Telaprevir

Hepatitis C protease inhibitor that significantly increases atorvastatin AUC. Avoid concomitant use due to increased myopathy risk.

Strong CYP3A4 inhibitor. Should not be coadministered with everolimus.

Strong CYP3A4 inhibitor; co-administration with everolimus is not recommended.

] Ezetimibe and Simvastatin Tablets Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.8 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil, diltiazem, dronedarone Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Amiodarone, amlodipine, ranolazine Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets 1 Daptomycin Temporally suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1.

Strong CYP3A4 inhibitor; concomitant use is contraindicated due to increased risk of hypotension and syncope.

CYP3A4 inhibitor may increase systemic exposure to irinotecan or SN-38. Do not administer unless no therapeutic alternatives.

Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated.

Strong CYP3A4 inhibitor increases risk of myopathy by reducing lovastatin elimination.

Protease inhibitor and strong CYP3A4/P-gp inhibitor that increases sirolimus concentrations. Avoid concomitant use.

Telaprevir Decrease AUC by 92% Systemic Hormonal Contraceptives Prevention or Management Advise patients to change to non-hormonal methods of birth control during rifampin therapy Estrogens Decrease exposure Progestins Anticonvulsants Phenytoin § Decrease exposure § Antiarrhythmics Disopyramide Decrease exposure Mexiletine Decrease exposure Quinidine Decrease exposure Propafenone Decrease AUC by 50% to 67% Tocainide Decrease exposure Antiestrogens Tamoxifen Decrease AUC by 86% Toremifene Decrease steady state concentrations of toremifene in serum Antithrombotic Agents Clopidogrel Prevention or Management Concomitant use of clopidogrel and rifampin should be discouraged Increase active metabolite exposure and risk of bleeding Ticagrelor Prevention or Management Avoid use Decrease exposure Antipsychotics Haloperidol Decrease plasma concentrations by 70% Lurasidone Prevention or Management: Concomitant use is contraindicated (See CONTRADICTIONS ) Decrease exposure Oral Anticoagulants Prevention or Management Perform prothrombin time daily or as frequently as necessary to establish and maintain the required dose of anticoagulant Warfarin Decrease exposure Antifungals Fluconazole Decrease AUC by 23% Itraconazole Prevention or Management Not recommended 2 weeks before and during itraconazole treatment Decrease exposure Ketoconazole Decrease exposure Beta-blockers Metoprolol Decrease exposure Propranolol Decrease exposure Benzodiazepines Diazepam *,¶ Decrease exposure Benzodiazepine-Related Drugs Zopiclone Decrease AUC by 82% Zolpidem Decrease AUC by 73% Calcium Channel Blockers ¶ Diltiazem Decrease exposure Nifedipine # Decrease exposure Verapamil Decrease exposure Corticosteroids Þ Prednisolone Decrease exposure Cardiac Glycosides Digoxin Prevention or Management Measure serum digoxin concentrations before initiating rifampin.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.

Strong CYP3A inhibitor; concomitant use not recommended due to increased suvorexant exposure.

Increases digoxin serum concentration by 50% and AUC by 85%. Requires monitoring and dose reduction.

Strong CYP3A4 inhibitor that significantly increases nimodipine plasma concentration and blood pressure lowering effect. Concomitant administration should generally be avoided.

Telaprevir decreases plasma concentrations of estrogen and progestin, potentially reducing contraceptive effectiveness.

HCV protease inhibitor that may significantly decrease plasma concentrations of norethindrone and ethinyl estradiol, potentially diminishing contraceptive effectiveness.

HCV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin, potentially reducing contraceptive effectiveness.

Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole).

Strong CYP3A Inhibitors 3 : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). Telaprevir: In a single-dose study in 9 healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized C max by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)] .

Strong CYP3A Inhibitors : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS.

HCV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin, potentially diminishing contraceptive effectiveness.

HCV protease inhibitor that may decrease plasma concentrations of etonogestrel.

Potent CYP3A4 inhibitor that may increase itraconazole bioavailability. Monitor for increased itraconazole exposure.

Telaprevir, an HCV protease inhibitor, may significantly decrease plasma concentrations of estrogen and/or progestin.

HCV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin.

HCV protease inhibitor that may decrease plasma concentrations of estrogen and/or progestin.

Significant decrease in systemic concentrations of norethindrone may occur.

Strong CYP3A inhibitor that increases paricalcitol exposure. Dose adjustment may be necessary; monitor iPTH and serum calcium.

No dose adjustment recommended when coadministered with eltrombopag.

No dose adjustment recommended when coadministered with eltrombopag.

Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD Once daily for 28 days 8.69 10.66 Tipranavir 500 mg BID Twice daily /ritonavir 200 mg BID , 7 days 10 mg SD Single dose 9.36 8.58 Glecaprevir 400 mg QD /pibrentasvir 120 mg QD , 7 days 10 mg QD for 7 days 8.28 22.00 Telaprevir 750 mg q8h Every 8 hours , 10 days 20 mg SD 7.88 10.60 , The dose of saquinavir plus ritonavir in this study is not the clinically used dose.

Telaprevir Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and C max of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and non­-nucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).

Paradoxical Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone.

Paradoxical Effects of Anti-Retroviral Agents on Methadone Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone.

Telaprevir Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.

Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors : Significant decreases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (eg, boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine).