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REBETRON™ (rebetol and intron a combination therapy)
Combination Therapy containing
REBETOL® (ribavirin, USP) Capsules and INTRON® A (interferon alfa-2b, recombinant) Injection
CONTRAINDICATIONS AND WARNINGS
Combination REBETOL/INTRON A therapy is contraindicated in females who are pregnant and in the male partners of females who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in female patients, and in female partners of male patients who are taking combination REBETOL/INTRON A therapy. Females of childbearing potential and males must use two reliable forms of effective contraception during treatment and during the 6-month posttreatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species studied. See CONTRAINDICATIONS and WARNINGS. REBETOL monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication. See WARNINGS.
Alpha interferons, including INTRON® A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping INTRON A therapy. See WARNINGS, and ADVERSE REACTIONS.
REBETOL is Schering Corporation's brand name for ribavirin, a nucleoside analog with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:
 |
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, 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 is Schering Corporation's 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 108 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.
The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with REBETOL and INTRON A has not been established.
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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.
INTRON A Injection should be administered subcutaneously and REBETOL Capsules should be administered orally. REBETOL may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.)
The recommended dose of REBETOL Capsules depends on the patient's body weight. The recommended doses of REBETOL and INTRON A for adults are given in TABLE 7.
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 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 7. Recommended Adult 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. |
Efficacy of REBETOL and INTRON A for pediatric patients has not been established. Based on pharmacokinetic data, the following doses of REBETOL and INTRON A provide similar exposures in pediatric patients as observed in adult patients treated with the approved doses of REBETOL and INTRON A (see TABLE 8).
Table 8. Pediatric Dosing
| Body weight | REBETOL Capsules | INTRON A Injection |
| 25-36 kg | 1 x 200 mg capsule AM 1 x 200 mg capsule PM daily p.o. |
3 million IU/m² 3 times weekly s.c. |
| 37-49 kg | 1 x 200 mg capsule AM 2 x 200 mg capsules PM daily p.o. |
3 million IU/m² 3 times weekly s.c. |
| 50-61 kg | 2 x 200 mg capsules AM 2 x 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 |
Under no circumstances should REBETOL capsules be opened, crushed or broken (see CONTRAINDICATIONS and WARNINGS).
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 ≥ 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 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, poor 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 9. Guidelines for Dose Modifications
| Dose Reduction* REBETOL – Adults 600 mgdaily Pediatrics: half the dose INTRON A – Adults 1.5 million IU TIW Pediatrics: 1.5 million IU/m² TIW |
Permanent Discontinuation of Treatment REBETOL and INTRON A |
|
| Hemoglobin | < 10 g/dL (REBETOL) Cardiac History Patients only. ≥ 2 g/dL decrease during any 4-week period during treatment (REBETOL/INTRON A) | < 8.5 g/dL Cardiac History Patients only. < 12 g/dL after 4 weeks of dose reduction |
| White blood count | < 1.5 x 109/L (INTRON A) | < 1.0 x 109/L |
| Neutrophil count | < 0.75 x 109/L (INTRON A) | < 0.5 x 109/L |
| Platelet count | Adults: < 50 x 109/L (INTRON A) Pediatrics: < 80 x 109/L (INTRONA) |
Adults: < 25 x 109/L Pediatrics: < 50 x 109/L |
| *Study medication to be dose reduced is shown in parenthesis | ||
At the discretion of the physician, the patient may self-administer the INTRON A. (See illustrated MEDICATION GUIDE for instructions.)
The Intron A Injection is supplied as a clear and colorless solution. The appropriate INTRON A dose should be withdrawn from the vial or set on the multidose pen and injected subcutaneously. The INTRON A Injection supplied with the B-D Safety Lok™ syringes contain a plastic sleeve to be pulled over the needle after use. The syringe locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle. After administration of INTRON A Injection, it is essential to follow the procedure for proper disposal of syringes and needles. (See MEDICATION GUIDE for detailed instructions.)
| Vial/Pen Label Strength | Fill Volume | Concentration |
| 3 million IU vial | 0.5 mL | 3 million IU/0.5 mL |
| 18 million IU multidose vial† | 3.8 mL | 3 million IU/0.5 mL |
| 18 million IU multidose pen† † | 1.5 mL | 3 million IU/0.2 mL |
| † This is a multidose vial
which contains a total of 22.8 million IU of interferon alfa-2b, recombinant
per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each
containing 3 million IU of interferon alfa-2b, recombinant (for a label
strength of 18 million IU). † † This is a multidose pen which contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide the delivery of six 0.2-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU). |
||
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INTRON A Injection may be administered using either sterilized glass or plastic disposable syringes.
INTRON A Injection provided in vials is stable at 35°C (95°F) for up to 7 days and at 30°C (86°F) for up to 14 days. INTRON A Injection provided in a multidose pen is stable at 30°C (86°F) for up to 2 days. The solution is clear and colorless.
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.
INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.
