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7.       MARKETING AUTHORISATION HOLDER

​​

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

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10.     DATE OF REVISION OF THE TEXT

15 March 2018

4.       CLINICAL PARTICULARS

4.1     Therapeutic indications

Chronic hepatitis B

Adult patients

Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased ALTalanine aminotransferase (ALT) and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1).

Paediatric patients 3 years of age and older

Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 and 5.1.

[…]

4.2     Posology and method of administration

[…]

Table 2: Predictive value of week 12 virological response at the recommended dosing regimen while on Pegasys combination therapy in adult patients with chronic hepatitis C

[…]

Haematological (see also Table 3)

For adults, dose reduction is recommended if the absolute neutrophil count (ANC) is 500 to < 750 cells/mm³. For patients with Absolute Neutrophil Count (ANC) < 500 cells/mm³ treatment should be suspended until ANC values return to > 1000 cells/mm³. Therapy should initially be re-instituted at 90 micrograms Pegasys and the neutrophil count monitored. Guidance for dose reduction based on ANC levels for paediatric patients is provided in Table 7.

Dose reduction to 90 micrograms is recommended if the platelet count is 25,000 to < 50,000 cells/mm³. Cessation of therapyTreatment discontinuation is recommended when platelet count decreases to levels < 25,000 cells/mm³.

[…]

[…]

Liver function

Fluctuations in abnormalities of liver function tests are common in patients with chronic hepatitis C.CHC. Increases in ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including patients with a virological response.

In chronic hepatitis CCHC clinical trials with adult patients, isolated increases in ALT (≥ 10x upper limit of normal [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). Guidance for dose reduction based on ALT levels for paediatric patients is provided in Table 7.

For chronic hepatitis BCHB patients, transient flares of ALT levels sometimes exceeding 10 times the upper limit of normal10x ULN are not uncommon, and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10 times the upper limit of normal.10x ULN . Consideration should be given to continuing treatment with more frequent monitoring of liver function during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is subsiding (see section 4.4).

[…]

For children and adolescents aged 5 to 17 years with chronic hepatitis C, and having a Body Surface Area (BSA) greater than 0.7 m², the recommended doses for Pegasys and ribavirin are provided in Table 4 and Table 5. It is recommended that Pegasys pre-filled syringes be used for paediatric patients. The Pegasys pre-filled pens do not allow for appropriate adjustment of dosing in these patients. Patients who initiate treatment prior to their 18^th birthday should maintain paediatric dosing through the completion of therapy.

The posology of Pegasys should not be used in children with ain paediatric patients is based on the Body Surface Area (BSA) less than 0.71 as there is no available data for this subpopulation.

[…]

The recommended duration of therapy is 48 weeks in patients with CHB.

Before initiating therapy for CHB, persistently elevated serum ALT levels should have been documented. The response rate was lower in patients with no to minimal increase in ALT level at baseline (see Section 5.1).

For children and adolescents aged 3 to 17 years with CHB and having a BSA greater than 0.54 m² and for children and adolescents aged 5 to 17 years with CHC and having a BSA greater than 0.71 m², the recommended doses for Pegasys are provided in Table 4.

Table 4: Pegasys dosing recommendations for paediatric patients aged 5 to 17 yearswith chronic hepatitis B and chronic hepatitis C

[…]

ALT levels above upper limit of normal should repeatedly have been documented before initiating therapy for hepatitis B. The response rate was lower in patients with no to minimal increase in ALT level at baseline (see Section 5.1).

For paediatric patients, based on toxicities, up to three levels of dose modification can be made before dose interruption or discontinuation is considered (see Table 5).

Table 5: Pegasys dose modification recommendations in paediatric patients with chronic hepatitis B or chronic hepatitis C

[…]

Recommendations for dose modifications of Pegasys for toxicities in the CHB and CHC paediatric populations are presented in Table 6.

Table 6: Pegasys dose modification recommendations for toxicities in paediatric patients with chronic hepatitis B or chronic hepatitis C

[…]

Table 57: Ribavirin dosing recommendations for paediatric patients with chronic hepatitis C aged 5 to 17 years

[…]

If toxicities occur which may be related to Pegasys and/or ribavirin administration, the dose of one or both medicinal products can be reduced. Additionally, ribavirin or Pegasys plus ribavirin combination therapy can be discontinued. It is important to note that ribavirin should never be given as monotherapy. Recommendations for dose modifications for toxicities known to have an association with Pegasys administration that are specific for the paediatric population are presented in Table 7. Unless otherwise noted, the management of all other toxicities should follow the adult recommendations.

