PEGINTRON 150mcg powder + solvent for injection in pre-filled pen medication leaflet

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 50 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each pre-filled pen provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted asrecommended.

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 80 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each pre-filled pen provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted asrecommended.

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 100 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each pre-filled pen provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted asrecommended.

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 120 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each pre-filled pen provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted asrecommended.

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 150 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each pre-filled pen provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted asrecommended.

The active substance is a covalent conjugate of recombinant interferon alfa-2b* with monomethoxypolyethylene glycol. The potency of this product should not be compared to that of another pegylatedor non-pegylated protein of the same therapeutic class (see section 5.1).

*produced by rDNA technology in E. coli cells harbouring a genetically engineered plasmid hybridencompassing an interferon alfa-2b gene from human leukocytes.

Each pre-filled pen contains 40 mg of sucrose per 0.5 ml.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection in pre-filled pen.

White powder.

Clear and colourless solvent.

Adults (tritherapy)

PegIntron in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment ofchronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) withcompensated liver disease who are previously untreated or who have failed previous therapy (seesection 5.1).

Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when

PegIntron is to be used in combination with these medicines.

Adults (bitherapy and monotherapy)

PegIntron is indicated for the treatment of adult patients (18 years of age and older) with CHC who arepositive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/orco-infected with clinically stable HIV (see section 4.4).

PegIntron in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection inadult patients who are previously untreated including patients with clinically stable HIV co-infectionand in adult patients who have failed previous treatment with interferon alpha (pegylated ornonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1).

Interferon monotherapy, including PegIntron, is indicated mainly in case of intolerance orcontraindication to ribavirin.

Please refer to the ribavirin SmPC when PegIntron is to be used in combination with ribavirin.

Paediatric population (bitherapy)

PegIntron is indicated in a combination regimen with ribavirin for the treatment of children 3 years ofage and older and adolescents, who have chronic hepatitis C, previously untreated, without liverdecompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combinationtherapy induced a growth inhibition that may be irreversible in some patients. The decision to treatshould be made on a case by case basis (see section 4.4).

Please refer to the ribavirin SmPC for capsules or oral solution when PegIntron is to be used incombination with ribavirin.

Treatment should be initiated and monitored only by a physician experienced in the management ofpatients with hepatitis C.

PegIntron should be administered as a once weekly subcutaneous injection. The dose administered inadults depends on whether it is used in combination therapy (bitherapy or tritherapy) or asmonotherapy.

PegIntron combination therapy (bitherapy or tritherapy)

Bitherapy (PegIntron with ribavirin): applies to all adult and paediatric patients 3 years of age andolder.

Tritherapy (PegIntron with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC.

Adults - Dose to be administered

PegIntron 1.5 micrograms/kg/week in combination with ribavirin capsules.

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

Table 1 Dosing for combination therapy*

Body weight PegIntron Ribavirin capsules(kg) PegIntron strength Administer once Total daily Number of(µg/0.5 ml) weekly ribavirin dose capsules(ml) (mg) (200 mg)< 40 50 0.5 800 4a40-50 80 0.4 800 4a51-64 80 0.5 800 4a65-75 100 0.5 1,000 5b76-80 120 0.5 1,000 5b81-85 120 0.5 1,200 6c86-105 150 0.5 1,200 6c> 105 150 0.5 1,400 7da: 2 morning, 2 eveningb: 2 morning, 3 eveningc: 3 morning, 3 eveningd: 3 morning, 4 evening

* Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy.

Adults - Duration of treatment - Naïve patients

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - Patients infected with virus genotype 1who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4or 12 are highly unlikely to become sustained virological responders and should be evaluated fordiscontinuation (see also section 5.1).

- Genotype 1:

- Patients who have undetectable HCV-RNA at treatment week 12, treatment should becontinued for another nine month period (i.e., a total of 48 weeks).

- Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatmentweek 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, theyshould continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA isstill detectable at treatment week 24, discontinuation of therapy should be considered.

- In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) whobecome HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24,the treatment could either be stopped after this 24 week treatment course or pursued for anadditional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weekstreatment duration may be associated with a higher risk of relapse than a 48 weeks treatmentduration (see section 5.1).

- Genotypes 2 or 3:

It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIVco-infected patients who should receive 48 weeks of treatment.

- Genotype 4:

In general, patients infected with genotype 4 are considered harder to treat and limited studydata (n=66) indicate they are compatible with a duration of treatment with bitherapy as forgenotype 1.

Adults - Duration of treatment - HCV/HIV co-infection

Bithe rapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weekswith bitherapy, regardless of genotype.

Predictability of response and non-response in HCV/HIV co-infection - Early virological response byweek 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shownto be predictive for sustained response. The negative predictive value for sustained response in

HCV/HIV co-infected patients treated with PegIntron in combination with ribavirin was 99 % (67/68;

Study 1) (see section 5.1). A positive predictive value of 50 % (52/104; Study 1) was observed for

HCV/HIV co-infected patients receiving bitherapy.

Adults - Duration of treatment - Retreatment

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, whohave demonstrated serum HCV-RNA below the limits of detection at week 12 should receive48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNAbelow the limits of detection) at week 12 are unlikely to become sustained virological responders after48 weeks of therapy (see also section 5.1).

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

Paediatric population (bitherapy only) - Dose to be administered

Dosing for children 3 years of age and older and adolescent patients is determined by body surfacearea for PegIntron and by body weight for ribavirin. The recommended dose of PegIntron is60 g/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divideddoses with food (morning and evening).

Paediatric population (bitherapy only) - Duration of treatment

- Genotype 1:

The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinicaldata on combination therapy with standard interferon in paediatric patients (negative predictivevalue 96 % for interferon alfa-2b/ribavirin), patients who fail to achieve virological response at12 weeks are highly unlikely to become sustained virological responders. Therefore, it isrecommended that children and adolescent patients receiving PegIntron/ribavirin combinationbe discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared topretreatment or if they have detectable HCV-RNA at treatment week 24.

- Genotype 2 or 3:

The recommended duration of treatment with bitherapy is 24 weeks.

- Genotype 4:

Only 5 children and adolescents with Genotype 4 were treated in the PegIntron/ribavirin clinicaltrial. The recommended duration of treatment with bitherapy is 1 year. It is recommended thatchildren and adolescent patients receiving PegIntron/ribavirin combination be discontinuedfrom therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if theyhave detectable HCV-RNA at treatment week 24.

PegIntron monotherapy - Adults

Dose to be administered

As monotherapy the PegIntron regimen is 0.5 or 1.0 µg/kg/week. The lowest PegIntron strengthavailable is 50 µg/0.5 ml; therefore for patients prescribed 0.5 µg/kg/week, doses must be adjusted byvolume as shown in Table 2. For the 1.0 µg/kg dose, similar volume adjustments can be made oralternate strengths can be used as shown in Table 2. PegIntron monotherapy was not studied in

HCV/HIV co-infected patients.

Table 2 Monotherapy dosing0.5 µg/kg 1.0 µg/kg

Body weight PegIntron Administer once PegIntron Administer once(kg) strength weekly strength weekly(µg/0.5 ml) (ml) (µg/0.5 ml) (ml)30-35 50* 0.15 80 0.236-45 50 0.2 50 0.446-56 50 0.25 50 0.557-72 80 0.2 80 0.473-88 50 0.4 80 0.589-106 50 0.5 100 0.5107-120** 80 0.4 120 0.5

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may requirecombinations of various PegIntron dose strengths and volumes.

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

Dose modification for all patients (monotherapy and combination therapy)

If severe adverse reactions or laboratory abnormalities develop during treatment with PegIntronmonotherapy or combination therapy, the dosages of PegIntron and/or ribavirin must be modified asappropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended.

