2 DOSAGE AND ADMINISTRATION Ribavirin capsules are administered according to body weight. ( 2.1 , 2.2 , 2.3 ) Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction. (2.5, 2.6, 12.3 ) 2.1 General Dosing Information Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see Clinical Pharmacology ( 12.3 ) ]. 2.2 Ribavirin/PegIntron Combination Therapy Adult Patients The recommended dose of ribavirin when used in combination with PegIntron is 800 mg to 1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling for PegIntron dosing information. Duration of Treatment – Interferon Alpha-naïve Patients The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log 10 drop or loss of hepatitis C virus (HCV)-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks. Duration of Treatment – Re-treatment with PegIntron/ Ribavirin of Prior Treatment Failures The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies ( 14.1 )] . Table 1 Recommended Adult Dosing for Ribavirin Capsules in Combination with PegIntron Body Weight (kg) Ribavirin Daily Dose Ribavirin Number of Capsules Less than 66 800 mg/day 2 x 200-mg capsules AM 2 x 200-mg capsules PM 66 to 80 1,000 mg/day 2 x 200-mg capsules AM 3 x 200-mg capsules PM 81 to 105 1,200 mg/day 3 x 200-mg capsules AM 3 x 200-mg capsules PM Greater than 105 1,400 mg/day 3 x 200-mg capsules AM 4 x 200-mg capsules PM Pediatric Patients Dosing of ribavirin in pediatric patients is determined by body weight. The recommended dose of ribavirin when used in combination with PegIntron in pediatric patients ages 3-17 years is 15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing information. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks. Table 2 Recommended Pediatric Ribavirin Capsules Dosing in Combination with PegIntron † Ribavirin Oral Solution may be used in any patient regardless of body weight. Body Weight (kg) Ribavirin Daily Dose Ribavirin Number of Capsules Less than 47 15 mg/kg/day Use Ribavirin Oral Solution † 47 to 59 800 mg/day 2 x 200-mg capsules AM 2 x 200-mg capsules PM 60 to 73 1,000 mg/day 2 x 200-mg capsules AM 3 x 200-mg capsules PM Greater than 73 1,200 mg/day 3 x 200-mg capsules AM 3 x 200-mg capsules PM 2.3 Ribavirin/INTRON A Combination Therapy Adults Duration of Treatment – Interferon Alpha-naïve Patients The recommended dose of ribavirin when used in combination with INTRON A depends on the patient's body weight (see Table 3). Refer to Intron A labeling for interferon dosing information. The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage ( 1.1 ) , Adverse Reactions ( 6.1 ) a nd Clinical Studies ( 14 ) ]. 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 for treatment duration lasting longer than 48 weeks in the previously untreated patient population. Duration of Treatment – Re-treatment with INTRON A/ Ribavirin capsules in Relapse Patients In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks. Table 3 Recommended Ribavirin Capsules Dosing in Combination with INTRON A Body Weight Ribavirin Capsules At least 75 kg 2 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally Greater than 75 kg 3 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally Pediatrics The recommended dose of ribavirin when used in combination with INTRON A is 15 mg/kg per day orally in two divided doses (see Table 2). Refer to Intron A labeling for interferon dosing information. The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2 and 3 is 24 weeks. 2.4 Testing Prior to Initiation of Ribavirin The following laboratory tests are recommended in all patients treated with ribavirin capsules, prior to initiation of treatment and periodically thereafter. Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions ( 5.2 , 5.6 ) ], complete and differential white blood cell counts, and platelet count. Blood chemistries - liver function tests and TSH. Pregnancy - in women of childbearing potential. ECG [ see Warnings and Precautions ( 5.2 ) ]. 2.5 Dose Modifications If severe adverse reactions or laboratory abnormalities develop during ribavirin combination therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity (see Table 4) [see Warnings and Precautions ( 5 )] . If intolerance persists after dose adjustment, combination therapy should be discontinued. Refer to PegIntron labeling for additional information regarding dose reduction of PegIntron. Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4). Ribavirin is contraindicated in patients with creatinine clearance less than 50 mL/min [see Contraindications ( 4 )] . Patients with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.5 ), and Clinical Pharmacology ( 12.3 )] . Ribavirin should be administered with caution to patients with pre-existing cardiac disease. Assess cardiovascular status before initiation of treatment and during therapy. If there is any deterioration of cardiovascular status, discontinue combination therapy [see Warnings and Precautions ( 5.2 )] . In patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by 2 g/dL or more during any 4-week period. If the hemoglobin level remains below 12 g/dL after 4 weeks on a reduced dose, discontinue combination therapy. Modify or discontinue ribavirin dosing in any patient whose hemoglobin level falls below 10 g/dL (see Table 4) [see Warnings and Precautions ( 5.2 )] . Table 4 Guidelines for Dose Modification and Discontinuation of Ribavirin Capsules in combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and Pediatrics Note 1: Adult patients: 1 st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2 nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. Pediatric patients: 1 st dose reduction of ribavirin is to 12 mg/kg/day, 2 nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: Adult patients treated with ribavirin and PegIntron: 1 st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2 nd dose reduction of PegIntron is to 0.5 mcg/kg/week. Pediatric patients treated with ribavirin and PegIntron: 1 st dose reduction of PegIntron is to 40 mcg/m 2 /week, 2 nd dose reduction of PegIntron is to 20 mcg/m 2 /week. For patients on ribavirin capsules/INTRON A combination therapy: reduce INTRON A dose by 50%. * Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing. †These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron /ribavirin combination therapy [see Warnings and Precautions ( 5.2 )]. Laboratory Parameters Reduce Ribavirin Capsules Daily Dose (see note 1) if: Reduce PegIntron or INTRON A Dose (see note 2) if: Discontinue Therapy if: WBC N/A 1 to < 1.5 x 10 9 /L < 1 x 10 9 /L Neutrophils N/A 0.5 to < 0.75 x 10 9 /L < 0.5 x 10 9 /L Platelets N/A 25 to < 50 x 10 9 /L (adults) < 25 x 10 9 /L (adults) N/A 50 to < 70 x 10 9 /L (pediatrics) < 50 x 10 9 /L (pediatrics) Creatinine N/A N/A > 2 mg/dL (pediatrics) Hemoglobin in patients without history of cardiac disease 8.5 to < 10 g/dL N/A < 8.5 g/dL Reduce Ribavirin Capsules Dose by 200 mg/day and PegIntron or INTRON A Dose by Half if: Hemoglobin in patients with history of stable cardiac disease *† ≥ 2 g/dL decrease in hemoglobin during any four-week period during treatment < 8.5 g/dL or < 12 g/dL after four weeks of dose reduction Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an INTRON A or PegIntron dose. 2.6 Discontinuation of Dosing Adults In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron in combination with ribavirin, discontinue therapy if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered. Pediatrics (3 to 17 years of age) In patients receiving PegIntron/ribavirin combination (excluding HCV Genotype 2 and 3), discontinue therapy at 12 weeks if HCV-RNA has dropped less than 2 log 10 compared to pretreatment level, or at 24 weeks if HCV-RNA is still detectable.