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4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions are considered clinically relevant for DAAs. Only those drug-drug interactions classified as clinical significance of contraindicated or those considered life-threatening which have not yet been classified will be reviewed. 

Table 14. DAA drug-drug interactions2
Target DrugInteracting DrugInteractionRecommendationClinical Significance Level
elbasvir/grazoprevirbosentanbosentan is a moderate CYP3A inducer. May lead to decreased plasma concentrations of target drug and decreased virologic responseconcurrent administration should be avoided, if possiblemajor
 etravirineetravirine is a moderate CYP3A inducer. Concurrent use may result in decreased plasma concentrations of target drug and decreased virologic responseconcurrent use is not recommendedmajor
 modafinilmodafinil is a moderate CYP3A inducer. Concurrent use may result in decreased plasma concentrations of target drug and decreased virologic responseconcurrent use is not recommendedmajor
 nafcillinnafcillin is a moderate CYP3A inducer. May lead to decreased therapeutic effect of target drugscoadministration is not recommendedmajor
 oral ketoconazoleketoconazole is a strong CYP3A inhibitor. May lead to increased exposure to target drugs.coadministration is not recommendedmajor
 statin therapy (atorvastatin, rosuvastatin)increased risk of myopathy and rhabdomyolysisdo not exceed 20 mg daily of atorvastatin, and do not exceed 10 mg daily of rosuvastatinmajor
 statin therapy (fluvastatin, lovastatin, simvastatin)concurrent use may result in increased statin plasma levelsuse lowest effective dose and monitor for statin related side effectsmoderate
 strong CYP3A inducers (eg., barbiturates, apalutamide, carbamazepine, efavirenz, encorafenib, enzalutamide, phenytoin, rifampin, mitotanetarget drugs are CYP3A substrates. Concurrent administration may result in decreased concentrations of target drug and may decrease virologic response    concurrent use is contraindicated.Concurrent use with moderate CYP3A inducers is not recommended.Contraindicated
 strong CYP3A inhibitors (eg., cobicistat, cyclosporine, ritonavir, saquinavir, tipranavir)target drugs are CYP3A substrates. Concurrent use may increase plasma concentrations of elbasvir resulting in adverse effectsconcurrent use is contraindicatedcontraindicated
 OATP1B1 and OATP1B1/3 inhibitors (eg., asciminib, atazanavir, darunavir, elexacaftor, enasidenib, encorafenib, fostemsavir, gemfibrozil, leniolisib, lopinavir, midostaurin, velpatasvir, teriflunomide, tipranavir, trofinetide, voclosporingrazoprevir is a substrate of OATP1B1/3. Concurrent use may result in increased grazoprevir exposureconcurrent use is contraindicatedcontraindicated
 tacrolimustacrolimus concentrations may increase when used concurrently due to changes in liver function while on target drugfrequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse eventsmoderate
glecaprevir/pibrentasviratazanavirincreased risk of ALT elevationscoadministration of drugs is contraindicatedcontraindicated
 carbamazepinecarbamazepine is a CYP3A4 and P-gp inducer. Concurrent use may lead to decreased efficacy of target drugcoadministration is not recommendedmajor
 colchicinerisk of increased colchicine exposure in patients with renal or hepatic impairmentconcurrent use is contraindicated for patients with renal or hepatic impairment and/ or use of colchicine for cardiovascular risk reductioncontraindicated in patients with renal or hepatic impairment and/ or using colchicine for cardiovascular risk reduction
 cyclosporinecyclosporine inhibits CYP3A4, P-gp, OATP1B1, and BCRP, and it is a substrate of P-gp. Concurrent use may increase serum concentrations of target drug, and it may increase serum concentrations of cyclosporinedo not exceed 100 mg of cyclosporine dailymajor
 dabigatrandabigatran is a P-gp substrate. Concurrent use may result in increased serum concentrations of dabigatran.monitor for increased adverse effects associated with dabigatran. Concurrent use is not recommended when dabigatran is used for treatment or risk reduction of DVT, PE following hip replacement and CrCl less than 50 mL/min. concurrent use is not recommended in patients with non-valvular atrial fibrillation and severe renal impairmentmoderate
 darunavirdarunavir is a CYP3A4 inhibitor. Concurrent use may increase serum concentrations of target drug and increase the risk of adverse effectsconcurrent use is not recommendedmajor
