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©2013 UpToDate ® Print Email Major drug interactions with protease inhibitors for treatment of chronic hepatitis C virus (genotype 1)*: Boceprevir Interacting class Sample agents Effect Management suggestions Boceprevir is partly metabolized by CYP3A4/5. Co-administration of drugs that are strong inducers of CYP3A are known to REDUCE boceprevir serum concentrations and should be avoided whenever possible. Anticonvulsants Carbamazepine Δ , fosphenytoin, oxcarbazepine, pentobarbital, phenobarbital Δ , phenytoin Δ , primidone Reduced boceprevir serum concentrations. Risk of HCV resistance and treatment failure. Co-administration of boceprevir with these agents is contraindicated or not recommended according to the US prescribing information for boceprevir and/or the interacting drug. Consider substituting non-interacting agents. Note that metabolic effects may persist for weeks following discontinuation of a strong inducer. Anti-infectives Nafcillin, rifampin Δ , rifabutin, rifapentine, certain HIV antiretrovirals ◊ Other Bosentan, dexamethasone, St. John's wort Δ Boceprevir is a potent inhibitor of CYP3A4/5. Boceprevir may increase systemic exposure of a large number of drugs dependent on CYP3A clearance. The following is NOT a complete list of all potential interactions. See Lexi-Interact™ program included with UpToDate to check for additional boceprevir interactions. Analgesic Opioid Buprenorphine, methadone Variable effect reported (increased or decreased exposure). Monitor opioid effect. No specific dose adjustment recommended. Fentanyl, oxycodone Increased opioid concentration and effects possible. Anti-infectives Antibiotics, macrolide Clarithromycin, erythromycin, telithromycin Increased serum concentrations of macrolide antibiotics. Risk of QTc prolongation and potential cardiotoxicity. Consider substituting a non-interacting antibiotic such as azithromycin. Antifungals, triazole (systemic) Itraconazole, ketoconazole, posaconazole, voriconazole Serum concentrations of boceprevir and azole anti-fungals may be elevated. Risk of QTc prolongation and potential cardiotoxicity. If concurrent treatment required, monitor for toxicity including QTc interval prolongation. Itraconazole and ketoconazole doses greater than 200 mg per day should be avoided. Anti-malarials Halofantrine, lumefantrine, quinine, quinidine Anti-malarial toxicity including cinchonism (quinine and quinidine), QTc prolongation and risk of cardiotoxicity.

If concurrent treatment required, monitor for toxicity including QTc interval prolongation. Itraconazole and ketoconazole doses greater than 200 mg per day should be avoided. Anti-malarials Halofantrine, lumefantrine, quinine, quinidine Anti-malarial toxicity including cinchonism (quinine and quinidine), QTc prolongation and risk of cardiotoxicity. Avoid co-administration of boceprevir with these anti-malarial drugs if possible. HIV antiretrovirals ◊ Protease inhibitors, non-nucleoside reverse transcriptase inhibitors and tenofovir Interactions between HIV antiretrovirals and boceprevir can result in viral resistance and therapeutic failure. These interactions are discussed separately. For additional information, refer to topic Treatment of hepatitis C virus infection in the HIV-infected patient. Early consultation with HIV/HCV infectious diseases specialist is recommended. Antineoplastic Docetaxel, crizotinib Δ , doxorubicin, gefitinib, imatinib, paclitaxel, pazopanib, sunitinib Increased serum concentration of antineoplastic and risk of toxicity. Closely monitor antineoplastic effects and adjust dose as needed. Avoid crizotinib. Cardiovascular Anticoagulants, orally active § Apixaban Δ , dabigatran, rivaroxaban Δ , warfarin Boceprevir has the potential to increase the risk of bleeding when used with rivaroxaban or apixaban. A significant interaction with dabigatran is not anticipated. However, clinical data are unavailable. Variable anticoagulant effects have been associated with co-administration of boceprevir and warfarin. Concurrent treatment with rivaroxaban is contraindicated. According to the licensed product information in some countries, avoidance of apixaban or dose reduction is recommended. Avoid dabigatran in patients with renal insufficiency (CrCl <30 mL/minute). Warfarin may be preferred due to the availability of international normalized ratio (INR) monitoring. § Close INR monitoring and warfarin dose adjustment may be needed until INR is stabilized. Antiarrhythmics Amiodarone, bepridil, digoxin, dronedarone, flecainide, lidocaine (systemic), propafenone, quinidine Elevated risk of cardiotoxicity including hypotension and arrhythmias. Close monitoring of antiarrhythmic effects suggested, including serum concentrations, if available. Dose alteration of antiarrhythmic may be necessary. Initiate digoxin at lowest dose with titration according to digoxin serum concentrations.

