PEGASYS 180mcg / 0.5ml injection solution in pre-filled syringe medication leaflet

Pegasys 90 micrograms solution for injection in pre-filled syringe

Pegasys 135 micrograms solution for injection in pre-filled syringe

Pegasys 180 micrograms solution for injection in pre-filled syringe

Pegasys 90 micrograms solution for injection in pre-filled syringe

Each syringe of 0.5 mL solution contains 90 micrograms peginterferon alfa-2a*.

Pegasys 135 micrograms solution for injection in pre-filled syringe

Each syringe of 0.5 mL solution contains 135 micrograms peginterferon alfa-2a*.

Pegasys 180 micrograms solution for injection in pre-filled syringe

Each syringe of 0.5 mL solution contains 180 micrograms peginterferon alfa-2a*.

The strength indicates the quantity of the interferon alfa-2a moiety of peginterferon alfa-2a withoutconsideration of the pegylation.

*The active substance, peginterferon alfa-2a, is a covalent conjugate of the protein interferon alfa-2aproduced by recombinant DNA technology in Escherichia coli with bis-[monomethoxy polyethyleneglycol].

The potency of this medicinal product should not be compared to the one of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1.

Each pre-filled syringe of 0.5 mL contains 5 mg benzyl alcohol.

Each pre-filled syringe of 0.5 mL contains 0.025 mg polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

The solution is clear and colourless to light yellow.

Polycythaemia vera

Pegasys is indicated as monotherapy in adults for the treatment of polycythaemia vera.

Essential thrombocythaemia

Pegasys is indicated as monotherapy in adults for the treatment of essential thrombocythaemia.

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 ofviral replication, increased alanine aminotransferase (ALT) and histologically verified liverinflammation 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 andadolescents 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, pct. 4.4and 5.1.

Chronic hepatitis C

Adult patients

Pegasys is indicated in combination with other medicinal products, for the treatment of chronichepatitis C (CHC) in patients with compensated liver disease (see sections 4.2, pct. 4.4 and 5.1).

For hepatitis C virus (HCV) genotype specific activity, see sections 4.2 and 5.1.

Paediatric patients 5 years of age and older

Pegasys in combination with ribavirin is indicated for the treatment of CHC in treatment-naïvechildren and adolescents 5 years of age and older who are positive for serum HCV-RNA.

When deciding to initiate treatment in childhood, it is important to consider growth inhibition inducedby combination therapy. The reversibility of growth inhibition is uncertain. The decision to treatshould be made on a case by case basis (see section 4.4).

Treatment should be initiated only by a physician experienced in the treatment of patients withpolycythaemia vera, essential thrombocythaemia, or hepatitis B or C.

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

Monotherapy for hepatitis C should only be considered in case of contraindication to other medicinalproducts.

Polycythemia vera and essential thrombocythemia - adult patients

The dose should be titrated individually with a recommended starting dose of 45 micrograms onceweekly subcutaneously. The dose should be gradually increased by 45 micrograms monthly untilstabilisation of the haematological parameters is achieved. The dose may be adapted and/or theadministration interval prolonged, as appropriate for the patient.

For polycythemia vera a stabilisation of the haematological parameters is defined as haematocrit(HCT) <45% without phlebotomy and platelets ≤400x109/L and leukocytes <10x109/L.

For essential thrombocythemia the stabilisation of the haematological parameters is defined asplatelets ≤400x109/L and leukocytes <10x109/L.

The maximum recommended single dose is 180 micrograms injected once weekly subcutaneously.

If adverse reactions develop during therapy, the administered dose should be reduced or treatmentdiscontinued temporarily until adverse reactions abate; further, treatment should be re-initiated with alower dose than the dose that caused adverse reactions (see section 4.4).

If an increase of haematological parameters (HCT, platelets, leukocytes) is observed, the dose and/ordosing interval needs to be adapted individually.

Chronic hepatitis B - adult patients

The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative

CHB is 180 micrograms once weekly for 48 weeks. For information on predictive values for on-treatment response, see section 5.1.

Chronic hepatitis C - adult patients

Treatment-naïve adult patients

The recommended dose for Pegasys is 180 micrograms once weekly given in combination with oralribavirin 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 CHC depends on viral genotype. Patientsinfected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatmentviral 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 4who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, anoverall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weekstreatment duration (see section 5.1). In these patients, tolerability to combination therapy andadditional prognostic factors such as degree of fibrosis should be taken into account when deciding ontreatment 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 dataavailable 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 ofpre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may beconsidered in selected patients infected with genotype 2 or 3 with LVL (≤ 800 000 IU/mL) at baselinewho become HCV negative by week 4 of treatment and remains HCV negative by week 16. Anoverall 16 weeks treatment duration may be associated with a lower chance of response and isassociated with a higher risk of relapse than a 24-week treatment duration (see section 5.1). In thesepatients, tolerability to combination therapy and the presence of additional clinical or prognosticfactors such as degree of fibrosis should be taken into account when considering deviations fromstandard 24 weeks treatment duration. Shortening the treatment duration in patients infected withgenotype 2 or 3 with HVL (> 800 000 IU/mL) at baseline who become HCV negative by week 4should be considered with more caution as this may significantly negatively impact the sustainedvirological response (SVR) (see Table 1).

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

Table 1: Dosing recommendations for combination therapy for adult patients with chronichepatitis C

Genotype Pegasys dose Ribavirin dose Duration

Genotype 1 LVL with RVR* 180 micrograms <75 kg = 1 000 mg 24 weeks or≥75 kg = 1 200 mg 48 weeks

Genotype 1 HVL with RVR* 180 micrograms <75 kg = 1 000 mg 48 weeks≥75 kg = 1 200 mg

Genotype 4 with RVR* 180 micrograms <75 kg = 1 000 mg 24 weeks or≥75 kg = 1 200 mg 48 weeks

Genotype 1 or 4 without RVR* 180 micrograms <75 kg = 1 000 mg 48 weeks≥75 kg = 1 200 mg

Genotype 2 or 3 without RVR** 180 micrograms 800 mg 24 weeks

Genotype 2 or 3 LVL with RVR** 180 micrograms 800 mg(a) 16 weeks(a) or24 weeks

Genotype 2 or 3 HVL with RVR** 180 micrograms 800 mg 24 weeks

*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. 1 000/1 200 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 isunknown, taking into account the need for re-treating non-responding and relapsing patients.

The recommended duration of Pegasys monotherapy is 48 weeks.

Treatment-experienced adult patients

The recommended dose of Pegasys in combination with ribavirin is 180 micrograms once weekly bysubcutaneous administration. For patients <75 kg and ≥75 kg, 1 000 mg daily and 1 200 mg daily ofribavirin, respectively, and regardless of genotype, should be administered.

Patients who have detectable virus at week 12 should stop therapy. The recommended total duration oftherapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment withpeginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is72 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 onceweekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and ≥75 kg,1 000 mg daily and 1 200 mg daily of ribavirin, respectively, should be administered. Patients infectedwith HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration oftherapy 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 incombination 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 14).

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

Genotype Negative Positive

No No Responseresponse by sustained Predictive by week Sustained Predictiveweek 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 monotherapywas 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 andgenotype 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 ifviral 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 oftreatment 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

Where dose adjustment is required for moderate to severe adverse reactions (clinical and/orlaboratory) initial dose reduction to 135 micrograms is generally adequate for adult patients. In somecases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towardsthe original dose may be considered when the adverse reaction abates (see sections 4.4 and 4.8).

Haematological (see also Table 3)

For adults, dose reduction is recommended if the absolute neutrophil count (ANC) is 500 to < 750cells/mm3. For patients with ANC < 500 cells/mm3 treatment should be suspended until ANC valuesreturn to > 1 000 cells/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys andthe neutrophil count monitored.

Dose reduction to 90 micrograms is recommended if the platelet count is 25 000 to < 50 000cells/mm3. Treatment discontinuation is recommended when platelet count decreases to levels< 25 000 cells/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 milligramsin the evening) if either of the following apply: (1) a patient without significant cardiovascular diseaseexperiences a fall in haemoglobin to < 10 g/dL and ≥ 8.5 g/dL, or (2) a patient with stablecardiovascular 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 thefollowing applies: (1) a patient without significant cardiovascular disease experiences a fall inhaemoglobin confirmed to < 8.5 g/dL; (2) a patient with stable cardiovascular disease maintains ahaemoglobin 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 thediscretion of the treating physician. A return to original dosing is not recommended.

Table 3: Dose adjustment for adverse reactions in adult patients (for further guidance see alsotext above)

Reduce Withhold Reduce Pegasys Withhold Discontinueribavirin ribavirin to 135/90/45 Pegasys combinationto 600 mg micrograms

Absolute 500 to < 750 < 500

Neutrophil cells/mm3 cells/mm3

Count

Platelet Count 25 000 to < 25 000< 50 000 cells/mm3cells/mm3

Haemoglobin < 10 g/dL, and < 8.5 g/dL

- no cardiac ≥ 8.5 g/dLdisease

Haemoglobin decrease < 12 g/dL

- stable cardiac ≥ 2 g/dL during despite 4disease any 4 weeks weeks atreduced dose

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

Fluctuations in abnormalities of liver function tests are common in patients with CHC. Increases in

ALT levels above baseline (BL) have been observed in patients treated with Pegasys, includingpatients with a virological response.