Table 7: Pegasys dose modification recommendations for toxicities in paediatric patients

[…]

Table 8: Ribavirin dose modification recommendations in paediatric patients with chronic hepatitis C

[…]

4.4     Special warnings and precautions for use

[…]

Growth and development (children and adolescents):

During the course oftherapy with Pegasys plus+/-  ribavirin therapy lasting up to 48 weeks in patients aged 53 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1).

The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials on a case by case basis (see sections 4.8 and 5.1). It is important to consider the treatment with Pegasys +/- ribavirin the combination therapy for CHC induced a growth inhibition during treatment, the reversibility of which is uncertain.

-        It is important to consider that the combination therapy induced a growth inhibition during treatment, the reversibility of which is uncertain.

-           This risk

The risk of growth inhibition should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral loadfor HBV-infection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotype and HCV-RNA levels) (see section 5.1).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long -term effects on sexual maturation.

[…]

4.8     Undesirable effects

Summary of the safety profile

Chronic hepatitis C

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9). The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.

Chronic hepatitis B in adult patients

[…]

Chronic hepatitis C in adult patients

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9). The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.

[…]

Tabulated list of adverse reactions

Table 9 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC adult patients and with Pegasys in combination with ribavirin in CHC patients. Undesirable effects reported in clinical studies are grouped according to frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000). For spontaneous reports of undesirable effects from post-marketing experience, the frequency is not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.

In HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for Pegasys, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patientspatients and with Pegasys in combination with ribavirin in CHC patients.Table 9: Undesirable effects reported with Pegasys monotherapy for HBVCHB or HCVCHC or in combination with ribavirin for HCVCHC patients in clinical trials and post marketing

[…]

Chronic hepatitis B

In a clinical trial (YV25718) with 111 paediatric patients (3 to 17 years of age) treated with Pegasys for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in paediatric patients with CHC.

The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment in study YV25718 were -0.07 and -0.21(n=108 and n= 106 respectively) for Pegasys-treated patients as compared to - 0.01 and -0.08 (n=47 each) in untreated patients. At Week 48 of Pegasys treatment, a height or weight percentile decrease of more than 15 percentiles on the normative growth curves was observed in 6% of patients for height and 11% of patient for weight, whereas in the untreated group it was 2% of patients for height and 9% for weight. No data is available on long-term follow-up post-treatment in these patients (see section 4.4).

Chronic hepatitis C

[…]

Growth inhibition was observed in paediatric patients (see section 4.4). Paediatric patients treated with Pegasys plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of the normative population decreased during treatment. At the end of 2 years follow-up after treatment, most patients had returned to baseline normative growth curve percentiles for weight and height (mean weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.

55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related causative factor has been identified. The extent of available data is not sufficient to conclude that growth inhibition due to Pegasys exposure is always reversible.

[…]

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5.1     Pharmacodynamic properties

[…]

Chronic hepatitis B

Study YV25718 was conducted in previously untreated paediatric patients aged 3 to 17 years (51% < 12 years old) with HBeAg positive CHB  and ALT > ULN but < 10 x ULN in two blood samples taken ≥ 14 days apart during the 6 months before the first dose of study drug. Patients with cirrhosis were not enrolled in this study. A total of 151 patients without advanced fibrosis were 2:1 randomized to Pegasys (group A, n=101) or untreated control (group B, n=50), respectively. Patients with advanced fibrosis were assigned to Pegasys treatment (group C, n=10). Patients in groups A and C (n=111) were treated with Pegasys once weekly for 48 weeks according to BSA categories, whereas patients in group B were observed for a period of 48 weeks (principal observation period). Patients in group B had the choice to switch to treatment with Pegasys after Week 48 of the principal observation period. All patients were followed up for 24 weeks post-treatment (groups A and C), or post-principal observation period (group B). After the Week 24 follow-up visit, patients from group A, B and C entered a long-term follow-up period (lasting for 5 years after end of treatment). Response rates in groups A and B at the end of 24 weeks follow-up are presented in Table 22. Efficacy response in group C to Pegasys treatment was in line with that seen in group A. For paediatric patients, efficacy has not been established in HBV genotypes other than genotypes A-D.

