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Boceprevir

Pronunciation

(boe SE pre vir)

Index Terms

  • SCH503034

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Victrelis: 200 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Brand Names: U.S.

  • Victrelis [DSC]

Pharmacologic Category

  • Antihepaciviral, Protease Inhibitor (Anti-HCV)
  • NS3/4A Inhibitor

Pharmacology

Binds reversibly to nonstructural protein 3 (NS 3) serine protease and inhibits replication of the hepatitis C virus. Considered a direct-acting antiviral treatment for HCV, also called a specifically targeted antiviral therapy for HCV (STAT-C).

Absorption

Food (type or timing is not important) enhances absorption by up to 65%

Distribution

Vd: ~772 L

Metabolism

Primarily hepatic via aldo-ketoreductase pathway to inactive metabolites; also some oxidative CYP 3A4/5 metabolism

Excretion

Feces (79%); urine (9%)

Time to Peak

Serum: 2 hours

Half-Life Elimination

Plasma: Adults: ~3.4 hours

Protein Binding

~75%

Special Populations: Renal Function Impairment

Mean AUC of boceprevir was 10% lower in subjects with ESRD requiring hemodialysis relative to subjects with healthy renal function. Hemodialysis removed less than 1% of the boceprevir dose.

Special Populations: Hepatic Function Impairment

Mean AUC of the active metabolite was 32% and 45% higher in subjects with moderate and severe hepatic impairment, respectively, relative to subjects with healthy hepatic function. Mean Cmax values were 28% and 62% higher in subjects with moderate and severe hepatic impairment, respectively. Subjects with mild hepatic impairment had similar exposure as subjects with healthy hepatic function.

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C (CHC) genotype 1 (in combination with peginterferon alfa and ribavirin) in adult patients with compensated liver disease (including cirrhosis) who were previously untreated or have failed prior therapy with peginterferon alfa and ribavirin therapy including prior null responders, partial responders, and relapsers

Contraindications

Hypersensitivity to boceprevir or any component of the formulation; pregnancy; male partners of pregnant women

Coadministration with CYP3A4/5 highly-dependent substrates (alfuzosin, cisapride, doxazosin, drospirenone, ergot derivatives [dihydroergotamine, ergonovine, ergotamine, methylergonovine], lovastatin, midazolam [oral], pimozide, sildenafil/tadalafil [when used for treatment of pulmonary arterial hypertension], silodosin, simvastatin, tamsulosin, triazolam) or strong CYP3A4/5 inducers (carbamazepine, phenobarbital, phenytoin, rifampin, St John’s wort)

Refer to Peginterferon Alfa and Ribavirin monographs for individual product contraindications.

Canadian labeling: Additional contraindications (not in U.S. labeling): Autoimmune hepatitis, hepatic decompensation (Child-Pugh class B or C); coadministration with amiodarone, astemizole, propafenone, quinidine, terfenadine

Dosing: Adult

Note: Victrelis is no longer available in the US.

Treatment of chronic hepatitis C (CHC): Oral: 800 mg 3 times daily (in combination with peginterferon alfa and ribavirin). Missed doses: If a dose is missed, skip dose if it is <2 hours before the next dose; if ≥2 hours before next dose is due, take dose with food and resume normal dosing schedule. Note: Boceprevir-containing regimens are not recommended for treatment-naive patients or for prior relapse patients nonresponsive to peginterferon/ribavirin regimens with or without an HCV protease inhibitor (AASLD/IDSA, 2014)

Treatment-naive patients without cirrhosis (interferon-responsive [≥1-log10 HCV-RNA decline in viral load] at week 4):

Weeks 1 to 4: Peginterferon alfa with concomitant ribavirin only

Weeks 5 to 8: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

Weeks 9 to 24 (based on HCV-RNA results at week 8):

HCV-RNA undetectable or detectable at a level of <100 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

HCV-RNA ≥100 units/mL but <1,000 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin. Recheck HCV-RNA at week 12. If HCV-RNA ≥100 units/mL at week 12, discontinue treatment (boceprevir, peginterferon alfa, and ribavirin).

