ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ViraferonPeg 50 micrograms powder and solvent for solution for injection
2.
Each vial of ViraferonPeg, powder contains 50 micrograms of peginterferon alfa-2b as measured on a
protein basis.
Each vial provides 50 micrograms/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.
Powder and solvent for solution for injection.
White powder.
Clear and colourless solvent.
4.
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).
2
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.
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
(
μ
g/0.5ml)
Administer
once weekly
(ml)
Total daily
dose (mg)
Number of
capsules
(200 mg)
< 40
50
0.5
800
4
a
40-50
80
0.4
800
4
a
51-64
80
0.5
800
4
a
65-75
100
0.5
1,000
5
b
76-80
120
0.5
1,000
5
b
81-85
120
0.5
1,200
6
c
86-105
150
0.5
1,200
6
c
> 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 ≥ 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
3
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 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/m
2
/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 log
10
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
4
therapy if their week 12 HCV-RNA dropped < 2 log
10
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
μ
g/kg
1.0
μ
g/kg
Body weight
(kg)
Vial/Pen
strength
(
μ
g/0.5ml)
Administer once
weekly
(ml)
Vial/Pen
strength
(
μ
g/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
≥ 2 g/dl decrease in haemoglobin during any
four week period during treatment
(permanent dose reduction)
< 12 g/dl after four
weeks of dose
reduction
5
adolescents: not
applicable
Leukocytes
-
< 1.5 x 10
9
/l
< 1.0 x 10
9
/l
Neutrophils
-
< 0.75 x 10
9
/l
< 0.5 x 10
9
/l
Platelets
-
< 50 x 10
9
/l (adults)
<70 x 10
9
/l (children and
adolescents)
< 25 x 10
9
/l (adults)
< 50 x 10
9
/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)
-
-
2 x baseline and
> 10 x ULN
*
2 x baseline and
> 10 x ULN
*
or
Aspartate
aminotransferase
(AST)
*
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/m
2
/week, 2
nd
dose reduction of ViraferonPeg is to 20 μg/m
2
/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/m
2
/week, to 40 μg/m
2
/week, then to 20 μg/m
2
/week, if needed.
6
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
Viraferon
Peg
strength
to use
Amount of
ViraferonPeg
(µg) to
administer
Volume
(ml)
of
ViraferonP
eg to
administer
Body
weight
kg
Viraferon
Peg
strength to
use
Amount of
ViraferonPe
g
(µg) to
administer
Volume (ml)
of
ViraferonPe
g
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
30
0.3
65 – 75
72
0.45
65 – 75
50 µg per
0.5 ml
35
0.35
76 – 85
80
0.5
76 – 85
45
0.45
86 –
105
86 - 105
120 µg
per
0.5 ml
96
0.4
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:
< 0.75 x 10
9
/l
< 0.5 x 10
9
/l
Neutrophils
Platelets
< 50 x 10
9
/l
< 25 x 10
9
/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
μ
g/kg monotherapy regimen in adults
Body weight
(kg)
Target reduced
dose (
μ
g)
Vial/Pen
strength
(
μ
g/0.5ml)
Administer once
weekly
(ml)
Amount
delivered
(
μ
g)
30-35
15
50*
0.15
15
36-45
20
50*
0.20
20
46-56
25
50*
0.25
25
7
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 (≥ 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.
-
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.
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.
8
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 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).
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
of disease progression (notably fibrosis), co-morbidities that may negatively influence the
disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the
risk of growth inhibition. There are no data on long term effects on sexual maturation.
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.
9
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
10
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 SPC).
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 Summary of Product Characteristics of the antiretroviral medicinal
products that are to be taken concurrently with HCV therapy for awareness and management of
toxicities specific for each product and the potential for overlapping toxicities with 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.
11
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:
•
Platelets
≥ 100,000/mm
3
•
Neutrophil count
≥ 1,500/mm
3
•
TSH level
must be within normal limits
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".
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 SPC).
12
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.
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 and their partners must
each use an effective contraceptive during treatment and for 4 months after treatment has been concluded.
Male patients and their female partners must each use an effective contraceptive during treatment and for
7 months after treatment has been concluded (see ribavirin SPC).
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.
Patients who develop fatigue, somnolence or confusion during treatment with ViraferonPeg are cautioned
to avoid driving or operating machines.