Table 22: Serological, virological and biochemical responses in paediatric patients with chronic hepatitis B

[…]

The response rate of HBeAg seroconversion was lower in patients with HBV genotype D, also in patients with no to minimal increase in ALT level at baseline (see Table 23).

Table 23: HBeAg seroconversion rates (%) by HBV genotype and baseline ALT levels

[…]

For paediatric patients, efficacy has not been established in HBV genotypes other than genotypes A-D.Exploratory analyses based on limited data show paediatric patients with greater decline in HBV-DNA at week 12 of therapy were more likely to achieve HBeAg seroconversion at 24 weeks of follow-up (Table 24).

Table 24: HBeAg seroconversion rates (%) by HBV-DNA decline from baseline to week 12 of Pegasys treatment in paediatric patients

[…]

5.2     Pharmacokinetic properties

[…]

Paediatric population

In a population pharmacokinetic study (NR16141Pegasys pharmacokinetics have been characterized in paediatric patients with CHB (YV25718), as well as in paediatric patients with CHC (NR16141), using population pharmacokinetics.  In both studies, Pegasys apparent clearance and apparent volume of distribution were related linearly to body size ie. either BSA (NR16141) or body weight (YV25718).

From the YV25718 study, 31 paediatric patients 3 to 17 years of age with CHB participated in the PK sub-study and received Pegasys according to a BSA category dosing regimen. Based on the population pharmacokinetic model, the mean exposure (AUC) during the dosing interval for each BSA category was comparable with that observed in adults receiving 180 mcg fixed dosing.

[…]

4.2     Posology and method of administration

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. For information on predictive values for on-treatment response, see section 5.1.

5.1     Pharmacodynamic properties

Predictability of response

A patient-level meta-analysis of 9 Pegasys clinical studies (n=1,423) in CHB HBeAg positive and HBeAg-negative patients demonstrated that HBsAg and HBV DNA levels at Week 12 of treatment, are predictive of final treatment outcome at Week 24 post-treatment in certain genotypes. Operating characteristics of these biomarkers are presented in Table 11. No single biomarker with a cut-off can be identified to optimize all the operating characteristics (negative predictive value [NPV], sensitivity, specificity) and practical characteristics (simplicity, convenience). Consideration for early treatment discontinuation should be evaluated in the context of a particular clinical situation.

For HBeAg-positive patients with HBV genotype B and C infection, HBsAg > 20,000 IU/mL or HBV DNA > 8 log₁₀ IU/mL at Week 12 following commencement of treatment is associated with high likelihood of failure to achieve HBeAg seroconversion and HBV-DNA <2,000 IU/mL at 24 week post-treatment (NPV > 90%). For HBV genotype A and D, subgroup size was insufficient to be analyzed.

For HBeAg-negative patients with HBV genotype D infection, HBsAg > 20,000 IU/mL or HBV DNA > 6.5 log₁₀ IU/mL at Week 12 following commencement of treatment is associated with high likelihood of failure to achieve HBV-DNA <2,000 IU/mL and ALT normalization at Week 24 post treatment. HBV genotype A subgroup size was insufficient to be analyzed. No biomarker can be identified with acceptable performance for HBeAg-negative patients with HBV genotype B or C infection.

Other published on-treatment biomarkers that are predictive of the final outcome of Pegasys treatment may be considered.

Table 11: Performance of individual biomarkers at Week 12 of therapy in CHB HBeAg-positive and HBeAg-negative patients according to genotype

NPV= negative predictive value; Sensitivity = % of all responders not meeting the stopping rule; Specificity = % of all non-responders meeting stopping rule

(a)               Treatment response for HBeAg-positive patients was defined as HBeAg seroconversion (defined as loss of HBeAg and presence of anti-HBe) + HBV DNA <2,000 IU/mL at 6 months post-treatment and treatment response for HBeAg-negative patients was defined as HBV DNA < 2,000 IU/mL + ALT normalization at 6 months post-treatment.

10.     DATE OF REVISION OF THE TEXT

5 May 2017

4.2     Posology and method of administration

[...]

