Ribavirin (Page 7 of 9)

12.4 Microbiology

Mechanism of Action

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct antiviral activity has been observed in tissue culture of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell containing self-replicating HCV-RNS (HCV replicon cells) or HCV infection.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between non-pegylated interferons and ribavirin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult).

Mutagenesis

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24 hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment of Fertility

Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24 hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24 hour dose of ribavirin) [see Contraindications (4), and Warnings and Precautions (5.1)].

Fertile women and partners of fertile women should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t½ ) of ribavirin of 12 days, effective contraception must be utilized for 6 months post-therapy (e.g., 15 half-lives of clearance for ribavirin).

Ribavirin should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 to 0.8 times the maximum human 24 hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

13.2 Animal Toxicology and Pharmacology

Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively (estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24 hour dose of ribavirin)] have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.

14 CLINICAL STUDIES

14.2 Ribavirin/INTRON A Combination Therapy

Adult Subjects

Previously Untreated Subjects

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 multicenter, double-blind trials (U.S. and international) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The international trial did not contain a 24 week INTRON A and placebo treatment arm. The U.S. trial enrolled 912 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Trial results are summarized in Table 18.

Table 18: Virologic and Histologic Responses: Previously Untreated Subjects *
*
Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.

U.S. Trial

International Trial

24 weeks of treatment

48 weeks of treatment

24 weeks of treatment

48 weeks of treatment

INTRON A/ Ribavirin (N = 228)

INTRON A/ Placebo (N = 231)

INTRON A/Ribavirin (N = 228)

INTRON A/ Placebo (N = 225)

INTRON A/ Ribavirin (N = 265)

INTRON A/ Ribavirin (N = 268)

INTRON A/ Placebo (N = 266)

Virologic Response

Responder

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

Improvement

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 subjects 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 subjects 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 subjects with HCV non-genotype 1 randomized to ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Subjects

Subjects 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 (U.S. and international) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The U.S. trial enrolled 153 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Trial results are summarized in Table 19.

Table 19: Virologic and Histologic Responses: Relapse Subjects *
*
Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.

U.S. Trial

International Trial

INTRON A/ Ribavirin

(N = 77)

INTRON A/ Placebo

(N = 76)

INTRON A/ Ribavirin

(N = 96)

INTRON A/ Placebo

(N = 96)

Virologic Response

Responder

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

Improvement

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 subjects in both the previously untreated and relapse trials.

Pediatric Subjects

Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with ribavirin 15 mg/kg per day and INTRON A 3 MIU/m2 three times weekly for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 subjects received treatment of which 57% were male, 80% Caucasian, and 78% genotype 1. Subjects less than 5 years of age received ribavirin oral solution and those 5 years of age or older received either ribavirin oral solution or capsules.

Trial results are summarized in Table 20.

Table 20: Virologic Response: Previously Untreated Pediatric Subjects *
*
Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.

INTRON A 3 MIU/m2 three times weekly/

Ribavirin 15 mg/kg/day

Overall Response (N = 118)

54 (46)

Genotype 1 (N = 92)

33 (36)

Genotype non-1 (N = 26)

21 (81)

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/ribavirin combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

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