ViraferonPeg 50, 80, 100, 120 and 150 micrograms, powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen of ViraferonPeg 50, 80, 100, 120 and 150 micrograms contains a sufficient amount of peginterferon alfa-2b as measured on a protein basis in a powder , and the corresponding amount of solvent, to provide 50, 80, 100, 120 and 150 micrograms in 0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

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

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

Excipients:

ViraferonPeg contains 40 mg of sucrose per 0.5 ml.

For a 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):

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

Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when ViraferonPeg is to be used in combination with these medicines.

Adults (bitherapy and monotherapy):

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

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

Interferon monotherapy, including ViraferonPeg, is indicated mainly in case of intolerance or contraindication to ribavirin.

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

Paediatric population (bitherapy):

ViraferonPeg is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).

Please refer to the ribavirin SmPC for capsules or oral solution when ViraferonPeg is to be used in combination with ribavirin.

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

• Dose to be administered

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

ViraferonPeg combination therapy (bitherapy or tritherapy)

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

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

- Adults:

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

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

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

d: 3 morning, 4 evening

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

Duration of treatment – Naïve patients

Tritherapy:

Refer to the SmPC for boceprevir.

Bitherapy:

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

• Genotype 1:

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

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

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

• Genotypes 2 or 3:

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

• Genotype 4:

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

Duration of treatment - HCV/HIV co-infection

Bitherapy:

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

Predictability of response and non-response in HCV/HIV co-infection

Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with ViraferonPeg 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.

Duration of treatment - Retreatment

Tritherapy:

Refer to the SmPC for boceprevir.

Bitherapy:

Predictability of sustained virological response: All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1).

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

- Paediatric population 3 years of age and older (bitherapy only):

Dosing for children and adolescent patients is determined by body surface area for ViraferonPeg and by body weight for ribavirin. The recommended dose of ViraferonPeg is 60 μg/m²/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening).

Duration of treatment

• Genotype 1:

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

ViraferonPeg monotherapy – Adults

As monotherapy the ViraferonPeg regimen is 0.5 or 1.0 μg/kg/week. The lowest vial or pen strength available is 50 μg/0.5 ml; therefore for patients prescribed 0.5 μg/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 μg/kg dose, similar volume adjustments can be made or alternate vial strengths can be used as shown in Table 2. ViraferonPeg monotherapy was not studied in HCV/HIV co-infected patients.

Duration of treatment

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

• Dose modification for all patients (monotherapy and combination therapy)

If severe adverse reactions or laboratory abnormalities develop during treatment with ViraferonPeg monotherapy or combination therapy, modify the dosages of ViraferonPeg and/or ribavirin as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of ViraferonPeg and ribavirin.

As adherence might be of importance for outcome of therapy, the dose of ViraferonPeg and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification.

Combination therapy dose reduction guidelines

^* Upper limit of normal

Note 1: In adult patients 1^st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2^nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

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

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

In children and adolescent patients 1^st dose reduction of ViraferonPeg is to 40 μg/m²/week, 2^nd dose reduction of ViraferonPeg is to 20 μg/m²/week.

Dose reduction of ViraferonPeg in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of ViraferonPeg in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 μg/m²/week, to 40 μg/m²/week, then to 20 μg/m²/week, if needed.

* Must use vial. Minimum delivery for pen 0.3 ml

ViraferonPeg monotherapy dose reduction guidelines in adults

Dose modification guidelines for adult patients who use ViraferonPeg monotherapy are shown in Table 3a.

Dose reduction for adult patients who use 0.5 μg/kg ViraferonPeg monotherapy must be accomplished by reducing the prescribed volume by one-half. The 50 μg/0.5 ml vial must be used if necessary since the pen can only deliver a minimum volume of 0.3 ml.

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

• Special populations

Use in renal impairment:

Monotherapy:

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

Combination therapy:

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

Use in hepatic impairment:

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

Use in the elderly ( ≥ 65 years of age):

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

Use in paediatric patients:

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

Method of administration:

ViraferonPeg should be administered as subcutaneous injection. For special handling information see section 6.6.