Special populations

Older peopleElderly

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

No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduced dose of 135 mcg once weekly is recommended in adult patients with severe renal impairment orIn 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.

4.4     Special warnings and precautions for use

[...]

In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

[...]

5.2     Pharmacokinetic properties

[...]

Patients with renal impairment

A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease (ESRD) requiring chronic hemodialysis (HD). Patients with moderate renal impairment receiving Pegasys 180 mcg once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to patients with normal renal function. Patients with severe renal impairment receiving Pegasys 180 mcg once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal function, therefore a reduced dose of Pegasys 135 mcg once weekly is recommended in patients with severe renal impairment. In 13 patients with ESRD requiring chronic HD, administration of Pegasys 135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with normal renal function. However, several independent studies have demonstrated the 135mcg dose to be safe, efficacious and well tolerated, in patients with ESRD.Renal impairment is associated with slightly decreased CL/F and prolonged half-life. In patients (n=3) with CL_crea between 20 and 40 ml/min, the average CL/F is reduced by 25% compared with patients with normal renal function. In patients with end stage renal disease undergoing haemodialysis, there is a 25% to 45% reduction in the clearance, and doses of 135 micrograms result in similar exposure as 180 micrograms doses in patients with normal renal function (see section 4.2).

6.3     Shelf life

Pre-filled syringe 90 mcg: 3 years.

Pre-filled syringe 135 mcg and 180 mcg: 4 years.

Pre-filled pen: 2 years.

10.     DATE OF REVISION OF THE TEXT

8 January14 June 2016

6.5     Nature and contents of container

Pre-filled syringe: 0.5 ml of solution for injection in pre-filled syringe (siliconised Type I glass) with a plunger stopper and tip cap (butyl rubber laminated on the product facing side with fluororesin) with a needle.

The 90 microgram syringe is labeled with graduations corresponding to doses of 90 mcg, 65 mcg, 45 mcg, 30 mcg, 20 mcg and 10 mcg. Available in packs of 1 pre-filled syringe.

The 135 microgram syringe is labeled with graduations corresponding to doses of 135 mcg, 90 mcg and 45 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes.

The 180 microgram syringe is labeled with graduations corresponding to doses of 180 mcg, 135 mcg and 90 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes.

Not all pack-sizes may be marketed.

Pre-filled pen: 0.5 ml of solution for injection in pre-filled syringe (siliconised Type I glass) with a fixed needle (stainless steel), plunger stopper (butyl rubber laminated with fluororesin) and a needle shield (polyisoprene) in a pre-filled pen.

The 135 and 180 micrograms pens are available in packs containing 1, 4 or 12 pre-filled pens.

Not all pack-sizes may be marketed.

6.5     Nature and contents of container

Pre-filled syringe: 0.5 ml of solution for injection in pre-filled syringe (siliconised Type I glass) with a plunger stopper and tip cap (butyl rubber laminated on the product facing side with fluororesin) with a needle.

The 90 microgram syringe is labeled with graduations corresponding to doses of 90 mcg, 65 mcg, 45 mcg, 30 mcg, 20 mcg and 10 mcg. Available in packs of 1 pre-filled syringe.

The 135 microgram syringe is labeled with graduations corresponding to doses of 135 mcg, 90 mcg and 45 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes.

The 180 microgram syringe is labeled with graduations corresponding to doses of 180 mcg, 135 mcg and 90 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes.

Not all pack-sizes may be marketed.

Pre-filled pen: 0.5 ml of solution for injection in pre-filled syringe (siliconised Type I glass) with a fixed needle (stainless steel), plunger stopper (butyl rubber laminated with fluororesin) and a needle shield (polyisoprene) in a pre-filled pen.

The 135 and 180 micrograms pens are available in packs containing 1, 4 or 12 pre-filled pens.

Not all pack-sizes may be marketed.

10.     DATE OF REVISION OF THE TEXT

8 September 20158 January 2016

Table 9: Undesirable effects reported with Pegasys monotherapy for HBV or HCV or in combination with ribavirin for HCV patients in clinical trials and post marketing

*These adverse reactions were common (≥1/100 to < 1/10) in CHB patients treated with Pegasys monotherapy

^§ Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions

Pulmonary arterial hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.

