Rebetol

Rebetol Manufacturers

• Merck Sharp & Dohme Corp.
  

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  Rebetol | Merck Sharp & Dohme Corp.

  

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

  2.1 REBETOL/PegIntron Combination Therapy

  Adult Patients

  The recommended dose of PegIntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg REBETOL capsules orally based on patient body weight (see Table 1). The volume of PegIntron to be injected depends on the strength of PegIntron and patient's body weight, refer to labeling for PegIntron 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 PegIntron/REBETOL 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 REBETOL in Combination Therapy with PegIntron (Adults) Body Weight
  kg
  (lbs) REBETOL Daily Dose REBETOL Number of Capsules <66
  (<144) 800 mg/day 2 × 200-mg capsules A.M.
  2 × 200-mg capsules P.M. 66-80
  (145-177) 1000 mg/day 2 × 200-mg capsules A.M.
  3 × 200-mg capsules P.M. 81-105
  (178-231) 1200 mg/day 3 × 200-mg capsules A.M.
  3 × 200-mg capsules P.M. >105
  (231) 1400 mg/day 3 × 200-mg capsules A.M.
  4 × 200-mg capsules P.M.

  Pediatric Patients

  Dosing for pediatric patients is determined by body surface area for PegIntron and by body weight for REBETOL. The recommended dose of PegIntron is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of REBETOL orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving PegIntron/REBETOL 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 REBETOL* Dosing in Combination Therapy (Pediatrics) Body Weight
  kg
  (lbs) REBETOL Daily Dose REBETOL Number of Capsules * REBETOL to be used in combination with PegIntron 60 mcg/m 2 weekly. † REBETOL Oral Solution may be used for any patient regardless of body weight. <47
  (<103) 15 mg/kg/day Use REBETOL Oral Solution† 47-59
  (103-131) 800 mg/day 2 × 200-mg capsules A.M.
  2 × 200-mg capsules P.M. 60-73
  (132-162) 1000 mg/day 2 × 200-mg capsules A.M.
  3 × 200-mg capsules P.M. >73
  (>162) 1200 mg/day 3 × 200-mg capsules A.M.
  3 × 200-mg capsules P.M. 2.2 REBETOL/INTRON A Combination Therapy

  Adults

  Duration of Treatment – Interferon Alpha-naïve Patients

  The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of REBETOL 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 INTRON A/REBETOL 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 REBETOL Capsules ≤75 kg 2 × 200-mg capsules AM
  3 × 200-mg capsules PM daily orally >75 kg 3 × 200-mg capsules AM
  3 × 200-mg capsules PM daily orally

  Pediatrics The recommended dose of REBETOL is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of REBETOL in combination with INTRON A. INTRON A 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.

  2.3 Laboratory Tests

  The following laboratory tests are recommended for all patients treated with REBETOL, 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)]. 2.4 Dose Modifications

  If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy or REBETOL/PegIntron 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 PegIntron in adult patients on REBETOL/PegIntron 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 PegIntron for additional information regarding dose reduction of PegIntron.

  In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving PegIntron 1.5 mcg/kg and REBETOL 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron 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 PegIntron 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 PegIntron 60 mcg/m2 weekly and REBETOL 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended REBETOL 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).

  REBETOL 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)].

  REBETOL 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 REBETOL dose modified or discontinued per Table 4 [see Warnings and Precautions (5.2)].

  Table 4: Guidelines for Dose Modification and Discontinuation of REBETOL in combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and Pediatrics Laboratory Parameters Reduce REBETOL Daily Dose (see note 1) if: Reduce PegIntron or INTRON A 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 REBETOL and PegIntron: 1st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 mcg/kg/week.
  Pediatric patients treated with REBETOL and PegIntron: 1st dose reduction of PegIntron is to 40 mcg/m2/week, 2nd dose reduction of PegIntron is to 20 mcg/m2/week.
  For patients on REBETOL/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 /REBETOL combination therapy [see Warnings and Precautions (5.2)]. WBC N/A 1.0 to <1.5 × 109/L <1.0 × 109/L Neutrophils N/A 0.5 to <0.75 × 109/L <0.5 × 109/L Platelets N/A 25 to < 50 × 109/L (adults) <25 × 109/L (adults) N/A 50 to <70 × 109/L (pediatrics) <50 × 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 REBETOL 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.

  2.5 Discontinuation of Dosing

  Adults In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron 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 PegIntron/REBETOL 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 pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

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