Posology : מינונים

4.2 Posology and method of administration
Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C.
Posology
PegIntron should be administered as a once weekly subcutaneous injection. The dose administered depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy.

PegIntron combination therapy (bitherapy or tritherapy)
Bitherapy (PegIntron with ribavirin): applies to all adult patients.
Tritherapy (PegIntron with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC.

Dose to be administered
PegIntron 1.5 micrograms/kg/week in combination with ribavirin capsules.
The intended dose of 1.5 μg/kg of PegIntron to be used in combination with ribavirin may be delivered in weight categories with the PegIntron strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening).

Table 1 - Dosing for Combination Therapy*
Body Weight                   PegIntron                            Ribavirin Capsules (kg)
PegIntron Strength      Administer             Total Daily       Number of (g/0.5 ml)      Once Weekly              Dose (mg)         Capsules (ml)                                    (200 mg)
< 40                     50                0.5                     800               4a 
40-50                      80                    0.4               800                4a

51-64                      80                    0.5               800                4a 65-75                      100                   0.5              1,000               5b 76-80                      120                   0.5              1,000               5b 81-85                      120                   0.5              1200                6c 86-105                     150                   0.5              1,200               6c > 105                      150                   0.5              1,400               7d a: 2 morning, 2 evening b: 2 morning, 3 evening c: 3 morning, 3 evening d: 3 morning, 4 evening
* Refer to the Physician's Insert of boceprevir for details about the dose of boceprevir to be administered in tritherapy.

Duration of treatment – Naïve patients
Tritherapy: Refer to the Physician's Insert for boceprevir.

Bitherapy: 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:
- 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 - HCV/HIV Co-infection
Bitherapy:The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype.

Predictability of response and non-response in 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 PegIntron in combination with ribavirin 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 combination therapy.

Duration of treatment - Retreatment
Tritherapy: Refer to the Physician's Insert for boceprevir.

Bitherapy: 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.

PegIntron monotherapy
Dose to be administered
As monotherapy the PegIntron regimen is 0.5 or 1.0 μg/kg/week. The lowest PegIntron strength available is 80 μg/0.5 ml; therefore for patients prescribed 0.5 μg/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 μg/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. PegIntron monotherapy was not studied in HCV/HIV co-infected patients.

Table 2- Monotherapy Dosing

0.5 μg/kg                            1.0 μg/kg
Body Weight         PegIntron         Administer         PegIntron        Administer (kg)              Strength        Once Weekly          Strength       Once Weekly (μg/0.5ml)          (ml)             (μg/0.5ml)         (ml)
30-35                   50*             0.15                 80*             0.2 36-45                   50*               0.2                50                0.4  46-56                   50*               0.25               50                0.5
57-72                   80*               0.2                80                0.4 73-88                   50                0.4                80                0.5 89-106                  50                0.5                100               0.5 106-120**               80                0.4                120               0.5 

* Minimum delivery for pen is 0.3 ml.
** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Duration of treatment
For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients (monotherapy and combination therapy) If severe adverse reactions or laboratory abnormalities develop during treatment with PegIntron monotherapy or combination therapy, the dosages of PegIntron and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of PegIntron and ribavirin.
As adherence might be of importance for outcome of therapy, the dose of PegIntron and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification.

Combination Therapy Dose Reduction Guidelines

Table 2a Dose modification guidelines for combination therapy based on laboratory parameters
Laboratory values         Reduce only              Reduce only              Discontinue ribavirin daily dose           PegIntron       combination therapy if: (see note 1) if:      dose (see note 2) if:
Haemoglobin               ≥ 8.5 g/dl, and                 -                   < 8.5 g/dl < 10 g/dl
Haemoglobin in
Patients with history   2 g/dl decrease in haemoglobin during any   < 12 g/dl after four weeks of stable cardiac            four week period during treatment           of dose reduction disease                          (permanent dose reduction)
Leukocytes                        -              ≥ 1.0 x 109/l, and          < 1.0 x 109/l 9
< 1.5 x 10 /l
Neutrophils                       -              ≥ 0.5 x 109/l, and          < 0.5 x 109/l 9
< 0.75 x 10 /l
Platelets                         -               ≥ 25 x 109/l, and          < 25 x 109/l 9
< 50 x 10 /l
Bilirubin – direct                -                       -                   2.5 x ULN* Bilirubin – indirect        > 5 mg/dl                     -                   > 4 mg/dl (for > 4 weeks)
Serum Creatinine                  -                       -                  > 2.0 mg/dl Creatinine Clearance              -                       -            Discontinue ribavirin if CrCL < 50ml/min
Alanine                           -                       -               2 x baseline and Aminotransferase                                                             > 10 x ULN* (ALT) or
Aspartate                                                                 2 x baseline and Aminotransferase                                                             > 10 x ULN* (AST)
* Upper limit of normal
 st
Note 1: In adult patients 1 dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 nd mg, dose reduction should be by 400 mg/day). If needed, 2 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.


st                                                            nd
Note 2: In adult patients 1 dose reduction of PegIntron is to 1 μg/kg/week. If needed, 2 dose reduction of PegIntron is to 0.5 μg/kg/week. For patients on PegIntron monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction.