Amiodarone, bepridil, digoxin, dronedarone, flecainide, lidocaine (systemic), propafenone, quinidine Elevated risk of cardiotoxicity including hypotension and arrhythmias. Close monitoring of antiarrhythmic effects suggested, including serum concentrations, if available. Dose alteration of antiarrhythmic may be necessary. Initiate digoxin at lowest dose with titration according to digoxin serum concentrations. Calcium channel blockers (CCB) dihydropyridine Amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine More pronounced blood pressure lowering and/or cardiac effects due to elevated CCB concentration. If concurrent use is necessary, monitor for exaggerated CCB effects and adjust CCB dose as needed. HMG-CoA reductase inhibitors ("statins") Atorvastatin, lovastatin Δ , simvastatin Δ Increased statin concentrations and elevated risk of myopathy. Concurrent treatment with lovastatin or simvastatin is contraindicated. Limit daily dose of atorvastatin to 20 mg with boceprevir. Pravastatin and fluvastatin are less likely to interact. Gastrointestinal Antiemetic Aprepitant, fosaprepitant Increased antiemetic exposure. Monitor effect. No specific dose adjustment available. GI motility agent Cisapride Δ , domperidone Increased QTc prolongation and risk of cardiotoxicity. Concurrent treatment with cisapride is contraindicated. Monitor domperidone effect. Glucocorticoids and anti-gout Glucocorticoids (systemic) Methylprednisolone, dexamethasone Increased methylprednisolone exposure. Dexamethasone may decrease boceprevir efficacy (see strong inducers, above). Monitor methylprednisolone for increased effect. No specific dose adjustment available. For dexamethasone recommendation, see strong inducers, above. Glucocorticoids (inhaled or nasal) Budesonide, fluticasone Increased systemic exposure of inhaled/intranasal glucocorticoids. Avoid concurrent use with inhaled/intranasal budesonide or fluticasone. Beclomethasone and triamcinolone are less likely to interact. See interaction for long-acting beta agonist, salmeterol, below. Anti-gout Colchicine Increased risk of colchicine toxicity including severe diarrhea, nausea and vomiting. For patients with normal renal/hepatic function the following colchicine dose reductions are suggested: Acute gout: 0.6 mg once followed by 0.3 mg one hour later. Do not repeat before 72 hours. Gout prophylaxis: reduce dose by 50 percent; double interval

Increased risk of colchicine toxicity including severe diarrhea, nausea and vomiting. For patients with normal renal/hepatic function the following colchicine dose reductions are suggested: Acute gout: 0.6 mg once followed by 0.3 mg one hour later. Do not repeat before 72 hours. Gout prophylaxis: reduce dose by 50 percent; double interval Familial Mediterranean fever: maximum daily dose 0.6 mg Immunosuppressants Calcineurin inhibitors mTOR kinase inhibitors Cyclosporine [1] , tacrolimus [1] , everolimus, sirolimus, temsirolimus Significantly elevated serum concentrations of calcineurin inhibitors and mTOR kinase inhibitors which could lead to renal failure, cardiotoxicity, or other serious or life-threatening toxicity. Closely monitor immunosuppressant serum concentrations for signs of toxicity (eg, nephrotoxicity). Significant immunosuppressant dosage reductions may be needed. Numerous drugs taken by transplant recipients can interact with boceprevir. Drug therapy should be managed by transplant specialists with expertise in pharmacokinetic-based dose adjustment and management of high-risk drug interactions. Pulmonary arterial hypertension and urologic agents Phosphodiesterase-5 inhibitors (PDE-5) Sildenafil Δ , tadalafil Δ , vardenafil Increased risk of hypotension, syncope, visual changes, and priapism. Concurrent use of boceprevir with PDE-5 inhibitors for treatment of pulmonary arterial hypertension is contraindicated. For treatment of erectile dysfunction, dose limits are suggested: Limit sildenafil to single 25 mg dose per 48 hours Limit tadalafil to single 10 mg dose per 72 hours Limit vardenafil to single 2.5 mg dose per 24 hours Alpha-1 antagonists Alfuzosin Δ , silodosin Δ , tamsulosin Increased risk of hypotension, syncope. Concurrent use of alpha-1 antagonists with boceprevir is contraindicated. Endothelin antagonist Bosentan Toxicities due to elevated bosentan exposure may include edema, hypotension, syncope, hematologic and hepatic abnormalities. In addition, bosentan may decrease boceprevir exposure. Bosentan interacts with numerous drugs. Consider alternate non-interacting therapy. Also see CYP3A4 strong inducers section "other", above. Psychiatry, sedatives and hypnotics Antidepressants Buspirone, citalopram, desipramine, escitalopram, mirtazapine, nefazodone, trazodone, venlafaxine Increased antidepressant exposure possible. Dose alteration may be needed, but no specific guidance is available. Benzodiazepines