10.     DATE OF REVISION OF THE TEXT

8 September 2015

4.4     Special warnings and precautions for use

 [...]

4.8     Undesirable effects

 [...]

Growth inhibition was observed in paediatric patients (see section 4.4). Paediatric patients treated with Pegasys plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of the normative population decreased during treatment. At the end of 2 years follow-up after treatment, most patients had returned to baseline normative growth curve percentiles for weight and height (mean weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 or 53) experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.

55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related causative factor has been identified. The extent of available data is not sufficient to conclude that growth inhibition due to Pegasys exposure is always reversible.

[....]

10.     DATE OF REVISION OF THE TEXT

23 October 2014

Underlined text has been added, text with strike through deleted
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 Summary of Product Characteristics (SmPC) when Pegasys is to be used in combination with ribavirin.

Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Pegasys.

Monotherapy for hepatitis C should only be considered in cases of contraindication to other medicinal products.

Posology

Chronic hepatitis B – adult patients

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 adult 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– dual therapy with Pegasys and ribavirin

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 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

*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 – treatment-experienced adult patients

The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by subcutaneous administration. For patients <75 kg and ³75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, and regardless of genotype, should be administered.

Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).

HIV-HCV co-infected adult patients

The recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and ³75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration of therapy less than 48 weeks has not been adequately studied.

Duration of therapy when Pegasys is used in combination with other medicinal products.

Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Pegasys.

Predictability of response and non-response with Pegasys and ribavirin dual therapy– 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 12).

Table 2: Predictive value of week 12 virological response at the recommended dosing regimen while on Pegasys combination therapy

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 with Pegasys and ribavirin dual therapy – 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 in adult patients

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 for adult patients. 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)

For adults, 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. Guidance for dose reduction based on ANC levels for paediatric patients is provided in Table 7.

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 in adults 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.

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 with adult patients, 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). Guidance for dose reduction based on ALT levels for paediatric patients is provided in Table 7.

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 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

*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).

For children and adolescents aged 5 to 17 years with chronic hepatitis C, and having a Body Surface Area (BSA) greater than 0.7 m², the recommended doses for Pegasys and ribavirin are provided in Table 4 and Table 5. It is recommended that Pegasys pre-filled syringes be used for paediatric patients. The Pegasys pre-filled pens do not allow for appropriate adjustment of dosing in these patients. Patients who initiate treatment prior to their 18^th birthday should maintain paediatric dosing through the completion of therapy.

Pegasys should not be used in children with a Body Surface Area (BSA) less than 0.71 as there is no available data for this subpopulation.

To calculate BSA), it is recommended to use Mosteller’s equation:

Duration of treatment

The duration of treatment with Pegasys in combination with ribavirin in paediatric patients with chronic hepatitis C depends on viral genotype.  Patients infected with viral genotypes 2 or 3 should receive 24 weeks of treatment, while patients infected with any other genotype should receive 48 weeks of therapy.

Patients who still have detectable levels of HCV-RNA despite an initial 24 weeks of therapy, should discontinue therapy, as it is unlikely they will be able to achieve a sustained virological response with continued therapy.

Table 4: Pegasys dosing recommendations for paediatric patients aged 5 to 17 years

For children and adolescents aged 5 to 17 years with chronic hepatitis C, the recommended dose of ribavirin is based on the patient’s body weight, with a target dose of 15 mg/kg/day, divided in two daily doses. For children and adolescents 23 kg or greater, a dosing schedule using 200 mg ribavirin tablets is provided in Table 5. Patients and caregivers must not attempt to break the 200 mg tablets.

Table 5: Ribavirin dosing recommendations for paediatric patients aged 5 to 17 years

Dose adjustment for adverse reactions in paediatric patients

For paediatric patients, based on toxicities (see Table 6), up to three levels of dose modification can be made before dose interruption or discontinuation is considered.

Table 6: Pegasys dose modification recommendations in paediatric patients

If toxicities occur which may be related to Pegasys and/or ribavirin administration, the dose of one or both medicinal products can be reduced. Additionally, ribavirin or Pegasys plus ribavirin combination therapy can be discontinued. It is important to note that ribavirin should never be given as monotherapy. Recommendations for dose modifications for toxicities known to have an association with Pegasys administration that are specific for the paediatric population are presented in Table 7. Unless otherwise noted, the management of all other toxicities should follow the adult recommendations.