In CHC 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-modificationwere observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive orpersistent, the dose should be reduced initially to 135 micrograms. When increases in ALT levels areprogressive despite dose reduction, or are accompanied by increased bilirubin or evidence of hepaticdecompensation, therapy should be discontinued (see section 4.4).

For CHB patients, transient flares of ALT levels sometimes exceeding 10x ULN are not uncommon,and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10x ULN.

Consideration should be given to continuing treatment with more frequent monitoring of liver functionduring ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare issubsiding (see section 4.4).

Chronic hepatitis B and C - paediatric patients

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

Patients who initiate treatment prior to their 18th birthday should maintain paediatric dosing throughthe completion of therapy.

The posology of Pegasys in paediatric patients is based on the Body Surface Area (BSA). To calculate

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

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

Before initiating therapy for CHB, persistently elevated serum ALT levels should have beendocumented. The response rate was lower in patients with no to minimal increase in ALT level atbaseline (see section 5.1).

The duration of treatment with Pegasys in combination with ribavirin in paediatric patients with CHCdepends on viral genotype. Patients infected with viral genotypes 2 or 3 should receive 24 weeks oftreatment, 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, shoulddiscontinue therapy, as it is unlikely, they will be able to achieve a sustained virological response withcontinued therapy.

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

Table 4: Pegasys dosing recommendations for paediatric patients with chronic hepatitis B andchronic hepatitis C

Body Surface Area (BSA) range (m2)

CHC CHB Weekly dose (mcg)0.71-0.74 0.54-0.74 650.75-1.08 901.09-1.51 135>1.51 180

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

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

Starting dose 1 level reduction 2 level reduction 3 level reduction(mcg) (mcg) (mcg) (mcg)65 45 30 2090 65 45 20135 90 65 30180 135 90 45

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

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

Toxicity Pegasys Dose Modification

Neutropenia 500 to <750 cells/mm3: Immediate 1 level adjustment.

250 to <500 cells/mm3: interrupt dosing until ≥1 000 cells/mm3, thenresume dose with 2 level adjustments and monitor.

<250 cells/mm3 (or febrile neutropenia): discontinue treatment.

Thrombocytopenia Platelet 25 000 to <50 000 cells/mm3: 2 level adjustment.

Platelet <25 000 cells/mm3: discontinue treatment.

Increased alanine For persistent or increasing elevations ≥5 but <10 x ULN, reduce doseaminotransferase with a 1 level adjustment and monitor weekly ALT level to ensure it is(ALT) stable or decreasing.

For persistent ALT values ≥10 x ULN discontinue treatment.

Dose adjustment in paediatric patients - dual therapy with Pegasys and ribavirin

For children and adolescents aged 5 to 17 years with CHC, the recommended dose of ribavirin isbased 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 isprovided in Table 7. Patients and caregivers must not attempt to break the 200 mg tablets.

Table 7: Ribavirin dosing recommendations for paediatric patients with chronic hepatitis Caged 5 to 17 years

Body weight kg (lbs) Ribavirin daily dose Ribavirin number of tablets(Approx. 15 mg/kg/day)23 - 33 (51-73) 400 mg/day 1 x 200 mg tablets A.M.1 x 200 mg tablets P.M.

34 - 46 (75-101) 600 mg/day 1 x 200 mg tablets A.M.2 x 200 mg tablets P.M.

47 - 59 (103-131) 800 mg/day 2 x 200 mg tablets A.M.2 x 200 mg tablets P.M.

60 - 74 (132-163) 1 000 mg/day 2 x 200 mg tablets A.M.3 x 200 mg tablets P.M.

≥75 (>165) 1 200 mg/day 3 x 200 mg tablets A.M.3 x 200 mg tablets P.M.

It is important to note that ribavirin should never be given as monotherapy. Unless otherwise noted,the management of all other toxicities should follow the adult recommendations.

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 with chronichepatitis C

Full dose One step dose modification Ribavirin number of tablets(Approx. 15 mg/kg/day) (Approx. 7.5 mg/kg/day)400 mg/day 200 mg/day 1 x 200 mg tablets A.M.

600 mg/day 400 mg/day 1 x 200 mg tablets A.M.1 x 200 mg tablets P.M.

800 mg/day 400 mg/day 1 x 200 mg tablets A.M.1 x 200 mg tablets P.M.

1 000 mg/day 600 mg/day 1 x 200 mg tablets A.M.2 x 200 mg tablets P.M.

1 200 mg/day 600 mg/day 1 x 200 mg tablets A.M.2 x 200 mg tablets P.M.

Adjustments in the recommended dosage for PEG-IFN-α-2a are not necessary when instituting

Pegasys therapy in elderly patients (see section 5.2).

No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduceddose of 135 mcg once weekly is recommended in adult patients with severe renal impairment or endstage renal disease (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 therapyshould be made in the event of adverse reactions.

In patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effectiveand safe. No PEG-IFN-α-2a dose adjustment is required for adult patients with mild liver impairment.

Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B or C orbleeding oesophageal varices) and is contraindicated in these patients (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 = µmol/L) 34-51 2>51 3

S-Albumin (g/dL) >3.5 13.5-2.8 2<2.8 3

INR <1.7 11.7-2.3 2>2.3 3

*Grading according to Trey, Burns and Saunders (1966)

Paediatric population (myeloproliferative neoplasms)

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

The safety and efficacy of Pegasys in children and adolescents with myeloproliferative neoplasms hasnot been established. No data are available.

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

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

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

Appropriate training is recommended for non-healthcare professionals administering this medicinalproduct. The “Instructions for the User”, provided in the carton, must be followed carefully by thepatient.

* Hypersensitivity to the active substance, to alfa interferons, or to any of the excipients listed insection 6.1

* History or presence of autoimmune diseases

* Pre-existing thyroid disease unless it can be controlled with conventional treatment

* Severe hepatic dysfunction or decompensated cirrhosis of the liver

* A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiacdisease 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 indirecthyperbilirubinemia 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 (seesection 4.4 for benzyl alcohol

* In paediatric patients, the presence of, or history of severe psychiatric condition, particularlysevere depression, suicidal ideation or suicidal attempt

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression,suicidal ideation and attempted suicide have been observed in some patients during Pegasystherapy, and even after treatment discontinuation mainly during the 6-month follow-up period.

Other CNS effects including aggressive behaviour (sometimes directed against others such ashomicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have beenobserved with alfa interferons. All patients should be closely monitored for any signs or symptomsof psychiatric disorders. If symptoms of psychiatric disorders appear, the potential seriousness ofthese undesirable effects must be borne in mind by the prescribing physician and the need foradequate therapeutic management should be considered. If psychiatric symptoms persist or worsen,or suicidal ideation is identified, it is recommended that treatment with Pegasys be discontinued,and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys isjudged necessary in patients with existence or history of severe psychiatric conditions, this shouldonly be initiated after having ensured appropriate individualised diagnostic and therapeuticmanagement of the psychiatric condition.

The use of Pegasys in children and adolescents with existence of or history of severe psychiatricconditions is contraindicated (see section 4.3).

Patients with substance use/abuse: HCV infected patients having a co-occurring substance usedisorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders orexacerbation of already existing psychiatric disorders when treated with alfa interferon. If treatmentwith alfa interferon is judged necessary in these patients, the presence of psychiatric co-morbiditiesand the potential for other substance use should be carefully assessed and adequately managedbefore initiating therapy. If necessary, an inter-disciplinary approach including a mental health careprovider or addiction specialist should be considered to evaluate, treat and follow the patient.

Patients should be closely monitored during therapy and even after treatment discontinuation. Earlyintervention for re-emergence or development of psychiatric disorders and substance use isrecommended.

Growth and development (children and adolescents):

During therapy with Pegasys +/- ribavirin lasting up to 48 weeks in patients aged 3 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 observedfor children and adolescents in the clinical trials on a case by case basis (see sections 4.8 and 5.1). Itis important to consider the treatment with Pegasys +/- ribavirin induced a growth inhibition duringtreatment, the reversibility of which is uncertain.

The risk of growth inhibition should be weighed against the disease characteristics of the child, suchas evidence of disease progression (notably fibrosis), co-morbidities that may negatively influencethe disease progression (such as HIV co-infection), as well as prognostic factors of response (for

HBV-infection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotypeand HCV-RNA levels) (see section 5.1).