INTRON A Injection and REBETOL Capsules are available in the following combination package presentations:
| Each REBETRON Combination Package Consists of: | ||
| For Patients ≤ 75 kg | A box containing 6 vials of INTRON A Injection (3 million IU in 0.5 mL per vial), 6 syringes, alcohol swabs and one bottle containing 70 REBETOL Capsules . | (NDC 0085-1241-02) |
| One 18 million IU multidose vial of INTRON A Injection (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL), 6 syringes, alcohol swabs and one bottle containing 70 REBETOL. | (NDC 0085-1236-02) | |
| One 18 million IU INTRON A Injection multidose pen (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL), 6 disposable needles, alcohol swabs and one bottle containing 70 REBETOL Capsules. | (NDC 0085-1258-02) | |
| For Patients > 75 kg | A box containing 6 vials of INTRON A Injection (3 million IU in 0.5 mL per vial), 6 syringes, alcohol swabs and one bottle containing 84 REBETOL Capsules. | (NDC 0085-1241-01) |
| One 18 million IU multidose vial of INTRON A Injection (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL), 6 syringes, alcohol swabs and one bottle containing 84 REBETOL Capsules. | (NDC 0085-1236-01) | |
| One 18 million IU INTRON A Injection multidose pen (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL), 6 disposable needles, alcohol swabs, and one bottle containing 84 REBETOL Capsules. | (NDC 0085-1258-01) | |
| For REBETOL Dose Reduction | A box containing 6 vials of INTRON A Injection (3 million IU in 0.5 mL per vial), 6 syringes, alcohol swabs, and one bottle containing 42 REBETOL Capsules. | (NDC 0085-1241-03) |
| One 18 million IU multidose vial of INTRON A Injection (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL), 6 syringes, alcohol swabs and one bottle containing 42 REBETOL Capsules. | (NDC 0085-1236-03) | |
| One 18 million IU INTRON A Injection multidose pen (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL), 6 disposable needles, alcohol swabs and one bottle containing 42 REBETOL Capsules. | (NDC 0085-1258-03) | |
Store the REBETOL Capsules plus INTRON A Injection combination package refrigerated between 2° C and 8° C (36° and 46° F).
When separated, the individual bottle of REBETOL Capsules should be stored refrigerated between 2° and 8° C (36° and 46° F) or at 25° C (77° F); excursions are permitted between 15° and 30° C (59° and 86° F).
When separated, the individual vials of INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8° C (36° and 46° F).
12/21/01. Schering Corporation, Kenilworth, NJ 07033 USA.
The safety of combination REBETOL/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination REBETOL/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination REBETOL/INTRON A therapy. (See Description of Clinical Studies.) Overall, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-2 weeks of therapy (see WARNINGS). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with REBETOL/INTRON A therapy. (See WARNINGS.)
The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with REBETOL/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. (See WARNINGS.) In addition, the following spontaneous adverse events have been reported during the marketing surveillance of REBETOL/INTRON A therapy: hearing disorder and vertigo. Very rarely, combination REBETOL/INTRON A therapy may be associated with aplastic anemia.
Selected treatment-emergent adverse events that occurred in the US studies with ≥ 5% incidence are provided in TABLE 5 by treatment group. In general, the selected treatment-emergent adverse events reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.
TABLE 5. Selected Treatment-Emergent Adverse Events: Previously
Untreated and Relapse Patients
| Patients Reporting Adverse Events* | Percentage of Patients | |||||
| US Previously Untreated Study | US Relapse Study | |||||
| 24 weeks of treatment | 48 weeks of treatment | 24 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=77) |
INTRON A plus Placebo (N=76) |
|
| Application Site Disorders | ||||||
| injection site inflammation | 13 | 10 | 12 | 14 | 6 | 8 |
| injection site reaction | 7 | 9 | 8 | 9 | 5 | 3 |
| Body as a Whole - General Disorders | ||||||
| headache | 63 | 63 | 66 | 67 | 66 | 68 |
| fatigue | 68 | 62 | 70 | 72 | 60 | 53 |
| rigors | 40 | 32 | 42 | 39 | 43 | 37 |
| fever | 37 | 35 | 41 | 40 | 32 | 36 |
| influenza-like symptoms | 14 | 18 | 18 | 20 | 13 | 13 |
| asthenia | 9 | 4 | 9 | 9 | 10 | 4 |
| chest pain | 5 | 4 | 9 | 8 | 6 | 7 |
| Central & Peripheral Nervous System Disorders | ||||||
| dizziness | 17 | 15 | 23 | 19 | 26 | 21 |
| Gastrointestinal System Disorders | ||||||
| nausea | 38 | 35 | 46 | 33 | 47 | 33 |
| anorexia | 27 | 16 | 25 | 19 | 21 | 14 |
| dyspepsia | 14 | 6 | 16 | 9 | 16 | 9 |
| vomiting | 11 | 10 | 9 | 13 | 12 | 8 |
| Musculoskeletal System Disorders | ||||||
| myalgia | 61 | 57 | 64 | 63 | 61 | 58 |
| arthralgia | 30 | 27 | 33 | 36 | 29 | 29 |
| musculoskeletal pain | 20 | 26 | 28 | 32 | 22 | 28 |
| Psychiatric Disorders | ||||||
| insomnia | 39 | 27 | 39 | 30 | 26 | 25 |
| irritability | 23 | 19 | 32 | 27 | 25 | 20 |
| depression | 32 | 25 | 36 | 37 | 23 | 14 |
| emotional lability | 7 | 6 | 11 | 8 | 12 | 8 |
| concentration impaired | 11 | 14 | 14 | 14 | 10 | 12 |
| nervousness | 4 | 2 | 4 | 4 | 5 | 4 |
| Respiratory System Disorders | ||||||
| dyspnea | 19 | 9 | 18 | 10 | 17 | 12 |
| sinusitis | 9 | 7 | 10 | 14 | 12 | 7 |
| Skin and Appendages Disorders | ||||||
| alopecia | 28 | 27 | 32 | 28 | 27 | 26 |
| rash | 20 | 9 | 28 | 8 | 21 | 5 |
| pruritus | 21 | 9 | 19 | 8 | 13 | 4 |
| Special Senses, Other Disorders | ||||||
| taste perversion | 7 | 4 | 8 | 4 | 6 | 5 |
| * Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category. | ||||||
Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during combination REBETOL/INTRON A treatment are described below (see TABLE 6).