Adults
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
13
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.
Table 4 Adverse reactions reported in clinical trials or through post-marketing
surveillance in patients treated with peginterferon alfa-2b, including
ViraferonPeg monotherapy or ViraferonPeg + ribavirin
Infections and infestations
Very common:
Viral infection
*
,
pharyngitis
*
Common:
Bacterial infection (including sepsis), fungal infection, influenza, upper
respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis
media, rhinitis
Uncommon:
Injection site infection, lower respiratory tract infection
Blood and lymphatic system disorders
Very common: Anaemia, neutropenia
Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy
Very rare: Aplastic anaemia
Not known: Aplasia pure red cell
Immune system disorders
Uncommon:
Drug hypersensitivity
Rare:
Sarcoidosis
Not known:
Acute hypersensitivity reactions including angioedema, anaphylaxis
and anaphylactic reactions including anaphylactic shock, idiopathic
thrombocytopenic purpura, thrombotic thrombocytopenic purpura,
systemic lupus erythematosus
Endocrine disorders
Common: Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:
Anorexia
Common:
Hypocalcemia, hyperuricemia, dehydration, increased appetite
Uncommon:
Diabetes mellitus, hypertriglyceridaemia
Rare:
Diabetic ketoacidosis
Psychiatric disorders
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,
panic attack
Rare: Bipolar disorders
Not known: Homicidal ideation, mania
Nervous system disorders
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
14
Very rare:
Cerebrovascular haemorrhage, cerebrovascular ischaemia,
encephalopathy
Not known:
Facial palsy, mononeuropathies
Eye disorders
Common: Visual disturbance, vision blurred, photophobia, conjunctivitis, eye
irritation, 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
Ear and labyrinth disorders
Common:
Hearing impaired/loss, tinnitus, vertigo
Uncommon
Ear pain
Cardiac disorders
Common:
Palpitations, tachycardia
Uncommon:
Myocardial infarction
Rare:
Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis
Very rare:
Cardiac ischaemia
Not known:
Pericardial effusion
Vascular disorders
Common: Hypotension, hypertension, flushing
Rare: Vasculitis
Respiratory, thoracic and mediastinal disorders
Very common: Dyspnoea
*
, cough
*
Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion,
sinus congestion, nasal congestion, rhinorrhea, increased upper airway
secretion, pharyngolaryngeal pain
Very rare: Interstitial lung disease
Gastrointestinal disorders
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
Hepatobiliary disorders
Common: Hyperbilirubinemia, hepatomegaly
Skin and subcutaneous tissue disorders
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
Musculoskeletal and connective tissue disorders
Very common:
Myalgia, arthralgia, musculoskeletal pain
Common:
Arthritis, back pain, muscle spasms, pain in extremity
Uncommon:
Bone pain, muscle weakness
15
Rare: Rhabdomyolysis, myositis, rheumatoid arthritis
Renal and urinary disorders
Common: Micturition frequency, polyuria, urine abnormality
Rare: Renal failure, renal insufficiency
Reproductive system and breast disorders
Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian
disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile
dysfunction
General disorders and administration site conditions
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
Investigations
Very common:
Weight decreased
*
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, Autoimmune
disorders).
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:
16
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/mm
3
was observed in 4 % (8/194) of
patients and decrease in platelets below 50,000/mm
3
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 Summary of Product Characteristics of the antiretroviral medicinal products
that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific
for each product and the potential for overlapping toxicities with 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).