Table 7: Pegasys dose modification recommendations for toxicities in paediatric patients

In paediatric patients, ribavirin treatment-associated toxicities, such as treatment-emergent anaemia, will be managed by reduction of the full dose. The dose reduction levels are provided in Table 8.

Table 8: Ribavirin dose modification recommendations in paediatric patients

There is limited experience with Pegasys in treating paediatric patients with HCV aged 3 to 5 years, or who have failed to be adequately treated previously. There are no data in paediatric patients coinfected with HCV/HIV or with renal impairment.

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 syringe/pen 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 the User”, provided in the carton, must be followed carefully by the patient.

4.3       Contraindications

·          Hypersensitivity to the active substance, to alfpha interferons, or to any of the excipients listed in section 6.1

·          Autoimmune hepatitis

·          Severe hepatic dysfunction or decompensated cirrhosis of the liver

·          A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4)

·          HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by medicinal products such as atazanavir and indinavir

·          Combination with telbivudine (see section 4.5).

·          Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see            section 4.4 for benzyl alcohol)

·          In paediatric patients, the presence of, or history of severe psychiatric condition, particularly            severe depression, suicidal ideation or suicidal attempt.

For contraindications to ribavirin, please refer also to the ribavirin Summary of Product Characteristics (SmPC) when Pegasys is to be used in combination with ribavirin.

4.4       Special warnings and precautions for use

Please refer also to the ribavirin Summary of Product Characteristics (SmPC) when Pegasys is to be used in combination with ribavirin.

In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file.

Liver histology prior to therapy

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e., patients with genotype 2 or 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.

In patients with normal ALT, progression of fibrosis occurs on average at a slower rate than in patients with elevated ALT. This should be considered in conjunction with other factors, such as HCV genotype, age, extrahepatic manifestations, risk of transmission, etc. which influence the decision to treat or not.

Laboratory tests prior to and during therapy

Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are recommended for all patients.

The following may be considered as baseline values for initiation of treatment:

-           Platelet count ³ 90,000/mm³

-           Absolute neutrophil counts ³ 1500/mm³

-           Adequately controlled thyroid function (TSH and T4)

Haematological tests should be repeated after 2 and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy (including glucose monitoring).

In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell (WBC) count and absolute neutrophil count (ANC), usually starting within the first 2 weeks of treatment (see section 4.8). Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the majority of patients and returned to baseline in all patients after about 16 weeks.

Pegasys treatment has been associated with decreases in platelet count, which returned to pre-treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose modification may be necessary (see section 4.2).

The occurrence of anaemia (haemoglobin <10 g/dl) has been observed in up to 15% of chronic hepatitis C patients in clinical trials on the combined treatment of Pegasys with ribavirin. The frequency depends on the treatment duration and the dose of ribavirin (see section 4.8). The risk of developing anaemia is higher in the female population.

Caution should be exercised when administering Pegasys in combination with other potentially myelosuppressive agents.

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon re-introduction of either treatment alone (see section 4.5).

The use of Pegasys and ribavirin combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse reactions. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.

Endocrine system

Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with the use of alfpha interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels should be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintained in the normal range bypharmaceutical means. TSH levels should be determined during the course of therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (see section 4.8). Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys (see section 4.8). Patients with these conditions who cannot be effectively controlled by medication should not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys or Pegasys/ribavirin therapy.

Cardiovascular system

Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alfpha interferon therapies, including Pegasys. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or discontinuation of ribavirin (see section 4.2).

Liver function

In patients who develop evidence of hepatic decompensation during treatment, Pegasys should be discontinued. Increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a viral response. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued (see sections 4.2 and 4.8).

In chronic hepatitis B, unlike chronic hepatitis C, disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, marked transaminase flares have been accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. In approximately half the cases of flares exceeding 10 times the upper limit of normal, Pegasys dosing was reduced or withheld until the transaminase elevations subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic function was recommended in all instances.

Hypersensitivity

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alfpha interferon therapy. If this occurs, therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alfpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be re-assessed (see also Endocrine system in sections 4.4 and 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Fever/infections

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and sepsis have been reported during treatment with alfpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Ocular changes

Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction which may result in loss of vision have been reported in rare instances with Pegasys. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Adult and paediatric patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Pulmonary changes

Pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis have been reported during therapy with Pegasys. In case of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.

