March 6, 2012
The primary objective of this ongoing randomized, multicenter, double-blinded Phase IIb study is to compare the efficacy of 800 mg of VICTRELIS three times daily in combination with peginterferon alfa-2b (P) 1.5 mcg/kg weekly plus ribavirin (R) 600 to 1,400 mg/daily to therapy with PR alone in adult patients coinfected with chronic HCV genotype 1 and HIV-1. Patients were randomized in a 2:1 ratio to the treatment arm with VICTRELIS plus PR or the PR control arm, respectively. Patients were stratified by cirrhosis (yes/no) and baseline HCV-RNA (less than 800,000 IU/mL vs. equal to or greater than 800,000 IU/mL). The majority of patients were non-cirrhotic (95 percent), white (82 percent) and male (69 percent), with a median age of about 43 years. Most patients had high HCV-RNA (88 percent) at baseline and HCV genotype 1a infection (65 percent).
Antiretroviral regimens for HIV-1 that included non-nucleoside reverse transcriptase inhibitors (NNRTIs), or zidovudine, stavudine or didanosine were not permitted. Ritonavir-boosted HIV protease inhibitors could be included in antiretroviral regimens for HIV-1. Patients with detectable HCV-RNA and less than a 2 log HCV-RNA decline at treatment week 12 or detectable HCV-RNA at treatment week 24 were considered treatment failures and discontinued all HCV treatment.
The study was a single-center, three-arm, open-label, drug-interaction study in 39 healthy adults. Patients received 800 mg of VICTRELIS three times daily on Days 1-6. Following a 4-day "washout" period, patients received either 300 mg of atazanavir/100 mg of ritonavir once daily, 400 mg of lopinavir/100mg of ritonavir twice daily, or 600 mg of darunavir/100 mg of ritonvair twice daily on Days 10-31. From Days 25-31, patients also received 800 mg of VICTRELIS three times daily. Blood samples were collected for the pharmacokinetic assessment of the HIV medicines and VICTRELIS.
In the study, co-administration of VICTRELIS reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in AUC and Cmax of atazanavir, lopinavirand darunavir. Co-administration of ritonavir-boosted atazanavir with VICTRELIS did not alter the exposure of VICTRELIS, but co-administration of VICTRELIS with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the exposure of VICTRELIS by 45 and 32 percent, respectively. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered.
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.
VICTRELIS is contraindicated in 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. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.
Anemia and/or Neutropenia -- The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.
Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. 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.
The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.
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.
Please see U.S. prescribing information at: www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.
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