Pegasys

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Pegasys 180 micrograms solution for injection
Each vial of 1 ml solution contains 180 micrograms peginterferon alfa-2a*. 

The strength indicates the quantity of the interferon alfa-2a moiety of peginterferon alfa-2a without 
consideration of the pegylation.

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

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

Excipient with known effect: Benzyl alcohol (10 mg/ 1 ml)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

The solution is clear and colourless to light yellow.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B

Adult patients

Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg-
negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of 
viral replication, increased alanine aminotransferase (ALT) and histologically verified liver 
inflammation and/or fibrosis (see sections 4.4 and 5.1).

Paediatric patients 3 years of age and older

Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and 
adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum 
ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 
and 5.1.



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Chronic hepatitis C

Adult patients

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

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

Paediatric patients 5 years of age and older

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

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

4.2 Posology and method of administration

Treatment should be initiated only by a physician experienced in the treatment of patients with 
hepatitis B or C.

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

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

Posology

Chronic hepatitis B – adult patients

The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative 
CHB is 180 micrograms once weekly for 48 weeks. For information on predictive values for on-
treatment response, see section 5.1.

Chronic hepatitis C

Treatment-naïve adult patients

The recommended dose for Pegasys is 180 micrograms once weekly given in combination with oral 
ribavirin or as monotherapy.

The dose of ribavirin to be used in combination with Pegasys is given in Table 1.
The ribavirin dose should be administered with food.

Duration of treatment – dual therapy with Pegasys and ribavirin

The duration of combination therapy with ribavirin for CHC depends on viral genotype. Patients 
infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment 
viral load should receive 48 weeks of therapy.
Treatment for 24 weeks may be considered in patients infected with
- genotype 1 with low viral load (LVL) ( 800,000 IU/ml) at baseline or
- genotype 4
who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an 
overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks 



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treatment duration (see section 5.1). In these patients, tolerability to combination therapy and 
additional prognostic factors such as degree of fibrosis should be taken into account when deciding on 
treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load 
(HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV 
RNA negative at week 24 should be considered with even more caution since the limited data 
available suggest that this may significantly negatively impact the sustained virologic response.

Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of 
pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be 
considered in selected patients infected with genotype 2 or 3 with LVL ( 800,000 IU/ml) at baseline 
who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 
16 weeks of treatment may be associated with a lower chance of response and is associated with a 
higher risk of relapse than a 24-week treatment duration (see section 5.1). In these patients, tolerability 
to combination therapy and the presence of additional clinical or prognostic factors such as degree of 
fibrosis should be taken into account when considering deviations from standard 24 weeks treatment 
duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL 
(> 800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more 
caution as this may significantly negatively impact the sustained virological response (see Table 1). 

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

Table 1: Dosing recommendations for combination therapy for adult patients with chronic 
hepatitis C
Genotype Pegasys dose Ribavirin dose Duration
Genotype 1 LVL 
with RVR* 

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

24 weeks or
48 weeks

Genotype 1 HVL 
with RVR* 

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

48 weeks 

Genotype 4 with 
RVR*

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

24 weeks or
48 weeks

Genotype 1 or 4 
without RVR*

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

48 weeks

Genotype 2 or 3 
without RVR**

180 micrograms 800 mg 24 weeks

Genotype 2 or 3 
LVL with RVR**

180 micrograms 800 mg(a) 16 weeks(a) or 24 
weeks

Genotype 2 or 3 
HVL with RVR**

180 micrograms 800 mg 24 weeks

*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;
**RVR = rapid viral response (HCV RNA negative) by week 4
LVL = ≤ 800,000 IU/ml; HVL = > 800,000 IU/ml
(a) It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher 
SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is 
unknown, taking into account the need for re-treating non-responding and relapsing patients.

The recommended duration of Pegasys monotherapy is 48 weeks.

Treatment-experienced adult patients

The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by 
subcutaneous administration. For patients <75 kg and 75 kg, 1000 mg daily and 1200 mg daily of 
ribavirin, respectively, and regardless of genotype, should be administered.
Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of 
therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with 



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peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 
72 weeks (see section 5.1).

HIV-HCV co-infected adult patients

The recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once 
weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and 75 kg, 
1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected 
with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration of 
therapy less than 48 weeks has not been adequately studied.

Duration of therapy when Pegasys is used in combination with other medicinal products

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

Predictability of response and non-response with Pegasys and ribavirin dual therapy – treatment-
naïve patients

Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of 
HCV RNA has been shown to be predictive for sustained response (see Tables 2 and 13).

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

Genotype Negative Positive
No 

response 
by week 

12

No 
sustained 
response

Predictive 
Value

Response 
by week 

12
Sustained 
response

Predictive 
Value

Genotype 1 
(N= 569)

102 97 95%
(97/102)

467 271 58%
(271/467)

Genotype 2 and 3 
(N=96) 3 3

100%
(3/3) 93 81

87%
(81/93)

The negative predictive value for sustained response in patients treated with Pegasys in monotherapy 
was 98%.
A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with 
Pegasys monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). 
Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and 
genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.

Predictability of response and non-response with Pegasys and ribavirin dual therapy – treatment-
experienced patients

In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable 
HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. 
The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if 
viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), 
respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of 
treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100),
respectively.

Dose adjustment for adverse reactions in adult patients

General
Where dose adjustment is required for moderate to severe adverse reactions (clinical and/or 
laboratory) initial dose reduction to 135 micrograms is generally adequate for adult patients. In some 



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cases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towards 
the original dose may be considered when the adverse reaction abates (see sections 4.4 and 4.8).

Haematological (see also Table 3)
For adults, dose reduction is recommended if the absolute neutrophil count (ANC) is 500 to 
< 750 cells/mm3. For patients with ANC < 500 cells/mm3 treatment should be suspended until ANC 
values return to > 1000 cells/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys 
and the neutrophil count monitored. 

Dose reduction to 90 micrograms is recommended if the platelet count is 25,000 to < 50,000 cells/mm3. 
Treatment discontinuation is recommended when platelet count decreases to levels < 25,000 cells/mm3.

Specific recommendations for management of treatment-emergent anaemia in adults are as follows: 
ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams 
in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease 
experiences a fall in haemoglobin to < 10 g/dl and ≥ 8.5 g/dl, or (2) a patient with stable 
cardiovascular disease experiences a fall in haemoglobin by ≥ 2 g/dl during any 4 weeks of treatment. 
A return to original dosing is not recommended. Ribavirin should be discontinued if either of the 
following applies: (1) a patient without significant cardiovascular disease experiences a fall in 
haemoglobin confirmed to < 8.5 g/dl; (2) a patient with stable cardiovascular disease maintains a 
haemoglobin value < 12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, 
ribavirin may be restarted at 600 milligrams daily, and further increased to 800 milligrams daily at the 
discretion of the treating physician. A return to original dosing is not recommended.