Boceprevir must not be administered in the absence of PegIntron and ribavirin.

As adherence might be of importance for outcome of therapy, the dose of PegIntron and ribavirin shouldbe kept as close as possible to the recommended standard dose. Guidelines were developed in clinicaltrials for dose modification.

Combination therapy dose reduction guidelines

Table 2a Dose modification guidelines for combination therapy based on laboratoryparameters

Laboratory values Reduce only ribavirin Reduce only PegIntron Discontinuedaily dose (see note 1) dose (see note 2) if: combination therapyif: if:

Haemoglobin ≥ 8.5 g/dl, and - < 8.5 g/dl< 10 g/dl

Adults: Haemoglobinin Patients with history  2 g/dl decrease in haemoglobin during any < 12 g/dl after fourof stable cardiac four week period during treatment weeks of dosedisease (permanent dose reduction) reduction

Children andadolescents: notapplicable

Leukocytes - ≥ 1.0 x 109/l, and < 1.0 x 109/l< 1.5 x 109/l

Neutrophils - ≥ 0.5 x 109/l, and < 0.5 x 109/l< 0.75 x 109/l

Laboratory values Reduce only ribavirin Reduce only PegIntron Discontinuedaily dose (see note 1) dose (see note 2) if: combination therapyif: if:

Platelets - ≥ 25 x 109/l, and < 25 x 109/l (adults)< 50 x 109/l (adults) < 50 x 109/l (children≥ 50 x 109/l, and and adolescents)<70 x 109/l (children andadolescents)

Bilirubin - direct - - 2.5 x ULN*

Bilirubin - indirect > 5 mg/dl - > 4 mg/dl(for > 4 weeks)

Serum Creatinine - - > 2.0 mg/dl

Creatinine Clearance - - Discontinue ribavirinif CrCL < 50ml/min

Alanine - - 2 x baseline andaminotransferase > 10 x ULN*(ALT)or 2 x baseline and

Aspartate > 10 x ULN*aminotransferase(AST)

* Upper limit of normal

Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receivingthe 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction ofribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in theevening.

In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dosereduction of ribavirin is to 8 mg/kg/day.

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

In children and adolescent patients 1st dose reduction of PegIntron is to 40 g/m2/week, 2nddose reduction of PegIntron is to 20 g/m2/week.

Dose reduction of PegIntron in adults may be accomplished by reducing the prescribed volume or byutilizing a lower dose strength as shown in Table 2b. Dose reduction of PegIntron in children andadolescents is accomplished by modifying the recommended dose in a two-step process from theoriginal starting dose of 60 g/m2/week, to 40 g/m2/week, then to 20 g/m2/week, if needed.

Table 2b Two-step dose reduction of PegIntron in combination therapy in adults

First dose reduction to PegIntron 1 µg/kg Second dose reduction to PegIntron 0.5 µg/kg

Body PegIntron Amount of Volume of Body PegIntron Amount of Volume ofweight strength PegIntron PegIntron weight strength PegIntron PegIntron(kg) (µg/0.5 ml) to to (kg) (µg/0.5 ml) to toadminister administer administer administer(µg) (ml) (µg) (ml)< 40 50 35 0.35 < 40 50 20 0.240 - 50 120 40 - 50 50 25 0.250.251 - 64 80 56 0.35 51 - 64 8032 0.235 0.3565 - 75 100 70 65 - 75 500.3576 - 85 80 80 0.5 76 - 85 120 0.286 - 105 120 96 0.4 86 - 105 50 50 0.5> 105 150 105 0.35 > 105 80 64 0.4

PegIntron monotherapy dose reduction guidelines in adults

Dose modification guidelines for adult patients who use PegIntron monotherapy are shown in

Table 3a.

Table 3a Dose modification guidelines for PegIntron monotherapy in adults based onlaboratory parameters

Laboratory values Reduce PegIntron Discontinue PegIntron if:to one-half dose if:

Neutrophils ≥ 0.5 x 109/l, and < 0.75 x 109/l < 0.5 x 109/l

Platelets ≥ 25 x 109/l, and < 50 x 109/l < 25 x 109/l

For adult patients who use 0.5 g/kg PegIntron monotherapy, dose reduction may be accomplished byreducing the prescribed volume by one-half as shown in Table 3b.

Table 3b Reduced PegIntron dose (0.25 g/kg) for the 0.5 g/kg monotherapy regimen inadults

Body weight PegIntron strength Amount of PegIntron Volume of PegIntron to(kg) (g/0.5 ml) to administer administer(g) (ml)30-35 50* 8 0.0836-45 50* 10 0.146-56 50* 13 0.1357-72 80* 16 0.173-88 50 20 0.289-106 50 25 0.25107-120** 80 32 0.2

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may requirecombinations of various PegIntron dose strengths and volumes.

For adult patients who use 1.0 µg/kg PegIntron monotherapy, dose reduction may be accomplished byredu cing the prescribed volume by one-half or by utilizing a lower dose strength as shown in

Table 3c.

Table 3c Reduced PegIntron dose (0.5 g/kg) for the 1.0 g/kg monotherapy regimen inadults

Body weight PegIntron Amount of Volume of(kg) strength PegIntron to PegIntron to(µg/0.5 ml) administer administer(g) (ml)30-35 50* 15 0.1536-45 50 20 0.2046-56 50 25 0.2557-72 80 32 0.273-88 50 40 0.489-106 50 50 0.5107-120** 80 64 0.4

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may requirecombinations of various PegIntron dose strengths and volumes.

PegIntron should be used with caution in patients with moderate to severe renal impairment. In patientswith moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of PegIntronshould be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance15-29 ml/minute) should have the starting dose of PegIntron reduced by 50 %. Data are not availablefor the use of PegIntron in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patientswith severe renal impairment, including those on hemodialysis, should be closely monitored. If renalfunction decreases during treatment, PegIntron therapy should be discontinued.

Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combinationwith ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impairedrenal function should be more carefully monitored with respect to the development of anaemia.

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

Elderly ( 65 years of age)

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

PegIntron can be used in combination with ribavirin in paediatric patients 3 years of age and older.

PegIntron should be administered as a subcutaneous injection. For special handling information seesection 6.6. Patients may self-inject PegIntron if their physician determines that it is appropriate and withmedical follow-up as necessary.

- Hypersensitivity to the active substance or to any interferon or to any of the excipients listed insection 6.1;

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

- Severe, debilitating medical conditions;

- Autoimmune hepatitis or a history of autoimmune disease;

- Severe hepatic dysfunction or decompensated cirrhosis of the liver;

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

- Epilepsy and/or compromised central nervous system (CNS) function;

- HCV/HIV patients with cirrhosis and a Child-Pugh score ≥ 6.

- Combination of PegIntron with telbivudine.

- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidalideation or suicidal attempt.

Also see SmPCs for ribavirin and boceprevir if PegIntron is to be administered in combination therapyin patients with chronic hepatitis C.

Psychiatric and Central Nervous System (CNS)

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observedin some patients during PegIntron therapy, and even after treatment discontinuation mainly during the6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed againstothers such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental statushave been observed with alpha interferons. Patients should be closely monitored for any signs orsymptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of theseundesirable effects must be borne in mind by the prescribing physician and the need for adequatetherapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidalor homicidal ideation is identified, it is recommended that treatment with PegIntron be discontinued,and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions

If treatment with peginterferon alfa-2b is judged necessary in adult patients with existence or historyof severe psychiatric conditions, this should only be initiated after having ensured appropriateindividualised diagnostic and therapeutic management of the psychiatric condition.

- The use of PegIntron in children and adolescents with existence of or history of severe psychiatricconditions is contraindicated (see section 4.3). Among children and adolescents treated with interferonalfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequentlycompared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up aftertreatment. As in adult patients, children and adolescents experienced other psychiatric adverse events(e.g. depression, emotional lability, and somnolence).

