Boceprevir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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Overview
Boceprevir is an antiviral and protease inhibitor that is FDA approved 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, including prior null responders, partial responders, and relapsers. Common adverse reactions include fatigue, anemia, nausea, headache and dysgeusia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Boceprevir FDA-Labeled Indications and Dosage (Adult) in the drug label.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Boceprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in pediatric patients.
Contraindications
Contraindications to peginterferon alfa and ribavirin also apply to VICTRELIS combination treatment. Refer to the respective prescribing information for a list of the contraindications for peginterferon alfa and ribavirin.
VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in:
- Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.
- Patients with a history of a hypersensitivity reaction to boceprevir.
- Coadministration with drugs that are highly dependent on CYP3A4/CYP3A5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, including those in TABLE 2, is contraindicated.
Coadministration with potent CYP3A4/5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy, including those in TABLE 2, is contraindicated.
Warnings
Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa)
Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Refer to the prescribing information for ribavirin for additional information.
Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this time.
Anemia (Use with Ribavirin and Peginterferon Alfa)
Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and [ribavirin]] is associated with an additional decrease in hemoglobin concentrations. Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended. If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and VICTRELIS must also be discontinued.
Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation.
In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of VICTRELIS with PegIntron®/REBETOL® than in those treated with PegIntron/REBETOL alone (see TABLE 4). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g per dL.
In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of VICTRELIS and PegIntron/REBETOL (71 days with a range of 15-337 days), compared to those who received PegIntron/REBETOL (71 days with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of VICTRELIS with PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone [see ADVERSE REACTIONS (6.1)].
In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL (26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents (ESAs) was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was 43% in those treated with the combination of VICTRELIS with PegIntron/REBETOL compared to 24% in those treated with PegIntron/REBETOL alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of VICTRELIS with PegIntron/REBETOL compared to less than 1% in subjects who received PegIntron/REBETOL alone.
Thromboembolic events have been associated with ESA use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use.
A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with VICTRELIS in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA.
Ribavirin dose reduction is recommended for the initial management of anemia.
5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa) In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 × 109 per L compared to 4% of subjects receiving PegIntron/REBETOL alone (see TABLE 4). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION (2.3)].
Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation.
5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa) Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.
5.5 Hypersensitivity Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted [see CONTRAINDICATIONS (4) and ADVERSE REACTIONS (6.2)].
5.6 Drug Interactions See TABLE 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity [see CONTRAINDICATIONS (4)]. Please refer to TABLE 5 for established and other potentially significant drug interactions [see DRUG INTERACTIONS (7.3)].
5.7 Laboratory Tests HCV-RNA levels should be monitored at Treatment Weeks 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 equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result (reported as "Target Not Detected" or "HCV-RNA Not Detected").
Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Boceprevir Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Boceprevir Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Boceprevir Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Boceprevir in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Boceprevir in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Boceprevir during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Boceprevir in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Boceprevir in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Boceprevir in geriatric settings.
Gender
There is no FDA guidance on the use of Boceprevir with respect to specific gender populations.
Race
There is no FDA guidance on the use of Boceprevir with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Boceprevir in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Boceprevir in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Boceprevir in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Boceprevir in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Boceprevir Administration in the drug label.
Monitoring
There is limited information regarding Boceprevir Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Boceprevir and IV administrations.
Overdosage
There is limited information regarding Boceprevir overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Boceprevir Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Boceprevir Mechanism of Action in the drug label.
Structure
There is limited information regarding Boceprevir Structure in the drug label.
Pharmacodynamics
There is limited information regarding Boceprevir Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Boceprevir Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Boceprevir Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Boceprevir Clinical Studies in the drug label.
How Supplied
There is limited information regarding Boceprevir How Supplied in the drug label.