 digoxindigoxin is a substrate of P-gp. Concurrent use may result in increased serum concentrations of digoxinmeasure serum digoxin prior to initiating target drug; reduce digoxin concentrations by decreasing dose by 50% or by modifying dosing frequencymajor
 efavirenzefavirenz is a CYP3A4 inducer. Concurrent use may decrease concentrations of target drug and decrease therapeutic effect of target drugconcurrent use is not recommendedmajor
 elagolixelagolix is a substrate of CYP3A, P-gp, and OATP1B1. Glecaprevir inhibits P-gp and OATP1B1concurrent use is contraindicatedcontraindicated
 ethinyl estradiol containing productsconcurrent administration may result in increased risk of ethinyl estradiol associated ALT elevationsconcurrent use with products containing more than 20 mcg of ethinyl estradiol is not recommendedmajor
 lopinavir; ritonavirlopinavir inhibits OATP1B1. Ritonavir inhibits CYP3A4 and P-gp. Concurrent use may increase serum concentrations of target drug and ritonavirconcurrent use is not recommendedmajor
 rifampinglecaprevir is a substrate for CYP3A4 and P-glycoprotein (P-gp). Rifampin is a CYP3A4 and P-gp inducer. Coadministration decreases plasma concentrations of glecaprevir by 88%concurrent use is contraindicatedcontraindicated
     statin therapy (atorvastatin, fluvastatin, lovastatin, pitavastatin. pravastatin, rosuvastatin, simvastatin)increased risk of myopathy and rhabdomyolysisconcurrent use is not recommended for atorvastatin, lovastatin, and simvastatin. Decrease pravastatin dose by 50%. Do not exceed 10 mg daily of rosuvastatin, and use the lowest effective dose of fluvastatin or pitavastatin    major
ledipasvir/sofosbuvir amiodaroneconcurrent use may result in serious symptomatic bradycardiaconcurrent administration is not recommended. If it is required cardiac monitoring is recommendedmajor
 antacids (eg., aluminum and magnesium hydroxide)concurrent use may decrease concentrations of target drug as solubility decreases as pH increasesseparate administrations by at least 4 hoursmoderate
 carbamazepine, phenytoin, phenobarbitalconcurrent use may decrease concentrations of target drug resulting in decreased therapeutic effectcoadministration is not recommendedmajor
 colchicinecolchicine is a P-gp substrate and ledipasvir is a P-gp inhibitorconcurrent use is contraindicated in patients with renal or hepatic impairment and/ or using colchicine for cardiovascular risk reductioncontraindicated in patients with renal or hepatic impairment and/ or using colchicine for cardiovascular risk reduction
 digoxincoadministration may result in increased digoxin concentrationstherapeutic concentration monitoring of digoxin is recommended if used concurrentlymoderate
 H2-receptor antagonistsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesmay be administered simultaneously or 12 hours apart with a dose that does not exceed doses comparable to famotidine 40 mg twice dailymajor
 HIV antiretroviral therapy containing tenofovir DF without HIV protease inhibitor/ritonavir or cobicistatmay increase serum concentrations of tenofovirmonitor for tenofovir related adverse reactionsmoderate
 HIV antiretroviral therapy containing tenofovir DF with HIV protease inhibitor/ritonavir or cobicistatmay increase serum concentrations of tenofovirconsider alternate HCV or antiretroviral therapy. If use is necessary, monitor for tenofovir associated adverse effectsmoderate
 proton pump inhibitorsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesmay administered at the same time under fasting conditions at a maximum dose comparable to omeprazole 20 mgmajor
 rifabutin, rifampin, rifapentineconcurrent use may decrease serum concentrations of target drugconcurrent use is not recommendedmajor
 statin therapy (atorvastatin, rosuvastatin)concurrent use may increase risk of myopathy and rhabdomyolysisconcurrent use with rosuvastatin is not recommended. Monitor for statin related adverse reactions if atorvastatin is usedmajor
 tipranavir/ritonavirconcurrent use may decrease serum concentrations of target drugconcurrent use is not recommendedmajor
sofosbuvir/velpatasviramiodaroneconcurrent use may result in serious symptomatic bradycardiaconcurrent administration is not recommended. If it is required cardiac monitoring is recommendedmajor
 antacids (e.g., aluminum and magnesium hydroxide)concurrent use may decrease concentrations of target drug as solubility decreases as pH increasesseparate administration by at least 4 hoursmoderate