HCV-RNA ≥1,000 units/mL: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Weeks ≥24:

HCV-RNA undetectable at week 8 and week 24: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 4 additional weeks (through week 28)

HCV-RNA detectable (≥100 units/mL but <1,000 units/mL) at week 8 and undetectable at week 24:

U.S. labeling: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 12 additional weeks (through week 36), followed by peginterferon alfa and ribavirin for additional 12 weeks (through week 48)

Canadian labeling: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 4 additional weeks (through week 28), followed by peginterferon alfa and ribavirin for additional 20 weeks (through week 48)

HCV-RNA detectable at week 24: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Treatment-naive patients (interferon nonresponsive [<0.5-log10 HCV-RNA decline in viral load] at week 4): Note: Manufacturer also recommends consideration of treatment of poor responders [<1-log10 HCV-RNA decline in viral load at week 4] in order to maximize rate of sustained virologic response (SVR):

Weeks 1 to 4: Peginterferon alfa with concomitant ribavirin only

Weeks 5 to 48: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

Previously-treated patients without cirrhosis (partial response or relapser): Note: Previously treated does not include prior treatment with boceprevir. "Partial response" includes patients with a ≥2-log10 HCV-RNA decrease by week 12, but a nonsustained virologic response thereafter. "Relapser" includes patients with an undetectable HCV-RNA upon completion of previous treatment, but with detectable HCV-RNA during the follow-up period.

Weeks 1 to 4: Peginterferon alfa with concomitant ribavirin only

Weeks 5 to 8: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

Weeks 9 to 24 (based on HCV-RNA results at week 8):

HCV-RNA undetectable or <100 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

HCV-RNA ≥100 units/mL but <1,000 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin. Recheck HCV-RNA at week 12. If HCV-RNA ≥100 units/mL at week 12, discontinue treatment (boceprevir, peginterferon alfa, and ribavirin).

HCV-RNA ≥1,000 units/mL: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Weeks ≥24:

HCV-RNA undetectable at week 8 and week 24: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 12 additional weeks (through week 36)

HCV-RNA detectable (≥100 units/mL but <1,000 units/mL) at week 8 and undetectable at week 24: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 12 additional weeks (through week 36), followed by peginterferon alfa and ribavirin for additional 12 weeks (through week 48)

HCV-RNA detectable at week 24: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Previously treated patients with <2-log10 HCV-RNA decline by week 12 (prior null responders):

Weeks 1 to 4: Peginterferon alfa with concomitant ribavirin only

Weeks 5 to 8: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

Weeks 9 to 24 (based on HCV-RNA results at week 8):

HCV-RNA undetectable or <100 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

HCV-RNA ≥100 units/mL but <1,000 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin. Recheck HCV-RNA at week 12. If HCV-RNA ≥100 units/mL at week 12, discontinue treatment (boceprevir, peginterferon alfa, and ribavirin).

HCV-RNA ≥1,000 units/mL: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Weeks ≥24:

HCV-RNA undetectable at week 24: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 24 additional weeks (through week 48)

HCV-RNA detectable at week 24: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Cirrhosis, compensated:

Weeks 1 to 4: Peginterferon alfa with concomitant ribavirin only

Weeks 5 to 8: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

Weeks 9 to 24 (based on HCV-RNA results at week 8):

HCV-RNA undetectable or <100 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin

HCV-RNA ≥100 units/mL but <1,000 units/mL: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin. Recheck HCV-RNA at week 12. If HCV-RNA ≥100 units/mL at week 12, discontinue treatment (boceprevir, peginterferon alfa, and ribavirin).

HCV-RNA ≥1,000 units/mL: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Weeks ≥24:

HCV-RNA undetectable at week 24: Boceprevir 800 mg 3 times daily with continued peginterferon alfa and ribavirin for 24 additional weeks (through week 48)

HCV-RNA detectable at week 24: Discontinue treatment (boceprevir, peginterferon alfa, and ribavirin)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild-to-severe impairment: No dosage adjustment necessary.