Hemoglobin decreases among patients on combination therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 - 8 weeks of cessation of therapy in most patients.
There were decreases in neutrophil counts in both the combination REBETOL/INTRON A and INTRON A plus placebo dose groups. In previously untreated patients treated for 48 weeks the mean maximum decrease in neutrophil count in the US study was 1.3 x 109 /L and in the International study was 1.5 x 109 /L. In relapse patients the mean maximum decrease in neutrophil count in the US study was 1.3 x 109 /L and in the International study was 1.6 x 109 /L. Neutrophil counts returned to pretreatment levels within 4 weeks of cessation of therapy in most patients.
In both previously untreated and relapse patients mean platelet counts generally remained in the normal range in all treatment groups, however, mean platelet counts were 10% to 15% lower in the INTRON A plus placebo group than the REBETOL/INTRON A group. Mean platelet counts returned to baseline levels within 4 weeks after treatment discontinuation.
Of patients who entered the previously untreated (24 and 48 week treatment) and relapse (24 week treatment) studies without thyroid abnormalities, approximately 3% to 6% and 1% to 2%, respectively, developed thyroid abnormalities requiring clinical intervention.
Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.
TABLE 6. Selected Hematologic Values During Treatment with
REBETOL plus INTRON A: Previously Untreated and Relapse Patients
| Percentageof Patients | ||||||
| US Previously Untreated Study | US Relapse Study | |||||
| 24weeks of treatment | 48 weeks of treatment | 24 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=77) |
INTRON A plus Placebo (N=76) |
|
| Hemoglobin (g/dL) | ||||||
| 9.5-10.9 | 24 | 1 | 32 | 1 | 21 | 3 |
| 8.0-9.4 | 5 | 0 | 4 | 0 | 4 | 0 |
| 6.5-7.9 | 0 | 0 | 0 | 0.4 | 0 | 0 |
| < 6.5 | 0 | 0 | 0 | 0 | 0 | 0 |
| Leukocytes (x109/L) | ||||||
| 2.0-2.9 | 40 | 20 | 38 | 23 | 45 | 26 |
| 1.5-1.9 | 4 | 1 | 9 | 2 | 5 | 3 |
| 1.0-1.4 | 0.9 | 0 | 2 | 0 | 0 | 0 |
| < 1.0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neutrophils (x109/L) | ||||||
| 1.0-1.49 | 30 | 32 | 31 | 44 | 42 | 34 |
| 0.75-0.99 | 14 | 15 | 14 | 11 | 16 | 18 |
| 0.5-0.74 | 9 | 9 | 14 | 7 | 8 | 4 |
| < 0.5 | 11 | 8 | 11 | 5 | 5 | 8 |
| Platelets (x109/L) | ||||||
| 70-99 | 9 | 11 | 11 | 14 | 6 | 12 |
| 50-69 | 2 | 3 | 2 | 3 | 0 | 5 |
| 30-49 | 0 | 0.4 | 0 | 0.4 | 0 | 0 |
| < 30 | 0.9 | 0 | 1 | 0.9 | 0 | 0 |
| Total Bilirubin (mg/dL) | ||||||
| 1.5 -3.0 | 27 | 13 | 32 | 13 | 21 | 7 |
| 3.1-6.0 | 0.9 | 0.4 | 2 | 0 | 3 | 0 |
| 6.1-12.0 | 0 | 0 | 0.4 | 0 | 0 | 0 |
| > 12.0 | 0 | 0 | 0 | 0 | 0 | 0 |
Administration of nucleoside analogues has resulted in fatal and nonfatal lactic acidosis. Coadministration of ribavirin and nucleoside analogues should be undertaken with caution and only if the potential benefit outweighs the potential risks.
Category X, may cause birth defects. See BOXED CONTRAINDICATIONS AND WARNINGS. See CONTRAINDICATIONS.
HEMOLYTIC ANEMIA (HEMOGLOBIN < 10 G/DL) WAS OBSERVED IN APPROXIMATELY 10% OF REBETOL/INTRON A-TREATED PATIENTS IN CLINICAL TRIALS (SEE ADVERSE REACTIONS LABORATORY VALUES - HEMOGLOBIN). ANEMIA OCCURRED WITHIN 1 - 2 WEEKS OF INITIATION OF RIBAVIRIN THERAPY. BECAUSE OF THIS INITIAL ACUTE DROP IN HEMOGLOBIN, IT IS ADVISED THAT COMPLETE BLOOD COUNTS (CBC) SHOULD BE OBTAINED PRETREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. PATIENTS SHOULD THEN BE FOLLOWED AS CLINICALLY APPROPRIATE.
The anemia associated with REBETOL/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (See DOSAGE AND ADMINISTRATION.) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use combination REBETOL/INTRON A therapy. (See ADVERSE REACTIONS.)
Similarly, patients with hemoglobinopathies (eg, thalassemia, sickle-cell anemia) should not be treated with combination REBETOL/INTRON A therapy.
Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides) and rare instances of homicidal ideation have occurred during combination Rebetol/Intron A therapy, both in patients with and without a previous psychiatric disorder. Rebetol/Intron A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders, and all patients should be carefully monitored for evidence of depression and other psychiatric symptoms. Suspension of Rebetol/Intron A therapy should be considered if psychiatric intervention and/or dose reduction is unsuccessful in controlling psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention sought. (See ADVERSE REACTIONS.)
INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil ( < 0.5 x 109/L) or platelet counts ( < 25 x 109/L) (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications).
