet aggregation inhibitors: Ticagrelor: Co-administration of PREZISTA/rtv with ticagrelor may increase concentrations of ticagrelor. Co-administration of PREZISTA/rtv and ticagrelor is not recommended.
Sedatives/hypnotics: Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zolpidem: Co-administration of PREZISTA/rtv with these sedatives/hypnotics may increase concentrations of the sedative/hypnotic (inhibition of CYP3A). Co-administration of PREZISTA/rtv with oral midazolam or triazolam is contraindicated. Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered. Clinical monitoring is recommended when co-administering PREZISTA/rtv with the other sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
Treatment of premature ejaculation: Co-administration of PREZISTA/rtv with dapoxetine is contraindicated.
Urinary antispasmodics: Fesoterodine, solifenacin: Use with caution: monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