ESRD requiring hemodialysis: No dosage adjustment necessary. Not removed by hemodialysis.

Dosing: Hepatic Impairment

Mild, moderate, or severe impairment: No dosage adjustment necessary.

Compensated cirrhosis: Consider risks and benefits before initiating therapy in patients with compensated cirrhosis who have platelet count less than 100,000/mm3 and serum albumin less than 3.5 g/dL at baseline. Monitor closely for signs of infection and worsening of liver function. Also refer to Peginterferon Alfa and Ribavirin individual monographs.

Decompensated cirrhosis: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied); not approved for use in decompensated cirrhosis (safety/efficacy not established). Also refer to Peginterferon Alfa and Ribavirin individual monographs.

Administration

Administer with food (a meal or light snack). Doses should be taken approximately every 7-9 hours. Administer concurrently with peginterferon alfa and ribavirin.

Dietary Considerations

Take with food. The type or timing of a meal is not important as long as dose is taken with food.

Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F). After dispensing, may be stored at room temperature of up to 25°C (77°F ) for 3 months; keep container closed tightly; avoid excessive heat.

Drug Interactions

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Boceprevir may increase the serum concentration of ALPRAZolam. Management: In patients receiving boceprevir, consider lower alprazolam doses and monitor closely for symptoms of toxicity (including prolonged sedation and respiratory depression). Consider therapy modification

Amiodarone: Boceprevir may increase the serum concentration of Amiodarone. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Astemizole: Boceprevir may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Boceprevir may increase the serum concentration of AtorvaSTATin. Management: Limit the atorvastatin maximum adult dose to 40 mg daily in patients receiving boceprevir. Monitor clinical response to ensure that the lowest necessary atorvastatin dose is used. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Bepridil: Boceprevir may increase the serum concentration of Bepridil. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosentan: May decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Bosentan. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Buprenorphine: Boceprevir may decrease the serum concentration of Buprenorphine. Boceprevir may increase the serum concentration of Buprenorphine. Monitor therapy

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Boceprevir. Avoid combination

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cisapride: Boceprevir may increase the serum concentration of Cisapride. Avoid combination

Clarithromycin: May increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Clarithromycin. Monitor therapy

CloZAPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of Boceprevir. Management: Avoid concomitant use of boceprevir with cobicistat. US prescribing information for the combination product containing elvitegravir, cobicistat, emtricitabine, and tenofovir does not address this potential interaction. Avoid combination

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Contraceptives (Estrogens): Boceprevir may decrease the serum concentration of Contraceptives (Estrogens). Management: Patients receiving boceprevir, ribavirin, and peginterferon alfa should use two reliable forms of contraception. Norethindrone/ethinyl estradiol may be used for one of these when norethindrone dose is at least 1 mg/day. Consider therapy modification

Contraceptives (Progestins): Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with norethindrone. Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with drospirenone. Management: Patients receiving boceprevir, ribavirin, and peginterferon alfa should use two reliable forms of contraception. Norethindrone/ethinyl estradiol may be used for one of these when norethindrone dose is at least 1 mg/day. Avoid drospirenone. Consider therapy modification

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of CycloSPORINE (Systemic). Management: Cyclosporine dose adjustments will likely be necessary when used together with boceprevir. Monitor serum cyclosporine concentrations closely, and monitor patients for evidence of cyclosporine toxicity. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Boceprevir. Avoid combination

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Buprenorphine; Gefitinib; HYDROcodone; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Desipramine: Boceprevir may increase the serum concentration of Desipramine. Management: Consider lower doses of desipramine in patients treated with boceprevir and monitor for symptoms of desipramine toxicity (including dizziness, hypotension and syncope), due to a possible increase in desipramine concentrations. Consider therapy modification