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with REBETOL/INTRON A; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination REBETOL/INTRON A treatment should be discontinued.
Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). REBETOL/INTRON A therapy should be used with caution in patients with other autoimmune disorders.
There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore, combination REBETOL/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.
The safety and efficacy of REBETOL/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.
The safety and efficacy of REBETOL Capsule monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and REBETOL Capsules should not be used for these indications.
There is no information regarding the use of REBETOL Capsules with other interferons.
Elevated triglyceride levels have been observed in patients treated with interferon including REBETOL/INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. Severe hypertriglyceridemia (triglycerides > 1000 mg/dL) may result in pancreatitis. Discontinuation of REBETOL/INTRON A therapy should be considered for patients with persistently elevated triglycerides (triglycerides > 1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting (see WARNINGS - Other).
Combination REBETOL/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination REBETOL/INTRON A therapy. Combination REBETOL/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Females of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during combination REBETOL/INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS.)
If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians are encouraged to report such cases by calling (800) 727-7064.
Patients receiving combination REBETOL/INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the patient MEDICATION GUIDE. There are no data evaluating whether REBETOL/INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with REBETOL/INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.
If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see MEDICATION GUIDE). To avoid possible transmission of disease, do not share your multidose pen with anyone; it is for you and you alone.
The most common adverse experiences occurring with combination REBETOL/INTRON A therapy are “flu-like&rdqo; symptoms, such as headache, fatigue, myalgia, and fever (see ADVERSE REACTIONS) and appear to decrease in severity as treatment continues. Some of these “flu-like” symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair.
Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.
The following laboratory tests are recommended for all patients on combination REBETOL/INTRON A therapy, prior to beginning treatment and then periodically thereafter.
Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.
Adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted. However, ribavirin is a nucleoside analog that has produced positive findings in multiple in vitro and animal in vivo genotoxicity assays, and should be considered a potential carcinogen. Further studies to assess the carcinogenic potential of ribavirin in animals are ongoing.
Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. 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 20-200 mg/kg (estimated human equivalent of 1.67 - 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 - 1 X 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.
No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa-2b recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in females treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.
Fertile females and partners of fertile females should not receive combination REBETOL/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2 ) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (eg, 15 half-lives of clearance for ribavirin).
Combination REBETOL/INTRON A therapy should be used with caution in fertile males. 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 - 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 - 0.8 X 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.
(see CONTRAINDICATIONS) Interferon alfa-2b, recombinant has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant females.
Ribavirin produced significant embryocidal and/or teratogenic effects 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 X 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 X the maximum recommended human 24-hour dose of ribavirin).
Potential Risk to the Fetus Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 - 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 X the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Females of childbearing potential should not receive combination REBETOL/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t1/2 ) of ribavirin of 12 days.
Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination REBETOL/INTRON A therapy and for the 6-month posttherapy period (eg, 15 half-lives for ribavirin clearance from the body).
If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling (800) 727-7064.
It is not known whether REBETOL and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or to discontinue combination REBETOL/INTRON A therapy, taking into account the importance of the therapy to the mother.
One hundred twenty-five pediatric patients between three and sixteen years of age with chronic hepatitis C virus infection (median duration 10.7 years) received REBETOL Capsules with INTRON A for up to 48 weeks. The overall sustained response rate cannot be calculated since all patients have not yet completed 24-weeks of off-therapy follow-up.
Suicidal ideation or attempts occurred more frequently among pediatric patients compared to adult patients (2.4% versus 1%) during treatment and off therapy follow-up (see WARNINGS). As in adult patients, pediatric patients experienced other psychiatric adverse events (e.g., depression, emotional lability, somnolence), anemia, and neutropenia (see WARNINGS). During a 48 week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24 week post treatment period.
Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients compared to adult patients. Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritis compared to adult patients.
Clinical studies of REBETRON (rebetol and intron a combination therapy) Combination Therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (see WARNINGS).
In general, REBETOL (ribavirin) should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of concomitant disease or other drug therapy.
REBETOL (ribavirin) is known to be substantially excreted by the kidney, and the risk of adverse reactions to ribavirin may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments of ribavirin should be made accordingly (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modification).
REBETOL should not be used in elderly patients with creatinine clearance < 50mL/min (see WARNINGS).
REBETRON (rebetol and intron a combination therapy) Combination Therapy should be used very cautiously in elderly patients with a history of psychiatric disorders (see WARNINGS).
There is limited experience with overdosage. Acute ingestion of up to 20 grams of REBETOL Capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and REBETOL. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.
There is no specific antidote for INTRON A or REBETOL, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of either agent.
Combination REBETOL/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination REBETOL/INTRON A therapy. Combination REBETOL/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential and males must use two forms of effective contraception during treatment and during the 6 months after treatment has been concluded. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL Capsules. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064. See BOXED CONTRAINDICATIONS AND WARNINGS. See WARNINGS.
REBETOL Capsules in combination with INTRON A Injection is contraindicated in patients with a history of hypersensitivity to ribavirin and/or alpha interferon or any component of the capsule and/or injection.
Patients with autoimmune hepatitis must not be treated with combination REBETOL/INTRON A therapy.
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.
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.
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.)
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.
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).
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.
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) |
Pharmacokinetic evaluations for elderly subjects have not been performed.
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.
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.
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.
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.