Patients with substance use/abuse

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at anincreased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorderswhen treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients,the presence of psychiatric co-morbidities and the potential for other substance use should be carefullyassessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approachincluding a mental health care provider or addiction specialist should be considered to evaluate, treat andfollow the patient. Patients should be closely monitored during therapy and even after treatmentdiscontinuation. Early intervention for re-emergence or development of psychiatric disorders andsubstance use is recommended.

Grow th and development (children and adolescents)

During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight lossand growth inhibition were common. Long-term data available in children treated with thecombination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation.

Thirty two percent (30/94) of subjects demonstrated > 15 percentile decrease in height-for-agepercentile 5 years after completion of therapy (see sections 4.8 and 5.1).

Case by case benefit/risk assessment in children

The expected benefit of treatment should be carefully weighed against the safety findings observed forchildren and adolescents in the clinical trials (see sections 4.8 and 5.1).

- It is important to consider that the combination therapy induced a growth inhibition, thatresulted in reduced height in some patients.

- This risk should be weighed against the disease characteristics of the child, such as evidence ofdisease progression (notably fibrosis), co-morbidities that may negatively influence the diseaseprogression (such as HIV co-infection), as well as prognostic factors of response (HCVgenotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce therisk of growth inhibition. Although data are limited, no evidence of long-term effects on sexualmaturation was noted in the 5-year observational follow-up study.

More significant obtundation and coma, including cases of encephalopathy, have been observed in somepatients, usually elderly, treated at higher doses for oncology indications. While these effects are generallyreversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurredwith high doses of interferon alpha.

All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certaincases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation.

Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior tocommencing treatment.

Acute hypersensitivity

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) havebeen observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with

PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashesdo not necessitate interruption of treatment.

Cardiovascular system

As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarctionand/or previous or current arrhythmic disorders, receiving PegIntron therapy require close monitoring. Itis recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms takenprior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usuallyrespond to conventional therapy but may require discontinuation of PegIntron therapy. There are no datain children or adolescents with a history of cardiac disease.

Hepatic Failure

PegIntron increases the risk of hepatic decompensation and death in patients with cirrhosis. As with allinterferons, discontinue treatment with PegIntron in patients who develop prolongation of coagulationmarkers which might indicate liver decompensation. Liver enzymes and hepatic function should beclosely monitored in cirrhotic patients.

While pyrexia may be associated with the flu-like syndrome reported commonly during interferontherapy, other causes of persistent pyrexia must be ruled out.

Hydration

Adeq uate hydration must be maintained in patients undergoing PegIntron therapy since hypotensionrelated to fluid depletion has been seen in some patients treated with alpha interferons. Fluidreplacement may be necessary.

Pulmonary changes

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observedrarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or otherrespiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates orthere is evidence of pulmonary function impairment, the patient is to be monitored closely, and, ifappropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration andtreatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatmentwith alpha 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 reassessed (see alsosection 4.4 Thyroid changes and section 4.8).

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

Ocular changes

Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment,and retinal artery or vein occlusion have been reported in rare instances after treatment with alphainterferons (see section 4.8). All patients should have a baseline eye examination. Any patientcomplaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt andcomplete eye examination. Periodic visual examinations are recommended during PegIntron therapy,particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus orhypertension. Discontinuation of PegIntron should be considered in patients who develop new orworsening ophthalmological disorders.

Thyroid changes

Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developedthyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of childrentreated with PegIntron/ribavirin combination therapy developed increase in thyroid stimulatinghormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal.

Prior to initiation of PegIntron therapy, TSH levels must be evaluated and any thyroid abnormalitydetected at that time must be treated with conventional therapy. Determine TSH levels if, during thecourse of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In thepresence of thyroid dysfunction, PegIntron treatment may be continued if TSH levels can bemaintained in the normal range by medicine. Children and adolescents should be monitored every3 months for evidence of thyroid dysfunction (e.g. TSH).

Metabolic disturbances

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed.

Monitoring of lipid levels is, therefore, recommended.

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis

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

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

Co-i nfected patients with advanced cirrhosis receiving HAART may be at increased risk of hepaticdecompensation and death. Adding treatment with alfa interferons alone or in combination withribavirin may increase the risk in this patient subset. Other baseline factors in co-infected patients thatmay be associated with a higher risk of hepatic decompensation include treatment with didanosine andelevated bilirubin serum concentration.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closelymonitored, assessing their Child-Pugh score during treatment. Patients progressing to hepaticdecompensation should have their anti-hepatitis treatment immediately discontinued and the ARVtreatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART maybe at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia andanaemia) compared to HCV mono-infected patients. Although, the majority of them could be managedby dose reduction, close monitoring of haematological parameters should be undertaken in thispopulation of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with PegIntron and ribavirin combination therapy and zidovudine are at increased riskof developing anaemia and therefore the concomitant use of this combination with zidovudine is notrecommended (see section 4.5).

Patients with low CD4 counts

In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available insubjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment ofpatients with low CD4 counts.

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be takenconcurrently with HCV therapy for awareness and management of toxicities specific for each productand the potential for overlapping toxicities with PegIntron and ribavirin.

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activationappears to be low.

All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C;patients co-infected with hepatitis B and C must then be monitored and managed according to currentclinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patientsreceiving PegIntron 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 PegIntron 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.

Organ transplant recipients

The safety and efficacy of PegIntron alone or in combination with ribavirin for the treatment ofhepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicatethat interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Livergraft rejection has also been reported.

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of

PegIntron in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifiesthe potential risk.

Stand ard haematologic tests, blood chemistry and a test of thyroid function must be conducted in allpatients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline priorto initiation of PegIntron therapy are:

- Platelets  100,000/mm3

- Neutrophil count  1,500/mm3

- TSH level must be within normal limits

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter asclinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).

Long term maintenance monotherapy

It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is noteffective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention ofdisease progression in non responders with compensated cirrhosis. No statistically significant effect on thetime to development of the first clinical event (liver decompensation, hepatocellular carcinoma, deathand/or liver transplantation) was observed as compared to the absence of treatment. PegIntron shouldtherefore not be used as long term maintenance monotherapy.

Important information about some of the ingredients of PegIntron

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially'sodium-free'.

Interaction studies have only been performed in adults.

Telbivudine

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferonalfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combinationis associated with an increased risk of developing peripheral neuropathy. The mechanism behind theseevents is not known (see sections pct. 4.3, pct. 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety andefficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has notbeen demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated (seesection 4.3).

Methadone

In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve topeginterferon alfa-2b, addition of 1.5 microgram/kg/week of PegIntron subcutaneously for 4 weeksincreased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 - 128 %).

The clinical significance of this finding is unknown; however, patients should be monitored for signsand symptoms of increased sedative effect, as well as respiratory depression. Especially in patients ona high dose of methadone, the risk for QTc prolongation should be considered.

Effect of Peginterferon alfa-2b on Co-administered Medicines

The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes wasevaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects ofmultiple-dose regimens of peginterferon alfa-2b (PegIntron) were investigated in Hepatitis C subjects(1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significantpharmacokinetic interaction was not observed between peginterferon alfa-2b (PegIntron) andtolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferonalfa-2b (PegIntron) is administered with medicines metabolized by CYP2C9, CYP3A4 and

N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (PegIntron) with caffeine ordesipramine modestly increased the exposure of caffeine and desipramine. When patients areadmi nistered PegIntron with medications metabolized by CYP1A2 or CYP2D6, the extent of thedecrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicineswhich have a narrow therapeutic margin (Table 5).

