Ribasphere Dosage

Generic name: ribavirin
Dosage form: capsule

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Under no circumstances should Ribasphere Capsules be opened, crushed, or broken. Ribasphere should be taken with food [see Clinical Pharmacology (12.3)]. Ribasphere should not be used in patients with creatinine clearance less than 50 mL/min.

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, refer to labeling for peginterferon alfa-2b for additional 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 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 – Re-treatment 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)].

Table 1: Recommended Dosing for Ribasphere in Combination Therapy with Peginterferon alfa-2b (Adults)

Body Weight kg (lbs)

Ribasphere

Daily Dose

Ribasphere Number of Capsules

<66

(<144)

800 mg/day

2 x 200-mg capsules A.M.

2 x 200 mg capsules P.M.

66-80

(145-177)

1000 mg/day

2 x 200-mg capsules A.M.

3 x 200-mg capsules P.M.

81-105

(178-231)

1200 mg/day

3 x 200-mg capsules A.M.

3 x 200-mg capsules P.M.

>105

(231)

1400 mg/day

3 x 200-mg capsules A.M.

4 x 200-mg capsules P.M.

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.

Table 2: Recommended Ribasphere* Dosing in Combination Therapy (Pediatrics)
*
Ribasphere to be used in combination with Peginterferon alfa-2b 60 mcg/m2 weekly.

Body weight    kg (lbs)

Ribasphere   
Daily Dose

Ribasphere Number of Capsules

47–59
(103–131)

800 mg/day

2 x 200 mg capsules A.M.  
2 x 200 mg capsules P.M.

60–73
(132–162)

1000 mg/day

2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.

>73
(>162)

1200 mg/day

3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M.

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 – Re-treatment with Interferon alfa-2b/Ribasphere in Relapse Patients

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

Table 3: Recommended Dosing

Body weight    

Ribasphere® (ribavirin capsules)

≤75 kg

2 × 200 mg capsules A.M.
3 × 200 mg capsules P.M.
daily orally

>75 kg

3 × 200 mg capsules A.M.
3 × 200 mg capsules P.M.
daily orally

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 greater than 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, modify, 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.

Refer to labeling for peginterferon alfa-2b for additional information regarding dose reduction of peginterferon alfa-2b.

In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving peginterferon alfa-2b 1.5 mcg/kg and 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 4). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving peginterferon alfa-2b 60 mcg/m2 weekly and and ribavirin 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 4).

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

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 greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 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 4 [see Warnings and Precautions (5.2)].

Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin in combination with Peginterferon alfa-2b or Interferon alfa-2b Based on Laboratory Parameters in Adults and Pediatrics
Laboratory Parameters Reduce Ribavirin Daily Dose
(see note 1) if:
Reduce Peginterferon alfa‑2b or Interferon alfa‑2b Dose (see note 2) if: Discontinue Therapy if:
Note 1: Adult patients: 1st 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, 2nd 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: 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day.
Note 2: Adult patients treated with Ribavirin and Peginterferon alfa-2b: 1st dose reduction of Peginterferon alfa-2b is to 1 mcg/kg/week. If needed, 2nd dose reduction of Peginterferon alfa-2b is to 0.5 mcg/kg/week.
Pediatric patients treated with Ribavirin and Peginterferon alfa-2b: 1st dose reduction of Peginterferon alfa-2b is to 40 mcg/m2/week, 2nd dose reduction of Peginterferon alfa-2b is to 20 mcg/m2/week.
For patients on Ribavirin/Interferon alfa-2b combination therapy: reduce Interferon alfa-2b 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 Peginterferon alfa-2b /Ribavirin combination therapy [see Warnings and Precautions (5.2)].

WBC

N/A

1.0 to <1.5 x 109/L

<1.0 x 109/L

Neutrophils

N/A

0.5 to <0.75 x 109/L

<0.5 x 109/L

Platelets

N/A

25 to <50 x 109/L (adults)

<25 x 109/L (adults)

N/A

50 to <70 x 109/L (pediatrics)

<50 x 109/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 Dose by 200 mg/day and Peginterferon alfa-2b or Interferon alfa-2b 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 Interferon alfa-2b or Peginterferon alfa-2b for additional information about how to reduce an Interferon alfa-2b or Peginterferon alfa-2b dose.

Discontinuation of Dosing

Adults

In HCV genotype 1 interferon-alfa-naïve patients receiving peginterferon alfa-2b in combination with ribavirin, discontinuation of therapy is recommended 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 (3-17 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 less than 2 log10 compared to a pre-treatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

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