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Laboratory tests prior to and during therapy

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

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

- Platelet count ≥ 90 000 cells/mm3

- ANC ≥ 1 500 cells/mm3

- Adequately controlled thyroid function (TSH and T4)

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

In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell(WBC) count and 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 reversibleupon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in themajority 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, dosemodification may be necessary (see section 4.2).

The occurrence of anaemia (haemoglobin <10 g/dL) has been observed in up to 15% of CHC patientsin clinical trials on the combined treatment of Pegasys with ribavirin. The frequency depends on thetreatment duration and the dose of ribavirin (see section 4.8). The risk of developing anaemia is higherin the female population.

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

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. Thismyelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy andconcomitant azathioprine and did not recur upon re-introduction of either treatment alone (see section4.5).

The use of Pegasys and ribavirin combination therapy in CHC patients who failed prior treatment hasnot been adequately studied in patients who discontinued prior therapy for haematological adversereactions. Physicians considering treatment in these patients should carefully weigh the risks versusthe benefits of re-treatment.

Endocrine system

Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported withthe use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levelsshould be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintainedin the normal range by pharmaceutical means. TSH levels should be determined during the course oftherapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (seesection 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 medicationshould not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients whodevelop these conditions during treatment and cannot be controlled with medication shoulddiscontinue Pegasys or Pegasys/ribavirin therapy (see section 4.3).

Cardiovascular system

Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardialinfarction have been associated with alfa interferon therapies, including Pegasys. It is recommendedthat patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiationof Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspendedor discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction ordiscontinuation of ribavirin (see section 4.2).

In patients who develop evidence of hepatic decompensation during treatment, Pegasys should bediscontinued. Increases in ALT levels above baseline have been observed in patients treated with

Pegasys, including CHC and CHB patients with a viral response. Liver enzymes and hepatic functionshould be regularly controlled in patients with long-term Pegasys therapy. When the increase in ALTlevels is progressive and clinically significant, despite dose reduction, or is accompanied by increaseddirect bilirubin, therapy should be discontinued (see sections 4.2 and 4.8).

In CHB, unlike CHC, disease exacerbations during therapy are not uncommon and are characterisedby 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 hepaticfunction and without evidence of hepatic decompensation. In approximately half the cases of flaresexceeding 10x ULN, Pegasys dosing was reduced or withheld until the transaminase elevationssubsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepaticfunction was recommended in all instances.

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction,anaphylaxis) have been rarely observed during alfa interferon therapy. If this occurs, therapy must bediscontinued and appropriate medical therapy instituted immediately. Transient rashes do notnecessitate interruption of treatment.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatmentwith alfa interferons. Patients predisposed to the development of autoimmune disorders may be atincreased risk. Patients with signs or symptoms compatible with autoimmune disorders should beevaluated 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 CHC treatedwith interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditorysystem, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawnand corticosteroid therapy discussed (see section 4.8).

Fever/infections

While fever may be associated with the flu-like syndrome reported commonly during interferontherapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) mustbe ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) andsepsis have been reported during treatment with alfa 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 andretinal artery or vein obstruction which may result in loss of vision have been reported in rareinstances with Pegasys. All patients should have a baseline eye examination. Any patient complaining ofdecrease or loss of vision must have a prompt and complete eye examination. Adult and paediatricpatients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) shouldreceive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should bediscontinued in patients who develop new or worsening ophthalmologic disorders.

Pulmonary changes

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

Skin disorder

Use of alfa interferons has been associated with exacerbation or provocation of psoriasis andsarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset orworsening 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 withliver and other transplantations. Liver and renal graft rejections have been reported with Pegasys,alone or in combination with ribavirin.

HIV-HCV co-infection

Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinalproducts that are to be taken concurrently with HCV therapy for awareness and management oftoxicities specific for each product and the potential for overlapping toxicities with Pegasys with orwithout ribavirin. In study NR15961, patients concurrently treated with stavudine and interferontherapy 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 beat 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 ofhepatic 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 withhepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkalinephosphatase or decreased platelet count, and treatment with didanosine (ddI).

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

During treatment, co-infected patients should be closely monitored for signs and symptoms of hepaticdecompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic syntheticfunction; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factorsrelated to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarilyattributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediatelyin 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 patientsreceiving Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damagingeffect on teeth and mucous membranes of the mouth during long-term treatment with the combinationof Pegasys and ribavirin. Patients should brush their teeth thoroughly twice daily and have regulardental examinations. In addition, some patients may experience vomiting. If this reaction occurs, theyshould be advised to rinse out their mouth thoroughly afterwards.

This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse events anddeath in neonates (“gasping syndrome”). Must not be given to premature babies or neonates. Maycause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

High volumes should be used with caution and only if necessary, especially in subjects with liver orkidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

This medicinal product contains polysorbate 80. Polysorbates may cause allergic reactions.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, that is to sayessentially “sodium-free”.

Interaction studies have only been performed in adults.

Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did notshow any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles,suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9,2C19 and 2D6 isozymes.

In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity.

Serum concentrations of theophylline should be monitored and appropriate dose adjustments oftheophylline made for patients taking theophylline and Pegasys concomitantly. The interactionbetween theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy.

HCV monoinfected patients and HBV monoinfected patients

In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenancetherapy (median dose 95 mg; range 30 mg to 150 mg), treatment with Pegasys 180 micrograms sconce weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higherthan at baseline. The clinical significance of this finding is unknown; nonetheless, patients should bemonitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose ofmethadone, the risk for QTc prolongation should be considered.

Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interferewith azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosinemonophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated withazathioprine. The use of peginterferon alfa-2a and ribavirin concomitantly with azathioprin should beavoided. In individual cases where the benefit of administering ribavirin concomitantly withazathioprine warrants the potential risk, it is recommended that close haematologic monitoring bedone during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatmentwith these medicinal products should be stopped (see section 4.4).

Results from pharmacokinetic substudies of pivotal phase III trials demonstrated no pharmacokineticinteraction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCVpatients.

A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferonalfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV,indicates that the combination is associated with an increased risk for developing peripheralneuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine andother interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of thecombination of telbivudine with interferon alfa (pegylated or standard) is not currently established.

Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).

HIV-HCV co-infected patients

No apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients whocompleted a 12-week pharmacokinetic substudy to examine the effect of ribavirin on the intracellularphosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine orstavudine). However, due to high variability, the confidence intervals were quite wide. Plasmaexposure of ribavirin did not appear to be affected by concomitant administration of nucleosidereverse transcriptase inhibitors (NRTIs).

Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or itsactive metabolite (dideoxyadenosine 5’-triphosphate) is increased in vitro when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure as well as peripheral neuropathy,pancreatitis, and symptomatic hyperlactataemia/lactic acidosis have been reported with use ofribavirin.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimenused to treat HIV although the exact mechanism remains to be elucidated. The concomitant use ofribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).

Consideration should be given to replacing zidovudine in a combination anti-retroviral therapyregimen if this is already established. This would be particularly important in patients with a knownhistory of zidovudine induced anaemia.

There are no or limited amount of data from the use of peginterferon alfa-2a in pregnant women.

Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and thepotential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potentialbenefit justifies the potential risk to the foetus.

It is unknown whether peginterferon alfa-2a/metabolites are excreted in human milk. Because of thepotential for adverse reactions in breastfed infants, breastfeeding should be discontinued prior toinitiation of treatment.

There are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of themenstrual cycle has been seen with peginterferon alfa-2a in female monkeys (see section 5.3).

Use with ribavirin

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal speciesexposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme caremust be taken to avoid pregnancy in female patients or in partners of male patients taking Pegasys incombination with ribavirin. Female patients of childbearing potential must use an effectivecontraceptive during treatment and for 4 months after treatment has been concluded. Male patients ortheir female partners must use an effective contraceptive during treatment and for 7 months aftertreatment has been concluded. Please refer to the ribavirin SmPC.

Pegasys has minor or moderate influence on the ability to drive and use machines. Patients whodevelop dizziness, confusion, somnolence or fatigue should be cautioned to avoid driving or operatingmachinery.

Polycythaemia vera and essential thrombocythaemia

Results from clinical studies and retrospective analyses in patients with polycythaemia vera andessential thrombocythaemia did not show any additional side effects than what is observed in patientswith CHB or CHC, and as listed in Table 9.

The most frequent side effects are flu-like symptoms, injection site reactions, peripheral sensoryneuropathies, visual disturbances, Grade 1/2 depression, leukopenia, increases in hepatic ASATtransaminases, hypertension, fatigue, lymphopenia, anaemia and lymphocytopenia, diarrhoea, nausea,headache, musculoskeletal pain, skin toxicity, asthenia, and gastrointestinal symptoms.