Table 4Effect of Peginterferon alfa-2b on Co-administered Medicines

Geometric Mean Ratio (Ratiowith/without peginterferon

Co-administered Dose of Study Population alfa-2b)

Medicine peginterferon AUC Cmaxalfa-2b (90% CI) (90% CI)

Caffeine 1.5 mcg/kg/week Chronic Hepatitis 1.39 1.02(CYP1A2 substrate) (4 weeks) C Subjects (N=22) (1.27, 1.51) (0.95, 1.09)1 mcg/kg/week Healthy Subjects 1.18 1.12(4 weeks) (N=24) (1.07, 1.31) (1.05, 1.19)3 mcg/kg/week Healthy Subjects 1.36 1.16(2 weeks) (N=13) (1.25, 1.49) (1.10, 1.24)

Tolbutamide 1.5 mcg/kg/week Chronic Hepatitis 1.1# NA(CYP2C9 substrate) (4 weeks) C Subjects (N=22) (0.94, 1.28)1 mcg/kg/week Healthy Subjects 0.90# NA(4 weeks) (N=24) (0.81, 1.00)3 mcg/kg/week Healthy Subjects 0.95 0.99(2 weeks) (N=13) (0.89, 1.01) (0.92, 1.07)

Dextromethorphan 1.5 mcg/kg/week Chronic Hepatitis 0.96## NAhydrobromide (4 weeks) C Subjects (N=22) (0.73, 1.26)(CYP2D6 and 1 mcg/kg/week Healthy Subjects 2.03# NA

CYP3A substrate) (4 weeks) (N=24) (1.55, 2.67)

Desipramine 3 mcg/kg/week Healthy Subjects 1.30 1.08(CYP2D6 substrate) (2 weeks) (N=13) (1.18, 1.43) (1.00, 1.16)

Midazolam 1.5 mcg/kg/week Chronic Hepatitis 1.07 1.12(CYP3A4 substrate) (4 weeks) C Subjects (N=24) (0.91, 1.25) (0.94, 1.33)1 mcg/kg/week Healthy Subjects 1.07 1.33(4 weeks) (N=24) (0.99, 1.16) (1.15, 1.53)3 mcg/kg/week Healthy Subjects 1.18 1.24(2 weeks) (N=13) (1.06, 1.32) (1.07, 1.43)

Dapsone 1.5 mcg/kg/week Chronic Hepatitis 1.05 1.03(N-acetyltransferase (4 weeks) C Subjects (N=24) (1.02, 1.08) (1.00, 1.06)substrate)# Calculated from urine data collected over an interval of 48-hours## Calculated from urine data collected over an interval of 24-hours

Table 5 Precautions for co-administration (PegIntron should be administered with carewhen co-administered with the following medicines)

Medicines Signs, Symptoms, and Treatment Mechanism and Risk Factors

Theophylline Co-administration of theophylline Metabolism of theophylline iswith the product (PegIntron) may suppressed by inhibitory action ofincrease the blood concentrations of the product (PegIntron) ontheophylline. Careful CYP1A2.co-administration of theophyllinewith the product (PegIntron) isrecommended. Package inserts oftheophylline should be referred towhen co-administering with theproduct (PegIntron)

Thioridazine Co-administration of thioridazine Metabolism of thioridazine iswith the product (PegIntron) may suppressed by inhibitory action ofincrease the blood concentrations of the product (PegIntron) onthioridazine. Careful CYP2D6.co-administration of thioridazinewith the product (PegIntron) isrecommended. Package inserts ofthioridazine should be referred towhen co-administering with theproduct (PegIntron)

Theophylline, Elevation of blood concentrations Metabolism of other medicines in

Antipyrine, of these medicines has been the liver may be suppressed.

Warfarin reported when administered incombination with other interferonpreparations and therefore careshould be taken.

Zidovudine When administered in combination Mechanism of action is unknown,with other interferon preparations, but it is considered that bothsuppressive effect on bone marrow medicines have bone marrowfunction may be strengthened and depressive effects.aggravation of blood cell reductionsuch as white blood cells decreasedmay occur.

Immuno-suppressive When administered in combination It is considered that graft rejectiontherapy with other interferon preparations, reactions may be induced.

effect of immunosuppressivetherapy may be weakened intransplant (kidney, bone marrow,etc.) patients.

No pharmacokinetic interactions were noted between PegIntron and ribavirin in a multiple-dosepharmacokinetic study.

HCV/HIV Co-infection

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lacticacidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides invitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs(e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended.

Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal,have been reported (see ribavirin SmPC).

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 treatment(ART) regimen if this is already established. This would be particularly important in patients with aknown history of zidovudine-induced anaemia.

Women of childbearing potential/contraception in males and females

PegIntron is recommended for use in fertile women only when they are using effective contraceptionduring the treatment.

Combination therapy with ribavirin

Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking

PegIntron in combination with ribavirin. Females of childbearing potential must use an effectivecontraceptive during treatment and for 4 months after treatment has been concluded. Male patients or theirfemale partners must use an effective contraceptive during treatment and for 7 months after treatment hasbeen concluded (see ribavirin SmPC).

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient inprimates. PegIntron is likely to also cause this effect.

The potential risk in humans is unknown. PegIntron is to be used during pregnancy only if the potentialbenefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapyis contraindicated in women who are pregnant.

It is not known whether the components of this medicinal product are excreted in human milk.

Because of the potential for adverse reactions in breast-fed infants, breast-feeding should bediscontinued prior to initiation of treatment.

There are no data available regarding potential effects of PegIntron treatment on male or femalefertility.

Patients who develop fatigue, somnolence or confusion during treatment with PegIntron are cautioned toavoid driving or operating machines.

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy

The most common treatment-related adverse reactions reported during clinical trials with PegIntron incombination with ribavirin in adults, seen in more than half of the study subjects, were fatigue,headache, and injection site reaction. Additional adverse reactions reported in more than 25 % ofsubjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia,anorexia, weight decreased, depression, rash and irritability. The most frequently reported adversereact ions were mostly mild to moderate in severity and were manageable without the need formodification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia,weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with

PegIntron monotherapy compared to those treated with combination therapy (see Table 6).

The following treatment-related adverse reactions were reported in adults in clinical trials or throughpost-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntronmonotherapy or PegIntron/ribavirin. These reactions are listed in table 6 by system organ class andfrequency (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) or not known (cannot be estimated from theavailable data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 6 Adverse reactions reported in adults in clinical trials or through post-marketingsurveillance in patients treated with peginterferon alfa-2b, including PegIntronmonotherapy or PegIntron + ribavirin

Very common: Viral infection*, pharyngitis*

Common: Bacterial infection (including sepsis), fungal infection, influenza, upperrespiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media,rhinitis

Uncommon: Injection site infection, lower respiratory tract infection

Not known: Hepatitis B reactivation in HCV/HBV co-infected patients

Very common: Anaemia, neutropenia

Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy

Very rare: Aplastic anaemia

Not known: Aplasia pure red cell

Uncommon: Drug hypersensitivity

Rare: Sarcoidosis

Not known: Acute hypersensitivity reactions including angioedema, anaphylaxis andanaphylactic reactions including anaphylactic shock, idiopathicthrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemiclupus erythematosus

Common: Hypothyroidism, hyperthyroidism

Very common: Anorexia

Common: Hypocalcemia, hyperuricemia, dehydration, increased appetite

Uncommon: Diabetes mellitus, hypertriglyceridaemia

Rare: Diabetic ketoacidosis

Very common: Depression, anxiety*, emotional lability*, concentration impaired, insomnia

Common: Aggression, agitation, anger, mood altered, abnormal behaviour,nervousness, sleep disorder, libido decreased, apathy, abnormal dreams,crying