Digoxin: Boceprevir may increase the serum concentration of Digoxin. Management: In patients initiating digoxin during boceprevir treatment, initiate at the lowest possible digoxin dose, monitor serum digoxin concentrations, and titrate carefully due to a possible risk of elevated digoxin concentrations. Consider therapy modification

Dihydroergotamine: Boceprevir may increase the serum concentration of Dihydroergotamine. Avoid combination

Dofetilide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxazosin: Boceprevir may increase the serum concentration of Doxazosin. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Drospirenone: Boceprevir may increase the serum concentration of Drospirenone. Avoid combination

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Efavirenz: May decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Efavirenz. Avoid combination

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergoloid Mesylates: Boceprevir may increase the serum concentration of Ergoloid Mesylates. Avoid combination

Ergonovine: Boceprevir may increase the serum concentration of Ergonovine. Avoid combination

Ergotamine: Boceprevir may increase the serum concentration of Ergotamine. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Escitalopram: Boceprevir may decrease the serum concentration of Escitalopram. Monitor therapy

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Etravirine: Boceprevir may decrease the serum concentration of Etravirine. Avoid combination

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Flecainide: Boceprevir may increase the serum concentration of Flecainide. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fluvastatin: Boceprevir may increase the serum concentration of Fluvastatin. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Boceprevir. Avoid combination

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when starting this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib. Monitor therapy

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Itraconazole: May increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Itraconazole. Management: Limit maximum adult itraconazole dose to 200 mg daily in patients receiving boceprevir, due to a possible increase in itraconazole concentrations. Consider therapy modification

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Ketoconazole (Systemic): May increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit maximum adult ketoconazole dose to 200 mg daily in patients receiving boceprevir, due to a possible increase in ketoconazole concentrations. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lovastatin: Boceprevir may increase the serum concentration of Lovastatin. Avoid combination

Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

Methadone: Boceprevir may increase the serum concentration of Methadone. Boceprevir may decrease the serum concentration of Methadone. Monitor therapy

Methylergonovine: Boceprevir may increase the serum concentration of Methylergonovine. Avoid combination

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Midazolam: Boceprevir may increase the serum concentration of Midazolam. Avoid combination

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 300 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Osimertinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osimertinib. Avoid combination

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PAZOPanib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Boceprevir. Avoid combination

Phenytoin: May decrease the serum concentration of Boceprevir. Avoid combination

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Boceprevir may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: Boceprevir may increase the serum concentration of Pitavastatin. Monitor therapy

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Posaconazole: May increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Posaconazole. Monitor therapy

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Pravastatin: Boceprevir may increase the serum concentration of Pravastatin. Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy

PrednisoLONE (Systemic): Boceprevir may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: Boceprevir may increase the serum concentration of PredniSONE. Monitor therapy

Primidone: May decrease the serum concentration of Boceprevir. Avoid combination

Propafenone: Boceprevir may increase the serum concentration of Propafenone. Monitor therapy

Protease Inhibitors: Boceprevir may decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Boceprevir. Management: Some combinations are not recommended. See full drug interaction monograph for details. Consider therapy modification

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce the quetiapine dose to one sixth of the regular dose following strong CYP3A4 inhibitor initiation. In patients receiving strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and up-titrate as needed. Consider therapy modification

QuiNIDine: Boceprevir may increase the serum concentration of QuiNIDine. Monitor therapy

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Rifabutin: May decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Rifabutin. Avoid combination

RifAMPin: May decrease the serum concentration of Boceprevir. Avoid combination

Rilpivirine: Boceprevir may increase the serum concentration of Rilpivirine. Monitor therapy

Ritonavir: May decrease the serum concentration of Boceprevir. Boceprevir may decrease the serum concentration of Ritonavir. Monitor therapy

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Rosuvastatin: Boceprevir may increase the serum concentration of Rosuvastatin. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Sildenafil: Boceprevir may increase the serum concentration of Sildenafil. Management: Avoid sildenafil when used for treatment of pulmonary arterial hypertension in patients receiving boceprevir. Sildenafil for erectile dysfunction should be limited to 25 mg every other day with close monitoring for sildenafil toxicity. Avoid combination