Chronic hepatitis B in adult patients

In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in CHBwas similar to that seen in CHC. With the exception of pyrexia the frequency of the majority of thereported adverse reactions was notably less in CHB patients treated with Pegasys monotherapycompared with CHC patients treated with Pegasys monotherapy (see Table 9). Adverse events wereexperienced by 88% of Pegasys-treated patients as compared with 53% of patients in the lamivudinecomparator group, while 6% of the Pegasys-treated and 4% of the lamivudine-treated patientsexperienced serious adverse events during the studies. Adverse events or laboratory abnormalities ledto 5% of patients withdrawing from Pegasys treatment, while less than 1% of patients withdrew fromlamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew fromtreatment was similar to that of the overall population in each treatment group.

Chronic hepatitis C in adult patients

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similarto those reported with interferon alfa-2a (see Table 9). The most frequently reported adverse reactionswith Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable withoutthe need for modification of doses or discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Pegasys in combination with ribavirin in prior non-responder patientswas similar to that in naïve patients. In a clinical trial of non-responder patients to prior pegylatedinterferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, thefrequency of withdrawal for adverse events or laboratory abnormalities from Pegasys treatment andribavirin treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively,in the 72 week arms. Similarly for patients with cirrhosis or transition to cirrhosis, the frequencies ofwithdrawal from Pegasys treatment and ribavirin treatment were higher in the 72-week treatment arms(13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapywith pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded fromenrolling in this trial.

In another clinical trial, non-responder patients with advanced fibrosis or cirrhosis (Ishak score of 3 to6) and baseline platelet counts as low as 50 000 cells/mm3 were treated for 48 weeks. Haematologiclaboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% ofpatients experienced a haemoglobin level of <10 g/dL), neutropenia (30% experienced an ANC<750 cells/mm3), and thrombocytopenia (13% experienced a platelet count <50 000 cells/mm3) (seesection 4.4).

Chronic hepatitis C and HIV co-infection

In HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for Pegasys, alone orin combination with ribavirin, were similar to those observed in HCV mono-infected patients. For

HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects havebeen reported in ≥ 1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia,affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy andchromaturia. Pegasys treatment was associated with decreases in absolute CD4+ cell counts within thefirst 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts wasreversible upon dose reduction or cessation of therapy. The use of Pegasys had no observable negativeimpact on the control of HIV viraemia during therapy or follow-up. Limited safety data are availablein co-infected patients with CD4+ cell counts <200/µL.

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

Table 9: Undesirable effects reported with Pegasys monotherapy or in combination withribavirin in clinical trials and post marketing

Body system Very Common Uncommon Rare Very rare Frequencycommon not known

Infections and Bronchitis, upper Pneumonia, Endocarditis, Sepsisinfestations respiratory skin otitis externainfection, oral infectioncandidiasis,herpes simplex,fungal, viral andbacterialinfections

Neoplasms Hepaticbenign, neoplasmmalignant andunspecified (inclcysts and polyps)

Blood and Thrombocyto- Pancytopenia Aplastic Pure red celllymphatic system penia, anaemia, anaemia aplasiadisorders lymphadenopathy

Immune system Sarcoidosis, Anaphylaxis, Idiopathic or Liver and renaldisorders thyroiditis systemic thrombotic graft rejection,lupus thrombocytop Vogt-erythema- enic purpura Koyanagi-tosus Harada diseaserheumatoidarthritis

Endocrine Hypothyroidism, Diabetes Diabeticdisorders hyperthyroidism ketoacidosis

Metabolism and Anorexia Dehydrationnutritiondisorders

Psychiatric Depression*, Aggression, mood Suicidal Suicide, Mania, bipolardisorders anxiety, alteration, ideation, psychotic disorders,insomnia* emotional hallucina- disorder homicidaldisorders, tions ideationnervousness,libido decreased

Nervous system Headache, Syncope, Peripheral Coma, Cerebraldisorders dizziness*, migraine, memory neuropathy convulsions, ischaemiaconcentration impairment, facial palsyimpaired weakness,hypoaesthesia,hyperaesthesia,paraesthesia,tremor, tastedisturbance,nightmares,somnolence

Eye disorders Vision blurred, Retinal Optic Vision loss Serous retinaleye pain, eye haemorrhage neuropathy, detachment,inflammation, papilloedema Optic neuritisxerophthalmia , retinalvasculardisorder,retinopathy,corneal ulcer

Ear and labyrinth Vertigo, earache Hearing lossdisorders

Body system Very Common Uncommon Rare Very rare Frequencycommon not known

Cardiac disorders Tachycardia, Myocardialoedema infarction,peripheral, congestivepalpitations heart failure,cardiomyopathy, angina,arrhythmia,atrialfibrillation,pericarditis,supraventriculartachycardia

Vascular Flushing Hypertension Cerebral Peripheraldisorders haemorrhage ischaemia, vasculitis

Respiratory, Dyspnoea, Dyspnoea Wheezing Interstitial Pulmonarythoracic and cough exertional, pneumonitis arterialmediastinal epistaxis, including hypertension§disorders nasopharyngitis, fatalsinus congestion, outcome,nasal congestion, pulmonaryrhinitis, sore embolismthroat

Gastrointestinal Diarrhoea*, Vomiting, Gastrointesti Peptic ulcer, Ischaemicdisorders nausea*, dyspepsia, nal bleeding pancreatitis colitis, tongueabdominal dysphagia, mouth pigmentationpain* ulceration,gingival bleeding,glossitis,stomatitis,flatulence, drymouth

Hepatobiliary Hepatic Hepaticdisorders dysfunction failure,cholangitis,fatty liver

Skin and Alopecia, Psoriasis, Stevens-subcutaneous dermatitis, urticaria, eczema, Johnsontissue disorders pruritis, dry rash, sweating syndrome,skin increased, skin toxicdisorder, epidermalphotosensitivity necrolysis,reaction, night angioedema,sweats erythemamultiforme

Musculoskeletal Myalgia, Back pain, Myositis Rhabdomyolysand connective arthralgia arthritis, muscle istissue disorders weakness, bonepain, neck pain,musculoskeletalpain, musclecramps

Renal and Renalurinary disorders insufficiency

Reproductive Impotencesystem andbreast disorders

Body system Very Common Uncommon Rare Very rare Frequencycommon not known

General Pyrexia, Chest pain,disorders and rigors*, pain*, influenza likeadministration asthenia, illness, malaise,site conditions fatigue, lethargy, hotinjection site flushes, thirstreaction*,irritability*

Investigations Weight decreased

Injury, poisoning Substanceand procedural overdosecomplications

*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.

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 withinterferon alfa.

Pegasys treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase,electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia,hypoglycaemia and elevated triglycerides (see section 4.4.). With both Pegasys monotherapy, and alsothe combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that ledto dose modification or discontinuation of the treatment.

Treatment with Pegasys was associated with decreases in haematological values (leucopenia,neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dosemodification, and returned to pre-treatment levels within 4-8 weeks upon cessation of therapy (seesections 4.2 and 4.4).

Moderate (ANC: 0.749 - 0.5 x 109/L) and severe (ANC: < 0.5 x 109/L) neutropenia was observedrespectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms andribavirin 1 000/1 200 milligrams for 48 weeks.

Anti-interferon antibodies1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with otherinterferons, a higher incidence of neutralising antibodies was seen in CHB. However, in neitherdisease was this correlated with lack of therapeutic response.

Thyroid function

Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory valuesrequiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving

Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred morefrequently in HIV-HCV patients, the majority could be managed by dose modification and the use ofgrowth factors and infrequently required premature discontinuation of treatment. Decrease in ANClevels below 500 cells/mm3 was observed in 13% and 11% of patients receiving Pegasys monotherapyand combination therapy, respectively. Decrease in platelets below 50 000 cells/mm3 was observed in10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively.

Anaemia (haemoglobin < 10 g/dL) was reported in 7% and 14% of patients treated with Pegasysmonotherapy or in combination therapy, respectively.

Chronic hepatitis B

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

The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment instudy YV25718 were -0.07 and -0.21(n=108 and n= 106 respectively) for Pegasys-treated patients ascompared to - 0.01 and -0.08 (n=47 each) in untreated patients. At Week 48 of Pegasys treatment, aheight or weight percentile decrease of more than 15 percentiles on the normative growth curves wasobserved in 6% of patients for height and 13% of patient for weight, whereas in the untreated group itwas 2% of patients for height and 9% for weight. Post-treatment recovery in growth was observed inthe majority of patients in short-term (81% up to 2 years) and long-term follow-up (82% up to 5 years)studies. .

Chronic hepatitis C

In a clinical trial with 114 paediatric patients (5 to 17 years of age) treated with Pegasys alone or incombination with ribavirin (see section 5.1), dose modifications were required in approximately one-third of patients, most commonly for neutropenia and anaemia. In general, the safety profile observedin paediatric patients was similar to that seen in adults. In the paediatric study, the most prevalentadverse reactions in patients treated with combination therapy for up to 48 weeks with Pegasys andribavirin were influenza-like illness (91%), headache (64%), gastrointestinal disorder (56%), andinjection-site reaction (45%). A full listing of adverse reactions reported in this treatment group (n=55)is provided in Table 10. Seven patients receiving combination Pegasys and ribavirin treatment for 48weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transientblindness, retinal exudates, hyperglycaemia, type 1 diabetes mellitus, and anaemia). Most of theadverse reactions reported in the study were mild or moderate in severity. Severe adverse reactionswere reported in 2 patients in the Pegasys plus ribavirin combination therapy group (hyperglycaemiaand cholecystectomy).

