Posology : מינונים

4.2   Posology and method of administration
Treatment should be initiated only by a physician experienced in the treatment of patients with hepatitis B or C.

Please refer also to the ribavirin prescribing information when Pegasys is to be used in combination with ribavirin.

PosologyChronic hepatitis B:

The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg- negative chronic hepatitis B is 180 micrograms once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.

Chronic hepatitis C – treatment-naïve patients:

The recommended dose for Pegasys is 180 micrograms once weekly by subcutaneous administration in the abdomen or thigh given in combination with oral ribavirin or as monotherapy.

The dose of ribavirin to be used in combination with Pegasys is given in Table 1.
The ribavirin dose should be administered with food.

Duration of treatment
The duration of combination therapy with ribavirin for chronic hepatitis C depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy.
Treatment for 24 weeks may be considered in patients infected with
-      genotype 1 with low viral load (LVL) ( 800,000 IU/ml) at baseline or -      genotype 4 who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24.
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). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.

Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 
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PEGASYS                                                                   MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                              December 2015 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL ( 800,000 IU/ml) at baseline who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24 week treatment duration (see section 5.1). In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration.
Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (> 800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).

Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1,000/1,200 mg of ribavirin for 48 weeks is recommended.

Table 1: Dosing recommendations for combination therapy for HCV patients Genotype            Pegasys dose      Ribavirin dose        Duration
Genotype 1 LVL     180 micrograms    <75 kg = 1000 mg     24 weeks or with RVR*                            75 kg = 1200 mg      48 weeks Genotype 1 HVL     180 micrograms    <75 kg = 1000 mg      48 weeks with RVR*                            75 kg = 1200 mg
Genotype 4 with    180 micrograms    <75 kg = 1000 mg     24 weeks or RVR*                                 75 kg = 1200 mg      48 weeks Genotype 1 or 4   180 micrograms     <75 kg = 1000 mg      48 weeks without RVR*                         75 kg = 1200 mg
Genotype 2 or 3   180 micrograms          800 mg           24 weeks without RVR**
Genotype 2 or 3   180 micrograms         800 mg(a)       16 weeks(a) or LVL with RVR**                                             24 weeks
Genotype 2 or 3   180 micrograms          800 mg           24 weeks
HVL with RVR**
*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24; **RVR = rapid viral response (HCV RNA negative) by week 4
LVL = ≤ 800,000 IU/ml; HVL = > 800,000 IU/ml
(a)
It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for re-treating non-responding and relapsing patients.

The recommended duration of Pegasys monotherapy is 48 weeks.

Chronic hepatitis C – Prior Treatment Non-responder and Relapser Patients: The recommended dosage of Pegasys and ribavirin combination therapy is Pegasys 180 g once a week by subcutaneous administration in the abdomen or thigh. For patients < 75 kg and  75 kg, 1000 mg and 1200 mg of ribavirin respectively, should be administered daily.Ribavirin should be administered in divided doses (moning and evening) with food.
Patients who have detectable virus at week 12 should stop therapy.

The recommended duration of therapy is up to 72 weeks in genotype 1 or 4 patients and 48 weeks in genotype 2 or 3 patients.


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PEGASYS                                                       MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                  December 2015 HIV-HCV co-infection
The recommended dosage for Pegasys, alone or in combination with 800 milligrams of ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks, regardless of genotype. The safety and efficacy of combination therapy with ribavirin doses greater than 800 milligrams daily is currently being studied. A duration of therapy less than 48 weeks has not been adquately studied.

Predictability of response and non-response – treatment-naïve patients 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 (see Tables 2 and 6).

Table 2: Predictive value of week 12 virological response at the recommended dosing regimen while on Pegasys combination therapy
Genotype                           Negative                             Positive No            No                       Response response      sustained   Predictive    by week   Sustained   Predictive by week 12    response    Value            12     response      Value Genotype 1               102           97         95%          467        271        58% (N= 569)                                        (97/102)                           (271/467) Genotype 2 and 3                                   100%                              87% (N=96)                    3            3           (3/3)      93          81        (81/93) 
The negative predictive value for sustained response in patients treated with Pegasys in monotherapy was 98%.
A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with Pegasys monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.

Predictability of response and non-response – treatment-experienced patients 
In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.

Dose adjustment for adverse reactions

General
Where dose adjustment is required for moderate to severe adverse reactions (clinical and/or laboratory) initial dose reduction to 135 micrograms is generally adequate. In some cases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towards the original dose may be considered when the adverse reaction abates (see section 4.4 for use and section 4.8).