 carbamazepine, phenytoin, phenobarbitalconcurrent use may decrease concentrations of target drug resulting in decreased therapeutic effectcoadministration is not recommendedmajor
 colchicinecolchicine is a P-gp substrate and velpatasvir is a P-gp inhibitorconcurrent use is contraindicated in patients with renal or hepatic impairment and/or using colchicine for cardiovascular risk reductioncontraindicated in patients with renal or hepatic impairment and/ or using colchicine for cardiovascular risk reduction
 digoxincoadministration may result in increased digoxin concentrationstherapeutic concentration monitoring of digoxin is recommended if used concurrentlymoderate
 efavirenzefavirenz is a CYP3A4 inducer. Concurrent use may decrease concentrations of target drug and decrease therapeutic effect of target drugconcurrent use is not recommendedmajor
 elagolixelagolix is a substrate of CYP3A, P-gp, and OATP1B1. Velpatsavir inhibits OATP1B1.concurrent use is contraindicatedcontraindicated
 H2-receptor antagonistsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesmay be administered simultaneously or 12 hours apart with a dose that does not exceed doses comparable to famotidine 40 mg twice dailymajor
 HIV antiretroviral therapy containing tenofovir DFmay increase serum concentrations of tenofovirmonitor for tenofovir related adverse reactionsmoderate
 proton pump inhibitorsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesconcurrent use is not recommended. If necessary, target drug should be taken 4 hours before omeprazole 20 mgmajor
 rifabutin, rifampin, rifapentineconcurrent use may decrease serum concentrations of target drugconcurrent use is not recommendedmajor
 statin therapy (atorvastatin, rosuvastatin)concurrent use may increase risk of myopathy and rhabdomyolysisdo not exceed 10 mg of rosuvastatin daily Monitor for statin related adverse reactions if atorvastatin is usedmajor
sofosbuvir/velpatasvir/ voxilapreviramiodaroneconcurrent use may result in serious symptomatic bradycardia.concurrent administration is not recommended. If it is required cardiac monitoring is recommendedmajor
 antacids (eg., aluminum and magnesium hydroxide)concurrent use may decrease concentrations of target drug as solubility decreases as pH increasesseparate administration by at least 4 hoursmoderate
 atazanavir, lopinavirmay increase serum concentrations of target drugcoadministration of drugs is not recommendedmajor
 carbamazepine, phenytoin, phenobarbitalconcurrent use may decrease concentrations of target drug resulting in decreased therapeutic effectcoadministration is not recommendedmajor
 cyclosporinemay increase serum concentrations of voxilaprevirconcurrent use is not recommendedmajor
 dabigatrandabigatran is a P-gp substrate. Concurrent use may result in increased serum concentrations of dabigatranmonitor for increased adverse effects associated with dabigatran.moderate
 digoxincoadministration may result in increased digoxin concentrationstherapeutic concentration monitoring of digoxin is recommended if used concurrentlymoderate
 efavirenzefavirenz is a CYP3A4 inducer. Concurrent use may decrease concentrations of target drug and decrease therapeutic effect of target drugconcurrent use is not recommendedmajor
 H2-receptor antagonistsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesmay be administered simultaneously or staggered with a dose that does not exceed doses comparable to famotidine 40 mg twice dailymajor
 HIV antiretroviral therapy containing tenofovir DFmay increase serum concentrations of tenofovirmonitor for tenofovir related adverse reactionsmoderate
 proton pump inhibitorsconcurrent use may decrease concentrations of target drug as solubility decreases as pH increasesomeprazole 20 mg may be administeredmajor
 rifampinconcurrent use may decrease serum concentrations and therapeutic effect of target drugconcurrent use is contraindicatedcontraindicated
 rifabutin, rifapentineconcurrent use may decrease serum concentrations and therapeutic effect of target drugconcurrent use is not recommendedmajor
 statin therapy (atorvastatin, fluvastatin, lovastatin, pitavastatin. pravastatin, rosuvastatin, simvastatin)increased risk of myopathy and rhabdomyolysisconcurrent use is not recommended for pitavastatin and rosuvastatin. Pravastatin should not exceed 40 mg daily. Use the lowest effective dose of atorvastatin, fluvastatin, lovastqatin, or simvastatinmajor
 tipranavir/ritonavirconcurrent use may decrease serum concentrations of target drugconcurrent use is not recommendedmajor