INDICATIONS AND USAGE
Ribavirin capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alpha interferon or in patients 18 years of age and older who have relapsed following alpha interferon therapy.
The safety and efficacy of ribavirin capsules with non-pegylated interferons other than the INTRON A product have not been established.
Description of Clinical Studies
Ribavirin/INTRON A Combination Therapy
Adult Patients
Previously Untreated Patients
Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multi-center, double-blind trials (US and International) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for patients weighing 75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).
Study results are summarized in TABLE 2.
TABLE 2. Virologic and Histologic Responses: Previously Untreated PatientsNumber (%) of patients.
US Study
International Study
24 weeks of treatment
48 weeks of treatment
24 weeks of
treatment
48 weeks of treatment
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=231)
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=225)
INTRON A
plus
Ribavirin
(N=265)
INTRON A
plus
Ribavirin
(N=268)
INTRON A
plus
Placebo
(N=266)
Virologic
Response
ResponderDefined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
65 (29)
13 (6)
85 (37)
27 (12)
86 (32)
113 (42)
46 (17)
Nonresponder
147 (64)
194 (84)
110 (48)
168 (75)
158 (60)
120 (45)
196 (74)
Missing Data
16 (7)
24 (10)
33 (14)
30 (13)
21 (8)
35 (13)
24 (9)
Histologic
Response
ImprovementDefined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of 2 points.
102 (45)
77 (33)
96 (42)
65 (29)
103 (39)
102 (38)
69 (26)
No improvement
77 (34)
99 (43)
61 (27)
93 (41)
85 (32)
58 (22)
111 (41)
Missing Data
49 (21)
55 (24)
71 (31)
67 (30)
77 (29)
108 (40)
86 (32)
Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.
Among patients with HCV Genotype 1 treated with ribavirin/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.
Relapse Patients
Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for patients weighing 75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).
Study results are summarized in TABLE 3.
TABLE 3. Virologic and Histologic Responses: Relapse PatientsNumber (%) of patients.
US Study
International Study
INTRON A
plus
Ribavirin
(N=77)
INTRON A
plus
Placebo
(N=76)
INTRON A
plus
Ribavirin
(N=96)
INTRON A
plus
Placebo
(N=96)
Virologic
Response
ResponderDefined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
33 (43)
3 (4)
46 (48)
5 (5)
Nonresponder
36 (47)
66 (87)
45 (47)
91 (95)
Missing Data
8 (10)
7 (9)
5 (5)
0 (0)
Histologic
Response
ImprovementDefined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of 2 points.
38 (49)
27 (36)
49 (51)
30 (31)
No improvement
23 (30)
37 (49)
29 (30)
44 (46)
Missing Data
16 (21)
12 (16)
18 (19)
22 (23)
Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.