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: Boceprevir may increase the serum concentration of Simvastatin. Avoid combination

Sirolimus: Boceprevir may increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions may be required if used with boceprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of Boceprevir. Avoid combination

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Boceprevir may increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus doses will need to be substantially reduced, and the tacrolimus dosing interval will likely need to be prolonged with concurrent boceprevir. Follow tacrolimus concentrations closely and monitor patients for evidence of tacrolimus toxicity. Consider therapy modification

Tadalafil: Boceprevir may increase the serum concentration of Tadalafil. Management: Avoid tadalafil when used for treatment of pulmonary arterial hypertension in patients receiving boceprevir. Tadalafil for erectile dysfunction should be limited to 10 mg every 72 hours with close monitoring for tadalafil toxicity. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Telithromycin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin. Monitor therapy

Terfenadine: Boceprevir may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Tipranavir: May decrease the serum concentration of Boceprevir. Boceprevir may decrease the serum concentration of Tipranavir. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

TraZODone: Boceprevir may increase the serum concentration of TraZODone. Monitor therapy

Triazolam: Boceprevir may increase the serum concentration of Triazolam. Avoid combination

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Vardenafil: Boceprevir may increase the serum concentration of Vardenafil. Management: Limit vardenafil maximum dose to 2.5 mg every 24 hours and monitor closely for symptoms of vardenafil toxicity (including hypotension, visual changes, syncope, and priapism) during treatment with boceprevir. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Voriconazole: Boceprevir may increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Boceprevir. Monitor therapy

Warfarin: Boceprevir may decrease the serum concentration of Warfarin. Boceprevir may increase the serum concentration of Warfarin. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Adverse Reactions

Frequency not always defined.

>10%:

Central nervous system: Fatigue (55% to 58%), chills (33% to 34%), insomnia (30% to 34%), irritability (21% to 22%), dizziness (16% to 19%), headache

Dermatologic: Alopecia (22% to 27%), xeroderma (18% to 22%), skin rash (16% to 17%)

Gastrointestinal: Nausea (43% to 46%), dysgeusia (35% to 44%), decreased appetite (25% to 26%), diarrhea (24% to 25%), vomiting (15% to 20%), xerostomia (11% to 15%)

Hematologic & oncologic: Anemia (45% to 50%), neutropenia (14% to 31%)

Neuromuscular & skeletal: Arthralgia (19% to 23%), weakness (15% to 21%)

Respiratory: Dyspnea (8% to 11%)

1% to 10%: Hematologic & oncologic: Thrombocytopenia

<1% (Limited to important or life-threatening): Agranulocytosis, angioedema, DRESS syndrome, exfoliative dermatitis, oral mucosa ulcer, pancytopenia, pneumonia, sepsis, skin toxicity, Stevens-Johnson syndrome, stomatitis, thromboembolism, toxoderma, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Anemia: Has been reported with peginterferon alfa and ribavirin; addition of boceprevir is associated with further hemoglobin decreases. With anemia management, average hemoglobin decrease in clinical trials was ~1 g/dL with a median time to onset of 71 days. Dose modifications of peginterferon alfa and ribavirin were needed more often in patients also taking boceprevir. Complete blood counts with differential should be obtained pretreatment and at weeks 2, 4, 8, and 12, as well as other times during treatment. Dose reduction of ribavirin therapy is recommended for the initial management of anemia if hemoglobin <10 g/dL; permanent discontinuation of ribavirin treatment is recommended if hemoglobin <8.5 g/dL. If ribavirin is permanently discontinued, boceprevir and peginterferon alfa must also be discontinued. In clinical trials comparing erythropoiesis-stimulating agents (ESAs) to ribavirin dose reduction for initial management of anemia during combination therapy, an increased risk of thromboembolic events were observed in patients receiving an ESA compared to the ribavirin dose reduction group.