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 48weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles ofthe 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 (meanweight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patientsexperienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced aheight 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 weightcurve 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 upextending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery ingrowth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects whowere more than 15 percentiles below their baseline height curve at 2 years post-treatment, they eitherreturned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment relatedcausative factor has been identified. The extent of available data is not sufficient to conclude thatgrowth inhibition due to Pegasys exposure is always reversible.

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

Body system Very common Common

Infections and infestations Infectious mononucleosis,pharyngitis streptococcal,influenza, gastroenteritis viral,candidiasis, gastroenteritis, toothabscess, hordeolum, urinary tractinfection, nasopharyngitis

Blood and lymphatic system Anaemiadisorders

Metabolism and nutrition disorders Decreased appetite Hyperglycaemia, type 1 diabetesmellitus

Psychiatric disorders Insomnia Depression, anxiety, hallucination,abnormal behaviour, aggression,anger, attention deficit /hyperactivity disorder

Nervous system disorders Headache Dizziness, disturbance in attention,migraine

Eye disorders Blindness transient, retinalexudates, visual impairment eyeirritation, eye pain, eye pruritis

Ear and labyrinth disorders Ear pain

Respiratory, thoracic and Dyspnoea, epistaxismediastinal disorders

Gastrointestinal disorders Gastrointestinal disorder Abdominal pain upper, stomatitis,nausea, aphthous stomatitis, oraldisorder

Skin and subcutaneous tissue Rash, pruritus, alopecia Swollen face, drug eruption,disorders

Musculoskeletal and connective Musculoskeletal pain Back pain, pain in extremitytissue disorders

Renal and urinary disorders Dysuria, incontinence, urinary tractdisorder

Reproductive system and breast Vaginal dischargedisorders

General disorders and Influenza-like illness, injection site Pyrexia, vessel puncture siteadministration site conditions reaction, irritability, fatigue haematoma, pain

Investigations Psychiatric evaluation abnormal

Surgical and medical procedures Tooth extraction, cholecystectomy

Social circumstances Educational problem

Decreases in haemoglobin, neutrophils, platelets or increased ALT may require dose reduction orpermanent discontinuation from treatment (see section 4.2). Most laboratory abnormalities notedduring the clinical trial returned to baseline levels shortly after discontinuation of treatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdoses involving between two injections on consecutive days (instead of weekly interval) up todaily injections for 1 week (i.e., 1 260 micrograms/week) have been reported. None of these patientsexperienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and630 micrograms have been administered in renal cell carcinoma and chronic myelogenous leukaemiaclinical trials, respectively. Dose limiting toxicities were fatigue, elevated liver enzymes, neutropeniaand thrombocytopenia, consistent with interferon therapy.

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB11

The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms apegylated interferon alfa-2a (Pegasys). Pegasys possesses the in vitro antiviral and antiproliferativeactivities that are characteristic of interferon alfa-2a.

Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree ofsubstitution of one mole of polymer/mole of protein. The average molecular mass is approximately60 000 of which the protein moiety constitutes approximately 20 000.

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who havereceived treatment with 180 micrograms Pegasys. The first phase of decline occurs 24 to 36 hoursafter the first dose of Pegasys and is followed by the second phase of decline which continues over thenext 4 to 16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect onthe initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of ribavirinand pegylated interferon alfa-2a or interferon alfa.

Polycythaemia vera and essential thrombocythemia

The efficacy results are primarily based on bibliographical data from two prospective, investigator-initiated, open-label studies, MPD-RC 112 and MPD-RC 111.

Study MPD-RC 112

The randomised, investigator-initiated, open-label, multicenter, phase III trial conducted by the

Myeloproliferative Disorders Research Consortium (MPD-RC) compared hydroxyurea (HU) to PEG-

IFN-α-2a in treatment-naïve (TN), high-risk patients with essential thrombocythaemia (ET; n=81) orpolycythaemia vera (PV; n=87) (NCT01259856/MPD-RC 112). The primary endpoint was completeresponse (CR) rate according to European LeukaemiaNet (ELN) criteria at 12 months of treatment.

CR was defined as a platelet count <400x109/L, HCT <45% without phlebotomy for patients with PVonly, white blood cell count <10x109/L, resolution of splenomegaly, and resolution of disease-relatedsymptoms (microvascular disturbances, headache, and pruritus). PEG-IFN-α-2a was self-administereds.c. at 45 micrograms/week and titrated in 45 micrograms increments monthly to a maximum of180 micrograms/week. HU was initiated at 500 mg twice daily.

A total of 168 patients were enrolled and randomised to treatment arms (86 HU, 82 PEG-IFN-α-2a).

At baseline, mean age was 63 and 60 years and mean duration of ET/PV was 3.1 and 2.6 months in the

HU and PEG-IFN-α-2a arms, respectively. The median duration of treatment was 81.0 weeks and 94.6weeks in the HU and PEG-IFN-α-2a arms, respectively. Seventy-four percent of patients receiving HUand 87% of patients receiving PEG-IFN-α-2a were treated for 12 months or longer. Table 11 displaysthe response by treatment arm.

Table 11: Response by treatment arm after 12 months in study MPD-RC 112

HU (n=86), % PEG (n=82), %

Complete response (CR) 32 (37%) 29 (35%)

ET 19 (45%) 17 (44)%

PV 13 (30%) 12 (28%)

Study MPD-RC 111

This single-arm, open-label, multicenter phase II trial also conducted by the MPD-RC, evaluated thehematologic response to PEG-IFN-α-2a in 50 PV and 65 ET patients who were resistant or intolerantto HU (NCT01259817/MPD-RC 111). The primary endpoint was CR or PR rate at 12 months oftreatment according to ELN criteria. PEG-IFN α 2a was self-administered s.c. at 45 micrograms/weekand titrated in 45 micrograms increments monthly to a maximum of 180 micrograms/week. Medianduration of treatment was 78.5 and 82 months in ET and PV patients, respectively.

In ET patients, CR and PR at 12 months were observed in 28 (43.1%) and 17 (26.2%) patients, for anoverall response rate (ORR) of 69.2% (95% CI, 56.6%-80.0%). In PV patients, 11 (22%) attained a

CR and 19 (38%) a PR, for an ORR of 60% (95% CI, 45.2%-73.6%).

The European Medicines Agency has waived the obligation to submit the results of studies with

Pegasys in all subsets of the paediatric population in the treatment of polycythaemia vera and essentialthrombocythaemia (see section 4.2 for information on paediatric use).

Chronic hepatitis B

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. Operatingcharacteristics of these biomarkers are presented in Table 12. No single biomarker with a cut-off canbe identified to optimize all the operating characteristics (negative predictive value [NPV], sensitivity,specificity) and practical characteristics (simplicity, convenience). Consideration for early treatmentdiscontinuation 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 highlikelihood of failure to achieve HBeAg seroconversion and HBV-DNA <2 000 IU/mL at 24 weekpost-treatment (NPV > 90%). For HBV genotype A and D, subgroup size was insufficient to beanalysed.

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 highlikelihood of failure to achieve HBV-DNA <2 000 IU/mL and ALT normalization at Week 24 posttreatment. HBV genotype A subgroup size was insufficient to be analysed. No biomarker can beidentified with acceptable performance for HBeAg-negative patients with HBV genotype B or Cinfection.

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

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

Genotype Cut-off (IU/mL) NPV Sensitivity Specificity

HBeAg-positive(a)

B HBsAg > 20 000 0.93 0.96 0.23

HBV DNA > 8 log10 0.90 0.94 0.26

C HBsAg > 20 000 0.96 0.97 0.22

HBV DNA > 8 log10 0.98 0.98 0.19

HBeAg-negative(a)

D HBsAg > 20 000 0.91 0.94 0.16

HBV DNA > 6.5 log10 1.00 1.00 0.11

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 HBeAgand 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.

All clinical trials recruited patients with CHB who had active viral replication measured by HBV

DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240recruited patients who were positive for HBeAg, while study WV16241 recruited patients who werenegative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks,with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasysplus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in theseclinical trials.

Response rates at the end of follow-up for the two studies are presented in Table 13. In study

WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105copies/mL. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-

DNA below 2 x 104 copies/mL. HBV-DNA was measured by the COBAS AMPLICOR HBV

MONITOR Assay (limit of detection 200 copies/mL).

A total of 283/1 351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1 351 (6%) had cirrhosis.

There was no difference in response rate between these patients and those without advanced fibrosis orcirrhosis.