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

- A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in 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 ViraferonPeg with telbivudine.

Paediatric patients:

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

Combination therapy: Also see the SmPCs for ribavirin and boceprevir if ViraferonPeg is to be administered in combination therapy in patients with chronic hepatitis C.

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

All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (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 to commencing treatment.

Acute hypersensitivity: Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with ViraferonPeg, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Cardiovascular system: As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving ViraferonPeg therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of ViraferonPeg therapy. There are no data in children or adolescents with a history of cardiac disease.

Liver function: As with all interferons, discontinue treatment with ViraferonPeg in patients who develop prolongation of coagulation markers which might indicate liver decompensation.

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

Hydration: Adequate hydration must be maintained in patients undergoing ViraferonPeg therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary.

Pulmonary changes: Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment 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 treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8).

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

Ocular changes: Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during ViraferonPeg therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of ViraferonPeg should be considered in patients who develop new or worsening ophthalmological disorders.

Thyroid changes: Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with ViraferonPeg/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of ViraferonPeg therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, ViraferonPeg treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 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 be at increased risk of developing lactic acidosis. Caution should be used when adding ViraferonPeg and ribavirin to HAART therapy (see ribavirin SmPC).

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

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

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

Haematological abnormalities in HCV/HIV co-infected patients:

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

Patients treated with ViraferonPeg and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (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 in subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg and ribavirin.

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

Organ transplant recipients: The safety and efficacy of ViraferonPeg alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Other: Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of ViraferonPeg in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Laboratory tests: Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ViraferonPeg therapy are:

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

Important information about some of the ingredients of ViraferonPeg:

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".

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

Results from a multiple-dose probe study assessing P450 substrates in chronic hepatitis C patients receiving once weekly ViraferonPeg (1.5 µg/kg) for 4 weeks demonstrated an increase in activity of CYP2D6 and CYP2C8/9. No change in activity of CYP1A2, CYP3A4, or N-acetyltransferase was observed.

Caution should be used when administering peginterferon alfa-2b with medicines metabolised by CYP2D6 and CYP2C8/9, especially those with narrow therapeutic window, such as warfarin and phenytoin (CYP2C9) and flecainide (CYP2D6).

These findings may partly relate to improved metabolic capacity due to reduced hepatic inflammation in patients undergoing treatment with ViraferonPeg. Caution is therefore advised when ViraferonPeg treatment is initiated for chronic hepatitis in patients treated with medicine with a narrow therapeutic window and sensitive to mild metabolic impairment of the liver.

No pharmacokinetic interactions were noted between ViraferonPeg and ribavirin in a multiple-dose pharmacokinetic study.

Methadone:

In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of ViraferonPeg subcutaneously for 4 weeks increased 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 signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

HCV/HIV Co-infection:

Nucleoside analogs: Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. 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 regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin 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 a known history of zidovudine-induced anaemia.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of ViraferonPeg with telbivudine is contraindicated (see section 4.3).

Women of childbearing potential/contraception in males and females

ViraferonPeg is recommended for use in fertile women only when they are using effective contraception during the treatment.

Combination therapy with ribavirin:

Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking ViraferonPeg in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC).

Pregnancy

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

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

Combination therapy with ribavirin:

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

Breast-feeding

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 be discontinued prior to initiation of treatment.

Fertility

There are no data available regarding potential effects of ViraferonPeg treatment on male or female fertility.

Patients who develop fatigue, somnolence or confusion during treatment with ViraferonPeg are cautioned to avoid driving or operating machines.

Adults

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy

The most common treatment-related adverse reactions reported during clinical trials with ViraferonPeg in combination 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 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification 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 ViraferonPeg monotherapy compared to those treated with combination therapy (see Table 4).

The following treatment-related adverse reactions were reported in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg/ribavirin. These reactions are listed in table 4 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, undesirable effects are presented in order of decreasing seriousness.

*These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with ViraferonPeg monotherapy.