MEDICATION GUIDE
REBETRON Combination Therapy containing REBETOL (ribavirin, USP) Capsules INTRON A (interferon alfa-2b, recombinant) Injection
REBETRON (rebetol and intron a combination therapy) (REB-eh-tron) is the name for the combination of REBETOL (REB-eh-tole) and INTRON A (IN-tron aye). Read this medication guide carefully before you begin taking REBETRON (rebetol and intron a combination therapy) Combination Therapy, and each time you refill your prescription in case there is new information. This summary does not tell you everything about REBETRON (rebetol and intron a combination therapy) Combination Therapy. Your health care provider is the best source of information about these medicines. After reading this medication guide, talk with your health care provider if you have any questions about this treatment.
What is the most important information I should know about REBETRON (rebetol and intron a combination therapy) Combination Therapy?
What is REBETRON (rebetol and intron a combination therapy) Combination Therapy?
REBETRON (rebetol and intron a combination therapy) Combination Therapy is a treatment for some people who have chronic hepatitis C infection. It consists of two separate medicines, REBETOL Capsules (ribavirin) and INTRON A Injection (interferon), used in combination. INTRON A helps the body's immune system fight infections. “REBETOL” is the name given to the antiviral drug ribavirin made by Schering. It is not known how REBETOL and INTRON A work together to fight hepatitis C infection. REBETOL should not be used alone to treat chronic hepatitis C infection.
It is not known if treatment with REBETRON (rebetol and intron a combination therapy) Combination Therapy will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known if treatment with REBETRON (rebetol and intron a combination therapy) Combination Therapy will prevent you from infecting another person with the hepatitis C virus.
You should use REBETRON (rebetol and intron a combination therapy) Combination Therapy only if you have never been treated or your hepatitis C has returned after interferon therapy.
Who should not take REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Do not use these medicines if:
Tell your health care provider before starting REBETRON (rebetol and intron a combination therapy) Combination Therapy if you have any of the following medical conditions or other serious medical problems:
How should I take REBETRON (rebetol and intron a combination therapy) Combination Therapy?
The recommended dose of INTRON A Injection and REBETOL Capsules are shown in the table below.
| If your weight is: | Take this many REBETOL Capsules each day: | Inject this amount of INTRON A under your skin (subcutaneously) |
| 165 pounds or less | 2 capsules in the AM 3 capsules in the PM |
3 million international units 3times a week |
| More than 165 pounds | 3 capsules in the AM 3 capsules in the PM |
3 million international units 3times a week |
Ask your health care provider about the right amount of INTRON A Injection and REBETOL Capsules needed to treat a child with hepatitis C. This amount will depend on a child's weight.
Instructions on how to inject INTRON A are at the end of this Medication Guide.
What should I avoid while taking REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Talk with your health care provider about how to avoid pregnancy. If you or your sexual partner becomes pregnant while being treated with REBETRON (rebetol and intron a combination therapy) Combination Therapy or during the 6 months after treatment ends, you must report the pregnancy to your health care provider right away. Your health care provider should call toll-free 1-800-727-7064. Your health care provider will be asked to give follow-up information about the pregnancy. Any information about your pregnancy that is reported about you will be confidential.
What are the possible side effects of REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Harm to unborn children. REBETRON (rebetol and intron a combination therapy) Combination Therapy can harm your unborn child. It can cause birth defects and may kill your unborn child. (For more details, see “What is the most important information I should know about REBETRON (rebetol and intron a combination therapy) Combination Therapy?” at the beginning of this Medication Guide.)
Tell your health care provider right away if you have any of the following symptoms. They may be signs of a serious side effect:
What are the most common side effects of REBETRON (rebetol and intron a combination therapy) Combination Therapy?
This summary does not include all possible side effects of combination therapy. You should talk to your health care provider, if you do not feel well while taking REBETOL and INTRON A. Your health care provider can give you more information about managing your side effects.
What should I know about the hepatitis C virus?
Hepatitis C infection is a disease caused by a virus that infects the liver. This liver infection becomes a continuing (chronic) condition in most patients. Patients with chronic hepatitis C infection may develop cirrhosis, liver cancer, and liver failure. The virus is spread from one person to another by contact with the infected person's blood. You should talk to your health care provider about ways to prevent you from infecting others.
How do I Inject INTRON A?
Preparing the INTRON A Dose
IMPORTANT: Before each use, the liquid in the vial (small bottle) should be clear, colorless to light yellow, and without particles. Do not use the medicine if you see particles or the color is not correct. Call your doctor, nurse, or pharmacist to find out what to do if this happens.
1. Check the date printed on the INTRON A carton to make sure that the expiration date has not passed.
2. Wash your hands well and remove the protective plastic cap from the top of the INTRON A vial.
3. Remove the protective plastic wrapper from the syringe provided (Figure A). The safety sleeve should be tight against the flange for use and moved over the needle only when ready for disposal, as instructed in step 6.
Figure A
 |
4. Clean the rubber stopper on the top of the INTRON A vial with an alcohol swab.
5. Remove the protective cap from the syringe needle. Ensure safety sleeve is pushed firmly against the syringe flange so that the needle is fully exposed. Fill the syringe with air by pulling the plunger to the level that represents your correct dose. (Figure B).
Figure B
 |
6. Hold the INTRON A vial upright without touching the cleaned top of the vial with your hands (Figure C).
Figure C
 |
7. Insert the needle into the vial containing the INTRON A solution and inject the air into the vial (Figure D).
Figure D
 |
8. Turn vial and syringe upside down in one hand. Be sure tip of needle is in the INTRON A solution. Your other hand will be free to move the plunger. Pull back on plunger slowly to draw the correct dose into syringe (Figure E).
Figure E
 |
9. Remove the needle from the vial (Figure F) and check for air bubbles in the syringe. If you see any bubbles, tap the syringe gently. Then, with the needle pointing up, push the plunger slowly until the bubbles disappear.
