VICTRELIS™ (boceprevir) Capsules

VICTRELIS™ (boceprevir) Capsules
Initial U.S. Approval: 2011

VICTRELIS (boceprevir) is an inhibitor of the hepatitis C virus (HCV) non-structural protein 3 (NS3) serine protease.

Boceprevir has the following chemical name: (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide. The molecular formula is C27H45N5O5 and its molecular weight is 519.7.

Boceprevir is manufactured as an approximately equal mixture of two diastereomers. Boceprevir is a white to off-white amorphous powder. It is freely soluble in methanol, ethanol and isopropanol and slightly soluble in water.

Microbiology
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.

VICTRELIS™ (boceprevir) is indicated for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic hepatitis C infection:

VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.

VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.

VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2-log10 HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included subjects who were poorly interferon responsive. Subjects with less than 0.5-log10 HCV-RNA decline in viral load at Treatment Week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than 2-log10 viral load decline at Treatment Week 12) to peginterferon alfa and ribavirin therapy.

Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.

USE IN SPECIFIC POPULATIONS
Cirrhosis: Safety and efficacy have not been studied in patients with decompensated cirrhosis or in patients with an organ transplant.

Co-infection with Human Immunodeficiency Virus (HIV): Safety and efficacy have not been established in patients co-infected with HCV and HIV.

Co-infection with Hepatitis B Virus (HBV): Safety and efficacy have not been studied in patients co-infected with HCV and HBV.

Pediatrics: Safety and efficacy have not been studied in pediatric patients.
Ribavirin Pregnancy Registry available.

Because ribavirin may cause birth defects and fetal death, boceprevir in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant.

Coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

Potent CYP3A4/5 inducers where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy.

Anemia - The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone.

Neutropenia - The addition of VICTRELIS to peginterferon alfa and ribavirin may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone.

DRUG INTERACTIONS
VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. The dose of VICTRELIS is 800 mg (four 200-mg capsules) three times daily (every 7–9 hours) with food [a meal or light snack] (see Table 1). Refer to the peginterferon alfa and ribavirin Package Inserts for instructions on dosing.

The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials [see Clinical Studies (14)]. Response-Guided Therapy (RGT) is recommended for most individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).

2.1 VICTRELIS Combination Therapy: Patients Without Cirrhosis Who Are Previously Untreated or Who Are Previous Partial Responders or Relapsers to Interferon and Ribavirin Therapy

Initiate therapy with peginterferon alfa and ribavirin for 4 weeks (Treatment Weeks 1–4).
Add VICTRELIS 800 mg (four 200-mg capsules) orally three times daily (every 7–9 hours) to peginterferon alfa and ribavirin regimen after 4 weeks of treatment. Based on the patient's HCV-RNA levels at Treatment Week (TW) 8, TW12 and TW24, use the following Response-Guided Therapy (RGT) guidelines to determine duration of treatment (see Table 1).

Response-Guided Therapy was not studied in subjects who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin. If considered for treatment, these subjects should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin. In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW 4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin in order to maximize rates of SVR .

2.2 VICTRELIS Combination Therapy: Patients with Cirrhosis

Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks VICTRELIS 800 mg (four 200-mg capsules) three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin.

2.3 Dose Modification
Dose reduction of VICTRELIS is not recommended.

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. Refer to the peginterferon alfa and ribavirin Package Inserts for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

2.4 Discontinuation of Dosing Based on Treatment Futility

Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 100 IU/mL at TW 12; or 2) confirmed detectable HCV-RNA levels at TW24.

How Supplied
VICTRELIS 200 mg capsules are comprised of a red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink. The capsules are packaged into a carton with 28 bottles containing 12 capsules (NDC 0085-0314-02).

Storage and Handling
VICTRELIS Capsules should be refrigerated at 2–8°C (36–46°F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated capsules of VICTRELIS can remain stable until the expiration date printed on the label. VICTRELIS can also be stored at room temperature up to 25°C (77°F) for 3 months. Keep container tightly closed.