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of ViraferonPeg in combination with 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 ViraferonPeg or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-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 patients without prior evidence of cardiac disease.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including 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 interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients

For HCV/HIV co-infected patients receiving ViraferonPeg in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger 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 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity:

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen 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 more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving ViraferonPeg in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 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) of patients receiving ViraferonPeg in combination with ribavirin. Anaemia (hemoglobin < 9.4g/dl) was reported in 12% (23/194) of patients treated with ViraferonPeg in combination with ribavirin.

CD4 lymphocytes decrease:

Treatment with ViraferonPeg 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 decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of ViraferonPeg in combination with ribavirin had no observable negative impact on the control of HIV viraemia during 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 taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ViraferonPeg in combination with ribavirin.

Paediatric patients

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of ViraferonPeg and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with ViraferonPeg and ribavirin, growth inhibition is observed, the reversibility of which is uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3^rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3^rd percentile). Based on interim data from the long-term follow-up portion of this study, 22 % (16/74) of children had a >15 percentile decrease in height percentile, of whom 3 (4 %) children had a > 30 percentile decrease despite being off treatment for more than 1 year. In particular, decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children (see section 4.4).

In 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). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse 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 levothyroxine treatment for hypothyroidism/elevated TSH.

The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with ViraferonPeg in combination with ribavirin. These reactions are listed in Table 5 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.

^§class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with ViraferonPeg reported in adult patients.

Most of the changes in laboratory values in the ViraferonPeg/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with ViraferonPeg used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving ViraferonPeg are consistent with the known safety profile for ViraferonPeg; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for ViraferonPeg is available; therefore, symptomatic treatment 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: Interferons, ATC code: L03AB10.

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

• Mechanism of action

In vitro and in vivo studies suggest that the biological activity of ViraferonPeg is derived from its interferon alfa-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 monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

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

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

• Pharmacodynamic effects

ViraferonPeg pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes 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 ViraferonPeg showed mild dose-related elevations in body temperature. Following single doses of ViraferonPeg between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of ViraferonPeg.

• Clinical efficacy and safety – Adults

Tritherapy with ViraferonPeg, ribavirin and boceprevir:

Refer to the SmPC for boceprevir.

Monotherapy with ViraferonPeg and bitherapy with ViraferonPeg and ribavirin:

- Naïve patients

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

In the ViraferonPeg monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with ViraferonPeg (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that ViraferonPeg was superior to interferon alfa-2b (Table 6).

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

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

- ViraferonPeg (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 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 ViraferonPeg (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 6), particularly in patients infected with Genotype 1 (Table 7). Sustained response was assessed by the response rate six months 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 ribavirin administered in combination with ViraferonPeg 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 7), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher.

In the ViraferonPeg monotherapy study, the Quality of Life was generally less affected by 0.5 microgram/kg of ViraferonPeg than by either 1.0 microgram/kg of ViraferonPeg once weekly or 3 MIU of interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received ViraferonPeg, 1.5 micrograms/kg subcutaneously, 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 8). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window 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 the pivotal 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 ViraferonPeg, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two ViraferonPeg/ribavirin regimens [ViraferonPeg 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon 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. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 9).

* (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) was a criterion for discontinuation of treatment.

In all 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 ViraferonPeg (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to ViraferonPeg 1 µg/kg dose. At the ViraferonPeg 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with 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 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 10).

*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 4 or week 12.

^† These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log₁₀ decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log₁₀ from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with ViraferonPeg in monotherapy was 98 %.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 11. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either ViraferonPeg (100 or 150 µg/week based 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 with a 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.

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 ViraferonPeg and subjects ≥ 75 kg received 150 µg/week ViraferonPeg.

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 were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with ViraferonPeg in combination with ribavirin. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

- ViraferonPeg/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with ViraferonPeg, 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 a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were 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 as undetectable HCV-RNA at 24 weeks post-treatment (Table 12).

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 central laboratory

*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 at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 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 SVR regardless of prior treatment or prior response.

- Long-term efficacy data

A large long-term follow-up study enrolled 567 patients after treatment in a prior study with ViraferonPeg (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic 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 sustained responders 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 ViraferonPeg (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 in patients 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 ViraferonPeg 60 μg/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 received treatment 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 moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ViraferonPeg with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 13

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit of detection=125IU/ml

b: 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 with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.

