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Boceprevir Stopping Rules (discontinuation or futility), Resistance
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DOSAGE AND ADMINISTRATION
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).
Boceprevir is partly metabolized by CYP3A4/5. It is also a substrate for p-glycoprotein. Coadministration of VICTRELIS with drugs that induce or inhibit CYP3A4/5 could decrease or increase exposure to boceprevir.
Resistance: The long-term clinical impact of the emergence or persistence of boceprevir-resistance-associated substitutions is unknown. No data are available regarding the efficacy of VICTRELIS among subjects who were previously exposed to VICTRELIS, or who previously failed treatment with a VICTRELIS-containing regimen. Baseline resistance associated polymorphisms were detected in 7% of subjects by a population-based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in subjects treated with VICTRELIS. However, among subjects with a relatively poor response to PegIntron/REBETOL during the 4-week lead-in period, the efficacy of VICTRELIS appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K detected at baseline. Subjects with these baseline polymorphisms and reduced response to PegIntron/REBETOL represented approximately 1% of the total number of subjects treated with VICTRELIS.
The data indicate that boceprevir is eliminated primarily by the liver. No dosage adjustment of VICTRELIS is required in patients with any degree of renal impairment. Population pharmacokinetic analysis of VICTRELIS indicated that race had no apparent effect on exposure. Population pharmacokinetic analysis of VICTRELIS showed that boceprevir exposure was not different across subjects 19 to 65 years old.
Hepatic Impairment
The pharmacokinetics of boceprevir was studied in adult non-HCV infected subjects with normal, mild (Child-Pugh score 5-6), moderate (Child-Pugh score 7-9), and severe (Child-Pugh score 10-12) hepatic impairment following a single 400 mg dose of VICTRELIS. The mean AUC of the active diastereomer of boceprevir (SCH534128) was 32% and 45% higher in subjects with moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. Mean Cmax values for SCH534128 were 28% and 62% higher in moderate and severe hepatic impairment, respectively. Subjects with mild hepatic impairment had similar SCH534128 exposure as subjects with normal hepatic function. A similar magnitude of effect is anticipated for boceprevir. No dosage adjustment of VICTRELIS is recommended for patients with hepatic impairment [see Use in Specific Populations (8.7)]. See peginterferon alfa Package Insert for contraindication in patients with hepatic decompensation.
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).
Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
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/mL, and a limit of HCV-RNA detection of approximately 10-15 IU/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.
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.
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 should be obtained pretreatment, and at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
Effects of Food on Oral Absorption
VICTRELIS should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, VICTRELIS may be taken without regard to either meal type or timing of the meal.
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 [see Clinical Studies (14)].
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