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

Reduce 
ribavirin

to 600 mg

Withhold
ribavirin

Reduce Pegasys
to 135/90/45
micrograms

Withhold
Pegasys

Discontinue 
combination

Absolute
Neutrophil 
Count 

500 to < 750
cells/mm3

< 500
cells/mm3

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

< 25,000
cells/mm3

Haemoglobin
- no cardiac 

disease

< 10 g/dl, and 
≥ 8.5 g/dl

< 8.5 g/dl

Haemoglobin
- stable cardiac 

disease

decrease 
≥ 2 g/dl during 
any 4 weeks

< 12 g/dl 
despite 4 weeks 
at reduced dose

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

Liver function
Fluctuations in abnormalities of liver function tests are common in patients with CHC. Increases in 
ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including 
patients with a virological response.
In CHC clinical trials with adult patients, isolated increases in ALT (≥ 10x upper limit of normal 
[ULN], or ≥ 2x BL for patients with a BL ALT ≥ 10x ULN) which resolved without dose-modification 
were observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive or 
persistent, the dose should be reduced initially to 135 micrograms. When increases in ALT levels are 
progressive despite dose reduction, or are accompanied by increased bilirubin or evidence of hepatic 
decompensation, therapy should be discontinued (see section 4.4).



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For CHB patients, transient flares of ALT levels sometimes exceeding 10x ULN are not uncommon, 
and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10x ULN. 
Consideration should be given to continuing treatment with more frequent monitoring of liver function 
during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is 
subsiding (see section 4.4).

Special populations

Elderly
Adjustments in the recommended dosage of 180 micrograms once weekly are not necessary when 
instituting Pegasys therapy in elderly patients (see section 5.2).

Renal impairment
No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduced 
dose of 135 mcg once weekly is recommended in adult patients with severe renal impairment or end 
stage renal disease (see section 5.2). Regardless of the starting dose or degree of renal impairment, 
patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy 
should be made in the event of adverse reactions.

Hepatic impairment
In patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effective 
and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B 
or C or bleeding oesophageal varices) (see section 4.3).

The Child-Pugh classification divides patients into groups A, B, and C, or "Mild", "Moderate" and 
"Severe" corresponding to scores of 5-6, 7-9 and 10-15, respectively.

Modified Assessment

Assessment Degree of abnormality Score
Encephalopathy None

Grade 1-2
Grade 3-4*

1 
2 
3

Ascites Absent
Slight
Moderate

1 
2 
3

S-Bilirubin (mg/dl)

SI unit = mol/l)

<2
2.0-3 
>3

<34 
34-51 
>51

1 
2 
3

1 
2 
3

S-Albumin (g/dl) >3.5 
3.5-2.8 
<2.8

1 
2 
3

INR <1.7 
1.7-2.3
>2.3

1 
2 
3

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

Paediatric population

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



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It is recommended that Pegasys pre-filled syringes be used for paediatric patients. The Pegasys pre-
filled pens do not allow for appropriate adjustment of dosing in these patients. Patients who initiate 
treatment prior to their 18th birthday should maintain paediatric dosing through the completion of 
therapy.

The posology of Pegasys in paediatric patients is based on the Body Surface Area (BSA). To calculate 
BSA, it is recommended to use Mosteller’s equation:

The recommended duration of therapy is 48 weeks in patients with CHB.
Before initiating therapy for CHB, persistently elevated serum ALT levels should have been 
documented. The response rate was lower in patients with no to minimal increase in ALT level at 
baseline (see Section 5.1). 

The duration of treatment with Pegasys in combination with ribavirin in paediatric patients with CHC 
depends on viral genotype.  Patients infected with viral genotypes 2 or 3 should receive 24 weeks of 
treatment, while patients infected with any other genotype should receive 48 weeks of therapy.
Patients who still have detectable levels of HCV-RNA despite an initial 24 weeks of therapy, should 
discontinue therapy, as it is unlikely they will be able to achieve a sustained virological response with 
continued therapy.

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

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

Body Surface Area (BSA) range (m2)
Weekly dose (mcg)

CHC CHB
0.71-0.74 0.54-0.74 65

0.75-1.08 90
1.09-1.51 135

>1.51 180

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

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

Starting dose
(mcg)

1 level reduction
(mcg)

2 level reduction
(mcg)

3 level reduction
(mcg)

65 45 30 20
90 65 45 20

135 90 65 30
180 135 90 45



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

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

Toxicity Pegasys Dose Modification
Neutropenia 500 to < 750 cells/mm3: Immediate 1 level adjustment.

250 to < 500 cells/mm3: interrupt dosing until ≥ 1000 cells/mm3, then 
resume dose with 2 level adjustments and monitor.

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

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

Increased alanine 
aminotransferase 
(ALT)

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

For persistent ALT values ≥10 x ULN discontinue treatment.

Dose adjustement in paediatric patients – dual therapy with Pegasys and ribavirin

For children and adolescents aged 5 to 17 years with CHC, the recommended dose of ribavirin is 
based on the patient’s body weight, with a target dose of 15 mg/kg/day, divided in two daily doses. 
For children and adolescents 23 kg or greater, a dosing schedule using 200 mg ribavirin tablets is 
provided in Table 7. Patients and caregivers must not attempt to break the 200 mg tablets.

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

Body weight kg (lbs) Ribavirin daily dose
(Approx. 15 mg/kg/day)

Ribavirin number of tablets

23 – 33 (51-73) 400 mg/day 1 x 200 mg tablets A.M.
1 x 200 mg tablets P.M.

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

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

60 – 74 (132-163) 1000 mg/day 2 x 200 mg tablets A.M.
3 x 200 mg tablets P.M.

≥75 (>165) 1200 mg/day 3 x 200 mg tablets A.M.
3 x 200 mg tablets P.M.

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

In paediatric patients, ribavirin treatment-associated toxicities, such as treatment-emergent anaemia, 
will be managed by reduction of the full dose. The dose reduction levels are provided in Table 8.



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Table 8: Ribavirin dose modification recommendations in paediatric patients with chronic 
hepatitis C

Full dose
(Approx. 15 mg/kg/day)

One step dose modification
(Approx. 7.5 mg/kg/day)

Ribavirin number of tablets

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

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

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

1000 mg/day 600 mg/day
1 x 200 mg tablets A.M.
2 x 200 mg tablets P.M.

1200 mg/day 600 mg/day
1 x 200 mg tablets A.M.
2 x 200 mg tablets P.M.

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

Method of administration

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

Pegasys is designed for administration by the patient or carer. Each vial should be used by one person 
only and is for single use.

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

4.3 Contraindications

 Hypersensitivity to the active substance, to alfa interferons, or to any of the excipients listed in 
section 6.1

 Autoimmune hepatitis
 Severe hepatic dysfunction or decompensated cirrhosis of the liver
 A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac 

disease in the previous six months (see section 4.4)
 HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect 

hyperbilirubinemia caused by medicinal products such as atazanavir and indinavir
 Combination with telbivudine (see section 4.5)
 Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see 

section 4.4 for benzyl alcohol)
 In paediatric patients, the presence of, or history of severe psychiatric condition, particularly 

severe depression, suicidal ideation or suicidal attempt.



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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 Pegasys 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 alfa interferons. All patients should be closely monitored for any signs or symptoms of 
psychiatric disorders. If symptoms of psychiatric disorders 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 Pegasys be discontinued, and the patient 
followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys 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 Pegasys in children and adolescents with existence of or history of severe psychiatric 
conditions is contraindicated (see section 4.3).