Uncommon: Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panicattack

Rare: Bipolar disorders

Not known: Homicidal ideation, mania

Very common: Headache, dizziness

Common: Amnesia, memory impairment, syncope, migraine, ataxia, confusion,neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia,somnolence, disturbance in attention, tremor, dysgeusia

Uncommon: Neuropathy, neuropathy peripheral

Rare: Convulsion

Very rare: Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy

Not known: Facial palsy, mononeuropathies

Common: Visual disturbance, vision blurred, photophobia, conjunctivitis, eyeirritation, lacrimal disorder, eye pain, dry eye

Uncommon: Retinal exudates

Rare: Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy,retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema,macular oedema

Not known: Serous retinal detachment

Ear and labyrinth disorders

Common: Hearing impaired/loss, tinnitus, vertigo

Uncommon Ear pain

Common: Palpitations, tachycardia

Uncommon: Myocardial infarction

Rare: Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis

Very rare: Cardiac ischaemia

Not known: Pericardial effusion

Common: Hypotension, hypertension, flushing

Rare: Vasculitis

Very common: Dyspnoea*, cough*

Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion,sinus congestion, nasal congestion, rhinorrhea, increased upper airwaysecretion, pharyngolaryngeal pain

Very rare: Interstitial lung disease

Not known: Pulmonary fibrosis, pulmonary arterial hypertension#

Very common: Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth*

Common: Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration,glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids,cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder

Uncommon: Pancreatitis, oral pain

Rare: Colitis ischaemic

Very rare: Colitis ulcerative

Not known Tongue pigmentation

Com mon: Hyperbilirubinemia, hepatomegaly

Very common: Alopecia, pruritus*, dry skin*, rash*

Common: Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis,erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle,erythema, urticaria, abnormal hair texture, nail disorder

Rare: Cutaneous sarcoidosis

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Very common: Myalgia, arthralgia, musculoskeletal pain

Common: Arthritis, back pain, muscle spasms, pain in extremity

Uncommon: Bone pain, muscle weakness

Rare: Rhabdomyolysis, myositis, rheumatoid arthritis

Common: Micturition frequency, polyuria, urine abnormality

Rare: Renal failure, renal insufficiency

Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovariandisorder, vaginal disorder, sexual dysfunction, prostatitis, erectiledysfunction

Very common: Injection site reaction*, injection site inflammation, fatigue, asthenia,irritability, chills, pyrexia, influenza like illness, pain

Common: Chest pain, chest discomfort, injection site pain, malaise, face oedema,oedema peripheral, feeling abnormal, thirst

Rare: Injection site necrosis

Very common: Weight decreased

*These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with PegIntron monotherapy.#Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions in adults

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some casesof more severe neutropenia in patients treated with the recommended doses of PegIntron in combinationwith ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]).

In a clinical trial, approximately 1.2 % of patients treated with PegIntron or interferon alfa-2b incombination with ribavirin reported life-threatening psychiatric events during treatment. These eventsincluded suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly withpre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy,that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patientswithout prior evidence of cardiac disease.

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.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies(incl uding macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates,loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4).

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferonsincluding thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated),idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies includingmononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients

For HCV/HIV co-infected patients receiving PegIntron in combination with ribavirin, otherundesirable effects (that were not reported in mono-infected patients) which have been reported in thelarger studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %),

CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased(9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytichepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTIregimen and associated ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred morefrequently in HCV/HIV co-infected patients, the majority could be managed by dose modification andrarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalitieswere more frequently reported in patients receiving PegIntron in combination with ribavirin whencompared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (seesection 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 %(8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) ofpatients receiving PegIntron in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) wasreported in 12 % (23/194) of patients treated with PegIntron in combination with ribavirin.

CD4 lymphocytes decrease

Treatment with PegIntron in combination with ribavirin was associated with decreases in absolute

CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decreasein CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of PegIntronin combination with ribavirin had no observable negative impact on the control of HIV viraemiaduring therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with

CD4+ cell counts < 200/µl (see section 4.4).

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be takenconcurrently with HCV therapy for awareness and management of toxicities specific for each product andthe potential for overlapping toxicities with PegIntron in combination with ribavirin.

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combinationtherapy of PegIntron and ribavirin, dose modifications were required in 25 % of patients, most commonlyfor anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children andadolescents was similar to that observed in adults, although there is a paediatric-specific concernregarding growth inhibition. During combination therapy for up to 48 weeks with PegIntron and ribavirin,growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weightloss and growth inhibition were very common during the treatment (at the end of treatment, meandecrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles,respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients).

At th e end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and heightpercentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the childrencontinued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjectsenrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjectstreated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % ofsubjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatmentto the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Elevenpercent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks wereobserved to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the endof the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks,respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentilesdecreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively.

Decrease in mean height percentile at year 1 of long-term follow-up was most prominent inprepubertal age children. The decline of height, weight and BMI Z scores observed during thetreatment phase in comparison to a normative population did not fully recover at the end of long-termfollow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia(80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema(29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). Themajority of adverse reactions reported in the study were mild or moderate in severity. Severe adversereactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain inextremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergentadverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger(2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxinetreatment for hypothyroidism/elevated TSH.

The following treatment-related adverse reactions were reported in the study in children andadolescent patients treated with PegIntron in combination with ribavirin. These reactions are listed in

Table 7 by system organ class and frequency (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) or not known(cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7 Adverse reactions very commonly, commonly and uncommonly reported in theclinical trial in children and adolescent patients treated with PegIntron incombination with ribavirin

Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitisstreptococcal, nasopharyngitis, sinusitis

Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tractinfection, gastroenteritis

Very common: Anaemia, leucopenia, neutropenia

Common: Thrombocytopenia, lymphadenopathy

Common: Hypothyroidism

Very common: Anorexia, decreased appetite

Com mon: Suicidal ideation§, suicide attempt§, depression, aggression, affect lability,anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia

Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

Very common: Headache, dizziness

Common: Dysgeusia, syncope, disturbance in attention, somnolence, poor qualitysleep

Uncommon: Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotorhyperactivity, tremor

Common: Eye pain

Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia

Ear and labyrinth disorders

Common: Vertigo

Common: Palpitations, tachycardia

Common: Flushing

Uncommon: Hypotension, pallor

Common: Cough, epistaxis, pharyngolaryngeal pain

Uncommon: Wheezing, nasal discomfort, rhinorrhoea

Very common: Abdominal pain, abdominal pain upper, vomiting, nausea

Common: Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomachdiscomfort, oral pain

Uncommon: Dyspepsia, gingivitis

Uncommon: Hepatomegaly

Very common: Alopecia, dry skin

Common: Pruritus, rash, rash erythematous, eczema, acne, erythema

Uncommon: Photosensitivity reaction, rash maculo-papular, skin exfoliation,pigmentation disorder, dermatitis atopic, skin discolouration

Very common: Myalgia, arthralgia

Common: Musculoskeletal pain, pain in extremity, back pain

Uncommon: Muscle contracture, muscle twitching

Uncommon: Proteinuria

Uncommon: Female: Dysmenorrhoea

Very common: Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness,asthenia, pain, malaise, irritability

Common: Injection site reaction, injection site pruritus, injection site rash injectionsite dryness, injection site pain, feeling cold

Uncommon: Chest pain, chest discomfort, facial pain

Very common: Growth rate decrease (height and/or weight decrease for age)

Common: Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon: Anti-thyroid antibody positive

Injury and poisoning

Uncommon: Contusion§class effect of interferon-alfa containing products - reported with standard interferon therapy in adult and paediatricpatients; with PegIntron reported in adult patients.