17
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 5 Adverse reactions very commonly, commonly and uncommonly reported in the
clinical trial in children and adolescent patients treated with ViraferonPeg in
combination with ribavirin
Infections and infestations
Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitis
streptococcal, nasopharyngitis, sinusitis
Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary
tract infection, gastroenteritis
Blood and lymphatic system disorders
Very common:
Anaemia, leucopenia, neutropenia
Common:
Thrombocytopenia, lymphadenopathy
Endocrine disorders
Common: Hypothyroidism
Metabolism and nutrition disorders
Very common:
Anorexia, decreased appetite
Psychiatric disorders
Common: 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
Nervous system disorders
Very common:
Headache, dizziness
Common:
Dysgeusia, syncope, disturbance in attention, somnolence, poor quality
sleep
Uncommon:
Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor
hyperactivity, tremor
Eye disorders
Common: Eye pain
Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred,
photophobia
Ear and labyrinth disorders
Common:
Vertigo
Cardiac disorders
Common:
Palpitations, tachycardia
Vascular disorders
Common: Flushing
Uncommon: Hypotension, pallor
Respiratory, thoracic and mediastinal disorders
Common: Cough, epistaxis, pharyngolaryngeal pain
Uncommon: Wheezing, nasal discomfort, rhinorrhoea
Gastrointestinal disorders
Very common:
Abdominal pain, abdominal pain upper, vomiting, nausea
Common:
Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach
discomfort, oral pain
Uncommon:
Dyspepsia, gingivitis
Hepatobiliary disorders
Uncommon: Hepatomagaly
Skin and subcutaneous tissue disorders
18
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
Musculoskeletal and connective tissue disorders
Very common: Myalgia, arthralgia
Common: Musculoskeletal pain, pain in extremity, back pain
Uncommon: Muscle contracture, muscle twitching
Renal and urinary disorders
Uncommon: Proteinuria
Reproductive system and breast disorders
Uncommon:
Female: Dysmenorrhoea
General disorders and administration site conditions
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
injection site dryness, injection site pain, feeling cold
Uncommon:
Chest pain, chest discomfort, facial pain
Investigations
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 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).
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Interferons, ATC code: L03AB10.
19
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.
•
Interferon alfa-2b
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.
•
ViraferonPeg
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.
ViraferonPeg clinical trials – adults
- 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).
20
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.
Table 6
Sustained virological response (% patients HCV negative)
ViraferonPeg monotherapy
ViraferonPeg + 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
ViraferonPeg 1.5 micrograms/kg
P 1.0
ViraferonPeg 1.0 microgram/kg
P 0.5
ViraferonPeg 0.5 microgram/kg
I
Interferon alfa-2b 3 MIU
P 1.5/R
ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg)
P 0.5/R
ViraferonPeg (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 7
Sustained response rates with ViraferonPeg + ribavirin
(by ribavirin dose, genotype and viral load)
HCV Genotype
Ribavirin dose
(mg/kg)
P 1.5/R
P 0.5/R
I/R
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
≤ 600,000 IU/ml
All
73 %
51 %
45 %
≤ 10.6
74 %
25 %
33 %
> 10.6
71 %
52 %
45 %
Genotype 1
> 600,000 IU/ml
All
30 %
27 %
29 %
≤ 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
ViraferonPeg (1.5 micrograms/kg) + ribavirin (800 mg)
P 0.5/R
ViraferonPeg (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 ViraferonPeg monotherapy study, the Quality of Life was generally less affected by
21
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).
Table 8 Virologic response at end of treatment, Sustained Virologic Response and relapse
by HCV Genotype and viral load*
ViraferonPeg 1.5 μg/kg once weekly plus Ribavirin 800-1,400 mg/day
End of treatment
response
Sustained Virologic Response
Relapse
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-
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
).
22
Table 9 Virologic response at treatment week 12, end of treatment response,
relapse rate *and Sustained Virologic Response (SVR)
Treatment group
% (number) of patients
ViraferonPeg
1.5 µg/kg +
ribavirin
ViraferonPeg
1 µg/kg +
ribavirin
peginterferon
alfa-2a 180 µg +
ribavirin
Undetectable
HCV-RNA at
treatment week
12
40 (407/1,019)
36 (366/1,016)
45 (466/1,035)
End of treatment
response
53 (542/1,019)
49 (500/1,016)
64 (667/1,035)
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
with
undetectable
HCV-RNA at
treatment week
12
81 (328/407)
83 (303/366)
74 (344/466)
* (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 log
10
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
).