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 alfa interferon. If treatment 
with alfa 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 therapy with Pegasys +/- ribavirin lasting up to 48 weeks in patients aged 3 to 17 years, 
weight loss and growth inhibition were common (see sections 4.8 and 5.1). 

The expected benefit of treatment should be carefully weighed against the safety findings observed 
for children and adolescents in the clinical trials on a case by case basis (see sections 4.8 and 5.1). It 
is important to consider the treatment with Pegasys +/- ribavirin induced a growth inhibition during 
treatment, the reversibility of which is uncertain.

The risk of growth inhibition 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 (for HBV-
infection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotype and 
HCV-RNA levels) (see section 5.1).

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.

In order to improve the traceability of biological medicinal products, the trade name and the batch 
number of the administered product should be clearly recorded (or stated) in the patient file.

Laboratory tests prior to and during therapy
Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are 
recommended for all patients.



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The following may be considered as baseline values for initiation of treatment:
- Platelet count  90,000 cells/mm3

- ANC  1500 cells/mm3

- Adequately controlled thyroid function (TSH and T4)

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

In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell 
(WBC) count and ANC, usually starting within the first 2 weeks of treatment (see section 4.8). 
Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible 
upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the 
majority of patients and returned to baseline in all patients after about 16 weeks.

Pegasys treatment has been associated with decreases in platelet count, which returned to pre-
treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose 
modification may be necessary (see section 4.2).

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

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

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 
7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This 
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and 
concomitant azathioprine and did not recur upon re-introduction of either treatment alone (see 
section 4.5).

The use of Pegasys and ribavirin combination therapy in CHC patients who failed prior treatment has 
not been adequately studied in patients who discontinued prior therapy for haematological adverse 
reactions. Physicians considering treatment in these patients should carefully weigh the risks versus 
the benefits of re-treatment.

Endocrine system
Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with 
the use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels 
should be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintained 
in the normal range by pharmaceutical means. TSH levels should be determined during the course of 
therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (see 
section 4.8). Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys 
(see section 4.8). Patients with these conditions who cannot be effectively controlled by medication 
should not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients who 
develop these conditions during treatment and cannot be controlled with medication should 
discontinue Pegasys or Pegasys/ribavirin therapy.

Cardiovascular system
Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial 
infarction have been associated with alfa interferon therapies, including Pegasys. It is recommended 
that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation 
of Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspended 
or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or 
discontinuation of ribavirin (see section 4.2).



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Liver function
In patients who develop evidence of hepatic decompensation during treatment, Pegasys should be 
discontinued. Increases in ALT levels above baseline have been observed in patients treated with 
Pegasys, including patients with a viral response. When the increase in ALT levels is progressive and 
clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy 
should be discontinued (see sections 4.2 and 4.8).

In CHB, unlike CHC, disease exacerbations during therapy are not uncommon and are characterised 
by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, 
marked transaminase flares have been accompanied by mild changes in other measures of hepatic 
function and without evidence of hepatic decompensation. In approximately half the cases of flares 
exceeding 10x ULN, Pegasys dosing was reduced or withheld until the transaminase elevations 
subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic 
function was recommended in all instances.

Hypersensitivity
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, 
anaphylaxis) have been rarely observed during alfa interferon therapy. If this occurs, therapy must be 
discontinued and appropriate medical therapy instituted immediately. Transient rashes do not 
necessitate interruption of treatment.

Autoimmune disease
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alfa 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 re-assessed (see also 
Endocrine system in sections 4.4 and 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with CHC 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).

Fever/infections
While fever may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must 
be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and 
sepsis have been reported during treatment with alfa interferons including Pegasys. Appropriate anti-
infective therapy should be started immediately and discontinuation of therapy should be considered.

Ocular changes
Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and 
retinal artery or vein obstruction which may result in loss of vision have been reported in rare 
instances with Pegasys. All patients should have a baseline eye examination. Any patient complaining of 
decrease or loss of vision must have a prompt and complete eye examination. Adult and paediatric 
patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should 
receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be 
discontinued in patients who develop new or worsening ophthalmologic disorders.

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



14

Skin disorder
Use of alfa interferons has been associated with exacerbation or provocation of psoriasis and 
sarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset or 
worsening of psoriatic lesions, discontinuation of therapy should be considered.

Transplantation
The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with 
liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, 
alone or in combination with ribavirin.

HIV-HCV co-infection
Please refer to the respective Summary of Product Characteristics of the antiretroviral 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 Pegasys with or 
without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon 
therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).

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

Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of 
hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, 
including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with 
hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline 
phosphatase or decreased platelet count, and treatment with didanosine (ddI).

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

During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic 
decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic 
function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors 
related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily 
attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately 
in patients with hepatic decompensation.

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

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving Pegasys 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 Pegasys 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.

Use of peginterferon as long term maintenance monotherapy (unapproved use)
In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees 
of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was 
studied, no significant reductions were observed in the rate of fibrosis progression or related clinical 
events.



15

Excipient
Pegasys contains benzyl alcohol. Must not be given to premature babies or neonates. May cause toxic 
reactions and anaphylactoid reactions in infants and children up to 3 years old.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not 
show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, 
suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 
2C19 and 2D6 isozymes.

In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 
activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. 
Serum concentrations of theophylline should be monitored and appropriate dose adjustments of 
theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction 
between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy.

HCV monoinfected patients and HBV monoinfected patients

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

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

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

A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, 
indicates that the combination is associated with an increased risk for developing peripheral 
neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and 
other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the 
combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.
Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).

HIV-HCV co-infected patients

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



16

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

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 therapy 
regimen if this is already established. This would be particularly important in patients with a known 
history of zidovudine induced anaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of peginterferon alfa-2a in pregnant women. 
Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and the 
potential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potential 
benefit justifies the potential risk to the foetus.

Breastfeeding

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

Fertility

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

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Chronic hepatitis B in adult patients

In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in CHB
was similar to that seen in CHC. With the exception of pyrexia, the frequency of the majority of the 
reported adverse reactions was notably less in CHB patients treated with Pegasys monotherapy 



17

compared with CHC patients treated with Pegasys monotherapy (see Table 9). Adverse events were 
experienced by 88% of Pegasys-treated patients as compared with 53% of patients in the lamivudine 
comparator group, while 6% of the Pegasys-treated and 4% of the lamivudine-treated patients 
experienced serious adverse events during the studies. Adverse events or laboratory abnormalities led 
to 5% of patients withdrawing from Pegasys treatment, while less than 1% of patients withdrew from 
lamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew from 
treatment was similar to that of the overall population in each treatment group.

Chronic hepatitis C in adult patients

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar 
to those reported with interferon alfa-2a (see Table 9). The most frequently reported adverse reactions 
with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without 
the need for modification of doses or discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

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

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

Chronic hepatitis C and HIV co-infection

In HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for Pegasys, alone or 
in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For 
HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have 
been reported in ≥ 1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, 
affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and 
chromaturia. Pegasys treatment 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 Pegasys had no observable negative 
impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available 
in co-infected patients with CD4+ cell counts <200/µl.

