Boceprevir

Hepatitis C antiviral agents Boceprevir ↓ boceprevir* Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration o efavirenz with elbasvir/grazoprevir is contraindicated [see Contraindications ( 4 )] because it may lead to loss of virologic response to elbasvir/grazoprevir.

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.

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.

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.

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily • Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin should not exceed 40 mg and close clinical monitoring is recommended.

Avoid co-administering erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

Avoid co-administering erlotinib tablets with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

HCV protease inhibitor; coadministration with fosamprenavir or fosamprenavir/ritonavir is not recommended due to predicted decreases in both amprenavir and boceprevir concentrations.

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

Boceprevir 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.

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). Boceprevir: In a single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus C max by 9.9-fold and AUC by 17-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.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered.

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.

Boceprevir, 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.

Increases pravastatin exposure (↑63% AUC). Coadministration increases risk of myopathy.

Strong CYP3A4 inhibitor that may increase midostaurin concentrations and risk of toxicity. Monitor for increased adverse reactions, especially during first week of administration.

No dose adjustment recommended when coadministered with eltrombopag.

No dose adjustment recommended when coadministered with eltrombopag.

Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.

40 mg SD 1.12 2.90 Rifampin 600 mg QD , 5 days (doses separated) 40 mg SD 0.20 0.60 Gemfibrozil 600 mg BID , 7 days 40 mg SD 1.35 1.00 Fenofibrate 160 mg QD , 7 days 40 mg SD 1.03 1.02 Boceprevir 800 mg TID Three times daily , 7 days 40 mg SD 2.32 2.66 Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of Cmax 80 mg QD Once daily for 15 days Antipyrine, 600 mg SD Single dose 1.03 0.89 80 mg QD for 10 days See Section 7 for clinical significance.

Boceprevir Coadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C max of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.

Hepatitis C antiviral agents boceprevir ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with EFV, which may result in loss of therapeutic effect.

Hepatitis C antiviral agents: Boceprevir Elbasvir/Grazoprevir Pibrentasvir/Glecaprevir Simeprevir Velpatasvir/Sofosbuvir Velpatasvir/Sofosbuvir/ Voxilaprevir Ledipasvir/Sofosbuvir ↓boceprevir* ↓elbasvir ↓grazoprevir ↓pibrentasvir ↓glecaprevir ↓simeprevir* ↔EFV ↓velpatasvir ↓velpatasvir ↓voxilaprevir ↑TDF Concomitant administration of boceprevir is not recommended.

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]).

For Boceprevir, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ritonavir and saquinavir, see also Table 1.

Boceprevir (in patients with normal renal function) No Dose Adjustment Boceprevir : Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered.

Hepatitis C direct acting antivirals: boceprevir* glecaprevir/pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilapre vir ombitasvir/paritaprevir/ ritonavir and dasabuvir* ↓ lopinavir ↓ boceprevir ↓ ritonavir ↑glecaprevir ↑ pibrentasvir ↑ simeprevir ↑ sofosbuvir ↑ velpatasvir ↑ voxilaprevir ↑ ombitasvir ↑ paritaprevir ↑ ritonavir ↔ dasabuvir It is not recommended to co-administer lopinavir and ritonavir and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.

Hepatitis C Antiviral Agents Boceprevir Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.

7.2 Drugs without Clinically Significant Interactions with ISENTRESS or ISENTRESS HD ISENTRESS In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/norgestimate, methadone, midazolam, lamivudine, tenofovir disoproxil fumarate, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir. No dose adjustment is recommended when ISENTRESS HD 1200 mg once daily is coadministered with atazanavir, atazanavir/ritonavir, hormonal contraceptives, methadone, lamivudine, tenofovir disoproxil fumarate, darunavir/ritonavir, boceprevir, efavirenz and omeprazole.

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).