23
Table 10
Predictive value of in-treatment Virologic Response while on ViraferonPeg
1.5 µg/kg/ribavirin 800-1,400 mg combination therapy
Negative
Positive
No
response
at
treatment
week
No
sustained
response
Negative
predictive
value
Response
at
treatment
week
Sustained
response
Positive
predictive
value
Genotype 1*
By week 4
***
(n=950)
HCV-RNA negative
834
539
65 %
(539/834)
116
107
92 %
(107/116)
HCV-RNA negative
or
≥ 1 log
decrease in
viral load
220
210
95 %
(210/220)
730
392
54 %
(392/730)
By week 12
***
(n=915
)
HCV-RNA negative
508
433
85 %
(433/508)
407
328
81 %
(328/407)
HCV-RNA negative
or
≥ 2 log decrease in
viral load
206
205
N/A
†
709
402
57 %
(402/709)
Genotype 2, 3**
By week 12
(n= 215)
HCV-RNA negative
or
≥ 2 log decrease in
viral load
2
1
50 %
(1/2)
213
177
83 %
(177/213)
*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 < 2log
10
decrease from baseline, patients to
stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log
10
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
Table11.
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
24
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.
Table 11
Sustained virological response based on genotype after ViraferonPeg in
combination with Ribavirin in HCV/HIV Co-infected patients
Study 1
1
Study 2
2
ViraferonPeg
(1.5 µg/kg/
week) +
ribavirin
(800 mg)
Interferon
alfa-2b
(3 MIU TIW) +
ribavirin
(800 mg)
p
value
a
ViraferonPeg
(100 or
150
c
µg/week)
+ ribavirin
(800-
1,200 mg)
d
Interferon
alfa-2b
(3 MIU TIW)
+ ribavirin
(800-
1,200 mg)
d
p
value
b
All
27 % (56/205) 20 % (41/205) 0.047 44 % (23/52)
21 % (9/43)
0.017
Genotype 1,
4
17 % (21/125)
6 % (8/129)
0.006 38 % (12/32)
7 % (2/27)
0.007
Genotype 2,
3
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 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.
1
Carrat 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 (
Table12
)
.
25
Table 12 Rates of response to retreatment in prior treatment failures
Patients with undetectable HCV–RNA
at treatment week 12 and SVR upon retreatement
interferon alpha/ribavirin
peginterferon alpha/ribavirin
Overall
population*
Response
week 12 %
(n/N)
SVR % (n/N)
99% CI
Response
week 12 %
(n/N)
SVR % (n/N)
99% CI
SVR % (n/N)
99 % CI
Overall
38.6 (549/1,423) 59.4 (326/549)
54.0,64.8
31.5 (272/863) 50.4 (137/272)
42.6, 58.2
21.7 (497/2,293)
19.5, 23.9
Prior response
Relapse
67.7 (203/300)
59.6 (121/203)
50.7, 68.5
58.1 (200/344) 52.5 (105/200)
43.4, 61.6
37.7 (243/645)
32.8, 42.6
Genotype 1/4 59.7 (129/216)
51.2 (66/129)
39.8, 62.5
48.6 (122/251) 44.3 (54/122)
32.7, 55.8
28.6 (134/468)
23.3, 34.0
Genotype 2/3 88.9 (72/81)
73.6 (53/72)
(60.2, 87.0)
83.7 (77/92)
64.9 (50/77)
50.9, 78.9
61.3 (106/173)
51.7, 70.8
NR
28.6 (258/903)
57.0 (147/258)
49.0, 64.9
12.4 (59/476) 44.1 (26/59)
27.4, 60.7
13.6 (188/1,385)
11.2, 15.9
Genotype 1/4 23.0 (182/790)
51.6 (94/182)
42.1, 61.2
9.9 (44/446)
38.6 (17/44)
19.7, 57.5
9.9 (123/1,242)
7.7, 12.1
Genotype 2/3 67.9 (74/109)
70.3 (52/74)
56.6, 84.0
53.6 (15/28)
60.0 (9/15)
27.4, 92.6
46.0 (63/137)
35.0, 57.0
Genotype
1
30.2 (343/1,135) 51.3 (176/343)
44.4, 58.3
23.0 (162/704) 42.6 (69/162)
32.6, 52.6
14.6 (270/1,846)
12.5, 16.7
2/3
77.1 (185/240)
73.0 (135/185)
64.6, 81.4
75.6 (96/127) 63.5 (61/96)
50.9, 76.2
55.3 (203/367)
48.6, 62.0
4
42.5 (17/40)
70.6 (12/17)
42.1, 99.1
44.4 (12/27)
50.0 (6/12)
12.8, 87.2
28.4 (19/67)
14.2, 42.5
METAVIR
Fibrosis score
F2
46.0 (193/420)
66.8 (129/193)
58.1, 75.6
33.6 (78/232) 57.7 (45/78)
43.3, 72.1
29.2 (191/653)
24.7, 33.8
F3
38.0 (163/429)
62.6 (102/163)
52.8, 72.3
32.4 (78/241) 51.3 (40/78)
36.7, 65.9
21.9 (147/672)
17.8, 26.0
F4
33.6 (192/572)
49.5 (95/192)
40.2, 58.8
29.7 (116/390) 44.8 (52/116)
32.9, 56.7
16.5 (159/966)
13.4, 19.5
Baseline Viral
Load
HVL (>600,000
IU/ml)
32.4 (280/864)
56.1 (157/280)
48.4, 63.7
26.5 (152/573) 41.4 (63/152)
31.2, 51.7
16.6 (239/1,441)
14.1, 19.1
30.2 (256/848)
26.1, 34.2
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
.