Tabulated list of adverse reactions

Table 9 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC adult 
patients and with Pegasys in combination with ribavirin in CHC patients. Undesirable effects reported 
in clinical studies are grouped according to frequency as follows: very common (≥ 1/10), common 
(≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare 
(< 1/10,000). For spontaneous reports of undesirable effects from post-marketing experience, the 
frequency is not known (cannot be estimated from the available data). Within each frequency grouping, 
adverse reactions are presented in decreasing order of seriousness.



18

Table 9: Undesirable effects reported with Pegasys monotherapy for CHB or CHC or in 
combination with ribavirin for CHC patients in clinical trials and post marketing
Body system Very 

common
Common Uncommon Rare Very rare Frequency 

not known
Infections and 
infestations

Bronchitis, 
upper 
respiratory 
infection, oral 
candidiasis, 
herpes 
simplex, 
fungal, viral 
and bacterial 
infections

Pneumonia, 
skin infection

Endocarditis, 
otitis externa 

Sepsis

Neoplasms 
benign and 
malignant

Hepatic 
neoplasm

Blood and 
lymphatic 
system 
disorders

Thrombocyto
penia, 
anaemia, 
lymphadenop
athy

Pancytopenia Aplastic 
anaemia

Pure red cell 
aplasia

Immune system 
disorders

Sarcoidosis, 
thyroiditis

Anaphylaxis, 
systemic 
lupus 
erythematosu
s, rheumatoid 
arthritis

Idiopathic or 
thrombotic 
thrombocytop
enic purpura 

Liver and 
renal graft 
rejection, 
Vogt-
Koyanagi-
Harada 
disease

Endocrine 
disorders

Hypothyroidis
m, 
hyperthyroidi
sm

Diabetes Diabetic 
ketoacidosis 

Metabolism and 
nutrition 
disorders

Anorexia Dehydration

Psychiatric 
disorders

Depression*, 
anxiety, 
insomnia* 

Aggression, 
mood 
alteration, 
emotional 
disorders, 
nervousness, 
libido 
decreased

Suicidal 
ideation, 
hallucinations

Suicide, 
psychotic 
disorder 

Mania,
bipolar 
disorders, 
homicidal 
ideation

Nervous system 
disorders

Headache, 
dizziness*, 
concentration 
impaired

Syncope, 
migraine, 
memory 
impairment, 
weakness, 
hypoaesthesia
, 
hyperaesthesi
a, 
paraesthesia, 
tremor, taste 
disturbance, 
nightmares, 
somnolence

Peripheral 
neuropathy

Coma, 
convulsions, 
facial palsy

Cerebral 
ischaemia



19

Body system Very 
common

Common Uncommon Rare Very rare Frequency 
not known

Eye disorders Vision 
blurred, eye 
pain, eye 
inflammation, 
xerophthalmia

Retinal 
haemorrhage

Optic 
neuropathy, 
papilloedema, 
retinal 
vascular 
disorder, 
retinopathy, 
corneal ulcer

Vision loss Serous retinal 
detachment

Ear and 
labyrinth 
disorders

Vertigo, 
earache

Hearing loss

Cardiac 
disorders

Tachycardia, 
oedema 
peripheral, 
palpitations,

Myocardial 
infarction, 
congestive 
heart failure, 
cardiomyopat
hy, angina, 
arrhythmia, 
atrial 
fibrillation, 
pericarditis, 
supraventricu
lar 
tachycardia

Vascular 
disorders

Flushing Hypertension Cerebral 
haemorrhage, 
vasculitis

Peripheral 
ischaemia

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea, 
cough

Dyspnoea 
exertional, 
epistaxis, 
nasopharyngit
is, sinus 
congestion, 
nasal 
congestion, 
rhinitis, sore 
throat

Wheezing Interstitial 
pneumonitis 
including 
fatal 
outcome, 
pulmonary 
embolism 

Pulmonary 
arterial 
hypertension§

Gastrointestinal 
disorders

Diarrhoea*, 
nausea*, 
abdominal 
pain*

Vomiting, 
dyspepsia, 
dysphagia, 
mouth 
ulceration, 
gingival 
bleeding, 
glossitis, 
stomatitis, 
flatulence, dry 
mouth

Gastrointestin
al bleeding

Peptic ulcer, 
pancreatitis

Ischaemic 
colitis, tongue 
pigmentation

Hepato-biliary 
disorders

Hepatic 
dysfunction

Hepatic 
failure, 
cholangitis, 
fatty liver



20

Body system Very 
common

Common Uncommon Rare Very rare Frequency 
not known

Skin and 
subcutaneous 
tissue disorders

Alopecia, 
dermatitis, 
pruritis, dry 
skin

Psoriasis, 
urticaria, 
eczema, rash, 
sweating 
increased, 
skin disorder, 
photosensitivi
ty reaction, 
night sweats

Stevens-
Johnson 
syndrome, 
toxic 
epidermal 
necrolysis,
angioedema, 
erythema 
multiforme

Musculoskeletal 
and connective 
tissue disorders

Myalgia, 
arthralgia

Back pain, 
arthritis, 
muscle 
weakness, 
bone pain, 
neck pain, 
musculoskelet
al pain, 
muscle 
cramps

Myositis Rhabdomyoly
sis

Renal and 
urinary 
disorders

Renal 
insufficiency

Reproductive 
system and 
breast disorders

Impotence

General 
disorders and 
administration 
site conditions

Pyrexia, 
rigors*, 
pain*, 
asthenia, 
fatigue, 
injection site 
reaction*, 
irritability*

Chest pain, 
influenza like 
illness, 
malaise, 
lethargy, hot 
flushes, thirst

Investigations Weight 
decreased

Injury, 
poisoning and 
procedural 
complications

Substance 
overdose

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

Description of selected adverse reactions

Pulmonary arterial hypertension
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

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

Treatment with Pegasys was associated with decreases in haematological values (leucopenia, 
neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose 



21

modification, and returned to pre-treatment levels within 4-8 weeks upon cessation of therapy (see 
sections 4.2 and 4.4).

Moderate (ANC: 0.749 - 0.5 x 109/l) and severe (ANC: < 0.5 x 109/l) neutropenia was observed 
respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and 
ribavirin 1000/1200 milligrams for 48 weeks.

Anti-interferon antibodies
1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other 
interferons, a higher incidence of neutralising antibodies was seen in CHB. However in neither disease 
was this correlated with lack of therapeutic response.

Thyroid function
Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values 
requiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving 
Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more 
frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of 
growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC 
levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving Pegasys monotherapy 
and combination therapy, respectively. Decrease in platelets below 50,000 cells/mm3 was observed in 
10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. 
Anaemia (haemoglobin < 10 g/dl) was reported in 7% and 14% of patients treated with Pegasys 
monotherapy or in combination therapy, respectively.

Paediatric population

Chronic hepatitis B 

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

The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment in 
study YV25718 were -0.07 and -0.21 (n=108 and n= 106 respectively) for Pegasys-treated patients as 
compared to -0.01 and -0.08 (n=47 each) in  untreated patients. At Week 48 of Pegasys treatment, a 
height or weight percentile decrease of more than 15 percentiles on the normative growth curves was 
observed in 6% of patients for height and 11% of patient for weight, whereas in the untreated group it 
was 2% of patients for height and 9% for weight. No data is available on long-term follow-up post-
treatment in these patients (see section 4.4).