Description of selected adverse reactions in children and adolescents

Most of the changes in laboratory values in the PegIntron/ribavirin clinical trial were mild ormoderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubinmay require dose reduction or permanent discontinuation from therapy (see section 4.2). Whilechanges in laboratory values were observed in some patients treated with PegIntron used incombination with ribavirin in the clinical trial, values returned to baseline levels within a few weeksafter the end of therapy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is1,200 µg for one day. In general, the adverse events seen in overdose cases involving PegIntron areconsistent with the known safety profile for PegIntron; however, the severity of the events may beincreased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have notbeen shown to be useful. No specific antidote for PegIntron is available; therefore, symptomatictreatment and close observation of the patient are recommended in cases of overdose. If available,prescribers are advised to consult with a poison control centre (PCC).

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10.

Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at anaverage degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass isapproximately 31,300 daltons of which the protein moiety constitutes approximately 19,300.

In vitro and in vivo studies suggest that the biological activity of PegIntron is derived from its interferonalfa-2b moiety.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface.

Studies with other interferons have demonstrated species specificity. However, certain monkeyspecies, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure tohuman type 1 interferons.

Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events thatinclude the induction of certain enzymes. It is thought that this process, at least in part, is responsiblefor the various cellular responses to interferon, including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and such immunomodulating activities as enhancementof the phagocytic activity of macrophages and augmentation of the specific cytotoxicity oflymp hocytes for target cells. Any or all of these activities may contribute to interferon’s therapeuticeffects.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exactantiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cellmetabolism. This action inhibits viral replication or if replication occurs, the progeny virions areunable to leave the cell.

PegIntron pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examiningchanges in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5’-oligoadenylate synthetase (2’5’-OAS), as well as white cell and neutrophil counts. Subjects treated with

PegIntron showed mild dose-related elevations in body temperature. Following single doses of PegIntronbetween 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-relatedmanner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of

PegIntron.

Clinical efficacy and safety - Adults

Tritherapy with PegIntron, ribavirin and boceprevir

Refer to the SmPC for boceprevir.

Monotherapy with PegIntron and bitherapy with PegIntron and ribavirin

Naïve patients

Two pivotal trials have been conducted, one (C/I97-010) with PegIntron monotherapy; the other(C/I98-580) with PegIntron in combination with ribavirin. Eligible patients for these trials had chronichepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), aliver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for thechronic hepatitis, and abnormal serum ALT.

In the PegIntron monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with

PegIntron (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. Inaddition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times aweek) as a comparator. This study showed that PegIntron was superior to interferon alfa-2b (Table 8).

In the PegIntron combination trial, 1,530 naïve patients were treated for one year with one of thefollowing combination regimens:

- PegIntron (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511).

- PegIntron (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for11 months) + ribavirin (1,000/1,200 mg/day), (n = 514).

- Interferon alfa-2b (3 MIU three times a week) + ribavirin (1,000/1,200 mg/day) (n = 505).

In this trial, the combination of PegIntron (1.5 micrograms/kg/week) and ribavirin was significantlymore effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly inpatients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate sixmonths after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates.

However, response rates in this trial were shown to be dependent also on the dose of ribavirinadministered in combination with PegIntron or interferon alfa-2b. In those patients that received> 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load,response rates were significantly higher than in those patients that received  10.6 mg/kg ribavirin(Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher.

Table 8 Sustained virological response (% patients HCV negative)

PegIntron monotherapy PegIntron + ribavirin

Treatment regimen P 1.5 P 1.0 P 0.5 I P 1.5/R P 0.5/R I/R

Number of patients 304 297 315 303 511 514 505

Response at end of treatment 49 % 41 % 33 % 24 % 65 % 56 % 54 %

Sustained response 23 %* 25 % 18 % 12 % 54 %** 47 % 47 %

P 1.5 PegIntron 1.5 micrograms/kg

P 1.0 PegIntron 1.0 microgram/kg

P 0.5 PegIntron 0.5 microgram/kg

I Interferon alfa-2b 3 MIU

P 1.5/R PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

P 0.5/R PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

* p < 0.001 P 1.5 vs. I

** p = 0.0143 P 1.5/R vs. I/R

Table 9 Sustained response rates with PegIntron + ribavirin (by ribavirin dose, genotypeand viral load)

HCV Genotype Ribavirin dose P 1.5/R P 0.5/R I/R(mg/kg)

All Genotypes All 54 % 47 % 47 %≤ 10.6 50 % 41 % 27 %> 10.6 61 % 48 % 47 %

Genotype 1 All 42 % 34 % 33 %≤ 10.6 38 % 25 % 20 %> 10.6 48 % 34 % 34 %

Genotype 1 All 73 % 51 % 45 %≤ 600,000 IU/ml ≤ 10.6 74 % 25 % 33 %> 10.6 71 % 52 % 45 %

Genotype 1 All 30 % 27 % 29 %> 600,000 IU/ml ≤ 10.6 27 % 25 % 17 %> 10.6 37 % 27 % 29 %

Genotype 2/3 All 82 % 80 % 79 %≤ 10.6 79 % 73 % 50 %> 10.6 88 % 80 % 80 %

P 1.5/R PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

P 0.5/R PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

In the PegIntron monotherapy study, the Quality of Life was generally less affected by0.5 microgram/kg of PegIntron than by either 1.0 microgram/kg of PegIntron once weekly or 3 MIUof interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received PegIntron, 1.5 micrograms/kgsubcutaneously, once weekly, in combination with ribavirin 800 mg -1,400 mg p.o. for 6 months(based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose)(Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by

HCV Genotype and viral load*

PegIntron 1.5 µg/kg once weekly plus Ribavirin 800-1,400 mg/day

End of treatment Sustained Virologic Response Relapseresponse

All subjects 94 % (211/224) 81 % (182/224) 12 % (27/224)

HCV 2 100 % (42/42) 93 % (39/42) 7 % (3/42)≤ 600,000 IU/ml 100 % (20/20) 95 % (19/20) 5 % (1/20)> 600,000 IU/ml 100 % (22/22) 91 % (20/22) 9 % (2/22)

HCV 3 93 % (169/182) 79 % (143/182) 14 % (24/166)≤ 600,000 IU/ml 93 % (92/99) 86 % (85/99) 8 % (7/91)> 600,000 IU/ml 93 % (77/83) 70 % (58/83) 23 % (17/75)

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-upweek 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in thepivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received

PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjustedribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-onepercent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 oftherapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The highsustained response rate in this subgroup of patients was identified in an interim analysis (n=49) andprospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a highersustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two

PegIntron/ribavirin regimens [PegIntron 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both incombination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] andpeginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily(in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Responseto the treatment was measured by Sustained Virologic Response (SVR) which is defined asundetectable HCV-RNA at 24 weeks post-treatment (see Table 11).

Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate

*and Sustained Virologic Response (SVR)

Treatment group % (number) of patients

PegIntron 1.5 µg/kg + PegIntron 1 µg/kg + peginterferon alfa-2aribavirin ribavirin 180 µg + ribavirin

Undetectable HCV-

RNA at treatment 40 (407/1,019) 36 (366/1,016) 45 (466/1,035)week 12

End of treatment53 (542/1,019) 49 (500/1,016) 64 (667/1,035)response

Relapse 24 (123/523) 20 (95/475) 32 (193/612)

SVR 40 (406/1,019) 38 (386/1,016) 41 (423/1,035)

SVR in patients withundetectable HCV-81 (328/407) 83 (303/366) 74 (344/466)

RNA at treatmentweek 12

* (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml)

Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) wasa criterion for discontinuation of treatment.

In al l three treatment groups, sustained virologic response rates were similar. In patients of African

American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with

PegIntron (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic responserate compared to PegIntron 1 µg/kg dose. At the PegIntron 1.5 µg/kg plus ribavirin dose, sustainedvirologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, inpatients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patientshad a higher sustained virologic response rate compared to the African Americans. Among patientswith undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response - Naïve patients: Virological response by week 12 isdefined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological responseby week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. Thesetime points (treatment week 4 and treatment week 12) have been shown to be predictive for sustainedresponse (Table 12).