Figure F
 |
10. Replace the needle cap. If the solution is cold, warm the syringe between your hands. Lay the syringe down on a flat surface so that needle does not touch anything.
Subcutaneous (under the skin) Injection
1. Select the site for injection
 |
Use an alcohol swab to cleanse the skin where the injection is to be made. Wait for area to dry.
2. Remove the cap from the needle. Ensure the safety sleeve is pushed firmly against the syringe flange so that the needle is fully exposed. Hold the syringe with one hand, as you would hold a pencil. With the other hand, pinch approximately a 2-inch fold of loose skin.
3. With a quick dart-like motion, push the needle about 1/4 inch into the pinched skin at an angle of 45° to 90 °.
 |
After the needle is in, remove hand used to pinch skin and use it to hold syringe barrel. Pull back the plunger very slightly with one hand. If blood comes into the syringe, the needle has entered a blood vessel. Do not inject. Withdraw and discard needle and syringe as instructed in step 6 below. Prepare a new syringe and inject at a new site. (Follow steps 2 and 3.)
4. If blood does not appear in the syringe, gently push the plunger all the way down.
5. Hold an alcohol swab near the needle and pull the needle straight out of the skin. Press the alcohol swab over the injection site for several seconds. Do not massage (rub) the injection site. If there is bleeding, cover the area with an adhesive bandage.
6. After use, firmly grasp the safety sleeve and pull over the exposed needle until you hear a click, and the green stripe on the safety sleeve covers the red stripe on the needle.
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7. Use disposable syringe only once to ensure sterility of syringe and needle. Dispose of syringe and needle as directed.
Your health care professional should tell you about the proper handling and disposal of all syringes and needles and the importance of not reusing any syringes or needles.
Your health care professional should give you a container for throwing away used needles and syringes. Throw away the full container according to directions provided by your doctor.
8. After 2 hours, check injection site for signs of inflammation, such as redness, swelling, or tenderness. If there are signs of inflammation, contact your doctor.
Instructional leaflet and video are available through your health care provider.
How do I store my medications?
STORAGE OF REBETOL CAPSULES
REBETOL capsules should be stored in the refrigerator between 36° and 46° F (2° and 8° C) or at room temperature 77° F (25° C).
STORAGE OF INTRON A INJECTION VIAL
INTRON A Injection vial should be stored in the refrigerator between 36° and 46° F (2° and 8° C), not in the freezer.
General advice about prescription medicines
Do not use REBETOL Capsules or INTRON A for conditions for which they were not prescribed. If you have any concern about REBETRON (rebetol and intron a combination therapy) Combination Therapy, ask your health care provider. Your health care provider or pharmacist can give you information about REBETRON (rebetol and intron a combination therapy) Combination Therapy that was written for health care professionals. Do not give these medicines to other people, even if they have the same condition you have.
Ingredients:
REBETOL capsules contain ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin 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 contains interferon alfa-2b recombinant, sodium chloride, dibasic sodium phosphate, monobasic sodium phosphate, edetate disodium, polysorbate 80, m-cresol (as a preservative).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Combination Therapy containing REBETOL (ribavirin, USP) Capsules INTRON A (interferon alfa-2b, recombinant) Injection
REBETRON (rebetol and intron a combination therapy) (REB-eh-tron) is the name for the combination of REBETOL (REB-eh-tole) and INTRON A (IN-tron aye). Read this medication guide carefully before you begin taking REBETRON (rebetol and intron a combination therapy) Combination Therapy, and each time you refill your prescription in case there is new information. This summary does not tell you everything about REBETRON (rebetol and intron a combination therapy) Combination Therapy. Your health care provider is the best source of information about these medicines. After reading this medication guide, talk with your health care provider if you have any questions about this treatment.
What is the most important information I should know about REBETRON (rebetol and intron a combination therapy) Combination Therapy?
What is REBETRON (rebetol and intron a combination therapy) Combination Therapy?
REBETRON (rebetol and intron a combination therapy) Combination Therapy is a treatment for some people who have chronic hepatitis C infection. It consists of two separate medicines, REBETOL Capsules (ribavirin) and INTRON A Injection (interferon), used in combination. INTRON A helps the body's immune system fight infections. “REBETOL” is the name given to the antiviral drug ribavirin made by Schering. It is not known how REBETOL and INTRON A work together to fight hepatitis C infection. REBETOL should not be used alone to treat chronic hepatitis C infection.
It is not known if treatment with REBETRON (rebetol and intron a combination therapy) Combination Therapy will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known if treatment with REBETRON (rebetol and intron a combination therapy) Combination Therapy will prevent you from infecting another person with the hepatitis C virus.
You should use REBETRON (rebetol and intron a combination therapy) Combination Therapy only if you have never been treated or your hepatitis C has returned after interferon therapy.
Who should not take REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Do not use these medicines if:
Tell your health care provider before starting REBETRON (rebetol and intron a combination therapy) Combination Therapy if you have any of the following medical conditions or other serious medical problems:
How should I take REBETRON (rebetol and intron a combination therapy) Combination Therapy?
| If your weight is: | Take this many REBETOL Capsules each day: |
Inject this amount of INTRON A under your skin (subcutaneously) |
| 165 pounds or less | 2 capsules in the AM 3 capsules in the PM |
3 million international units 3times a week |
| More than 165 pounds | 3 capsules in the AM 3 capsules in the PM |
3 million international units 3times a week |
Instructions on how to inject INTRON A are at the end of this Medication Guide.
