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REBETOL ® (ribavirin, interferon alfa-2b, recombinant)
REBETOL is Schering Corporations brand name for ribavirin, a nucleoside analog with antiviral activity. The chemical name of ribavirin is 1-J-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8H12N4O5 and the molecular weight is 244.21.
REBETOL Capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin, sodium lauryl sulfate, silicon dioxide, and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD& C Blue #2 aluminum lake.
INTRON ® A
INTRON A is Schering Corporations brand name for interferon alfa-2b, recombinant, a purified, sterile, recombinant interferon product.
Interferon alfa-2b, recombinant has been classified as an alpha interferon and is a water-soluble protein composed of 165 amino acids with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon alfa-2b gene from human leukocytes. The fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable in the final product.
INTRON A Injection is a clear, colorless solution. The 3 million IU vial of INTRON A Injection contains 3 million IU of interferon alfa-2b, recombinant per 0.5 mL. The 18 million IU multidose vial of INTRON A Injection contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL (3 million IU/0.5 mL) in order to provide the delivery of six 0.5 mL doses, each containing 3 million IU of INTRON A (for a label strength of 18 million IU). The 18 million IU INTRON A Injection multidose pen contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL (3 million IU/0.2 mL) in order to provide the delivery of six 0.2 mL doses, each containing 3 million IU of Intron A (for a label strength of 18 million IU). Each mL also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.
Based on the specific activity of approximately 2.6 x 10 IU/mg protein as measured by HPLC assay, the corresponding quantities of interferon alfa-2b, recombinant in the vials and pen described above are approximately 0.012 mg, 0.088 mg, and 0.087 mg protein, respectively.
Mechanism of Action
Ribavirin/Interferon alfa-2b, recombinant The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with REBETOL and INTRON A has not been established.
REBETOL (ribavirin, USP) Capsules is indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy.
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 £75kg) 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 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
-Responder 1 -Nonresponder -Missing Data |
65(29) 147(64) 16(7) |
13(6) 194(84) 24(10) |
85(37) 110(48) 33(14) |
27(12) 168(75) 30(13) |
86(32) 158(60) 21(8) |
113(42) 120(45) 35(13) |
46(17) 196(74) 24(9) |
| Histologic Response
-Improvement2 -No improvement -Missing Data |
102(45) 77(34) 49(21) |
77(33) 99(43) 55(24) |
96(42) 61(27) 71(31) |
65(29) 93(41) 67(30) |
103(39) 85(32) 77(29) |
102(38) 58(22) 108(40) |
69(26) 111(41) 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 ³2 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 non-genotype 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 3 .
Table 3. 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 -Nonresponder -Missing Data |
33(43) 36(47) 8(0) |
3(4) 66(87) 7(9) |
46(48) 45(47) 5(5) |
5(5) 91(95) 0(0) |
| Histologic Response
-Improvement2 -No improvement -Missing Data |
38(49) 23(30) 16(21) |
27(36) 37(49) 12(16) |
49(51) 29(30) 18(19) |
30(31) 44(46) 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 post treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points.
Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.
INTRON A Injection should be administered subcutaneously and Rebetol Capsules should be administered orally (see Table 6).
The recommended dose of REBETOL Capsules depends on the patients body weight. The recommended doses of Rebetol and INTRON A are given in Table 6.
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
Description of Clinical Studies 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 interferon therapy, 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 6. Recommended Dosing
| Body weight | REBETOL Capsules | INTRON A Injection |
| £ 75 kg | 2 x 200 mg capsules Am,
3 x 200 mg capsules PM daily p.o. | 3 million IU 3 times weekly s. c. |
| > 75 kg | 3 x 200 mg capsules AM,
3 x 200 mg capsules PM, daily p.o. | 3 million IU 3 times weekly s. c. |
REBETOL may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.)
Dose Modifications ( TABLE 7 )
In clinical trials, approximately 26% of patients required modification of their dose of REBETOL Capsules, INTRON A Injection, or both agents. 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/INTRON A therapy 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 ³2 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 x 200 mg capsule AM , 2 x 200 mg capsules PM ). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL/INTRON A therapy. (See WARNINGS.)
It is recommended that a patient who experiences moderate depression (persistent low mood, loss of interest, p.o. self image, and/or hopelessness) have his/her INTRON A dose temporarily reduced and/or be considered for medical therapy. A patient experiencing severe depression or suicidal ideation/attempt should be discontinued from REBETOL/INTRON A therapy and followed closely with appropriate medical management. (See WARNINGS.)
TABLE 7. Guidelines for Dose Modifications
| Dose Reduction *
REBETOL - 600 mg daily INTRON A - 1.5 million IU TIW | Permanent Discontinuation of Treatment
REBETOL and INTRON A | |
| Hemoglobin |
