Posology : מינונים

4.2       Posology and method of administration

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Rebetol must be used in combination with either peginterferon alfa-2b or interferon alfa-2b (bitherapy), or, in adult patients with chronic hepatitis C genotype 1 infection, in combination with boceprevir and peginterferon alfa-2b (tritherapy).

Please refer also to the boceprevir, peginterferon alfa-2b or interferon alfa-2b Summary of Product Characteristics (SmPC) for prescribing information particular to that product.

Dose to be administered
The dose of Rebetol is based on patient body weight. Rebetol capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adult patients:
The dose of Rebetol is based on patient body weight (Table 1).
Rebetol must be used in combination with either peginterferon alfa-2b (1.5 micrograms/kg/week) or interferon alfa-2b (3 million international units [MIU] three times a week). The choice of combination regimen is based on the characteristics of the patient. The regimen administered should be selected based on the anticipated efficacy and safety of the combination treatment for an individual patient (see section 5.1). Refer to the SmPC for boceprevir for the details of how boceprevir is to be administered in tritherapy.

Table 1.       Rebetol dose based on body weight for HCV monoinfected or HCV/HIV co-infected patients and whatever the genotype
Patient weight (kg)                Daily Rebetol dose               Number of 200 mg capsules < 65                               800 mg                           4a 65 – 80                            1,000 mg                         5b 81- 105                            1,200 mg                         6c > 105                              1,400 mg                         7d a: 2 morning, 2 evening b: 2 morning, 3 evening c: 3 morning, 3 evening d: 3 morning, 4 evening

Rebetol capsules in combination with boceprevir and peginterferon alfa-2b, or with peginterferon alfa-2b:

Duration of treatment –Naïve patients
Tritherapy:
Refer to the SmPCs for boceprevir and peginterferon alfa-2b.

Bitherapy with peginterferon alfa-2b:
Predictability of sustained virological response: Patients infected with virus genotype 1 who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are highly unlikely to become sustained virological responders and should be evaluated for discontinuation (see also section 5.1).
•     Genotype 1:
- For patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks).
- Patients with detectable but ≥2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e., a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered.
- In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration).
However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1).
•     Genotypes 2 or 3: It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.
•     Genotype 4: In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1.

Duration of treatment- naïve HCV/HIV co-infected patients
Bitherapy:
The recommended duration of Rebetol weight-based dosing (see Table 1) for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype.

Predictability of response and non-response in naïve HCV/HIV Co-infection Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with Rebetol in combination with peginterferon alfa-2b was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value of 50% (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy.

Duration of treatment – Retreatment patients
Tritherapy:
Refer to the SmPC for boceprevir and peginterferon alfa-2b.

Bitherapy with peginterferon alfa-2b:
Predictability of sustained virological response: All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1).

Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

Rebetol capsules in combination with interferon alfa-2b (bitherapy only): 
Duration of treatment with interferon alfa-2b:
Based on the results of clinical trials, it is recommended that patients be treated with bitherapy for at least six months. During those clinical trials in which patients were treated for one year, patients who failed to show a virological response after six months of treatment (HCV-RNA below lower limit of detection) were unlikely to become sustained virological responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).
• Genotype 1: Treatment with bitherapy should be continued for another six month period (i.e., a total of one year) in patients who exhibit negative HCV-RNA after six months of treatment.
• Genotypes Non-1: The decision to extend therapy with bitherapy to one year in patients with negative HCV-RNA after six months of treatment should be based on other prognostic factors (e.g., age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients
Combination therapy:
If severe adverse reactions or laboratory abnormalities develop during combination therapy with Rebetol and peginterferon alfa-2b or interferon alfa-2b, or with Rebetol and peginterferon alfa-2b and boceprevir, modify the dosages as indicated in Table 3 if appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines, Table 3). As adherence might be of importance for outcome of therapy, the dose should be kept as close as possible to the recommended standard dose. The potential negative impact of ribavirin dose reduction on efficacy results could not be ruled out.


Table 3      Dosage modification guidelines for combination therapy based on laboratory parameters
Reduce only Rebetol           Reduce only              Discontinue
Laboratory Values daily dose (see note 1) if: peginterferon alfa-2b        combination therapy or interferon alfa-2b    when the below test dose (see note 2) if:    value is reported:**
Haemoglobin         < 10 g/dl                     -                        < 8.5 g/dl Adults:
Haemoglobin in:          2 g/dl decrease in haemoglobin during any        < 12 g/dl after 4 weeks patients with                  4 week period during treatment              of dose reduction history of stable                (permanent dose reduction) cardiac disease

Leukocytes             -                             < 1.5 x 109/l                < 1.0 x 109/l Neutrophils            -                             < 0.75 x 109/l               < 0.5 x 109/l Platelets              -                             < 50 x 109/l (adults)        < 25 x 109/l (adults) 
Bilirubin – Direct     -                             -                            2.5 x ULN* Bilirubin – Indirect   > 5 mg/dl                     -                            > 4 mg/dl (adults) (for > 4 weeks)
Serum Creatinine       -                             -                            > 2.0 mg/dl Creatinine             -                             -                            Discontinue Rebetol if Clearance                                                                         CrCl <50 ml/minute Alanine                -                             -                            2 x baseline and aminotransferase                                                                  > 10 x ULN* (ALT) or                                                                                or Aspartate                                                                         2 x baseline and aminotransferase                                                                  > 10 x ULN* (AST)
* Upper limit of normal
** Refer to the SmPC for pegylated interferon alfa-2b and interferon alfa-2b for dose modification and discontinuation.

Note 1: In adult patients, 1st dose reduction of Rebetol 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 Rebetol is by an additional 200 mg/day.Patients whose dose of Rebetol is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.
Note 2: In adult patients treated with Rebetol plus peginterferon alfa-2b, 1st dose reduction of peginterferon alfa-2b is to 1 µg/kg/week. If needed, 2nd dose reduction of peginterferon alfa-        2b is to 0.5 µg/kg/week. In adult patients treated with Rebetol plus interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose.

Special populations

Use in renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2).
Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol (see section 4.3). Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. If serum creatinine rises to  2.0 mg/dl (Table 3), Rebetol and peginterferon alfa-2b/interferon alfa-2b must be discontinued.


Use in hepatic impairment: No pharmacokinetic interaction appears between ribavirin and hepatic function (see section 5.2). Therefore, no dose adjustment of Rebetol is required in patients with hepatic impairment. The use of ribavirin is contraindicated in patients with severe hepatic impairment or decompensated cirrhosis (see section 4.3).

Use in the elderly ( 65 years of age): There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of Rebetol (see section 5.2).

Patients co-infected with HCV/HIV: Patients taking nucleoside reverse transcriptase inhibitor (NRTI) treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section 4.4). Please refer also to the relevant product information for antiretroviral medicinal products.

Method of administration:
Rebetol should be administered orally. No special precautions for disposal or handling are required.