Table 13: Serological, virological and biochemical responses in chronic hepatitis B

HBeAg positive HBeAg negative/anti-HBe positive

Study WV16240 Study WV16241

Response Pegasys Pegasys Lamivudine Pegasys Pegasys Lamivudine

Parameter 180 mcg 180 mcg 100 mg 180 mcg 180 mcg 100 mg& & & &

Placebo Lamivudine Placebo Lamivudine100 mg 100 mg(N=271) (N=271) (N=272) (N=177) (N=179) (N=181)

HBeAg Sero- 32% # 27% 19% N/A N/A N/Aconversion

HBV DNA 32% # 34% 22% 43% # 44% 29%response *

ALT 41% # 39% 28% 59% # 60% 44%

Normalisation

HBsAg Sero- 3% # 3% 0% 3% 2% 0%conversion

* For HBeAg-positive patients: HBV DNA < 105 copies/mL

For HBeAg-negative/anti-HBe-positive patients: HBV DNA < 2 x 104 copies/mL# p-value (vs. lamivudine) < 0.01 (stratified Cochran-Mantel-Haenszel test)

Histological response was similar across the three treatment groups in each study; however, patientsshowing a sustained response 24 weeks after the end of treatment were significantly more likely toalso show histological improvement.

All patients who completed the phase III studies were eligible for entry into a long-term follow-upstudy (WV16866). Among patients from study WV16240, who received Pegasys monotherapy andentered the long-term follow-up study, the rate of sustained HBeAg seroconversion 12 months afterthe end of therapy was 48% (73/153). In patients receiving Pegasys monotherapy in study WV16241,the rate of HBV DNA response and ALT normalisation 12 months after end of treatment were 42%(41/97) and 59% (58/99), respectively.

Chronic hepatitis C

Predictability of response

Please refer to section 4.2, in Table 2.

Dose-response in monotherapy

In a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superiorsustained virological response in patients with cirrhosis, but in a study in non-cirrhotic patients verysimilar results were obtained with doses of 135 micrograms and 180 micrograms.

Confirmatory clinical trials in adult treatment-naïve patients

All clinical trials recruited interferon-naïve patients with CHC confirmed by detectable levels of serum

HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsyconsistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histologicaldiagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infectedpatients were included in the study NR15961 (see Table 22). These patients had stable HIV diseaseand mean CD4 T-cell count was about 500 cells/µL.

For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, durationof therapy and study outcome see Tables 14, 15, 16 and Table 22, respectively. Virological responsewas defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test,version 2.0 (limit of detection 100 copies/mL equivalent to 50 International Units/mL) and sustainedresponse as one negative sample approximately 6 months after end of therapy.

Table 14: Virological response in CHC patients

Pegasys monotherapy Pegasys combination therapynon-cirrhotic and cirrhotic non-cirrhotic and cirrhoticcirrhotic

Study NV15496 + Study NV15495 Study Study NV15801

NV15497 + NV15801 NV15942

Pegasys Interferon Pegasys Interferon Pegasys Pegasys Interferonalfa-2a 180 mcg alfa-2a 180 mcg 180 mcg alfa-2b180 mcg 6 MIU/3 MIU 3 MIU 3 MIU& & & &3 MIU Ribavirin Ribavirin Ribavirin1 000/1 200 1 000/1 200 1 000/1 200mg mg mg(N=701) (N=478) (N=87) (N=88) (N=436) (N=453) (N=444)48 weeks 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks

Responseat End of 55 - 69% 22 - 28% 44% 14% 68% 69% 52%

Overall

Sustained 28 - 39% 11 - 19% 30%* 8%* 63% 54%** 45%**

Response

* 95% CI for difference: 11% to 33% p-value (stratified Cochran-Mantel-Haenszel test) = 0.001

** 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Pegasys and ribavirincombination therapy in relation to genotype and pre-treatment viral load and in relation to genotype,pre-treatment viral load and rapid virological response at week 4 are summarised in Table 15 and

Table 16, respectively. The results of study NV15942 provide the rationale for recommendingtreatment regimens based on genotype, baseline viral load and virological response at week 4 (see

Tables 1, 15 and 16).

The difference between treatment regimens was in general not influenced by presence/absence ofcirrhosis; therefore, treatment recommendations for genotype 1, 2 or 3 are independent of this baselinecharacteristic.

Table 15: Sustained virological response based on genotype and pre-treatment viral load after

Pegasys combination therapy with ribavirin in CHC patients

Study NV15942 Study NV15801

Pegasys Pegasys Pegasys Pegasys Pegasys Interferon180 mcg 180 mcg 180 mcg 180 mcg 180 mcg alfa-2b3 MIU& & & & & &

Ribavirin Ribavirin Ribavirin Ribavirin Ribavirin Ribavirin800 mg 1 000/1 200 mg 800 mg 1 000/1 200 mg 1 000/1 200 mg 1 000/1 200 mg24 weeks 24 weeks 48 weeks 48 weeks 48 weeks 48 weeks

Genotype 1 29% 42% (49/118)* 41% 52% 45% (134/298) 36% (103/285)(29/101) 52% (37/71) (102/250)* (142/271)* 53% (61/115) 44% (41/94)

Low viral 41% (21/51) 26% (12/47) 55% (33/60) 40% (73/182) 33% (62/189)load 16% (8/50) 36% (69/190) 65% (55/85)

High viral 47% (87/186)load

Genotype 2/3 84% (81/96) 81% (117/144) 79% (78/99) 80% (123/153) 71% (100/140) 61% (88/145)83% (39/47) 76% (28/37)

Low viral 85% (29/34) 80% (78/97) 88% (29/33) 77% (37/48) 70% (72/103) 65% (34/52)load 84% (52/62) 74% (49/66) 82% (86/105) 58% (54/93)

High viralload

Genotype 4 (0/5) (8/12) (5/8) (9/11) (10/13) (5/11)

Low viral load = ≤ 800 000 IU/mL; High viral load = > 800 000 IU/mL

*Pegasys 180 mcg & ribavirin 1 000/1 200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 800 mg, 48 w:

Odds Ratio (95% CI) = 1.52 (1.07 to 2.17), P-value (stratified Cochran-Mantel-Haenszel test) = 0.020

*Pegasys 180 mcg & ribavirin 1 000/1 200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 1 000/1 200 mg, 24 w:

Odds Ratio (95% CI) = 2.12 (1.30 to 3.46), P-value (stratified Cochran-Mantel-Haenszel test) = 0.002.

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients wasexamined based on a sustained rapid virological response observed in patients with rapid virologicalresponse at week 4 in studies NV15942 and ML17131 (see Table 16).

Table 16: Sustained virological response based on rapid viral response at week 4 for genotype 1and 4 after Pegasys combination therapy with ribavirin in CHC patients

Study NV15942 Study ML17131

Pegasys Pegasys Pegasys180 mcg 180 mcg 180 mcg& & &

Ribavirin Ribavirin Ribavirin1 000/1 200 mg 1 000/1 200 mg 1 000/1 200 mg24 weeks 48 weeks 24 weeks

Genotype 1 RVR 90% (28/31) 92% (47/51) 77% (59/77)

Low viral load 93% (25/27) 96% (26/27) 80% (52/65)

High viral load 75% (3/4) 88% (21/24) 58% (7/12)

Genotype 1 non RVR 24% (21/87) 43% (95/220) -

Low viral load 27% (12/44) 50% (31/62) -

High viral load 21% (9/43) 41% (64/158) -

Genotype 4 RVR (5/6) (5/5) 92% (22/24)

Genotype 4 non RVR (3/6) (4/6) -

Low viral load = ≤ 800 000 IU/mL; High viral load = > 800 000 IU/mL

RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with ahigher risk of relapse (see Table 17).

Table 17: Relapse of virological response at the end of treatment for rapid virological responsepopulation

Study NV15942 Study NV15801

Pegasys Pegasys Pegasys180 mcg 180 mcg 180 mcg& & &

Ribavirin Ribavirin Ribavirin1 000/1 200 mg 1 000/1 200 mg 1 000/1 200 mg24 weeks 48 weeks 48 weeks

Genotype 1 RVR 6.7% (2/30) 4.3% (2/47) 0% (0/24)

Low viral load 3.8% (1/26) 0% (0/25) 0% (0/17)

High viral load 25% (1/4) 9.1% (2/22) 0% (0/7)

Genotype 4 RVR (0/5) (0/5) 0% (0/4)

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examinedbased on a sustained virological response observed in patients with rapid virological response by week4 in study NV17317 (see Table 18).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received Pegasys180 mcg sc qw and a ribavirin dose of 800 mg and were randomised to treatment for either 16 or 24weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatmentfor 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment wasalso examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week4 and had a LVL at baseline (see Table 18).