Chronic hepatitis C

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



22

were reported in 2 patients in the Pegasys plus ribavirin combination therapy group (hyperglycaemia 
and cholecystectomy).

Growth inhibition was observed in paediatric patients (see section 4.4). Paediatric patients treated with 
Pegasys plus ribavirin combination therapy showed a delay in weight and height increases after 48 
weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of 
the normative population decreased during treatment. At the end of 2 years follow-up after treatment, 
most patients had returned to baseline normative growth curve percentiles for weight and height (mean 
weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 
54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients 
experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced a 
height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-
treatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight 
curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.

55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up 
extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in 
growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who 
were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either 
returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related 
causative factor has been identified. The extent of available data is not sufficient to conclude that 
growth inhibition due to Pegasys exposure is always reversible.

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

Body system Very common Common
Infections and infestations Infectious mononucleosis, 

pharyngitis streptococcal, influenza, 
gastroenteritis viral, candidiasis, 
gastroenteritis, tooth abscess, 
hordeolum, urinary tract infection, 
nasopharyngitis

Blood and lymphatic system 
disorders

Anaemia

Metabolism and nutrition disorders Decreased appetite Hyperglycaemia, type 1 diabetes 
mellitus 

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

Nervous system disorders Headache Dizziness, disturbance in attention, 
migraine

Eye disorders Blindness transient, retinal 
exudates, visual impairment eye 
irritation, eye pain, eye pruritis

Ear and labyrinth disorders Ear pain
Respiratory, thoracic and 
mediastinal disorders

Dyspnoea, epistaxis

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

Skin and subcutaneous tissue 
disorders

Rash, pruritus, alopecia Swollen face, drug eruption, 

Musculoskeletal and connective 
tissue disorders

Musculoskeletal pain Back pain, pain in extremity

Renal and urinary disorders Dysuria, incontinence, urinary tract 
disorder

Reproductive system and breast 
disorders

Vaginal discharge



23

Body system Very common Common
General disorders and 
administration site conditions

Influenza-like illness, injection site 
reaction, irritability, fatigue

Pyrexia, vessel puncture site 
haematoma, pain

Investigations Psychiatric evaluation abnormal

Surgical and medical procedures Tooth extraction, cholecystectomy

Social circumstances Educational problem

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

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

4.9 Overdose

Overdoses involving between two injections on consecutive days (instead of weekly interval) up to 
daily injections for 1 week (i.e., 1260 micrograms/week) have been reported. None of these patients 
experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and 
630 micrograms have been administered in renal cell carcinoma and chronic myelogenous leukaemia 
clinical trials, respectively. Dose limiting toxicities were fatigue, elevated liver enzymes, neutropenia 
and thrombocytopenia, consistent with interferon therapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB11

Mechanism of action

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

Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of 
substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 
60,000 of which the protein moiety constitutes approximately 20,000.

Pharmacodynamic effects

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


24

Clinical efficacy and safety

Chronic hepatitis B

Predictability of response

A patient-level meta-analysis of 9 Pegasys clinical studies (n=1,423) in CHB HBeAg positive and 
HBeAg-negative patients demonstrated that HBsAg and HBV DNA levels at Week 12 of treatment, 
are predictive of final treatment outcome at Week 24 post-treatment in certain genotypes. Operating 
characteristics of these biomarkers are presented in Table 11. No single biomarker with a cut-off can 
be identified to optimize all the operating characteristics (negative predictive value [NPV], sensitivity, 
specificity) and practical characteristics (simplicity, convenience). Consideration for early treatment 
discontinuation should be evaluated in the context of a particular clinical situation.

For HBeAg-positive patients with HBV genotype B and C infection, HBsAg > 20,000 IU/mL or HBV 
DNA > 8 log10 IU/mL at Week 12 following commencement of treatment is associated with high 
likelihood of failure to achieve HBeAg seroconversion and HBV-DNA <2,000 IU/mL at 24 week 
post-treatment (NPV > 90%). For HBV genotype A and D, subgroup size was insufficient to be 
analyzed. 

For HBeAg-negative patients with HBV genotype D infection, HBsAg > 20,000 IU/mL or HBV DNA 
> 6.5 log10 IU/mL at Week 12 following commencement of treatment is associated with high 
likelihood of failure to achieve HBV-DNA <2,000 IU/mL and ALT normalization at Week 24 post 
treatment. HBV genotype A subgroup size was insufficient to be analyzed. No biomarker can be 
identified with acceptable performance for HBeAg-negative patients with HBV genotype B or C 
infection. 

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

Table 11: Performance of individual biomarkers at Week 12 of therapy in CHB HBeAg-positive 
and HBeAg-negative patients according to genotype

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

HBeAg-positive(a)

B
HBsAg > 20,000 0.93 0.96 0.23

HBV DNA > 8 log10 0.90 0.94 0.26

C
HBsAg > 20,000 0.96 0.97 0.22

HBV DNA > 8 log10 0.98 0.98 0.19

HBeAg-negative(a)

D
HBsAg > 20,000 0.91 0.94 0.16

HBV DNA > 6.5 log10 1.00 1.00 0.11
NPV= negative predictive value; Sensitivity = % of all responders not meeting the stopping rule; Specificity = % of 
all non-responders meeting stopping rule
(a) Treatment response for HBeAg-positive patients was defined as HBeAg seroconversion (defined as loss of 
HBeAg and presence of anti-HBe) + HBV DNA <2,000 IU/mL at 6 months post-treatment and treatment response 
for HBeAg-negative patients was defined as HBV DNA < 2,000 IU/mL + ALT normalization at 6 months post-
treatment.

All clinical trials recruited patients with CHB who had active viral replication measured by HBV 
DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 
recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were 
negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, 
with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys 
plus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in these 
clinical trials.



25

Response rates at the end of follow-up for the two studies are presented in Table 12. In study 
WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105

copies/ml. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-
DNA below 2 x 104 copies/ml. HBV-DNA was measured by the COBAS AMPLICOR HBV 
MONITOR Assay (limit of detection 200 copies/ml).

A total of 283/1351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1351 (6%) had cirrhosis. 
There was no difference in response rate between these patients and those without advanced fibrosis or 
cirrhosis.

Table 12: Serological, virological and biochemical responses in chronic hepatitis B
HBeAg positive
Study WV16240

HBeAg negative / anti-HBe positive
Study WV16241

Response 
Parameter

Pegasys
180 mcg

&
Placebo

(N=271)

Pegasys
180 mcg

&
Lamivudine

100 mg
(N=271)

Lamivudine
100 mg

(N=272)

Pegasys
180 mcg

&
Placebo

(N=177)

Pegasys
180 mcg

&
Lamivudine

100 mg
(N=179)

Lamivudine
100 mg

(N=181)
HBeAg Sero-
conversion

32% # 27% 19% N/A N/A N/A

HBV DNA 
response *

32% # 34% 22% 43% # 44% 29%

ALT Normal-
isation

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

HBsAg Sero-
conversion

3% # 3% 0% 3% 2% 0%

* For HBeAg-positive patients: HBV DNA < 105 copies/ml
For HBeAg-negative/anti-HBe-positive patients: HBV DNA < 2 x 104 copies/ml

# p-value (vs. lamivudine) < 0.01 (stratified Cochran-Mantel-Haenszel test) 

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

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

Chronic hepatitis C

Predictability of response
Please refer to section 4.2, in Table 2.

