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Rebetron

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Rebetron

CLINICAL PHARMACOLOGY

Pharmacokinetics

Interferon alfa-2b, recombinant

Single- and multiple-dose pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant) are summarized in TABLE 1. Following a single 3 million IU (MIU) subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV*) serum concentrations peaked at 7 (44%) hours. Following 4 weeks of subcutaneous dosing with 3 MIU three times a week (TIW), interferon serum concentrations were undetectable predose. However, a twofold increase in bioavailability was noted upon multiple dosing of interferon; the reason for this is unknown. Mean half-life values following single- and multiple-dose administrations were 6.8 (24%) hours and 6.5 (29%) hours, respectively.

Ribavirin

Single- and multiple-dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in TABLE 1. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUCtf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400-600 mg.

Upon multiple oral dosing, based on AUC12hr, a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when REBETOL Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies were conducted without instructions with respect to food consumption. (See DOSAGE AND ADMINISTRATION.)

Effect of Antacid on Absorption of Ribavirin

Coadministration with an antacid containing magnesium, aluminum, and simethicone (Mylanta®) resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

TABLE 1. Mean (% CV) Pharmacokinetic Parameters for INTRON A and REBETOL When Administered Individually to Adults with Chronic Hepatitis C

Parameter INTRON A (N=12) REBETOL (N=12)
Single Dose
3 MIU
Multiple Dose
3 MIU TIW
Single Dose
600 mg
Multiple Dose
600 mg BID
Tmax (hr) 7 (44) 5 (37) 1.7 (46) *** 3 (60)
Cmax * 13.9 (32) 29.7 (33) 782 (37) 3680 (85)
AUCtf ** 142 (43) 333 (39) 13400 (48) 228000 (25)
T½ (hr) 6.8 (24) 6.5 (29) 43.6 (47) 298 (30)
Apparent Volume of Distribution(L)     2825 (9)†  
Apparent Clearance (L/hr) 14.3 (17)   38.2 (40)  
Absolute Bioavailability     64% (44)† †  
* IU/mL for INTRON A and ng/mL for REBETOL
** IU.hr/mL for INTRON A and ng.hr/mL for REBETOL
data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5
† † N = 6
*** N = 11

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an es -type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.

Special Populations

Renal Dysfunction

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to subjects with varying degrees of renal dysfunction. The mean AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance > 90 mL/min). This appears to be due to reduction of apparent clearance in these patients. Ribavirin was not removed by hemodialysis. Patients with creatinine clearance < 50 mL/min should not be treated with REBETOL (see WARNINGS).

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C), when compared to control subjects. However, the mean Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for ribavirin in pediatric patients with chronic hepatitis C between 5 and 16 years of age are summarized in TABLE 2.

TABLE 2. Mean (% CV) Pharmacokinetic Parameters for REBETOL When Administered to Pediatric Patients with Chronic Hepatitis C

Parameter 12 mg/kg/day as 2 divided doses
(n=19)
15 mg/kg/day as 2 divided doses
(n=19)
Tmax (hr) 1.4 (60) 1.9 (81)
Cmax (ng/mL) 2705 (17) 3243 (24)
AUC12 (ng*hr/mL) 25049 (16) 29620 (25)
Apparent Clearance (L/hr/kg) 0.25 (16) 0.27 (25)

Elderly Patients

Pharmacokinetic evaluations for elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

* In this section of the label, numbers in parenthesis indicate % coefficient of variation.

Description of Clinical Studies

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 multicenter, double-blind trials (US and International) and randomized to receive REBETOL 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 3.

TABLE 3. Virologic and Histologic Responses: Previously Untreated Patients*

  US Study International Study
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment
INTRON A
plus REBETOL
(N=228)
INTRON A
plus Placebo
(N=231)
INTRON A
plus REBETOL
(N=228)
INTRON A
plus Placebo
(N=225)
INTRON A
plus REBETOL
(N=265)
INTRON A
plus REBETOL
(N=268)
INTRON A
plus Placebo
(N=266)
Virologic Response
   -Responder1 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
   -Improvement2 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)
* Number (%) of Patients.
1 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
2 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥ 2 points.

Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV genotype 1 treated with REBETOL/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 REBETOL/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 REBETOL 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 4.

TABLE 4. Virologic and Histologic Responses: Relapse Patients*

  US Study International Study
INTRON A
plus REBETOL
N=77
INTRON A
plus Placebo
N=76
INTRON A
plus REBETOL
N=96
INTRON A
plus Placebo
N=96
Virologic Response
   -Responder1 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
   -Improvement2 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)
* Number (%) of Patients.
1 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
2 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥ 2 points.

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

Animal Toxicology

Long-term studies in the mouse and rat (18 - 24 months; doses of 20 - 75 and 10 - 40 mg/kg/day, respectively [estimated human equivalent doses of 1.67 - 6.25 and 1.43 - 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 - 0.4 X 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.

Last reviewed on RxList: 3/3/2009
This monograph has been modified to include the generic and brand name in many instances.

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