What should I avoid while taking REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Talk with your health care provider about how to avoid pregnancy. If you or your sexual partner becomes pregnant while being treated with REBETRON (rebetol and intron a combination therapy) Combination Therapy or during the 6 months after treatment ends, you must report the pregnancy to your health care provider right away. Your health care provider should call toll-free 1-800-727-7064. Your health care provider will be asked to give follow-up information about the pregnancy. Any information about your pregnancy that is reported about you will be confidential.
What are the possible side effects of REBETRON (rebetol and intron a combination therapy) Combination Therapy?
Harm to unborn children. REBETRON (rebetol and intron a combination therapy) Combination Therapy can harm your unborn child. It can cause birth defects and may kill your unborn child. (For more details, see “What is the most important information I should know about REBETRON (rebetol and intron a combination therapy) Combination Therapy?” at the beginning of this Medication Guide.)
Tell your health care provider right away if you have any of the following symptoms. They may be signs of a serious side effect:
What are the most common side effects of REBETRON (rebetol and intron a combination therapy) Combination Therapy?
This summary does not include all possible side effects of combination therapy. You should talk to your health care provider, if you do not feel well while taking REBETOL and INTRON A. Your health care provider can give you more information about managing your side effects.
What should I know about the hepatitis C virus?
Hepatitis C infection is a disease caused by a virus that infects the liver. This liver infection becomes a continuing (chronic) condition in most patients. Patients with chronic hepatitis C infection may develop cirrhosis, liver cancer, and liver failure. The virus is spread from one person to another by contact with the infected person's blood. You should talk to your health care provider about ways to prevent you from infecting others.
How do I Inject INTRON A?
The INTRON A Injection multidose pen (INTRON A multidose pen) is a pre-filled multidose syringe containing six doses of INTRON A (interferon alfa-2b, recombinant). This multidose pen is specially designed to deliver six doses of 3 MIU of INTRON A. If necessary, it can also be used to deliver different doses (i.e. if your health care provider wants you to increase or decrease your dose). The different doses that it can deliver are 1.5 MIU, 3 MIU, 4.5 MIU and 6 MIU. Six MIU is the maximum dose that this pen can give at one time.
Please note the following important points BEFORE using your INTRON A multidose pen:
Description of your INTRON A multidose pen
Diagrams A and B show you all the different parts of the pen and the Novofine* needle. The most important parts to note are as follows:
Diagram A
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Diagram B
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HOW TO USE YOUR INTRON A Multidose Pen
When you are ready to give your injection prepare your pen as follows. (NOTE: Boldface print indicates ACTION STEPS):
1. First check that you have the correct INTRON A multidose pen as prescribed by your health care provider, (i.e. the six doses of 3 MIU INTRON A multidose pen which have a brown push button and a brown color coding strip).
2. Pull off the cap of the pen and disinfect the rubber membrane (see Diagram C) with one alcohol wipe.
Diagram C
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3.Remove the protective tab from the Novofine* needle. Note that the rear portion of the needle is revealed once the protective tab is removed (see Diagram D).
Diagram D
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4. Gently push the Novofine* needle onto the pen as shown in Diagram E. (Notice that the rear portion of the needle described in Step 3 will pierce through the rubber membrane that you disinfected previously.) Now screw the needle onto the INTRON A multidose pen securely by turning it in a clockwise direction (see Diagram F).
Diagram E
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Diagram F
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5. First, pull off the outer needle cap (Diagram G). Then, pull off the inner needle cap carefully, bearing in mind that the needle will now be exposed (Diagram H). Keep the outer needle cap for later use.
Diagram G
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Diagram H
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The pen is now ready to use. Since a small amount of air may collect in the needle and reservoir during storage, the next step is to remove any air bubbles.
6. Hold the INTRON A multidose pen with the needle point upwards.
7. Tap the reservoir with your finger so that any air bubbles rise to the top of the reservoir, just below the needle (Diagram I).
Diagram I
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8. Hold the pen by the barrel and turn the reservoir in the direction as indicated by the arrow in Diagram J (clockwise) until you feel it click.
Diagram J
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9. Keeping the pen pointing upwards, press the push button up fully and see if a drop of INTRON A solution appears at the needle tip (notice the drop at the tip of needle in Diagram K).
Diagram K
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10. If no drop appears then repeat Steps 7, 8, and 9 until a drop appears at the needle tip. Note: Some air may still remain in the pen, but this is not important as you have removed the air from the needle and the dose will be accurate.
11. Replace the INTRON A multidose pen cap with the ‘triangle' opposite the dosage indicator as seen in Diagram L.
Diagram L
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The pen is now ready to set the dose. For the next step hold the pen in the middle of the barrel. This will allow the push button to move freely, ensuring that the correct dose is set.
12. To set the required dose, hold the pen horizontally by the barrel with one hand. With the other hand, turn the cap in a clockwise direction indicated by the arrow in Diagram M. You will observe the push button rising, indicating the dose set. To set a 3 MIU dose, turn the cap 2 full turns (10 clicks) = 3.0 MIU.
Diagram M
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Note: If your health care provider has prescribed a dose other than 3 MIU, the correct dose can be set by turning the cap as many times as indicated as follows:
1 full turn (5 clicks) = 1.5 MIU
3 full turns (15 clicks) = 4.5 MIU
4 full turns (20 clicks) = 6.0 MIU
The push button scale will show you the dose set (see Diagram N). At that point check that you have the correct dose.
Diagram N
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13. After each complete turn make sure that the triangle is opposite the dosage indicator (see Diagram O). If you have set a wrong dose, simply turn the cap back (counter-clockwise) as far as you can until the push button is fully home and start again. Once the correct dose is set, you are ready to give the injection.
Diagram O
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14. To give the injection, remove the pen cap from the needle. With one hand, pinch a 2-inch fold of loose skin.
