Class: Antiviral agent
- Tablets, oral 200 mg
Inhibitor of the hepatitis C virus (HCV) NS3/4A protease that is necessary for the proteolytic cleavage of the HCV-encoded polyprotein into mature forms of the NS4A, NS4B, NS5A, and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells.
Median T max is 2 hours. AUC Τ is 5,408 ng•h/mL, C max is 1,723 ng/mL, and C min is 88 ng/mL. Steady state is achieved after approximately 1 day. Food enhanced the exposure of boceprevir by up to 65%.
Vd/F is approximately 772 L and plasma protein binding is approximately 75%.
Primarily undergoes metabolism through the aldoketoreductase (AKR)–mediated pathway to ketone-reduced metabolites that are inactive against HCV; also undergoes oxidative metabolism mediated by CYP3A4/5.
Half-life is approximately 3.4 hours. Approximately 79% and 9% of the dose is excreted in feces and urine, respectively.
Special PopulationsRenal 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.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 C max 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.Elderly
Boceprevir exposure was not different across subjects 19 to 65 y of age.Children
The pharmacokinetic profile of boceprevir in pediatric patients has not been studied.
Indications and Usage
For the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Pregnant women and men whose female partners are pregnant; coadministration with drugs that are highly dependent on CYP3A4/5 for clearance (eg, alfuzosin, ergot derivatives [eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine], cisapride, lovastatin, simvastatin, drospirenone, phosphodiesterase type 5 (PDE5) enzyme inhibitors [eg, Revatio (sildenafil), Adcirca (tadalafil)] when used for the treatment of pulmonary arterial hypertension (PAH), pimozide, triazolam, orally administered midazolam; coadministration with potent CYP3A4/5 inducers (eg, anticonvulsants [eg, carbamazepine, phenobarbital, phenytoin], rifampin, St. John's wort).
Dosage and AdministrationChronic hepatitis C
PO Initiate therapy with peginterferon alfa and ribavirin for 4 wk (treatment wk 1 through 4). Add boceprevir 800 mg (four 200 mg capsules) 3 times daily (every 7 to 9 h) to peginterferon alfa and ribavirin regimen after 4 wk of treatment.Duration of therapy Patients with cirrhosis
44 wk.Patients without cirrhosis
In previously untreated patients with undetectable HCV-RNA at treatment wk 8 and/or treatment wk 24, complete 3-medicine regimen at treatment wk 28. In previously untreated patients with detectable HCV-RNA at treatment wk 8 and undetectable HCV-RNA at treatment wk 24, continue all 3 medicines and finish through treatment wk 36, and then administer peginterferon alfa and ribavirin and finish through treatment wk 48. In previous partial responders or relapsers with undetectable HCV-RNA at treatment wk 8 and/or treatment wk 24, complete 3-medicine regimen at treatment wk 36. In previous partial responders or relapsers with detectable HCV-RNA at treatment wk 8 and undetectable HCV-RNA at treatment wk 24, continue all 3 medicines and finish through treatment wk 36, and then administer peginterferon alfa and ribavirin and finish through treatment wk 48.Historical null responders to prior peginterferon alfa and ribavirin therapy
Response-guided therapy was not studied in subjects who had less than a 2 log 10 HCV-RNA decline by treatment wk 12 during prior therapy with peginterferon alfa and ribavirin. If considered for treatment, these subjects should receive 4 wk of peginterferon alfa and ribavirin followed by 44 wk of boceprevir 800 mg 3 times daily in combination with peginterferon alfa and ribavirin. In addition, consider treating previously untreated patients who are poorly interferon responsive (as determined at treatment wk 4) with 4 wk of peginterferon alfa and ribavirin followed by 44 wk of boceprevir 800 mg 3 times daily in combination with peginterferon alfa and ribavirin in order to maximize rates of sustained virological response.
- Administer with food (a meal or a light snack).
- If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Boceprevir must not be administered in the absence of peginterferon alfa and ribavirin.
- Dose reduction of boceprevir is not recommended.
- Discontinuation of therapy is recommended in all patients with HCV-RNA levels of at least 100 units/mL at treatment wk 12 or confirmed detectable HCV-RNA levels at treatment wk 24.
Refrigerate between 36° and 46°F. Avoid exposure to excessive heat. May also be stored at room temperature, up to 77°F, for 3 mo.