• Hypersensitivity: Serious acute hypersensitivity reactions (eg, angioedema, urticaria) have been reported with boceprevir, peginterferon alfa, and ribavirin combination therapy. Discontinuation of combination therapy and institution of supportive measures may be necessary.

• Neutropenia: Has been reported with peginterferon alfa and ribavirin; addition of boceprevir is associated with a higher incidence of neutropenia. Complete blood counts with differential should be obtained pretreatment and at weeks 2, 4, 8, and 12, as well as other times during treatment. May require dose reduction of peginterferon or ribavirin therapy. May be severe or life-threatening (rare); discontinuation of therapy may be necessary. If ribavirin and peginterferon alfa are permanently discontinued, boceprevir must also be discontinued.

• Pancytopenia: Serious cases have been reported in patients receiving boceprevir in combination with peginterferon alfa and ribavirin. Complete blood counts with differential should be obtained at pretreatment, and at weeks 2, 4, 8, and 12, as well as other time points during treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: Combination therapy with ribavirin and interferons may cause birth defects; avoid pregnancy in females and female partners of male patients during therapy and for 6 months following treatment; two forms of effective contraception should be used. Combination therapy with ribavirin and peginterferon alfa-2a is contraindicated in pregnancy.

Other warnings/precautions:

• Appropriate use: Should only be used in combination with peginterferon alfa and ribavirin (do not use as monotherapy). Safety and efficacy have not been established in patients who have received organ transplants or have decompensated cirrhosis. Efficacy has not been studied in patients who previously failed boceprevir therapy or therapy including another NS3/4A protease inhibitor for hepatitis C treatment.

• Poor responders: Patients who have less than 0.5-log10 HCV-RNA decline at treatment week 4 with peginterferon alfa and ribavirin when initiating boceprevir therapy are predicted to have less than a 2-log10 HCV-RNA decline by treatment week 12. Those poor responders treated with boceprevir will likely not have a sustained virologic response (SVR) and have a predisposition to viral resistance at treatment failure.

Monitoring Parameters

CBC with differential and platelet count at baseline and at weeks 2, 4, 8 and 12, then periodically (and when clinically indicated)

Baseline serum albumin (patients with compensated cirrhosis)

Serum HCV RNA at baseline, weeks 4, 8, 12 and 24, end of treatment, during treatment follow up, and when clinically indicated

Pretreatment and monthly pregnancy test up to 6 months following discontinuation of therapy for women of childbearing age

Signs of infection and worsening of liver function (especially in compensated cirrhosis)

Pregnancy Risk Factor

B / X (in combination with ribavirin and peginterferon alfa)

Pregnancy Considerations

Adverse events were not observed with boceprevir in animal reproduction studies; however, boceprevir must not be used as monotherapy (must be used in combination with peginterferon alfa and ribavirin). Adverse events have been observed with ribavirin and interferons (specific studies with peginterferon alfa-2a have not been conducted) in animal reproduction studies. Use of ribavirin in combination with peginterferon alfa-2a is contraindicated in pregnant women and males whose female partners are pregnant. A negative pregnancy test is required before initiation of therapy and pregnancy testing should be conducted monthly during treatment and for 6 months after therapy has ended. Women of childbearing potential and males must use at least 2 effective forms of contraception during treatment and continue contraceptive measures for at least 6 months after completion of therapy. One of the two forms of effective contraception may be a combined oral contraceptive product with at least 1 mg of norethindrone; oral contraceptives with <1 mg of norethindrone and other forms of hormonal contraception are contraindicated because they have not been studied. If patient or female partner becomes pregnant during treatment, she should be counseled about potential risks of exposure. Health care providers and patients are encouraged to enroll women exposed to ribavirin during pregnancy or within 6 months after treatment in the Ribavirin Pregnancy Registry (800-593-2214).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, change in taste, hair loss, diarrhea, lack of appetite, dry mouth, dry skin, joint pain, nausea, vomiting, or insomnia. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), severe loss of strength and energy, pale skin, severe dizziness, passing out, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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