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Boceprevir SVR 'Cure'-Study Results - dosing, effects of food, storage, missed doses
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DOSAGE AND ADMINISTRATION
VICTRELIS is a direct acting antiviral drug against the hepatitis C virus . 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). VICTRELIS 200 mg Capsules, red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink.
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).
The effect of boceprevir 800 mg and 1200 mg on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects ÉÉ..at the doses studied in the thorough QT study, no apparent concentration-QT relationship was identified. Thus, there is no expectation of a QTc effect under a higher exposure scenario.
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.
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.
Anemia
Patients should be informed that anemia may be increased when VICTRELIS is administered with peginterferon alfa and ribavirin. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter
Neutropenia
Patients should be informed that neutropenia may be increased when VICTRELIS is administered with peginterferon alfa and ribavirin. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter
Missed VICTRELIS Doses
If a patient misses a dose and it is less than 2 hours before the next dose is due, 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, the patient should take the missed dose with food and resume the normal dosing schedule.
CLINICAL STUDIES
Interferon Responsiveness during Lead-In Therapy with Peginterferon alfa and Ribavirin
Previously Untreated Subjects
In previously untreated subjects evaluated in SPRINT-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW 4) was predictive of SVR. VICTRELIS-treated subjects who demonstrated interferon responsiveness at TW 4 achieved SVR rates of 81% (203/252) in VICTRELIS-RGT arm and 79% (200/254) in VICTRELIS-PR48 arm, compared to 52% (134/260) in subjects treated with PegIntron/REBETOL.
VICTRELIS-treated subjects who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW 4), achieved SVR rates of 28% (27/97) in VICTRELIS-RGT arm and 38% (36/95) in VICTRELIS-PR48 arm, compared to 4% (3/83) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 achieved SVR rates of 28% (13/47) in VICTRELIS-RGT arm and 30% (11/37) in VICTRELIS-PR48 arm, compared to 0% (0/25) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 with peginterferon alfa plus ribavirin therapy alone are predicted to have a null response (less than 2-log10 viral load decline at TW12) to peginterferon alfa and ribavirin.
Subjects Who Failed Previous Therapy with Peginterferon Alfa and Ribavirin
In subjects who were previous relapsers and partial responders evaluated in RESPOND-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. VICTRELIS-treated subjects who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in VICTRELIS-RGT arm and 79% (90/114) in VICTRELIS-PR48 arm, compared to 27% (18/67) in subjects treated with PegIntron/REBETOL. VICTRELIS-treated subjects who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4) achieved SVR rates of 33% (15/46) in VICTRELIS-RGT arm and 34% (15/44) in VICTRELIS-PR48 arm, compared to 0% (0/12) in subjects treated with PegIntron/REBETOL.
Sustained Virologic Response (SVR) Based on TW 8 HCV-RNA Results
Table 11 presents sustained virologic response based on TW 8 HCV-RNA results in previously untreated subjects. Fifty-seven percent (208/368) of subjects in the VICTRELIS-RGT arm and 56% (204/366) of subjects in the VICTRELIS-PR48 arm had undetectable HCV-RNA at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.
Among subjects with detectable HCV-RNA at TW 8 who had attained undetectable HCV-RNA at TW 24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in VICTRELIS-RGT arm (4 weeks of PegIntron and REBETOL then 24 weeks of VICTRELIS with PegIntron and REBETOL followed by 20 weeks of PegIntron and REBETOL alone) and 75% (55/73) in VICTRELIS-PR48 arms (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).
Subjects Who Failed Previous Therapy with Peginterferon Alfa and Ribavirin
RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 μg/kg/week subcutaneously and weight-based ribavirin (600-1400 mg/day orally divided twice daily)] compared to PR alone in adult subjects with chronic hepatitis C (HCV genotype 1) infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load greater than or equal to 2-log10 by Week 12, but never achieved SVR [partial responders] or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma [relapsers]). Subjects with less than 2-log10 decrease in HCV-RNA by week 12 of previous treatment (prior null responders) were not eligible for enrollment in this trial. Subjects were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:
In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of VICTRELIS with PegIntron and REBETOL for 44 weeks after 4 weeks of lead-in therapy with PegIntron and REBETOL (17/22, 77%) compared to those who received RGT (6/17, 35%).
Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
Table 13 presents sustained virologic response based on TW 8 HCV-RNA results in subjects who have failed previous therapy. Forty-six percent (74/162) of subjects in the VICTRELIS-RGT arm and 52% (84/161) in the VICTRELIS-PR48 had undetectable HCV-RNA at TW 8 (early responders) compared with 9% (7/80) in the PR48 arm.
Among subjects with detectable HCV-RNA at TW 8 who attained an undetectable HCV-RNA at TW 12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in VICTRELIS-RGT arm (4 weeks of PegIntron and REBETOL then 32 weeks of VICTRELIS with PegIntron and REBETOL followed by 12 weeks of PegIntron and REBETOL alone) and 72% (29/40) in VICTRELIS-PR48 arm (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).
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