Drug InteractionsAlpha-1 adrenorecptor antagonists (eg, alfuzosin), cisapride, drospirenone, ergot derivative (eg, dihydroergotamine, ergonovine, methylergonovine), lovastatin, midazolam (oral), pimozide, sildenafil, simvastatin, tadalafil, triazolam
Plasma concentrations of these agents may be elevated, increasing the risk of serious and/or life-threatening adverse events. Coadministration with boceprevir is contraindicated. Coadministration of boceprevir is contraindicated when either sildenafil or tadalafil is used for the treatment of PAH.Antiarrhythmic agents (eg, amiodarone, bepridil, flecainide, propafenone, quinidine)
Antiarrhythmic agent concentrations may be elevated. The risk for serious and/or life-threatening adverse events may be increased. Use with caution. Therapeutic concentration monitoring of these agents is warranted.Anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin), rifampin, St. John's wort
Boceprevir concentrations may be reduced, decreasing the virologic response. Coadministration is contraindicated.Antidepressants (eg, desipramine, trazodone)
Desipramine and trazodone plasma concentrations may be elevated, increasing the risk of adverse reactions (eg, hypotension, syncope). Use with caution and consider a lower dose of antidepressant.Antifungal agents (eg, itraconazole, ketoconazole, posaconazole, voriconazole)
Plasma concentrations of boceprevir as well as the antifungal agent may be increased. When coadministered with boceprevir, ensure that dosages of itraconazole or ketoconazole do not exceed 200 mg/day.Benzodiazepines (eg, alprazolam, midazolam, triazolam)
The risk for prolonged sedation or respiratory depression is increased. Coadministration of boceprevir with oral midazolam or triazolam is contraindicated. Close clinical monitoring for respiratory depression and/or prolonged sedation is warranted during coadministration of boceprevir and alprazolam or IV midazolam. Consider lower doses of alprazolam or IV midazolam.Beta-agonist, inhaled (eg, salmeterol)
Increased risk of salmeterol cardiovascular effects. Coadministration is not recommended.Bosentan, dihydropyridine calcium channel blockers (eg, felodipine, nifedipine, nicardipine)
Concentrations of these agents may be increased. Use with caution. Clinical monitoring is warranted.Clarithromycin
Clarithromycin concentrations may be elevated; however, no dosage adjustment is needed in patients with healthy renal function.Colchicine
Clinically important increases in colchicine concentrations are expected. Fatal colchicine toxicity has been seen when coadministered with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not receive colchicine with boceprevir.Treatment of gout flares during coadministration of boceprevir
Give colchicine 0.6 mg for 1 dose, followed by colchicine 0.3 mg 1 h later. Dose to be repeated no earlier than 3 days.Prophylaxis of gout flares with colchicine during treatment with boceprevir
If the original regimen was colchicine 0.6 mg twice daily, reduce the dosage to colchicine 0.3 mg once daily. If the original regimen was colchicine 0.6 mg once daily, reduce the dosage to colchicine 0.3 mg once every other day.Treatment of familial Mediterranean fever with colchicine during coadministration of boceprevir
The max daily dose of colchicine is 0.6 mg, which may be given once daily or as 0.3 mg twice daily.Contraceptives, hormonal (eg, drospirenone, ethinyl estradiol)
The risk of hyperkalemia may be increased with coadministration of drospirenone. Coadministration is contraindicated. The effect of boceprevir on other progestins in not known; however, increased exposure is expected. Ethinyl estradiol concentrations may be reduced, decreasing the effectiveness. Advise patients to use 2 alternative methods of contraception during ribavirin treatment.Corticosteroids, inhaled (eg, budesonide, fluticasone); corticosteroids, systemic (eg, dexamethasone)
Boceprevir concentrations may be reduced by systemic corticosteroid administration, decreasing the clinical effect. If coadministration cannot be avoided, use with caution. Inhaled corticosteroid concentrations may be elevated, resulting in reduced serum cortisol concentrations. Avoid coadministration, particularly for extended durations.Digoxin
Digoxin serum concentrations may be elevated. Start digoxin therapy with the lowest dose with careful titration and monitoring of digoxin concentrations.HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin)
Risk of myopathy, including rhabdomyolysis, may be increased. Titrate the atorvastatin dose carefully, not exceeding a max dosage of atorvastatin 20 mg daily. Coadministration of boceprevir with lovastatin or simvastatin is contraindicated.Immunosuppressants (eg, cyclosporine, sirolimus, tacrolimus)
Immunosuppressant plasma concentrations are expected to greatly increase during boceprevir coadministration. Closely monitor immunosuppressant blood levels.NNRT inhibitors (eg, efavirenz)