Dose-response in monotherapy
In a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superior 
sustained virological response in patients with cirrhosis, but in a study in non-cirrhotic patients very 
similar results were obtained with doses of 135 micrograms and 180 micrograms.



26

Confirmatory clinical trials in adult treatment-naïve patients
All clinical trials recruited interferon-naïve patients with CHC confirmed by detectable levels of serum 
HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy 
consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological 
diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected 
patients were included in the study NR15961 (see Table 21). These patients had stable HIV disease 
and mean CD4 T-cell count was about 500 cells/µl. 
For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration 
of therapy and study outcome see Tables 13, 14, 15 and Table 21, respectively. Virological response 
was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, 
version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained 
response as one negative sample approximately 6 months after end of therapy.

Table 13: Virological response in CHC patients
Pegasys monotherapy Pegasys combination therapy

non-cirrhotic and 
cirrhotic

cirrhotic non-cirrhotic and cirrhotic

Study NV15496 + 
NV15497 + NV15801

Study NV15495 Study 
NV15942

Study NV15801

Pegasys
180 mcg

(N=701)
48 weeks

Interferon
alfa-2a

6 MIU/3 MIU
&

3 MIU

(N=478)
48 weeks

Pegasys
180 mcg

(N=87)
48 weeks

Interferon 
alfa-2a
3 MIU

(N=88)
48 weeks

Pegasys
180 mcg

&
Ribavirin
1000/1200

mg

(N=436)
48 weeks

Pegasys 
180 mcg

&
Ribavirin
1000/1200

mg

(N=453)
48 weeks

Interferon
alfa-2b
3 MIU

&
Ribavirin
1000/1200

mg

(N=444)
48 weeks

Response 
at End of 
Treatment 

55 - 69% 22 - 28% 44% 14% 68% 69% 52%

Overall 
Sustained 
Response

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

* 95% CI for difference: 11% to 33% p-value (stratified Cochran-Mantel-Haenszel test) = 0.001
** 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Pegasys and ribavirin 
combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, 
pre-treatment viral load and rapid virological response at week 4 are summarised in Table 14 and 
Table 15, respectively. The results of study NV15942 provide the rationale for recommending 
treatment regimens based on genotype, baseline viral load and virological response at week 4 (see 
Tables 1, 14 and 15).
The difference between treatment regimens was in general not influenced by presence/absence of 
cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline 
characteristic.



27

Table 14: Sustained virological response based on genotype and pre-treatment viral load after 
Pegasys combination therapy with ribavirin in CHC patients

Study NV15942 Study NV15801
Pegasys
180 mcg

&
Ribavirin

800 mg

24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

24 weeks

Pegasys
180 mcg

&
Ribavirin

800 mg

48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

48 weeks

Interferon
alfa-2b
3 MIU

&
Ribavirin

1000/1200 mg

48 weeks

Genotype 1
Low viral load
High viral load

29% 
(29/101)
41% (21/51)
16% (8/50)

42% (49/118)*
52% (37/71)
26% (12/47)

41% 
(102/250)*
55% (33/60)
36% (69/190)

52% (142/271)*
65% (55/85)
47% (87/186)

45% (134/298)
53% (61/115)
40% (73/182)

36% (103/285)
44% (41/94)
33% (62/189)

Genotype 2/3
Low viral load
High viral load

84% (81/96)
85% (29/34)
84% (52/62)

81% (117/144)
83% (39/47)
80% (78/97)

79% (78/99)
88% (29/33)
74% (49/66)

80% (123/153)
77% (37/48)
82% (86/105)

71% (100/140)
76% (28/37)
70% (72/103)

61% (88/145)
65% (34/52)
58% (54/93)

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

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
* Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 800 mg, 48 w: 
Odds Ratio (95% CI) = 1.52 (1.07 to 2.17)      P-value (stratified Cochran-Mantel-Haenszel test) = 0.020
* Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 1000/1200 mg, 24 w: 
Odds Ratio (95% CI) = 2.12 (1.30 to 3.46)       P-value (stratified Cochran-Mantel-Haenszel test) = 0.002.

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was 
examined based on a sustained rapid virological response observed in patients with rapid virological 
response at week 4 in studies NV15942 and ML17131 (see Table 15).

Table 15: Sustained virological response based on rapid viral response at week 4 for genotype 1 
and 4 after Pegasys combination therapy with ribavirin in CHC patients

                                         Study NV15942 Study ML17131
Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Genotype 1 RVR
Low viral load
High viral load

90% (28/31)
93% (25/27)

75% (3/4)

92% (47/51)
96% (26/27)
88% (21/24)

77% (59/77)
80% (52/65)
58% (7/12)

Genotype 1 non 
RVR
Low viral load
High viral load

24% (21/87)

27% (12/44)
21% (9/43)

43% (95/220)

50% (31/62)
41% (64/158)

-
-
-

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

Genotype 4 non 
RVR

(3/6) (4/6) -

Low viral load = ≤ 800,000 IU/ml; High viral load= > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a 
higher risk of relapse (see Table 16).



28

Table 16: Relapse of virological response at the end of treatment for rapid virological response 
population

Study NV15942 Study NV15801
Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Genotype 1 RVR

Low viral load
High viral load

6.7% (2/30)

3.8% (1/26)
25% (1/4)

4.3% (2/47)

0% (0/25)
9.1% (2/22)

0% (0/24)

0% (0/17)
0% (0/7)

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

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined 
based on a sustained virological response observed in patients with rapid virological response by week 
4 in study NV17317 (see Table 17).

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

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was 
also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 
4 and had a LVL at baseline (see Table 17).

Table 17: Sustained virological response overall and based on rapid viral response by week 4 for 
genotype 2 or 3 after Pegasys combination therapy with ribavirin in CHC patients

Study NV17317
Pegasys 180 mcg

&
Ribavirin 800 mg

16 weeks

Pegasys 180 mcg
&

Ribavirin 800 mg
24 weeks

Treatment difference
[95%CI]

p value

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

82%  (378/461)

89%  (147/166)
78%  (231/295)

90%  (370/410)

94%  (141/150)
88%  (229/260)

-8.2% [-12.8% ; -3.7%]

-5.4% [-12% ; 0.9%]
-9.7% [-15.9% ;-3.6%]

P=0.0006

P=0.11
P=0.002

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4 

It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body 
weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 
weeks.
The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse 
(see Table 18).