Dose reduction of PegIntron may be accomplished by either reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b.


Table 2b Two-step dose reduction of PegIntron in combination therapy
First dose reduction to PegIntron 1 μg/kg                          Second dose reduction to PegIntron 0.5 μg/kg Body         PegIntron Amount of Volume of                         Body       PegIntron Amount of Volume of weight       strength     PegIntron PegIntron                      weight     strength     PegIntron PegIntron (kg)         (μg/0.5 ml) to            to                          (kg)       (μg/0.5 ml) to           to administer administer                                            administer administer (μg)         (ml)                                                (μg)        (ml) < 40         50           35           0.35                        < 40       50*          20          0.2 40-50        120*         48           0.2                         40-50      50*          25          0.25
51-64        80           56           0.35                        51-64      80*          32          0.2 65-75        100          70           0.35                        65-75      50           35          0.35 76-85        80           80           0.5                         76-85      120*         48          0.2 86-105       120          96           0.4                         86-105     50           50          0.5 > 105        150          105          0.35                        > 105      80           64          0.4 * Minimum delivery for pen is 0.3 ml.

PegIntron monotherapy dose reduction guidelines

Dose modification guidelines for patients who use PegIntron monotherapy are shown in Table 3a.
Table 3a Dose modification guidelines for PegIntron monotherapy based on laboratory parameters
Laboratory values           Reduce PegIntron               Discontinue PegIntron if: to one-half dose if:
Neutrophils          ≥ 0.5 x 109/l, and < 0.75 x 109/l            < 0.5 x 109/l Platelets              ≥ 25 x 109/l, and < 50 x 109/l             < 25 x 109/l 
For patients who use 0.5 g/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b.

Table 3b Reduced PegIntron dose (0.25 g/kg) for the 0.5 μg/kg monotherapy regimen 
Body weight                  PegIntron strength              Amount of PegIntron             Volume of PegIntron to (kg)                         (μg/0.5 ml)                    to administer                      administer (μg)                             (ml)
30-35                              50*                            8                              0.08 36-45                              50*                           10                               0.1            46-56                              50*                           13                              0.13
57-72                              80*                           16                               0.1 73-88                              50*                           20                               0.2 89-106                              50*                           35                              0.25 107-120**                            80*                           32                               0.2 * Minimum delivery for pen is 0.3 ml.
** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

For patients who use 1.0 g/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in Table 3c.

Table 3c – Reduced PegIntron dose (0.5 μg/kg) for the 1.0 μg/kg monotherapy regimen
Body            PegIntron                                Amount of      Volume of Weight (kg)       strength                                PegIntron to    PegIntron (μg/0.5                                 administer         to ml)                                      (μg)        administer
(ml)
30-35           50*                                      15            0.15 36-45           50*                                                  20                0.20       46-56           50*                                                  25                0.25
57-72           80*                                                  32                 0.2 73-88           50                                                   40                 0.4 89-106           50                                                   50                 0.5 107-120**         80                                                   64                 0.4 * Minimum delivery for pen is 0.3 ml.
** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Special populations
Renal impairment
Monotherapy
PegIntron should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of PegIntron should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance 15-29 ml/minute) should have the starting dose of PegIntron reduced by 50 %. Data are not available for the use of PegIntron in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, PegIntron therapy should be discontinued.

Combination therapy
Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combination with ribavirin (see ribavirin Physician's Insert). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia.

Hepatic impairment
The safety and efficacy of PegIntron therapy has not been evaluated in patients with severe hepatic dysfunction, therefore PegIntron must not be used for these patients.

Elderly ( 65 years of age)
There are no apparent age-related effects on the pharmacokinetics of PegIntron. Data from elderly patients treated with a single dose of PegIntron suggest no alteration in PegIntron dose is necessary based on age (see section 5.2).

Method of administration
PegIntron should be administered as a subcutaneous injection. For special handling information see section 6.6. Patients may self-inject PegIntron if their physician determines that it is appropriate and with medical follow-up as necessary.