15. With your other hand, pick up the pen and hold it as you would a pencil. Insert the needle into the pinched skin at an angle of approximately 45° (see Diagram P) then press the push button down fully.
If blood comes into the pen, do not inject. Withdraw the needle and consult your physician or pharmacist.
Diagram P
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16. Leave the needle in place for a few seconds, while holding down the push button, to allow the INTRON A Solution to distribute under the skin.
17. Slowly release the push button, then remove the needle.
18. Carefully replace the outer needle cap using a scooping motion (See Diagram Q).
Diagram Q
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19. Completely unscrew the needle assembly using a counter-clockwise turning motion as show in Diagram R. Then carefully lift it off the pen and discard the capped needle (see Diagram S).
Diagram R
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Diagram S
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20. Replace the pen cap with the triangle once again opposite the dosage indicator as shown in Diagram T.
Diagram T
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Instructional leaflet and video are available through your health care provider.
How do I store my medications?
STORAGE OF REBETOL CAPSULES
REBETOL capsules should be stored in the refrigerator between 36° and 46° F (2° and 8° C) or at room temperature 77° F (25° C).
STORAGE OF INTRON A INJECTION MULTIDOSE PEN
INTRON A Injection multidose pen should be stored in the refrigerator between 36° and 46° F (2° and 8° C), not in the freezer.
* Novofine is a registered trademark of Novo Nordisk.
General advice about prescription medicines
Do not use REBETOL Capsules or INTRON A for conditions for which they were not prescribed. If you have any concern about REBETRON (rebetol and intron a combination therapy) Combination Therapy, ask your health care provider. Your health care provider or pharmacist can give you information about REBETRON (rebetol and intron a combination therapy) Combination Therapy that was written for health care professionals. Do not give these medicines to other people, even if they have the same condition you have.
Ingredients:
REBETOL capsules contain ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin 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 contains interferon alfa-2b recombinant, sodium chloride, dibasic sodium phosphate, monobasic sodium phosphate, edetate disodium, polysorbate 80, m-cresol (as a preservative).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
MEDICATION GUIDE
REBETOL
(ribavirin, USP) Capsules
Read this medication guide carefully before you begin taking REBETOL [REB-eh-tol] Capsules, and each time you refill your prescription in case new information has been included. This summary does not tell you everything about REBETOL Capsules. Your health care provider is the best source of information about this medicine. After reading this medication guide, talk with your health care provider if you have any questions about REBETOL.
What is the most important information I should know about therapy with REBETOL Capsules?
What is REBETOL (ribavirin)?
”REBETOL” is the antiviral drug ribavirin. It is used in combination with interferon alfa-2b to treat some patients with chronic hepatitis C infection. It is not known how REBETOL and interferon alfa-2b work together to fight hepatitis C infection.(see the REBETRON (rebetol and intron a combination therapy) Combination Therapy or PEG-INTRON Medication Guide).
It is not known if treatment with REBETOL and interferon alfa-2b will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known if treatment with REBETOL and interferon alfa-2b will prevent an infected person from infecting another person with the hepatitis C virus.
Who should not take REBETOL Capsules?
Do not use these medicines if:
Tell your health care provider before starting treatment with REBETOL Capsules in combination with interferon alfa-2b if you have any of the following medical conditions:
For more information see the Rebetron (rebetol and intron a combination therapy) Combination Therapy or PEG-INTRON Medication Guides.
How should I take REBETOL Capsules?
Your health care provider has determined the correct dose of REBETOL Capsules based on your weight. Your health care provider may lower your dose of REBETOL if you have side effects.
The recommended dose of REBETOL Capsules when used with INTRON A is shown in the table below. You can take REBETOL Capsules with or without food, but you should take them the same way every day.
| If your weight is: | Take this many REBETOL Capsules each day: |
| 165 pounds or less | 2 capsules in the AM 3 capsules in the PM |
| More than 165 pounds | 3 capsules in the AM 3 capsules in the PM |
The recommended dose of REBETOL Capsules when used in combination with PEG-INTRON is 800 mg per day. That is 400 mg (2 capsules) in the AM and 400 mg (2 capsules) in the PM. When taking REBETOL Capsules with PEG-INTRON, take your REBETOL Capsules with food.
What should I avoid while taking REBETOL Capsules?
Avoid the following during REBETOL Capsule treatment:
What are the most common side effects of REBETOL Capsules?
The most serious possible side effects of REBETOL Capsules are:
Tell your provider right away if you have any of the following symptoms. They may be signs of a serious side effect:
The most common side effects of REBETOL Capsules are:
This summary does not include all possible side effects of REBETOL therapy. Talk to your health care provider, if you do not feel well while taking REBETOL. Your health care provider can give you more information about managing your side effects.
What should I know about hepatitis C infection?
Hepatitis C infection is a disease caused by a virus that infects the liver. This liver infection becomes a continuing (chronic) condition in most patients. Patients with chronic hepatitis C infection may develop cirrhosis, liver cancer, and liver failure. The virus is spread from one person to another by contact with the infected person's blood. You should talk to your health care provider about ways to prevent you from infecting others.
How do I store my REBETOL Capsules?
Store REBETOL Capsules at room temperature 77°F (25°C).
General advice about prescription medicines
Do not use REBETOL Capsules for conditions for which they were not prescribed. If you have any concern about REBETOL Capsules, ask your health care provider. Your health care provider or pharmacist can give you information about REBETOL Capsules that was written for health care professionals. Do not give this medicine to other people, even if they have the same condition you have.
Ingredients:
REBETOL Capsules contain ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin 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.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