Table 12 Predictive value of in-treatment Virologic Response while on PegIntron1.5 µg/kg/ribavirin 800-1,400 mg combination therapy

Negative Positive

Noresponse Responseat No Negative at Positivetreatment sustained predictive treatment Sustained predictiveweek response value week response value

Genotype 1*

By week 4***(n=950)

HCV-RNA negative 834 539 65 % 116 107 92 %(539/834) (107/116)

HCV-RNA negative 220 210 95 % 730 392 54 %or (210/220) (392/730)≥ 1 logdecrease inviral load

By week 12***(n=915)

HCV-RNA negative 508 433 85 % 407 328 81 %(433/508) (328/407)

HCV-RNA negative 206 205 N/A† 709 402 57 %or (402/709)≥ 2 log decrease inviral load

Genotype 2, 3**

By week 12(n= 215)

HCV-RNA negative 2 1 50 % 213 177 83 %or (1/2) (177/213)≥ 2 log decrease inviral load

*Genotype 1 receive 48 weeks treatment

**Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4or week 12.† These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients tostop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at week 24and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with PegIntron in monotherapywas 98 %.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatmentin both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized,multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C whowere co-infected with HIV. Patients were randomized to receive either PegIntron (1.5 µg/kg/week)plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centrestudy that enrolled 95 previously untreated adult patients with chronic hepatitis C who wereco-infected with HIV. Patients were randomized to receive either PegIntron (100 or 150 µg/weekbased on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU

TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks witha follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load< 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

Table 13 Sustained virological response based on genotype after PegIntron in combinationwith Ribavirin in HCV/HIV Co-infected patients

Study 11 Study 22

PegIntron Interferon

PegIntron Interferon (100 or alfa-2b(1.5 µg/kg/ alfa-2b 150c µg/week) (3 MIU TIW)week) + (3 MIU TIW) + + ribavirin + ribavirinribavirin ribavirin p (800- (800- p(800 mg) (800 mg) valuea 1,200 mg)d 1,200 mg)d valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.a: p value based on Cochran-Mantel Haenszel Chi square test.b: p value based on chi-square test.c: subjects < 75 kg received 100 µg/week PegIntron and subjects ≥ 75 kg received 150 µg/week PegIntron.d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response: Liver biopsies were obtained before and after treatment in Study 1 and wereavailable for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased amongsubjects treated with PegIntron in combination with ribavirin. This decline was significant amongresponders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) amongnon-responders. In terms of activity, about one-third of sustained responders showed improvement andnone showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosiswas significantly improved in patients infected with HCV Genotype 3.

PegIntron/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previoustreatment with combination alpha interferon/ribavirin were retreated with PegIntron,1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin.

Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of aminimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks andwere followed for 24 weeks post-treatment. Response week 12 was defined as undetectable

HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined asundetectable HCV-RNA at 24 weeks post-treatment (Table 14).

Table 14 Rates of response to retreatment in prior treatment failures

Patients with undetectable HCV-RNAat treatment week 12 and SVR upon retreatment

Overallinterferon alpha/ribavirin peginterferon alpha/ribavirin population*

Response SVR % (n/N) Response SVR % (n/N) SVR % (n/N)week 12 % 99% CI week 12 % 99% CI 99 % CI(n/N) (n/N)

Overall 38.6 59.4 31.5 50.4 21.7(549/1,423) (326/549) (272/863) (137/272) (497/2,293)54.0,64.8 42.6, 58.2 19.5, 23.9

Prior response

Relapse 67.7 (203/300) 59.6 58.1 52.5 37.7 (243/645)(121/203) (200/344) (105/200) 32.8, 42.650.7, 68.5 43.4, 61.6

Genotype 1/4 59.7 (129/216) 51.2 (66/129) 48.6 44.3 (54/122) 28.6 (134/468)39.8, 62.5 (122/251) 32.7, 55.8 23.3, 34.0

Genotype 2/3 88.9 (72/81) 73.6 (53/72) 83.7 (77/92) 64.9 (50/77) 61.3 (106/173)(60.2, 87.0) 50.9, 78.9 51.7, 70.8

NR 28.6 (258/903) 57.0 12.4 (59/476) 44.1 (26/59) 13.6(147/258) 27.4, 60.7 (188/1,385)49.0, 64.9 11.2, 15.9

Genotype 1/4 23.0 (182/790) 51.6 (94/182) 9.9 (44/446) 38.6 (17/44) 9.9 (123/1,242)42.1, 61.2 19.7, 57.5 7.7, 12.1

Genotype 2/3 67.9 (74/109) 70.3 (52/74) 53.6 (15/28) 60.0 (9/15) 46.0 (63/137)56.6, 84.0 27.4, 92.6 35.0, 57.0

Genotype1 30.2 51.3 23.0 42.6 (69/162) 14.6(343/1,135) (176/343) (162/704) 32.6, 52.6 (270/1,846)44.4, 58.3 12.5, 16.72/3 77.1 (185/240) 73.0 75.6 (96/127) 63.5 (61/96) 55.3 (203/367)(135/185) 50.9, 76.2 48.6, 62.064.6, 81.44 42.5 (17/40) 70.6 (12/17) 44.4 (12/27) 50.0 (6/12) 28.4 (19/67)42.1, 99.1 12.8, 87.2 14.2, 42.5

METAVIR

Fibrosis score

F2 46.0 (193/420) 66.8 33.6 (78/232) 57.7 (45/78) 29.2 (191/653)(129/193) 43.3, 72.1 24.7, 33.858.1, 75.6

F3 38.0 (163/429) 62.6 32.4 (78/241) 51.3 (40/78) 21.9 (147/672)(102/163) 36.7, 65.9 17.8, 26.052.8, 72.3

F4 33.6 (192/572) 49.5 (95/192) 29.7 44.8 (52/116) 16.5 (159/966)40.2, 58.8 (116/390) 32.9, 56.7 13.4, 19.5

Patients with undetectable HCV-RNAat treatment week 12 and SVR upon retreatment

Overallinterferon alpha/ribavirin peginterferon alpha/ribavirin population*

Response SVR % (n/N) Response SVR % (n/N) SVR % (n/N)week 12 % 99% CI week 12 % 99% CI 99 % CI(n/N) (n/N)

Baseline Viral

Load

HVL (>600,000 32.4 (280/864) 56.1 26.5 41.4 (63/152) 16.6

IU/ml) (157/280) (152/573) 31.2, 51.7 (239/1,441)48.4, 63.7 14.1, 19.1

LVL (≤600,000 48.3 (269/557) 62.8 41.0 61.0 (72/118) 30.2 (256/848)

IU/ml) (169/269) (118/288) 49.5, 72.6 26.1, 34.255.2, 70.4

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.

Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a centrallaboratory

*Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels atweek 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In thissubgroup, there was a 56 % (463/823) sustained virological response rate. For patients with priorfailure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, thesustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viralreduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patientsthe SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve aweek 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin(12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVRregardless of prior treatment or prior response.

Long-term efficacy data-Adults

A large long-term follow-up study enrolled 567 patients after treatment in a prior study with PegIntron(with or without ribavirin). The purpose of the study was to evaluate the durability of sustainedvirologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes.327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustainedresponders relapsed during the study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99 %(95 % CI: 98-100 %). SVR after treatment of chronic HCV with PegIntron (with or without ribavirin)results in long-term clearance of the virus providing resolution of the hepatic infection and clinical“cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events inpatients with cirrhosis (including hepatocarcinoma).

Clinical efficacy and safety - paediatric population

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable

HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus

PegIntron 60 g/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load.