29

Table 18: Relapse of virological response after the end of treatment in genotype 2 or 3 patients 
with a rapid viral response

Study NV17317
Pegasys 
180 mcg

&
Ribavirin

800 mg
16 weeks

Pegasys 
180 mcg

& 
Ribavirin

800 mg
24 weeks

Treatment difference 
[95%CI]

p value

Genotype 2 or 3 RVR
Low viral load
High viral load

15%  (67/439)
6%  (10/155)

20%  (57/284)

6%  (23/386)
1%  (2/141)

9%  (21/245)

9.3% [5.2% ; 13.6%]
5% [0.6% ; 10.3%]

11.5% [5.6% ; 17.4%]

P<0.0001
P=0.04

P=0.0002

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4

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

Adult chronic hepatitis C prior treatment non-responder patients
In study MV17150, patients who were non-responders to previous therapy with pegylated interferon 
alfa-2b plus ribavirin were randomised to four different treatments:
 Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks
 Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks
 Pegasys 180 mcg/week for 72 weeks
 Pegasys 180 mcg/week for 48 weeks
All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment 
arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use 
of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for 
achieving a sustained virological response. Differences in sustained virological response (SVR) based 
on treatment duration, demographics and best responses to previous treatment are displayed in Table 
19.



30

Table 19: Week 12 virological response (VR) and sustained virological response (SVR) in 
patients with virological response at week 12 after treatment with Pegasys and ribavirin 
combination therapy in nonresponders to peginterferon alfa-2b plus ribavirin

Study MV17150
Pegasys 360/180 or 

180 mcg
&

Ribavirin 
1000/1200 mg

72 or 48 Weeks
(N = 942)
Pts with

VR at Wk 12 a

(N = 876)

Pegasys 360/180 or 
180 mcg

&
Ribavirin 

1000/1200 mg
72 Weeks
(N = 473)

SVR in Pts with 
VR at Wk 12 b

(N = 100)

Pegasys 360/180 or 
180 mcg 

&
Ribavirin 

1000/1200 mg
48 Weeks
(N = 469)

SVR in Pts with VR 
at Wk 12 b

(N = 57)
Overall
    Low viral load
    High viral load

   18% (157/876)
   35% (56/159)
   14% (97/686)

    57% (57/100)
    63% (22/35)
    54% (34/63)

     35% (20/57)
     38% (8/21)
     32% (11/34)

Genotype 1/4
   Low  viral load
   High viral load

   17% (140/846)
   35% (54/154)
   13% (84/663)

55% (52/94)
63% (22/35)
52% (30/58)

     35% (16/46)
     37% (7/19)
     35% (9/26)

Genotype 2/3
   Low  viral load
   High viral load

   58% (15/26)
           (2/5)
           (11/19)

             (4/5)
—
         (3/4)

             (3/10)
             (1/2)
             (1/7)

Cirrhosis Status
Cirrhosis
Noncirrhosis

     8% (19/239)
   22% (137/633)

             (6/13)
    59% (51/87)

              (3/6)
     34% (17/50)

Best Response during 
Previous Treatment
  2log10 decline in HCV RNA
   <2log10 decline in HCV RNA
Missing best previous response

   28% (34/121)
   12% (39/323)
   19% (84/432)

    68% (15/22)
    64% (16/25)
    49% (26/53)

              (6/12)
              (5/14)
     29% (9/31)

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

In the HALT-C study, patients with CHC and advanced fibrosis or cirrhosis who were non-responders 
to previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combination 
therapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. 
Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on 
Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 
weeks after the end of treatment. The probability for sustained virological response varied depending 
upon the previous treatment regimen; see Table 20.

Table 20: Sustained virological response in HALT-C by previous treatment regimen in non-
responder population
Previous Treatment Pegasys 180 mcg

&
Ribavirin 1000/1200 mg

48 weeks

Interferon 27% (70/255)

Pegylated interferon 34% (13/38)

Interferon plus ribavirin 13% (90/692)

Pegylated interferon plus ribavirin 11% (7/61)



31

HIV-HCV co-infected patients
The virological responses of patients treated with Pegasys monotherapy and with Pegasys and 
ribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-
infected patients are summarised below in Table 21.

Table 21: Sustained virological response based on genotype and pre-treatment viral load after 
Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients

Study NR15961
Interferon alfa-2a

3 MIU 
&

Ribavirin 800 mg
48 weeks

Pegasys
180 mcg

&
Placebo
48 weeks

Pegasys
180 mcg

&
Ribavirin 800 mg

48 weeks

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

Genotype 1 7% (12/171) 14% (24/175) 29% (51/176)
Low viral load 19% (8/42) 38% (17/45) 61% (28/46)
High viral load 3% (4/129) 5% (7/130) 18% (23/130)

Genotype 2-3 20% (18/89) 36% (32/90) 62% (59/95)
Low viral load 27% (8/30) 38% (9/24) 61% (17/28)
High viral load 17% (10/59) 35% (23/66) 63% (42/67)

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
* Pegasys 180 mcg & ribavirin 800 mg vs. Interferon alfa-2a 3 MIU & ribavirin 800 mg: 
Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001
* Pegasys 180 mcg & ribavirin 800 mg vs. Pegasys 180 mcg: 
Odds Ratio (95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001
* Interferon alfa-2a 3 MIU & ribavirin 800 mg vs. Pegasys 180 mcg: 
Odds Ratio (95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared 
treatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1000 mg (<75 kg)/1200 mg 
(75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety 
profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus 
ribavirin combination treatment and not indicative of any relevant differences, with the exception of a 
slight increase in anaemia in the high dose ribavirin arm.

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

Paediatric population

Chronic hepatitis B

Study YV25718 was conducted in previously untreated paediatric patients aged 3 to 17 years (51% < 
12 years old) with HBeAg positive CHB and ALT > ULN but < 10 x ULN in two blood samples taken 
≥ 14 days apart during the 6 months before the first dose of study drug. Patients with cirrhosis were 
not enrolled in this study. A total of 151 patients without advanced fibrosis were 2:1 randomized to 
Pegasys (group A, n=101) or untreated control (group B, n=50), respectively. Patients with advanced 
fibrosis were assigned to Pegasys treatment (group C, n=10). Patients in groups A and C (n=111) were 
treated with Pegasys once weekly for 48 weeks according to BSA categories, whereas patients in 
group B were observed for a period of 48 weeks (principal observation period). Patients in group B 
had the choice to switch to treatment with Pegasys after Week 48 of the principal observation period. 
All patients were followed up for 24 weeks post-treatment (groups A and C), or post-principal 
observation period (group B). After the Week 24 follow-up visit, patients from group A, B and C 
entered a long-term follow-up period (lasting for 5 years after end of treatment). Response rates in 



32

groups A and B at the end of 24 weeks follow-up are presented in Table 22. Efficacy response in 
group C to Pegasys treatment was in line with that seen in group A. For paediatric patients, efficacy 
has not been established in HBV genotypes other than genotypes A-D.

Table 22: Serological, virological and biochemical responses in paediatric patients with chronic 
hepatitis B

Group A
(Pegasys 

treatment)
(N=101)

Group B**
Untreated

(N=50)
Odds Ratio

(95% CI)
p-value

HBeAg Seroconversion 25.7% 6.0% 5.4
(1.5 – 19.2)

0.0043 1

HBV DNA < 20,000 IU/mL* 33.7% 4.0% 12.2
(2.9 – 108.3)

<0.0001 2

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

<0.0001 2

ALT Normalization 51.5% 12.0% 7.8
(2.9 – 24.1)

<0.0001 2

HBsAg Seroconversion 7.9% 0.0% - 0.0528 2

Loss of HBsAg 8.9% 0.0% - 0.0300 2

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

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

The response rate of HBeAg seroconversion was lower in patients with HBV genotype D, also in 
patients with no to minimal increase in ALT level at baseline (see Table 23).