Bosentan interacts with numerous drugs. Consider alternate non-interacting therapy. Also see CYP3A4 strong inducers section "other", above. Psychiatry, sedatives and hypnotics Antidepressants Buspirone, citalopram, desipramine, escitalopram, mirtazapine, nefazodone, trazodone, venlafaxine Increased antidepressant exposure possible. Dose alteration may be needed, but no specific guidance is available. Benzodiazepines Alprazolam, clonazepam, diazepam, midazolam (oral Δ > parenteral), triazolam Δ Increased benzodiazepine exposure. Prolonged or excessive sedation. Oral midazolam and triazolam are contraindicated with boceprevir. Dose reduction of other benzodiazepines listed may be needed. Consider substituting a non-interacting benzodiazepine such as lorazepam, oxazepam, or temazepam. Hypnotics Eszopiclone, zolpidem, zopiclone Increased hypnotic exposure possible. Dose alteration may be needed, but no specific guidance is available. Neuroleptics (antipsychotics) Aripiprazole, haloperidol, iloperidone, pimozide Δ , quetiapine QTc prolongation and elevated risk of cardiotoxicity. Concurrent treatment with pimozide is contraindicated. A 50 percent dose reduction with iloperidone is suggested. Dose reduction of other interacting neuroleptics may be needed, but no specific recommendation is available. Contraception Estrogen/progestogen hormonal contraception Ethinyl estradiol, mestranol, desogestrel, dienogest, drospirenone Δ , ethynodiol diacetate, etonogestrel, levonorgestrel, medroxyprogesterone, norelgestromin, norethindrone, norgestimate, norgestrel Boceprevir can decrease the serum concentrations of ethinyl estradiol and alter the serum concentrations of progestogens causing failure of hormonal contraception. Women of child bearing potential should use two effective NON-hormonal methods of birth control. This is particularly important because ribavirin is teratogenic. In addition, drospirenone is contraindicated with boceprevir due to risk of hyperkalemia. Other Long-acting beta-agonist (inhaled) Salmeterol Increased systemic exposure to salmeterol. Increased risk of tachycardia and other adverse cardiovascular effects. Avoid inhaled salmeterol with boceprevir. Formoterol may be less likely to interact. Ergot derivatives Dihydroergotamine Δ , ergotamine Δ , methylergonovine Δ Increased risk of ergotism characterized by peripheral vasospasm and ischemia. Combination of these agents with boceprevir is contraindicated. Consider non-interacting alternate.

Avoid inhaled salmeterol with boceprevir. Formoterol may be less likely to interact. Ergot derivatives Dihydroergotamine Δ , ergotamine Δ , methylergonovine Δ Increased risk of ergotism characterized by peripheral vasospasm and ischemia. Combination of these agents with boceprevir is contraindicated. Consider non-interacting alternate. Vasopressin receptor antagonist Conivaptan Δ Elevated serum concentration of conivaptan. CYP: cytochrome P450; P-gp: membrane P-glycoprotein multidrug resistance transporter; HCV: hepatitis C virus (genotype 1); CCB: calcium channel blocker; mTOR inhibitor: mammalian target of rapamycin inhibitor. * For information concerning specific interaction effects, see Lexi-Interact™ drug interactions application included with UpToDate. Δ Co-administration of boceprevir with these agents is contraindicated or not recommended according to the US prescribing information for boceprevir and/or the interacting drug. ◊ Treatment of HCV in HIV infected patient is discussed elsewhere. For additional information, refer to topic Treatment of hepatitis C virus infection in the HIV-infected patient. § For additional information on interactions of novel oral anticoagulants, refer to topic Anticoagulants other than heparin and warfarin. Data from: Victrelis™ (boceprevir) US prescribing information, available at: file://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ae879ebe-b620-4829-b6f8-74b58da1c771. Lexicomp Online. Copyright © 1978-2013 Lexicomp, Inc. All Rights Reserved. Additional references: Hulskotte E, Gupta S, Xuan F et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012; 56(5):1622.