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

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

ViraferonPeg C_max and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg.

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

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

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

Following multiple dosing of ViraferonPeg (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of ViraferonPeg is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of ViraferonPeg for monotherapy should be reduced in patients with moderate or severe renal impairment (see sections 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with ViraferonPeg in combination with ribavirin (bitherapy or tritherapy) (see section 4.3).

Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with ViraferonPeg (see section 4.2)

Hepatic function: The pharmacokinetics of ViraferonPeg have not been evaluated in patients with severe hepatic dysfunction.

Elderly patients ≥ 65 years of age: The pharmacokinetics of ViraferonPeg following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in ViraferonPeg dosage is necessary based on advancing age.

Paediatric patients: Multiple-dose pharmacokinetic properties for ViraferonPeg and ribavirin (capsules and oral solution) in children 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 ViraferonPeg at 60 μg/m²/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 μg/kg/week.

Interferon neutralising factors: Interferon neutralising factor assays were performed on serum samples of patients who received ViraferonPeg in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received ViraferonPeg 0.5 micrograms/kg is 1.1 %.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

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

Reproduction studies of ViraferonPeg have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. ViraferonPeg is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation). ViraferonPeg showed no genotoxic potential.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from ViraferonPeg by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.

ViraferonPeg plus ribavirin: When used in combination with ribavirin, ViraferonPeg did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible, mild to moderate anaemia, 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 ViraferonPeg on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SmPC if ViraferonPeg is to be administered in combination with ribavirin).

Powder for solution for injection:

- Disodium phosphate, anhydrous

- Sodium dihydrogen phosphate dihydrate

- Sucrose

- Polysorbate 80

Solvent:

- Water for injections

Deliverable volume from pen = 0.5 ml.

This medicinal product should only be reconstituted with the solvent provided (see section 6.6). In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Before reconstitution:

3 years.

After reconstitution:

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

- 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 be longer 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 a bromobutyl rubber plunger. The cartridge is sealed at one end with a polypropylene cap containing a bromobutyl rubber liner and at the other end by a bromobutyl rubber plunger.

ViraferonPeg 50, 80, 100, 120 or 150 micrograms is supplied as:

- 1 pen containing powder and solvent for solution for injection, 1 injection needle and 2 cleansing swabs;

- 4 pens containing powder and solvent for solution for injection, 4 injection needles and 8 cleansing swabs;

- 6 pens containing powder and solvent for solution for injection, 6 injection needles and 12 cleansing swabs;

- 12 pens containing powder and solvent for solution for injection, 12 injection needles and 24 cleansing swabs.

Not all pack sizes may be marketed.

Each pen is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of ViraferonPeg for injection when the dose is measured and injected. Therefore, each pen contains an excess amount of solvent and ViraferonPeg powder to ensure delivery of the labelled dose in 0.5 ml of ViraferonPeg, solution for injection. The reconstituted solution has a concentration of 50, 80, 100, 120 and 150 micrograms in 0.5 ml.

ViraferonPeg is injected subcutaneously after reconstituting the powder as instructed, attaching an injection needle and setting the prescribed dose. A complete and illustrated set of instructions is provided in the Annex to the Package Leaflet.

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

As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. After administering the dose, the ViraferonPeg pre-filled pen and any unused solution contained in it is to be discarded.

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

United Kingdom

ViraferonPeg 50 micrograms : EU/1/00/132/031-034

ViraferonPeg 80 micrograms : EU/1/00/132/035-038

ViraferonPeg 100 micrograms : EU/1/00/132/039-042

ViraferonPeg 120 micrograms : EU/1/00/132/043-046

ViraferonPeg 150 micrograms : EU/1/00/132/047-050

Date of first authorisation: 29 May 2000

Date of latest renewal: 29 May 2010

30 March 2012

Prescription Only Medicine

Detailed information on this product is available on the web-site of the European Medicines Agency http://www.ema.europa.eu/

ViraferonPeg/Pen/SPC/EU/05-12/32