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

1. Name Of The Medicinal Product

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

2. Qualitative And Quantitative Composition

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.

3. Pharmaceutical Form

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

White powder.

Clear and colourless solvent.

4. Clinical Particulars

4.1 Therapeutic Indications

Adult patients:

ViraferonPeg is indicated for the treatment of adult patients with chronic hepatitis C 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).

The best way to use ViraferonPeg in this indication is in combination with ribavirin.

This combination is indicated in naïve patients including patients with clinically stable HIV co-infection and in 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.

Paediatric patients 3 years of age and older:

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 also to the ribavirin Summary of Product Characteristics (SPC) for capsules or oral solution when ViraferonPeg is to be used in combination with ribavirin.

4.2 Posology And Method Of Administration

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 with ribavirin or as monotherapy.

ViraferonPeg and ribavirin combination therapy

- Adult patients:

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).

Table 1 Dosing for combination therapy
Body weight (kg)	ViraferonPeg	Ribavirin capsules
Vial/Pen strength (μg/0.5ml)	Administer once weekly (ml)	Total daily dose (mg)	Number of capsules (200 mg)
< 40	50	0.5	800	4a
40-50	80	0.4	800	4a
51-64	80	0.5	800	4a
65-75	100	0.5	1,000	5b
76-80	120	0.5	1,000	5b
81-85	120	0.5	1,200	6c
86-105	150	0.5	1,200	6c
> 105	150	0.5	1,400	7 d

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

d: 3 morning, 4 evening

Duration of treatment – Naïve patients

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

- 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 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 as for genotype 1.

Duration of treatment - HCV/HIV co-infection

The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks, 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 combination therapy.

Duration of treatment - Retreatment

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 therapy. 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 patients 3 years of age and older :

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 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 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 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.

Table 2 Monotherapy dosing
	0.5 μg/kg	1.0 μg/kg
Body weight (kg)	Vial/Pen strength (μg/0.5ml)	Administer once weekly (ml)	Vial/Pen strength (μg/0.5ml)	Administer once weekly (ml)
30-35	50*	0.15	50	0.3
36-45	50*	0.2	50	0.4
46-56	50*	0.25	50	0.5
57-72	50	0.3	80	0.4
73-88	50	0.4	80	0.5
89-106	50	0.5	100	0.5
106-120**	80	0.4	120	0.5
* Must use vial. Minimum delivery for pen is 0.3 ml. ** For patients > 120 kg, the ViraferonPeg dose should be calculated based on the individual patient weight.

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

If severe adverse reactions or laboratory abnormalities develop during treatment with ViraferonPeg monotherapy or ViraferonPeg in combination with ribavirin, modify the dosages of each product as appropriate, until the adverse reactions abate. As adherence might be of importance for outcome of therapy, the dose 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

Table 2a Dose modification guidelines for combination therapy (with ribavirin) based on laboratory parameters
Laboratory values	Reduce only ribavirin daily dose (see note 1) if:	Reduce only ViraferonPeg dose (see note 2) if:	Discontinue combination therapy if:
Haemoglobin	< 10 g/dl	-	< 8.5 g/dl
Adults:Haemoglobin in: Patients with history of stable cardiac disease Children and adolescents: not applicable		< 12 g/dl after four weeks of dose reduction
Leukocytes	-	< 1.5 x 109/l	< 1.0 x 109/l
Neutrophils	-	< 0.75 x 109/l	< 0.5 x 109/l
Platelets	-	< 50 x 109=/l (adults) <70 x 109/l (children and adolescents)	< 25 x 109/l (adults) < 50 x 109/l (children and adolescents)
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 ribavirin if CrCL < 50ml/min
Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST)	-	-	2 x baseline and > 10 x ULN*   2 x baseline and > 10 x ULN*

^* 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.

Table 2b Two-step dose reduction of ViraferonPeg in combination therapy in adults
First dose reduction to ViraferonPeg 1 µg/kg	Second dose reduction to ViraferonPeg 0.5 µg/kg
Body weight kg	ViraferonPeg strength to use	Amount of ViraferonPeg (µg) to administer	Volume (ml) of ViraferonPeg to administer	Body weight kg	ViraferonPeg strength to use	Amount of ViraferonPeg (µg) to administer	Volume (ml) of ViraferonPeg to administer
< 40	50 µg per 0.5 ml	35	0.35	< 40	50 µg per 0.5 ml*	20	0.2
40 – 50	45	0.45	40 – 50	25	0.25
51 – 64	80 µg per 0.5 ml	56	0.35	51 – 64	50 µg per 0.5 ml	30	0.3
65 – 75	72	0.45	65 – 75	35	0.35
76 – 85	80	0.5	76 – 85	45	0.45
86 - 105	120 µg per 0.5 ml	96	0.4	86 – 105	50	0.5
> 105	108	0.45	> 105	80 µg per 0.5 ml	64	0.4

* 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.

Table 3a Dose modification guidelines for ViraferonPeg monotherapy in adults based on laboratory parameters
Laboratory values	Reduce ViraferonPeg to one-half dose if:	Discontinue ViraferonPeg if:
Neutrophils	< 0.75 x 109/l	< 0.5 x 109/l
Platelets	< 50 x 109/l	< 25 x 109/l

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.

Table 3b Reduced ViraferonPeg dose for the 1.0 μg/kg monotherapy regimen in adults
Body weight (kg)	Target reduced dose (μg)	Vial/Pen strength (μg/0.5ml)	Administer once weekly (ml)	Amount delivered (μg)
30-35	15	50*	0.15	15
36-45	20	50*	0.20	20
46-56	25	50*	0.25	25
57-72	32	50	0.3	30
73-89	40	50	0.4	40
90-106	50	50	0.5	50
> 106	60	80	0.4	64
*Must use vial. Minimum delivery for pen is 0.3 ml.

• 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 SPC). When administered in combination with ribavirin, subjects 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 (

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.

4.3 Contraindications

- 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

- 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 with ribavirin: Also see ribavirin Summary of the Product Characteristics (SPC) if ViraferonPeg is to be administered in combination with ribavirin in patients with chronic hepatitis C.

4.4 Special Warnings And Precautions For Use

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during ViraferonPeg therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with ViraferonPeg 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 history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition. - The use of ViraferonPeg in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. 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 an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when 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 carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.

Growth and development (children and adolescents): During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment for more than 5 years. Case by case benefit/risk assessment in children: The expected benefit of treatment should be carefully weighed against the safety findings observed for children 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, the reversibility of which is uncertain. - This risk should be weighed against the disease characteristics of the child, such as evidence o