8.9Hepatitis B Virus (HBV) Co-Infection

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in patients co-infected with HBV and HCV have not been studied.

8.10Organ Transplantation

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied.

10 OVERDOSAGE

Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects.

There is no specific antidote for overdose with VICTRELIS. Treatment of overdosage with VICTRELIS should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status.

11 DESCRIPTION

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 has the following structural formula:

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.

VICTRELIS 200 mg capsules are available as hard gelatin capsules for oral administration. Each capsule contains 200 mg of boceprevir and the following inactive ingredients: sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, pre-gelatinized starch, and magnesium stearate. The red capsule cap consists of gelatin, titanium dioxide, D&C Yellow #10, FD&C Blue #1, and FD&C Red #40. The yellow capsule body contains gelatin, titanium dioxide, D&C Yellow #10, FD&C Red #40, and FD&C Yellow #6. The capsule is printed with red and yellow ink. The red ink contains shellac and red iron oxide, while the yellow ink consists of shellac, titanium dioxide, povidone and D&C Yellow #10 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action

VICTRELIS is a direct acting antiviral drug against the hepatitis C virus [see Microbiology (12.4)].

12.2 Pharmacodynamics

eva luation of Effect of VICTRELIS on QTc Interval

The effect of boceprevir 800 mg and 1200 mg on QTc interval was eva luated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 1200 mg yields a boceprevir maximum exposure increase of approximately 15% which may not cover exposures due to coadministration with strong CYP3A4 inhibitors or use in patients with s