Boceprevir trough concentrations may be decreased, resulting in loss of therapeutic effect. Avoid coadministration.Opioid analgesics (eg, buprenorphine, methadone)
Plasma concentrations of buprenorphine or morphine may be increased or decreased. Coadministration has not been studied. Closely monitor the clinical response and adjust the opioid dose as needed.PDE5 inhibitors (eg, sildenafil, tadalafil, vardenafil) Treatment of pulmonary arterial hypertension
The risk of PDE5 inhibitor–associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope, may be increased. Coadministration of boceprevir is contraindicated when sildenafil or tadalafil is used for the treatment of PAH.Treatment of erectile dysfunction
Use with caution and monitor for PDE5 inhibitor–associated adverse events when coadministered with boceprevir. Do not exceed the following doses:Sildenafil
25 mg every 48 h.Tadalafil
10 mg every 72 h.Vardenafil
2.5 mg every 24 h.Protease inhibitors (eg, ritonavir)
Boceprevir concentrations may be decreased. The effect of ritonavir-boosted protease inhibitors on boceprevir exposure is unknown.Rifabutin
Boceprevir concentrations may be decreased while rifabutin concentrations may be increased. Coadministration is not recommended.Warfarin
Warfarin concentrations may be altered. Closely monitor INR and adjust the warfarin dose as needed.
The following adverse reactions were reported with combined use of boceprevir, ribavirin, and peginterferon alfa:
Fatigue (59%); insomnia (34%); irritability (23%); asthenia (21%); dizziness (19%).
Alopecia (27%); dry skin (22%); rash (19%).
Nausea (46%); dysgeusia (44%); diarrhea (25%); vomiting (20%); dry mouth (15%).
Anemia (50%); neutropenia (25%).
Decreased hemoglobin (49%); decreased neutrophils (31%); decreased platelets (4%).
Chills (34%); decreased appetite (26%); arthralgia (23%); dyspnea exertional (11%).
Monitor HCV-RNA levels and CBCs (with WBC differential counts) at treatment wk 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of 25 units/mL or less, and a limit of HCV-RNA detection of approximately 10 to 15 units/mL. For the purposes of assessing response-guided therapy milestones, do not consider a confirmed “detectable but below limit of quantification” HCV-RNA equivalent to an “undetectable” HCV-RNA result. Perform routine monthly pregnancy tests during treatment and for 6 mo following discontinuation of treatment.
Category X (boceprevir in combination with peginterferon alfa and ribavirin); Category B (boceprevir alone).
Safety and efficacy have not been studied.
Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity.
Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of boceprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations.
None well documented.
- Advise patients to read the Medication Guide before starting therapy and with each refill.
- Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Do not initiate ribavirin therapy until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks of ribavirin and must be instructed to practice effective contraception during therapy and for 6 mo posttherapy. Advise patients to notify the health care provider immediately in the event of a pregnancy.
- Women of childbearing potential and men must use at least 2 forms of effective contraception during treatment and for at least 6 mo after treatment has been stopped; routine monthly pregnancy tests must be performed during this time. Because systemic hormonal contraceptives may not be as effective in women while taking boceprevir, advise women to use 2 alternative effective methods of contraception, such as intrauterine devices and barrier methods, during treatment with boceprevir and concomitant ribavirin.
- Inform patients that anemia and neutropenia may be increased when boceprevir is administered with peginterferon alfa and ribavirin. Advise patients that laboratory monitoring is required prior to starting therapy and periodically thereafter.
- Advise patients that boceprevir must not be used alone because of the high probability of resistance without combination anti-HCV therapies.
- Inform patients of the potential for serious drug interactions with boceprevir, and that some drugs should not be taken with boceprevir.
- Advise patients that the total daily dose of boceprevir is packaged into a single bottle containing 12 capsules and the patient should take 4 capsules 3 times daily with food.
- If a patient misses a dose and it is less than 2 hours before the next dose is due, advise patient that the missed dose should be skipped. If a patient misses a dose and it is 2 or more hours before the next dose is due, advise the patient to take the missed dose with food and resume the normal dosing schedule.
- Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and advise patients to take appropriate precautions to prevent transmission of HCV.
Copyright © 2009 Wolters Kluwer Health.