Haematological (see also Table 3)
Dose reduction is recommended if the neutrophil count is < 750/mm3. For patients with Absolute Neutrophil Count (ANC) < 500/mm3 treatment should be suspended until ANC values return to > 1000/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys and the neutrophil count monitored.

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PEGASYS                                                        MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                   December 2015 Dose reduction to 90 micrograms is recommended if the platelet count is < 50,000/mm3.
Cessation of therapy is recommended when platelet count decreases to levels < 25,000/mm3.

Specific recommendations for management of treatment-emergent anaemia are as follows: ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin to < 10 g/dl and ≥ 8.5 g/dl, or (2) a patient with stable cardiovascular disease experiences a fall in haemoglobin by ≥ 2 g/dl during any 4 weeks of treatment. A return to original dosing is not recommended. Ribavirin should be discontinued if either of the following applies: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin confirmed to < 8.5 g/dl; (2) a patient with stable cardiovascular disease maintains a haemoglobin value < 12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, ribavirin may be restarted at
600 milligrams daily, and further increased to 800 milligrams daily at the discretion of the treating physician. A return to original dosing is not recommended.

Table 3: Dose adjustment for adverse reaction (for further guidance see also text above)
Reduce         Withhold    Reduce          Withhold     Discontinue ribavirin      ribavirin   Pegasys         Pegasys      combination to 600 mg                  to 135/90/45 micrograms
Absolute                                    < 750/mm3       < 500/mm3 Neutrophil
Count
Platelet Count                              < 50,000/mm3                 < 25,000/mm3 3
> 25,000/mm
Haemoglobin      < 10 g/dl, and < 8.5 g/dl no cardiac       ≥ 8.5 g/dl disease

Haemoglobin        decrease        < 12 g/dl stable cardiac     ≥ 2 g/dl during despite 4 disease            any 4 weeks weeks at reduced dose

In case of intolerance to ribavirin, Pegasys monotherapy should be continued.

Liver function
Fluctuations in abnormalities of liver function tests are common in patients with chronic hepatitis C. Increases in ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including patients with a virological response.
In chronic hepatitis C clinical trials, isolated increases in ALT (≥ 10x ULN, or ≥ 2x BL for patients with a BL ALT ≥ 10x ULN) which resolved without dose-modification were observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive or persistent, the dose should be reduced initially to 135 micrograms. When increases in ALT levels are progressive despite dose reduction, or are accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be discontinued (see section 4.4).

For chronic hepatitis B patients, transient flares of ALT levels sometimes exceeding 10 times the upper limit of normal are not uncommon, and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10 times the upper limit of normal. Consideration should be given to continuing treatment with more frequent monitoring of liver function during 
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PEGASYS                                                     MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                December 2015 ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is subsiding (see section 4.4).

Special populations

Older people
Adjustments in the recommended dosage of 180 micrograms once weekly are not necessary when instituting Pegasys therapy in elderly patients (see section 5.2).

Renal impairment
In patients with end stage renal disease, a starting dose of 135 micrograms should be used (see section 5.2). Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions.

Hepatic impairment
In patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effective and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B or C or bleeding oesophageal varices) (see section 4.3).

The Child-Pugh classification divides patients into groups A, B, and C, or "Mild", "Moderate" and "Severe" corresponding to scores of 5-6, 7-9 and 10-15, respectively.

Modified Assessment
Assessment            Degree of abnormality        Score
Encephalopathy        None                         1
Grade 1-2                    2
Grade 3-4*                   3
Ascites               Absent                       1
Slight                       2
Moderate                     3
S-Bilirubin           <2                           1
(mg/dl)               2.0-3                        2
>3                           3

<34                     1
SI unit = mol/l)  34-51                   2
>51                     3
S-Albumin (g/dl)   >3.5                    1
3.5-2.8                 2
<2.8                    3
INR                <1.7                    1
1.7-2.3                 2
>2.3                    3
*Grading according to Trey, Burns and Saunders (1966)
Paediatric population

Pegasys is contraindicated in neonates and young children up to 3 years old due to the excipient benzyl alcohol (see sections 4.3 and 4.4).



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PEGASYS                                                        MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                   December 2015 Method of administration

Pegasys is administered subcutaneously in the abdomen or thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm (see section 5.2).

Pegasys is designed for administration by the patient or carer. Each pen and syringe should be used by one person only and is for single use.

Appropriate training is recommended for non-healthcare professionals administering this medicinal product. The “Instructions for self-injection”, provided in the package insert, must be followed carefully by the patient.