48.3 (269/557)
62.8 (169/269)
55.2, 70.4
41.0 (118/288) 61.0 (72/118)
49.5, 72.6
26
LVL
(≤600,000
IU/ml)
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).
ViraferonPeg clinical trials – paediatric patients
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/m
2
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
Table 13 Sustained virological response rates (n
a,b
(%)) in previously untreated
children and adolescents by genotype and treatment duration – All
subjects
n = 107
24 weeks
48 weeks
All Genotypes
26/27 (96 %)
44/80 (55 %)
Genotype 1
-
38/72 (53 %)
Genotype 2
14/15 (93 %)
-
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 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
.
27
Genotype 3
c
5.2
Pharmacokinetic properties
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 (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/m
2
/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
28
patients who received ViraferonPeg 0.5 micrograms/kg is 1.1 %.
5.3 Preclinical safety data
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 SPC if ViraferonPeg is to be administered in combination with
ribavirin).
6.
6.1
List of excipients
Powder for solution for injection:
-
Disodium phosphate, anhydrous
-
Sodium dihydrogen phosphate dihydrate
-
Polysorbate 80
Solvent:
-
Water for injections
6.2
Incompatibilities
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.
6.3
Shelf life
Before reconstitution:
3 years.
After reconstitution:
-
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC.
29
-
Sucrose
-
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.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5
Nature and contents of container
The powder is contained in a 2 ml vial (Type I flint glass) with a butyl rubber stopper in an aluminium
flip-off seal with a polypropylene bonnet. The solvent is presented in a 2 ml ampoule (Type I flint glass).
ViraferonPeg 50 micrograms is supplied as:
-
1 vial of powder for solution for injection, 1 ampoule of solvent for parenteral use, 1 injection
syringe, 2 injection needles and 1 cleansing swab;
-
4 vials of powder for solution for injection, 4 ampoules of solvent for parenteral use, 4 injection
syringes, 8 injection needles and 4 cleansing swabs;
-
6 vials of powder for solution for injection and 6 ampoules of solvent for parenteral use.
-
12 vials of powder for solution for injection, 12 ampoules of solvent for parenteral use, 12 injection
syringes, 24 injection needles and 12 cleansing swabs.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal and other handling
Each vial is to be reconstituted with 0.7 ml of 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 vial 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 micrograms/0.5 ml.
Using a sterilised injection syringe and injection needle, 0.7 ml of water for injections is injected into the
vial of ViraferonPeg. Dissolution of powder is completed by agitating it gently. The appropriate dose can
then be withdrawn with a sterilised injection syringe and injected. A complete 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 to
administration. The reconstituted solution should be clear and colourless. If discolouration or particulate
matter is present, the reconstituted solution should not be used. Any unused material is to be discarded.
7.
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
8.
EU/1/00/132/001
EU/1/00/132/002
30
-
1 vial of powder for solution for injection and 1 ampoule of solvent for parenteral use;
-
4 vials of powder for solution for injection and 4 ampoules of solvent for parenteral use;
EU/1/00/132/003
EU/1/00/132/004
EU/1/00/132/005
EU/1/00/132/026
9.
Date of first authorisation: 29 May 2000
Date of latest renewal: 29 May 2010
Detailed information on this product is available on the web-site of the European Medicines Agency
http://www.ema.europa.eu/
31
1.
482
Source: European Medicines Agency
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