Storage
There is limited information regarding Boceprevir Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Boceprevir Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Boceprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Boceprevir Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Boceprevir Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
Overview
Boceprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C.[1][2]It is being developed by Schering-Plough.[3] As of 2008, it is in phase II clinical trials.[3]The hepatitis C virus, often described as the “silent epidemic,” affects more than 170-180 million people around the world and as the most common blood borne infection worldwide it has become a serious global health crisis.2 [4] [5][6] It is currently the leading cause of chronic liver diseases which include cirrhosis, carcinoma and liver failure, and approximately 130 million patients with the disease are at high risk of developing one of these conditions.4 HCV is an enveloped virus with a 9.6 kb single-stranded RNA genome that serves as a template for viral replication that is translated into a polyprotein and cleaved by proteases to allow for viral assembly.5
Before the development of new, more successful drug therapies such as boceprevir, the leading standard treatment therapy included the combination of pegylated interferon and ribavirin over a prolonged period of 24 to 48 weeks.2 4 However, for the genotype 1 strain of the virus, which is the most prevalent, this regimen achieves the goal of sustained virologic response (SVR), in only about 50% of treated patients, and it tends to be poorly tolerated and requires injection.[7] [8] Boceprevir is part of a treatment regimen that has been found to easier to administer, less toxic, and overall more effective. It is expected that the development of boceprevir and other new treatment will significantly broaden the treatment options for infected individuals.4
The FDA has recently approved the drug boceprevir as a new and improved HCV therapy to be used in combination with peginterferon and ribavirin, the previous standard of treatment.[9] It is widely agreed that boceprevir seems to be a safe and effective treatment innovation. The drug will treat patients with hepatitis C genotype 1.1 Boceprevir, marketed as Victrelis by Merck, is the first HCV protease inhibitor to reach market and it expected to be a major advance in HCV treatment. Throughout its phases of study, boceprevir has been shown to provide more effective treatment than just the combination of peginterferon and ribavirin alone, and will offer a greater chance of cure than the previous standards of therapy.
Category
Antiviral
US Brand Names
VICTRELIS®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages
Mechanism of Action
Boceprevir is an inhibitor of the 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. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.
References
- ↑ Degertekin B, Lok AS (2008). "Update on viral hepatitis: 2007". Curr. Opin. Gastroenterol. 24 (3): 306–11. doi:10.1097/MOG.0b013e3282f70285. PMID 18408458. Unknown parameter
|month=ignored (help) - ↑ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Acc. Chem. Res. 41 (1): 50–9. doi:10.1021/ar700109k. PMID 18193821. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 "Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL - Forbes.com" (Press release). Forbes.com. Retrieved 2008-05-19.
- ↑ Susser, Simone, Christoph Welsch, Yalan Wang, Markus Zettler, Franciso S. Domingues, Ursula Karey, Eric Hughes, Robert Ralston, Xiao Tong, Eva Herrmann, Stefan Zeuzem, and Christoph Sarrazin. "Characterization of Resistance to the Protease Inhibitor Boceprevir in Hepatitis C Virus–infected Patients." Hepatology 50.6 (2009): 1709-718.
- ↑ Asselah, Tarik, and Patrick Marcellin. "New Direct-acting Antivirals' Combination for the Treatment of Chronic Hepatitis C." Liver International 31.S1 (2011): 68-22.
- ↑ Kwo, Paul Y., and Rakesh Vinayek. "The Therapeutic Approaches for Hepatitis C Virus: Protease Inhibitors and Polymerase Inhibitors." Gut and Liver 5.4 (2011): 406-17.
- ↑ DeNoon, Daniel J. "Boceprevir Boosts Hepatitis C Treatment Success." WebMD. WebMD Health News, 9 Aug. 2010. Web. <http://www.webmd.com/hepatitis/news/20100809/boceprevir-ups-hepatitis-c-treatment-success>.
- ↑ Flint, Mike, Stanley Mullen, Anne M. Deatly, Wei Chen, Lynn Z. Miller, Robert Ralston, Colin Broom, Emilio A. Emini, and Anita Y. M. Howe. "Selection and Characterization of Hepaitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-769 and Boceprevir." Antimicrobial Agents and Chemotherapy 53.2 (2009): 401-11.
- ↑ Walker, Emily P. "Boceprevir Wins FDA Approval to Treat Hepatitis C." MedPage Today. N.p., 13 May 2011. Web.<http://www.medpagetoday.com/InfectiousDisease/Hepatitis/26469>.