All patients were to be followed for 24 weeks post-treatment. A total of 107 patients receivedtreatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 %< 12 years of age. The population enrolled mainly consisted of children with mild to moderatehepatitis C. Due to the lack of data in children with severe progression of the disease, and the potentialfor undesirable effects, the benefit/risk of the combination of PegIntron with ribavirin needs to becarefully considered in this population (see sections 4.1, pct. 4.4 and 4.8). The study results aresummarized in Table 15.

Table 15 Sustained virological response rates (na,b (%)) in previously untreated children andadolescents by genotype and treatment duration - All subjects n = 10724 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit ofdetection=125IU/mlb: n = number of responders/number of subjects with given genotype, and assigned treatment duration.c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while those withgenotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.

Long-term efficacy data - paediatric population

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis Cpatients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. Thepurpose of the study was to annually evaluate the durability of sustained virologic response (SVR) andassess the impact of continued viral negativity on clinical outcomes for patients who were sustainedresponders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirintreatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustainedresponders completed the study. No paediatric subjects with SVR had relapsed during the 5 years offollow-up.

PegIntron is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferonalfa-2b and is predominantly composed of monopegylated species. The plasma half-life of PegIntronis prolonged compared with nonpegylated interferon alfa-2b. PegIntron has a potential to depegylate tofree interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, butweaker than free interferon alfa-2b.

Following subcutaneous administration, maximal serum concentrations occur between 15-44 hourspost-dose, and are sustained for up to 48-72 hours post-dose.

PegIntron Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume ofdistribution is 0.99 l/kg.

Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only amodest increase in biologic activity as measured by a bioassay.

Mean (SD) PegIntron elimination half-life is approximately 40 hours (13.3 hours), with apparentclearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet beenfully elucidated. However, renal elimination may account for a minority (approximately 30 %) of

PegIntron apparent clearance.

Renal clearance appears to account for 30 % of total clearance of PegIntron. In a single dose study(1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased inrelation to the degree of renal impairment.

Following multiple dosing of PegIntron (1.0 microgram/kg subcutaneously administered every weekfor four weeks) the clearance of PegIntron is reduced by a mean of 17 % in patients with moderaterenal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients withsevere renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normalrenal function. Based on single dose data, clearance was similar in patients with severe renalimpairment not on dialysis and in patients who were receiving hemodialysis. The dose of PegIntronfor monotherapy should be reduced in patients with moderate or severe renal impairment (seesecti ons 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with

PegIntron in combination with ribavirin (bitherapy or tritherapy) (see section 4.3).

Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended thatpatients with severe renal impairment be closely monitored during treatment with PegIntron (seesection 4.2)

The pharmacokinetics of PegIntron have not been evaluated in patients with severe hepaticdysfunction.

Elderly (≥ 65 years of age)

The pharmacokinetics of PegIntron following a single subcutaneous dose of 1.0 microgram/kg werenot affected by age. The data suggest that no alteration in PegIntron dosage is necessary based onadvancing age.

Multiple-dose pharmacokinetic properties for PegIntron and ribavirin (capsules and oral solution) inchildren and adolescent patients with chronic hepatitis C have been evaluated during a clinical study.

In children and adolescent patients receiving body surface area-adjusted dosing of PegIntron at60 g/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predictedto be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 g/kg/week.

Interferon neutralising factors

Interferon neutralising factor assays were performed on serum samples of patients who received PegIntronin the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity ofinterferon. The clinical incidence of neutralising factors in patients who received

PegIntron 0.5 micrograms/kg is 1.1 %.

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid isapproximately two-fold higher compared to serum. However, ribavirin systemic exposure of a femalepartner after sexual intercourse with a treated patient has been estimated and remains extremelylimited compared to therapeutic plasma concentration of ribavirin.

PegIntron

Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. Thesestudies were limited to four weeks due to the appearance of anti-interferon antibodies in mostmonkeys.

Reproduction studies of PegIntron have not been performed. Interferon alfa-2b has been shown to be anabortifacient in primates. PegIntron is likely to also cause this effect. Effects on fertility have not beendetermined. It is not known whether the components of this medicinal product are excreted intoexperimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation).

PegIntron showed no genotoxic potential.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from

PegIntron by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicitystudies in rodents and monkeys, standard embryo-foetal development studies and in in vitromutagenicity assays.

PegIntron plus ribavirin

Whe n used in combination with ribavirin, PegIntron did not cause any effects not previously seen witheither active substance alone. The major treatment-related change was a reversible, mild to moderateanaemia, the severity of which was greater than that produced by either active substance alone.

No studies have been conducted in juvenile animals to examine the effects of treatment with PegIntronon growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results havedemonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin(see section 5.3 of Rebetol SmPC if PegIntron is to be administered in combination with ribavirin).

Disodium phosphate, anhydrous

Sodium dihydrogen phosphate dihydrate

Sucrose

Polysorbate 80

Water for injections

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

Before reconstitution3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC.

From a microbiological point of view, the product is to be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not belonger than 24 hours at 2°C - 8°C.

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

For storage conditions of the reconstituted medicinal product, see section 6.3.

The powder and solvent are both contained in a two-chamber cartridge (Type I flint glass) separated by abromobutyl rubber plunger. The cartridge is sealed at one end with a polypropylene cap containing abromobutyl rubber liner and at the other end by a bromobutyl rubber plunger.

PegIntron is supplied as:

- 1 pre-filled pen (CLEARCLICK) containing powder and solvent for solution for injection,1 needle ('Push-On Needle'),2 cleansing swabs;

- 4 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection,4 needles ('Push-On Needle'),8 cleansing swabs;

- 12 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection,12 needles ('Push-On Needle'),24 cleansing swabs.

Not all pack sizes may be marketed.

PegIntron pre-filled pen is to be removed from the refrigerator before administration to allow the solventto reach room temperature (not more than 25°C).

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chambercartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lostduring preparation of PegIntron for injection when the dose is measured and injected. Therefore, eachpre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of thelabelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has aconcentration of 50 micrograms in 0.5 ml.

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chambercartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lostduring preparation of PegIntron for injection when the dose is measured and injected. Therefore, eachpre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of thelabelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentrationof 80 micrograms in 0.5 ml.

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chambercartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lostduring preparation of PegIntron for injection when the dose is measured and injected. Therefore, eachpre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of thelabelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentrationof 100 micrograms in 0.5 ml.

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chambercartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lostduring preparation of PegIntron for injection when the dose is measured and injected. Therefore, eachpre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of thelabelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentrationof 120 micrograms in 0.5 ml.

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chambercartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lostduring preparation of PegIntron for injection when the dose is measured and injected. Therefore, eachpre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of thelabelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentrationof 150 micrograms in 0.5 ml.

PegIntron is injected subcutaneously after reconstituting the powder as instructed, attaching a needle andsetting the prescribed dose. A complete and illustrated set of instructions is provided in the Annex to the

Package Leaflet.

As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior toadmi nistration. The reconstituted solution should be clear and colourless. If discolouration or particulatematter is present, the reconstituted solution should not be used. After administering the dose, the

PegIntron pre-filled pen and any unused solution contained in it is to be disposed of in accordance withlocal requirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

EU/1/00/131/031

EU/1/00/131/032

EU/1/00/131/034

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

EU/1/00/131/035

EU/1/00/131/036

EU/1/00/131/038

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

EU/1/00/131/039

EU/1/00/131/040

EU/1/00/131/042

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

EU/1/00/131/043

EU/1/00/131/044

EU/1/00/131/046

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

EU/1/00/131/047

EU/1/00/131/048

EU/1/00/131/050

Date of first authorisation: 25 May 2000

Date of latest renewal: 25 May 2010

Detailed information on this medicinal product is available on the web-site of the European Medicines

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