Skin disorder

Use of alfpha interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset or worsening of psoriatic lesions, discontinuation of therapy should be considered.

Transplantation

The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.

HIV-HCV coinfection

Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Pegasys with or without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should therefore be exercised when adding Pegasys and ribavirin to HAART therapy (see ribavirin SmPC).

Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI).

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation.

In patients co-infected with HIV-HCV, limited efficacy and safety data are available in patients with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Pegasys and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Use of peginterferon as long term maintenance monotherapy (unapproved use)

In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was studied, no significant reductions were observed in the rate of fibrosis progression or related clinical events.

Excipient

Pegasys contains benzyl alcohol. Must not be given to premature babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

5.2     Pharmacokinetic properties

Absorption

Following a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serum concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peak serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is 84% and is similar to that seen with interferon alfa-2a.

Distribution

Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (V_d) of 6 to 14 litres in humans after intravenous administration. From mass balance, tissue distribution and whole body autoradioluminography studies performed in rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.

Biotransformation

The metabolism of Pegasys is not fully characterised; however studies in rats indicate that the kidney is a major organ for excretion of radiolabelled material.

Elimination

In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa-2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of Pegasys.

Linearity/non-linearity

Dose-proportional increases in exposure of Pegasys are seen in healthy subjects and in patients with chronic hepatitis B or C after once-weekly dosing.

In chronic hepatitis B or C patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).

Patients with renal impairment

Renal impairment is associated with slightly decreased CL/F and prolonged half-life. In patients (n=3) with CL_crea between 20 and 40 ml/min, the average CL/F is reduced by 25% compared with patients with normal renal function. In patients with end stage renal disease undergoing haemodialysis, there is a 25% to 45% reduction in the clearance, and doses of 135 micrograms result in similar exposure as 180 micrograms doses in patients with normal renal function (see section 4.2).

Please refer also to the ribavirin Summary of Product Characteristics (SmPC) when Pegasys is to be used in combination with ribavirin.

Gender

The pharmacokinetics of Pegasys after single subcutaneous injections was comparable between male and female healthy subjects.

Paediatric population

In a population pharmacokinetic study (NR16141), 14 children 2 to 8 years of age with CHC received Pegasys monotherapy at a dose of: 180 mcg x BSA of the child/1.73 m². The PK model developed from this study shows a linear influence of BSA on the apparent clearance of the drug over the age range studied. Thus, the lower the BSA of the child, the lower the clearance of the drug and the higher the resultant exposure. The mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing.

Older people

In subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of 180 micrograms was delayed but still sustained compared to young healthy subjects (t_max of 115 hours vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 1295 ng·h/ml) but peak concentrations (9.1 vs. 10.3 ng/ml) were similar in subjects older than 62 years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys is not needed in the geriatric patient (see section 4.2).

Hepatic impairment

The pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis B or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) and non-cirrhotic patients.

Site of administration

Subcutaneous administration of Pegasys should be limited to the abdomen and thigh, as the extent of absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm compared to administration in the abdomen and thigh.

10.     DATE OF REVISION OF THE TEXT

28 April 2014

4.4     Special warnings and precautions for use

Laboratory tests prior to and during therapy

Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are recommended for all patients.

The following may be considered as baseline values for initiation of treatment:

-           Platelet count ³ 90,000/mm³

-           Absolute neutrophil counts ³ 1500/mm³

-           Adequately controlled thyroid function (TSH and T4)

Haematological tests should be repeated after 2 and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy (including glucose monitoring).

4.8     Undesirable effects

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

10.     DATE OF REVISION OF THE TEXT

23 April 2014

Underlined text has been added, text with strike through deleted:

4.2       Posology and method of administration

[…]

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

The ribavirin dose should be administered with food.

[…]

4.4       Special warnings and precautions for use

Please refer also to the ribavirin Summary of Product Characteristics (SmPC) when Pegasys is to be used in combination with ribavirin.

In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file.

[…]

4.8       Undesirable effects

[…]

Table 10: Adverse reactions reported among paediatric patients infected with HCV and assigned to Pegasys plus ribavirin in study NV17424