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| {{Interferon alfa-2a}} | | {{Interferon alfa-2a}} |
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| {{CMG}} | | {{CMG}}; {{AE}} {{SS}} |
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| ==Clinical Studies== | | ==Clinical Studies== |
| ===Chronic [[hepatitis]] C Studies 1, 2, and 3: PEGASYS Monotherapy===
| | Studies have shown that Roferon-A can normalize serum ALT, improve liver histology and reduce viral load in patients with chronic hepatitis C. Other studies have shown that Roferon-A can produce clinically meaningful tumor regression or disease stabilization in patients with hairy cell leukemia.4,5 In Ph-positive Chronic Myelogenous Leukemia, Roferon-A supplemented with intermittent chemotherapy has been shown to prolong overall survival and to delay disease progression compared to patients treated with chemotherapy alone.6 In addition, Roferon-A has been shown to produce sustained complete cytogenetic responses in a small subset of patients with CML in chronic phase. The activity of Roferon-A in Ph-negative CML has not been determined.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = ROFERON-A (INTERFERON ALFA-2A) INJECTION, SOLUTION [ROCHE PHARMACEUTICALS] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4c918b02-f158-4f7c-8ecc-fd49574ec228#nlm34090-1 | publisher = | date = | accessdate = 9 January 2014 }}</ref> |
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| The safety and effectiveness of PEGASYS for the treatment of [[hepatitis]] C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable [[hepatitis]] C virus (HCV), liver biopsy diagnosis of chronic [[hepatitis]], and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).
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| In Study 1 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, PEGASYS 135 mcg once weekly or PEGASYS 180 mcg once weekly. In Study 2 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or PEGASYS 180 mcg once weekly. In Study 3 (n=269), subjects received ROFERON-A 3 MIU three times a week, PEGASYS 90 mcg once weekly or PEGASYS 180 mcg once each week.
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| In all three studies, treatment with PEGASYS 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [less than 50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 3, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A. ==
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| Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of subjects. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.
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| Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log10 drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 mcg therapy, 2% (3/156) achieved a sustained virologic response [see Dosage and Administration (2.2)].
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| Averaged over Study 1, Study 2, and Study 3, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% among subjects with other viral genotypes. The treatment response rates were similar in men and women.
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| ===Chronic [[hepatitis]] C Studies 4, 5, and 6: PEGASYS/COPEGUS Combination Therapy===
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| ====Adult Patients====
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| The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of [[hepatitis]] C virus infection were assessed in two randomized controlled clinical trials. All subjects were adults, had compensated liver disease, detectable [[hepatitis]] C virus, liver biopsy diagnosis of chronic [[hepatitis]], and were previously untreated with interferon. Approximately 20% of subjects in both studies had compensated cirrhosis (Child-Pugh class A). Subjects coinfected with HIV were excluded from these studies.
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| In Study 4, subjects were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS 180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or Rebetron® (interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth). All subjects received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 12). In all treatment arms, subjects with viral genotype 1, regardless of viral load, had a lower response rate.
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| In Study 5 (see Table 13), all subjects received PEGASYS 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Subjects with genotype 1 and high viral titer (defined as greater than 2 × 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
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| ====HCV Genotypes====
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| HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS.
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| HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 13).
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| The numbers of subjects with genotype 5 and 6 were too few to allow meaningful assessment. | |
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| ====Other Treatment Response Predictors====
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| Treatment response rates are lower in subjects with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in subjects older than 40 years (50% vs. 66%), in subjects with cirrhosis (47% vs. 59%), in subjects weighing over 85 kg (49% vs. 60%), and in subjects with genotype 1 with high vs. low viral load (43% vs. 56%). African-American subjects had lower response rates compared to Caucasians.
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| Paired liver biopsies were performed on approximately 20% of subjects in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.
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| In studies 4 and 5, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of subjects who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of subjects who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.
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| ====Pediatric Patients==== | |
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| Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic [[hepatitis]] C, compensated liver disease and detectable HCV RNA were treated with COPEGUS approximately 15 mg/kg/day plus PEGASYS 180 mcg/1.73 m2 × body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of COPEGUS plus PEGASYS or PEGASYS monotherapy; subjects failing PEGASYS monotherapy at 24 weeks or later could receive open-label COPEGUS plus PEGASYS. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of COPEGUS plus PEGASYS and 59 received PEGASYS plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 14.
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| ===Chronic [[hepatitis]] C and Coinfection with HIV (CHC/HIV) Study 7: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy === | |
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| In Study 7, subjects with CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All subjects were adults, had compensated liver disease, detectable [[hepatitis]] C virus, liver biopsy diagnosis of chronic [[hepatitis]] C, and were previously untreated with interferon. Subjects also had CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 cells/mm3, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in [http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=de61685e-2b8c-4e22-84bb-869e13600440#t15 Table 15].
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| Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.
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| Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination therapy, 2% (2/85) achieved an SVR.
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| In CHC subjects with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.
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| ===Chronic [[hepatitis]] B Studies 8 and 9: PEGASYS Monotherapy===
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| The safety and effectiveness of PEGASYS for the treatment of chronic [[hepatitis]] B were assessed in controlled clinical trials in HBeAg positive (Study 8) and HBeAg negative (Study 9) subjects with chronic [[hepatitis]] B.
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| Subjects were randomized to PEGASYS 180 mcg subcutaneous once weekly, PEGASYS 180 mcg subcutaneous once weekly combined with [[lamivudine]] 100 mg once daily by mouth or [[lamivudine]] 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked.
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| All subjects were adults with compensated liver disease, had chronic [[hepatitis]] B virus (HBV) infection, and evidence of HBV replication (serum HBV greater than 500,000 copies/mL for Study 8 and greater than 100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR® HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic [[hepatitis]].
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| The results observed in the PEGASYS and [[lamivudine]] monotherapy groups are shown in Table 16.
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| PEGASYS co-administered with [[lamivudine]] did not result in any additional sustained response when compared to PEGASYS monotherapy.
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| Conclusions regarding comparative efficacy of PEGASYS and [[lamivudine]] treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of [[lamivudine]] are unlikely to persist 24 weeks after therapy is withdrawn.
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| ==References== | | ==References== |