Table 18: Sustained virological response overall and based on rapid viral response by week 4 forgenotype 2 or 3 after Pegasys combination therapy with ribavirin in CHC patients

Study NV17317

Pegasys 180 mcg Pegasys 180 mcg Treatment difference p value& & [95%CI]

Ribavirin 800 mg Ribavirin 800 mg16 weeks 24 weeks

Genotype 2 or 3 65% (443/679) 76% (478/630) -10.6% [-15.5%; -0.06%] P<0.0001

Genotype 2 or 3 82% (378/461) 90% (370/410) -8.2% [-12.8%; -3.7%] P=0.0006

RVR

Low viral load 89% (147/166) 94% (141/150) -5.4% [-12%; 0.9%] P=0.11

High viral load 78% (231/295) 88% (229/260) -9.7% [-15.9%;-3.6%] P=0.002

Low viral load = ≤ 800 000 IU/mL; High viral load = > 800 000 IU/mL

RVR = rapid viral response (HCV RNA undetectable) at week 4

It is presently not clear whether a higher dose of ribavirin (e.g. 1 000/1 200 mg/day based on bodyweight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse(see Table 19).

Table 19: Relapse of virological response after the end of treatment in genotype 2 or 3 patientswith a rapid viral response

Study NV17317

Pegasys Pegasys Treatment difference p value180 mcg 180 mcg [95%CI]& &

Ribavirin Ribavirin800 mg 800 mg16 weeks 24 weeks

Genotype 2 or 3 RVR 15% (67/439) 6% (23/386) 9.3% [5.2%; 13.6%] P<0.0001

Low viral load 6% (10/155) 1% (2/141) 5% [0.6%; 10.3%] P=0.04

High viral load 20% (57/284) 9% (21/245) 11.5% [5.6%; 17.4%] P=0.0002

Low viral load = ≤ 800 000 IU/mL; High viral load = > 800 000 IU/mL

RVR = rapid viral response (HCV RNA undetectable) at week 4

Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms ofhistological response, including patients with cirrhosis and/or HIV-HCV co-infection.

Adult chronic hepatitis C prior treatment non-responder patients

In study MV17150, patients who were non-responders to previous therapy with pegylated interferonalfa-2b plus ribavirin were randomised to four different treatments:

* Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks

* Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks

* Pegasys 180 mcg/week for 72 weeks

* Pegasys 180 mcg/week for 48 weeks

All patients received ribavirin (1 000 or 1 200 mg/day) in combination with Pegasys. All treatmentarms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and useof induction dosing clearly identified treatment duration for 72 weeks as the primary driver forachieving a sustained virological response. Differences in sustained virological response (SVR) basedon treatment duration, demographics and best responses to previous treatment are displayed in

Table 20.

Table 20: Week 12 virological response (VR) and sustained virological response (SVR) inpatients with virological response at week 12 after treatment with Pegasys and ribavirincombination therapy in nonresponders to peginterferon alfa-2b plus ribavirin

Study MV17150

Pegasys 360/180 Pegasys 360/180 Pegasys 360/180 oror 180 mcg or 180 mcg 180 mcg& & &

Ribavirin Ribavirin Ribavirin1 000/1 200 mg 1 000/1 200 mg 1 000/1 200 mg72 or 48 weeks 72 weeks 48 weeks(N = 942) (N = 473) (N = 469)

Pts with SVR in Pts with SVR in Pts with

VR at Wk 12 a VR at Wk 12 b VR at Wk 12 b(N = 876) (N = 100) (N = 57)

Overall 18% (157/876) 57% (57/100) 35% (20/57)

Low viral load 35% (56/159) 63% (22/35) 38% (8/21)

High viral load 14% (97/686) 54% (34/63) 32% (11/34)

Genotype 1/4 17% (140/846) 55% (52/94) 35% (16/46)

Low viral load 35% (54/154) 63% (22/35) 37% (7/19)

High viral load 13% (84/663) 52% (30/58) 35% (9/26)

Genotype 2/3 58% (15/26) (4/5) (3/10)

Low viral load (2/5) — (1/2)

High viral load (11/19) (3/4) (1/7)

Cirrhosis Status

Cirrhosis 8% (19/239) (6/13) (3/6)

Noncirrhosis 22% (137/633) 59% (51/87) 34% (17/50)

Best Response during

Previous Treatment≥2log10 decline in HCV RNA 28% (34/121) 68% (15/22) (6/12)<2log10 decline in HCV RNA 12% (39/323) 64% (16/25) (5/14)

Missing best previous response 19% (84/432) 49% (26/53) 29% (9/31)

High viral load = > 800 000 IU/mL, low viral load = ≤ 800 000 IU/mL.a Patients who achieved viral suppression (undetectable HCV RNA, < 50 IU/mL) at week 12 were considered to have avirological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up wereconsidered to be non-responders.

In the HALT-C study, patients with CHC and advanced fibrosis or cirrhosis who were non-respondersto previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combinationtherapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1 000/1 200 mg daily.

Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on

Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24weeks after the end of treatment. The probability for sustained virological response varied dependingupon the previous treatment regimen; see Table 21.

Table 21: Sustained virological response in HALT-C by previous treatment regimen in non-responder population

Previous Treatment Pegasys 180 mcg&

Ribavirin 1 000/1 200 mg48 weeks

Interferon 27% (70/255)

Pegylated interferon 34% (13/38)

Interferon plus ribavirin 13% (90/692)

Pegylated interferon plus ribavirin 11% (7/61)

HIV-HCV co-infected patients

The virological responses of patients treated with Pegasys monotherapy and with Pegasys andribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 22.

Table 22: Sustained virological response based on genotype and pre-treatment viral load after

Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients

Study NR15961

Interferon alfa-2a Pegasys Pegasys3 MIU 180 mcg 180 mcg& & &

Ribavirin 800 mg Placebo Ribavirin 800 mg48 weeks 48 weeks 48 weeks

All patients 12% (33/285)* 20% (58/286)* 40% (116/289)*

Genotype 1 7% (12/171) 14% (24/175) 29% (51/176)

Low viral load 19% (8/42) 38% (17/45) 61% (28/46)

High viral load 3% (4/129) 5% (7/130) 18% (23/130)

Genotype 2-3 20% (18/89) 36% (32/90) 62% (59/95)

Low viral load 27% (8/30) 38% (9/24) 61% (17/28)

High viral load 17% (10/59) 35% (23/66) 63% (42/67)

Low viral load = ≤ 800 000 IU/mL; High viral load = > 800 000 IU/mL

* Pegasys 180 mcg & ribavirin 800 mg vs. Interferon alfa-2a 3 MIU & ribavirin 800 mg:

Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001

* Pegasys 180 mcg & ribavirin 800 mg vs. Pegasys 180 mcg:

Odds Ratio (95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001

* Interferon alfa-2a 3 MIU & ribavirin 800 mg vs. Pegasys 180 mcg:

Odds Ratio (95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV comparedtreatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1 000 mg (<75 kg)/1 200 mg(≥75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safetyprofiles in both ribavirin groups were consistent with the known safety profile of Pegasys plusribavirin combination treatment and not indicative of any relevant differences, with the exception of aslight increase in anaemia in the high dose ribavirin arm.

HCV patients with normal ALT

In study NR16071, HCV patients with normal ALT values were randomised to receive Pegasys180 micrograms/week and ribavirin 800 milligrams/day for either 24 or 48 weeks followed by a24 week treatment free follow-up period or no treatment for 72 weeks. The SVRs reported in thetreatment arms of this study were similar to the corresponding treatment arms from study NV15942.

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 werenot 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 advancedfibrosis were assigned to Pegasys treatment (group C, n=10). Patients in groups A and C (n=111) weretreated with Pegasys once weekly for 48 weeks according to BSA categories, whereas patients ingroup B were observed for a period of 48 weeks (principal observation period). Patients in group Bhad 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-principalobservation period (group B). After the Week 24 follow-up visit, patients from group A, B and Centered a long-term follow-up period (lasting for 5 years after end of treatment). Response rates ingroups A and B at the end of 24 weeks follow-up are presented in Table 23. Efficacy response ingroup C to Pegasys treatment was in line with that seen in group A. For paediatric patients, efficacyhas not been established in HBV genotypes other than genotypes A-D.

Table 23: Serological, virological and biochemical responses in paediatric patients with chronichepatitis B

Group A Group B**(Pegasys treatment) Untreated Odds Ratio p-value(N=101) (N=50) (95% CI)

HBeAg Seroconversion 25.7% 6.0% 5.4 0.0043 1(1.5 - 19.2)

HBV DNA < 20 000 IU/mL* 33.7% 4.0% 12.2 <0.0001 2(2.9 - 108.3)

HBV DNA < 2 000 IU/mL 28.7% 2.0% 19.7 <0.0001 2(3.0 - 822.2)

ALT Normalization 51.5% 12.0% 7.8 <0.0001 2(2.9 - 24.1)

HBsAg Seroconversion 7.9% 0.0% - 0.0528 2

Loss of HBsAg 8.9% 0.0% - 0.0300 2

* Similar to end point of HBV DNA < 105 copies/mL. COBAS AMPLICOR HBV MONITOR: HBV-DNA (IU/mL) = HBV-DNA(copies/mL)/5.26)

** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.1 Cochran-Mantel-Haenszel test, stratified by genotype (A vs. non-A) and baseline ALT (< 5 × ULN and >= 5 × ULN)2 Fisher’s Exact Test

The response rate of HBeAg seroconversion was lower in patients with HBV genotype D, also inpatients with no to minimal increase in ALT level at baseline (see Table 24).

