Rebetol (Ribavirin) - Indications and Dosage

INDICATIONS AND USAGE

Adult Use

REBETOL® (ribavirin, USP) Capsules and Oral Solution are indicated in combination with INTRON® A (interferon alfa-2b, recombinant) for 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 and in patients 18 years of age and older who have relapsed following alpha interferon therapy.

REBETOL Capsules are indicated in combination with PegIntron™ (peginterferon alfa-2b) Powder for Injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

The safety and efficacy of REBETOL Capsules or Oral Solution with interferons other than INTRON A or PegIntron products have not been established.

Pediatric Use

REBETOL (ribavirin, USP) Capsules are indicated in combination with INTRON A for Injection for the treatment of chronic hepatitis C in patients 5 years of age and older with compensated liver disease previously untreated with alpha interferon and in patients who have relapsed following alpha interferon therapy.

REBETOL (ribavirin, USP) Oral Solution is indicated in combination with INTRON A for Injection for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease previously untreated with alpha interferon and in patients who have relapsed following alpha interferon therapy.

Evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load, should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed (see PRECAUTIONS, Pediatric Use section) for pediatric subjects in the clinical trials.

Description of Clinical Studies

REBETOL/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 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 for Injection 3 MIU TIW or INTRON A for 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 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 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
-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 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 PatientsNumber (%) of 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
-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.

Pediatric Patients

Pediatric patients 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 REBETOL 15 mg/kg per day plus INTRON A 3 MIU/m² TIW for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 patients received treatment who were 57% male, 80% Caucasian, and 78% genotype 1. Patients <5 years of age received REBETOL Oral Solution and those ≥5 years of age received either REBETOL Oral Solution or Capsules.

Study results are summarized in TABLE 5.

TABLE 5. Virologic Response: Previously Untreated Pediatric PatientsNumber (%) of patients

	INTRON A 3 MIU/m2 TIW Plus REBETOL 15 mg/kg/day
Overall ResponseDefined as HCV RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period. (N=118)	54 (46)
Genotype 1 (N=92)	33 (36)
Genotype non-1 (N=26)	21 (81)

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

REBETOL/PegIntron Combination Therapy

A randomized study compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PegIntron 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/REBETOL 1000/1200 mg PO daily (in divided doses)] with INTRON A [3 MIU SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve patients were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment (see TABLE 6).

TABLE 6. Rates of Response to Combination Treatment

	PegIntron 1.5µg/kg QW REBETOL 800 mg QD	INTRON A 3 MIU TIW REBETOL 1000/1200mg QD
Overall responseSerum HCV RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory., Difference in overall treatment response (PegIntron/REBETOL vs. INTRON A/REBETOL) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline.	52% (264/511)	46% (231/505)
Genotype 1	41% (141/348)	33% (112/343)
Genotype 2–6	75%(123/163)	73% (119/162)

The response rate to PegIntron 1.5→0.5µg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 µg/kg)/REBETOL combination therapy compared to patients with other viral genotypes. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/REBETOL combination therapy.

Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/REBETOL combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline approximately 2/3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

DOSAGE AND ADMINISTRATION

(see CLINICAL PHARMACOLOGY, Special Populations section and WARNINGS)

REBETOL®/INTRON® A Combination Therapy

Adults

The recommended dose of REBETOL Capsules depends on the patient's body weight. The recommended dose of REBETOL is provided in TABLE 11.

The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen (see INDICATIONS AND USAGE, Description of Clinical Studies section and ADVERSE REACTIONS). After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following non-pegylated interferon monotherapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

TABLE 11. Recommended Dosing

Body weight	REBETOL Capsules
≤ 75 kg	2 × 200-mg capsules AM, 3 × 200-mg capsules PM daily p.o.
> 75 kg	3 × 200-mg capsules AM, 3 × 200-mg capsules PM daily p.o.

Pediatrics

The recommended dose of REBETOL is 15 mg/kg per day orally (divided dose AM and PM). For children weighing ≤25 kg or who cannot swallow capsules, REBETOL Oral Solution is supplied in a concentration of 40 mg/mL. For children weighing >25 kg, either the Oral Solution or 200-mg capsule may be administered. Refer to TABLE 12 for dosing recommendations for the 200-mg capsule to achieve the recommended dose.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in pediatrics.

TABLE 12. Pediatric Dosing

Body weight	REBETOL Capsules	INTRON A for Injection
25–36 kg	1 × 200-mg capsule AM 1 × 200-mg capsule PM daily p.o.	3 million IU/m2 3 times weekly s.c.
37–49 kg	1 × 200-mg capsule AM 2 × 200-mg capsules PM daily p.o.	3 million IU/m2 3 times weekly s.c.
50–61 kg	2 × 200-mg capsules AM 2 × 200-mg capsules PM daily p.o.	3 million IU/m2 3 times weekly s.c.
>61 kg	Refer to adult dosing table	Refer to adult dosing table

REBETOL may be administered without regard to food, but should be administered in a consistent manner with respect to food intake (see CLINICAL PHARMACOLOGY).

Under no circumstances should REBETOL Capsules be opened, crushed, or broken (see CONTRAINDICATIONS and WARNINGS).

REBETOL/PegIntron Combination Therapy

The recommended dose of REBETOL Capsules is 800 mg/day in 2 divided doses: two capsules (400 mg) in the morning with food and two capsules (400 mg) in the evening with food.

Dose Modifications

(TABLE 13)

If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, REBETOL/INTRON A therapy should be discontinued.

REBETOL should not be used in patients with creatinine clearance <50 mL/min. Subjects with impaired renal function and/or those over the age of 50 should be carefully monitored with respect to development of anemia (see CLINICAL PHARMACOLOGY, Special Populations section and WARNINGS).

REBETOL should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped (see WARNINGS).

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose reduced to 600 mg daily (1 × 200-mg capsule AM, 2 × 200 mg capsules PM) for adults and 7.5 mg/kg per day (divided dose AM and PM) for pediatric patients. A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL therapy (see WARNINGS).

TABLE 13. Guidelines for Dose Modifications and Discontinuation for Anemia

	Dose Reduction REBETOL – 600 mg daily adults 7.5 mg/kg daily for pediatrics	Permanent Discontinuation of REBETOL Treatment
Hemoglobin
No Cardiac History	<10 g/dL	<8.5 g/dL
Cardiac History Patients	≥ 2 g/dL decrease during any 4- week period during treatment	<12 g/dL after 4 weeks of dose reduction

HOW SUPPLIED

REBETOL® 200-mg Capsules are white, opaque capsules with REBETOL, 200 mg, and the Schering Corporation logo imprinted on the capsule shell; the capsules are packaged in a bottle containing 42 capsules (NDC 0085-1327-04), 56 capsules (NDC 0085-1351-05), 70 capsules (NDC 0085-1385-07), and 84 capsules (NDC 0085-1194-03).

REBETOL Oral Solution 40 mg/mL is a clear, colorless to pale or light yellow bubble gum-flavored liquid and it is packaged in 4-oz amber glass bottles (100 mL/bottle) with child-resistant closures (NDC 0085-1318-01).

Storage Conditions

The bottle of REBETOL Capsules should be stored at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

REBETOL Oral Solution should be stored between 2°–8°C (36°–46°F) or at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

U.S. Patent Nos. 5,767,097; 5,914,128; 6,051,252; 6,063,772; 6,172,046; 6,177,074; 6,335,032; 6,337,090; 6,461,605; 6,472,373; and 6,524,570.
Copyright © 2003 Schering Corporation. All rights reserved.

B-XXXXXXXX Rev. 12/07