Ribasphere Dosage

Ribasphere/Peginterferon alfa-2b Combination Therapy

Adult Patients

The recommended dose of peginterferon alfa-2b is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg Ribasphere Capsules orally based on patient body weight (see Table 1). The volume of peginterferon alfa-2b to be injected depends on the strength of peginterferon alfa-2b and patient’s body weight (see Table 1).

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 log10 drop or loss of 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 – Retreatment with Peginterferon alfa-2b/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)].

Pediatric Patients

Dosing for pediatric patients is determined by body surface area for peginterferon alfa-2b and by body weight for Ribasphere. The recommended dose of peginterferon alfa-2b is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of Ribasphere orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving peginterferon alfa-2b/Ribasphere should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

Ribasphere/Interferon alfa-2b Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of interferon alfa-2b is 3 million IU three times weekly subcutaneously. The recommended dose of Ribasphere Capsules depends on the patient’s body weight (refer to Table 3). 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), and 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 on treatment for longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Retreatment with Interferon alfa-2b/Ribasphere in Relapse Patients

In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

Pediatrics

The recommended dose of Ribasphere is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of Ribasphere in combination with interferon alfa-2b. Interferon alfa-2b for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for > 61 kg body weight.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks.

Laboratory Tests

The following laboratory tests are recommended for all patients treated with Ribasphere, prior to beginning treatment and then 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, 5.7)], complete and differential white blood cell counts, and platelet count.
• Blood chemistries - liver function tests and TSH.
• Pregnancy - including monthly monitoring for women of childbearing potential.
• ECG [see Warnings and Precautions (5.2)].

Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination Ribasphere/interferon alfa-2b therapy or Ribasphere/peginterferon alfa-2b therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of peginterferon alfa-2b in adult patients on Ribasphere/peginterferon alfa-2b combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction of peginterferon alfa-2b in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 4.

In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving peginterferon alfa-2b 1.5 mcg/kg plus Ribasphere 800 mg daily including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of peginterferon alfa-2b to 1 mcg/kg in combination with Ribasphere, with an additional 4% requiring the second dose reduction of peginterferon alfa-2b to 0.5 mcg/kg due to adverse events [see Adverse Reactions (6.1)].

Dose reduction in pediatric patients is accomplished by modifying the recommended peginterferon alfa-2b dose in a two-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Table 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving peginterferon alfa-2b 60 mcg/m2 weekly plus Ribasphere 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended Ribasphere 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 5).

Ribasphere should not be used in patients with creatinine clearance < 50 mL/min. Subjects 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)].

Ribasphere 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 and Precautions (5.2)].

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 therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her Ribasphere dose modified or discontinued per Table 5[see Warnings and Precautions (5.2)].

Refer to the Intron A Package Insert or PegIntron Powder for Injection Package Insert for additional information about how to reduce an interferon alfa-2b or peginterferon alfa-2b dose.

Discontinuation of Dosing

Adults

It is recommended that HCV genotype 1 interferon-alfa-naïve patients receiving peginterferon alfa-2b in combination with ribavirin, be discontinued from therapy if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable (>10-20 IU/mL) 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 (3-17 years of age)

It is recommended that patients receiving peginterferon alfa-2b/Ribasphere combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped < 2 log10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA (>10-20 IU/mL) at treatment Week 24.