Table 24: HBeAg seroconversion rates (%) by HBV genotype and baseline ALT levels

Group A Group B**(Pegasys treatment) Untreated Odds Ratio(N=101) (N=50) (95% CI)

HBV genotype A 3/9 (33.3%) 1/3 (33.3%) 1.0 (0.04,78.4)

B 7/21 (33.3%) 0/6 (0.0%) -

C 13/34 (38.2%) 1/23 (4.3%) 13.62 (1.7,604.5)

D* 3/31 (9.7%) 1/18 (5.6%) 1.8 (0.1,101.2)

Other 0/6 (0.0%) 0/0 -

ALT <1xULN 0/7 (0.0%) 0/5 (0.0%) ->=1xULN - 2/22 (9.1%) 0/8 (0.0%) -<1.5xULN>=1.5xULN - 7/19 (36.8%) 0/11 (0.0%) -<2xULN>=2xULN - 15/43 (34.9%) 1/17 (5.9%) 8.6 (1.1,383.0)<5xULN>=5xULN - 2/8 (25.0%) 2/9 (22.2%) 1.2 (0.06,20.7)<10xULN>=10xULN 0/2 (0.0%) 0/0 -

* Subgroup of patients with genotype D had a higher proportion with baseline ALT < 1.5x ULN (13/31) compared to other genotype groups(16/70).

** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.

Exploratory analyses based on limited data show paediatric patients with greater decline in HBV-DNAat week 12 of therapy were more likely to achieve HBeAg seroconversion at 24 weeks of follow-up(Table 25).

Table 25: HBeAg seroconversion rates (%) by HBV-DNA decline from baseline to week 12 of

Pegasys treatment in paediatric patients

HBeAg By HBV-DNA (IU/mL) decline from baseline to week 12seroconversion rates <1 log10 decline 1 - <2 log10 decline ≥2 log10 decline

All genotypes (N=101)

Responder 26/101 (25.7 %) 6/44 (13.6 %) 5/24 (20.8 %) 15/30 (50.0 %)

Genotype-A (N=9)

Responder 3/9 (33.3 %) 0/6 (0.0 %) 2/2 (100.0 %) 1/1 (100.0 %)

Genotype-B (N=21)

Responder 7/21 (33.3 %) 1/6 (16.7 %) 1/5 (20.0 %) 5/10 (50.0 %)

Genotype-C (N=34)

Responder 13/34 (38.2 %) 3/10 (30.0 %) 2/12 (16.7 %) 8/12 (66.7 %)

Genotype-D (N=31)

Responder 3/31 (9.7 %) 2/20 (10.0 %) 0/5 (0.0 %) 1/5 (20.0 %)

Chronic hepatitis C

In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65children and adolescents (6-18 years) with chronic HCV infection were treated with Pegasys100 mcg/m2 sc once weekly and ribavirin 15 mg/kg/day for 24 weeks (genotypes 2 and 3) or 48 weeks(all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from theknown safety profile of the combination in adults with chronic HCV infection, but, importantly, thepotential impact on growth has not been reported. Efficacy results were similar to those reported inadults.

In the NV17424 (PEDS-C) study, previously untreated paediatric patients 5 to 17 years of age (55%< 12 years old) with compensated CHC and detectable HCV RNA were treated with Pegasys 180 mcgx BSA/1.73 m2 once weekly for 48 weeks with or without ribavirin 15 mg/kg/day. All patients werefollowed for 24 weeks post-treatment. A total of 55 patients received initial combination treatment of

Pegasys plus ribavirin, of whom 51% were female, 82% were Caucasian, and 82% were infected with

HCV genotype 1. The study efficacy results for these patients are summarised in Table 26.

Table 26: Sustained virological response in the NV17424 study

Pegasys180 mcg x BSA/1.73 m² + Ribavirin15 mg/kg (N=55)*

All HCV genotypes** 29 (53%)

HCV genotype 1 21/45 (47%)

HCV genotype 2 and 3 8/10 (80%)

*Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post-treatment using the

AMPLICOR HCV test v2.

**Scheduled treatment duration was 48 weeks regardless of the genotype

Following a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serumconcentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peakserum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is84% and is similar to that seen with interferon alfa-2a.

Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by thevolume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration.

From mass balance, tissue distribution and whole body autoradioluminography studies performed inrats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to beinghighly concentrated in the blood.

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

In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of thenative 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 standardinterferon. The terminal half-life after subcutaneous administration in patients is longer with a meanvalue of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phaseof the compound, but may also reflect the sustained absorption of Pegasys.

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

In CHB or CHC patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after8 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).

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 topatients with normal renal function. Patients with severe renal impairment receiving Pegasys 180 mcgonce weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renalfunction, therefore a reduced dose of Pegasys 135 mcg once weekly is recommended in patients withsevere renal impairment. In 13 patients with ESRD requiring chronic HD, administration of Pegasys135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients withnormal renal function. However, several independent studies have demonstrated the 135mcg dose tobe safe, efficacious and well tolerated, in patients with ESRD (see section 4.2).

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

Pegasys pharmacokinetics have been characterized in paediatric patients with CHB (YV25718), aswell as in paediatric patients with CHC (NR16141), using population pharmacokinetics. In bothstudies, Pegasys apparent clearance and apparent volume of distribution were related linearly to bodysize 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 PKsub-study and received Pegasys according to a BSA category dosing regimen. Based on the populationpharmacokinetic model, the mean exposure (AUC) during the dosing interval for each BSA categorywas comparable with that observed in adults receiving 180 mcg fixed dosing.

From the NR16141study, 14 children 2 to 8 years of age with CHC received Pegasys monotherapy at adose of: 180 mcg x BSA of the child/1.73 m2. The PK model developed from this study shows a linearinfluence 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 meanexposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed inadults receiving 180 mcg fixed dosing.

Pegasys pharmacokinetics have not been characterised in paediatric patients with polycythaemia veraand essential thrombocythaemia.

In subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hoursvs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1 663vs. 1 295 ng·h/mL) but peak concentrations (9.1 vs. 10.3 ng/mL) were similar in subjects older than 62years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys isnot needed in the geriatric patient (see section 4.2).

The pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis Bor 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 ofabsorption 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 armcompared to administration in the abdomen and thigh.

The non-clinical toxicity studies conducted with Pegasys were limited due to species specificity ofinterferons. Acute and chronic toxicity studies have been carried out in cynomolgus monkeys, and thefindings observed in peginterferon dosed animals were similar in nature to those produced byinterferon alfa-2a.

Reproductive toxicity studies have not been performed with Pegasys. As with other alfa interferons,prolongation of the menstrual cycle was observed following administration of peginterferon alfa-2a tofemale monkeys. Treatment with interferon alfa-2a resulted in a statistically significant increase inabortifacient activity in rhesus monkeys. Although no teratogenic effects were seen in the offspringdelivered at term, adverse effects in humans cannot be excluded.

Pegasys plus ribavirin

When used in combination with ribavirin, Pegasys did not cause any effects in monkeys not previouslyseen with either active substance alone. The major treatment-related change was reversible mild tomoderate anaemia, the severity of which was greater than that produced by either active substancealone.

Sodium chloride

Polysorbate 80

Benzyl alcohol

Sodium acetate

Acetic acid

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Pegasys 90 micrograms solution for injection in pre-filled syringe3 years

Pegasys 135 micrograms solution for injection in pre-filled syringe4 years

Pegasys 180 micrograms solution for injection in pre-filled syringe4 years

Store in a refrigerator (2°C-8°C). Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

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

Pegasys 90 micrograms solution for injection in pre-filled syringe

The syringe is labelled 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.

Pegasys 135 micrograms solution for injection in pre-filled syringe

The syringe is labelled 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. Not all pack-sizesmay be marketed.

Pegasys 180 micrograms solution for injection in pre-filled syringe

The syringe is labelled 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-sizesmay be marketed.

The solution for injection is for single use only. It should be inspected visually for particulate matterand discoloration before administration.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

pharmaand GmbH

Taborstrasse 11020 Wien

Austria

Pegasys 90 micrograms solution for injection in pre-filled syringe

EU/1/02/221/017

Pegasys 135 micrograms solution for injection in pre-filled syringe

EU/1/02/221/005

EU/1/02/221/006

EU/1/02/221/009

Pegasys 180 micrograms solution for injection in pre-filled syringe

EU/1/02/221/007

EU/1/02/221/008

EU/1/02/221/010

Date of first authorisation: 20 June 2002

Date of latest renewal: 21 June 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.