Table 23: HBeAg seroconversion rates (%) by HBV genotype and baseline ALT levels

Group A
(Pegasys treatment)

(N=101)

Group B**
Untreated

(N=50)

Odds Ratio
(95% CI)

HBV genotype A 3/9 (33.3%) 1/3 (33.3%) 1.0   (0.04,78.4)
  B 7/21 (33.3%) 0/6 (0.0%) -
  C 13/34 (38.2%) 1/23 (4.3%) 13.62 (1.7,604.5)
  D* 3/31 (9.7%) 1/18 (5.6%) 1.8   (0.1,101.2)
  Other 0/6 (0.0%) 0/0 -

ALT <1xULN 0/7 (0.0%) 0/5 (0.0%) -
>=1xULN -
<1.5xULN

2/22 (9.1%) 0/8 (0.0%) -

>=1.5xULN -
<2xULN

7/19 (36.8%) 0/11 (0.0%) -

>=2xULN -
<5xULN

15/43 (34.9%) 1/17 (5.9%) 8.6   (1.1,383.0)

>=5xULN -
<10xULN

2/8 (25.0%) 2/9 (22.2%) 1.2   (0.06,20.7)

>=10xULN 0/2 (0.0%) 0/0 -
* Subgroup of patients with genotype D had a higher proportion with baseline ALT < 1.5x ULN (13/31) compared to other genotype groups 

(16/70).
** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.

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



33

Table 24: HBeAg seroconversion rates (%) by HBV-DNA decline from baseline to week 12 of 

Pegasys treatment in paediatric patients

HBeAg 

seroconversion 

rates 

By HBV-DNA (IU/mL) decline from baseline to 

week 12

<1 log10

decline

1 - <2 log10

decline

2 log10

decline

All genotypes (N=101)

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

(50.0 %)

Genotype-A (N=9)

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

Genotype-B (N=21)

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

Genotype-C (N=34)

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

Genotype-D (N=31)

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

Chronic hepatitis C

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

In the NV17424 (PEDS-C) study, previously untreated paediatric patients 5 to 17 years of age (55% 
<12 years old) with compensated CHC and detectable HCV RNA were treated with Pegasys 180 mcg 
x BSA/1.73 m2 once weekly for 48 weeks with or without ribavirin 15 mg/kg/day. All patients were 
followed for 24 weeks post-treatment. A total of 55 patients received initial combination treatment of 
Pegasys plus ribavirin, of whom 51% were female, 82% were Caucasian, and 82% were infected with 
HCV genotype 1. The study efficacy results for these patients are summarised in Table 25.

Table 25: Sustained virological response in the NV17424 study

Pegasys

180 mcg x BSA/1.73 m² + Ribavirin 15 

mg/kg (N=55)*

All HCV genotypes** 29 (53%)

HCV genotype 1 21/45 (47%)

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

*Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/ml at 24 weeks post-treatment using the 
AMPLICOR HCV test v2.
**Scheduled treatment duration was 48 weeks regardless of the genotype



34

5.2 Pharmacokinetic properties

Absorption
Following a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serum 
concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 
80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peak 
serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is 
84% and is similar to that seen with interferon alfa-2a.

Distribution
Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the 
volume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration. 
From mass balance, tissue distribution and whole body autoradioluminography studies performed in 
rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being 
highly concentrated in the blood.

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

Elimination
In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the 
native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa-
2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard 
interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean 
value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase 
of the compound, but may also reflect the sustained absorption of Pegasys.

Linearity/non-linearity
Dose-proportional increases in exposure of Pegasys are seen in healthy subjects and in patients with
chronic hepatitis B or C after once-weekly dosing.

In CHB or CHC patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 
8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 
8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. 
Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).

Patients with renal impairment
A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) 
or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease 
(ESRD) requiring chronic hemodialysis (HD). Patients with moderate renal impairment receiving 
Pegasys 180 mcg once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to 
patients with normal renal function. Patients with severe renal impairment receiving Pegasys 180 mcg 
once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal 
function, therefore a reduced dose of Pegasys 135 mcg once weekly is recommended in patients with 
severe renal impairment. In 13 patients with ESRD requiring chronic HD, administration of Pegasys 
135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with 
normal renal function. However, several independent studies have demonstrated the 135mcg dose to 
be safe, efficacious and well tolerated, in patients with ESRD (see section 4.2).

Gender
The pharmacokinetics of Pegasys after single subcutaneous injections was comparable between male 
and female healthy subjects.

Paediatric population
Pegasys pharmacokinetics have been characterized in paediatric patients with CHB (YV25718), as 
well as in paediatric patients with CHC (NR16141), using population pharmacokinetics.  In both 



35

studies, Pegasys apparent clearance and apparent volume of distribution were related linearly to body 
size ie. either BSA (NR16141) or body weight (YV25718).

From the YV25718 study, 31 paediatric patients 3 to 17 years of age with CHB participated in the PK 
sub-study and received Pegasys according to a BSA category dosing regimen. Based on the population 
pharmacokinetic model, the mean exposure (AUC) during the dosing interval for each BSA category 
was comparable with that observed in adults receiving 180 mcg fixed dosing.

From the NR16141study, 14 children 2 to 8 years of age with CHC received Pegasys monotherapy at a 
dose of: 180 mcg x BSA of the child/1.73 m2. The PK model developed from this study shows a linear 
influence of BSA on the apparent clearance of the drug over the age range studied. Thus, the lower the 
BSA of the child, the lower the clearance of the drug and the higher the resultant exposure. The mean 
exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in 
adults receiving 180 mcg fixed dosing.

Elderly
In subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of 
180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hours 
vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 
1295 ng·h/ml) but peak concentrations (9.1 vs. 10.3 ng/ml) were similar in subjects older than 62 
years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys is 
not needed in the geriatric patient (see section 4.2).

Hepatic impairment
The pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis B 
or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) 
and non-cirrhotic patients.

Site of administration
Subcutaneous administration of Pegasys should be limited to the abdomen and thigh, as the extent of 
absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. 
Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm 
compared to administration in the abdomen and thigh.

5.3 Preclinical safety data

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

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

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



36

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride
Polysorbate 80
Benzyl alcohol
Sodium acetate
Acetic acid
Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Pegasys 180 micrograms solution for injection
4 years.

6.4 Special precautions for storage

Store in a refrigerator (2C-8C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.

6.5 Nature and contents of container

1 ml of solution for injection in vial (Type I glass) with stopper (rubber butyl). Available in packs of 1 
or 4 vials. Not all pack-sizes may be marketed.

6.6 Special precautions for disposal

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

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

7. MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

8. MARKETING AUTHORISATION NUMBERS

Pegasys 180 micrograms solution for injection
EU/1/02/221/003
EU/1/02/221/004



37

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 June 2002 
Date of latest renewal: 20 June 2007

10. DATE OF REVISION OF THE TEXT

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



38

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 90 micrograms solution for injection in pre-filled syringe
Pegasys 135 micrograms solution for injection in pre-filled syringe
Pegasys 180 micrograms solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Pegasys 90 micrograms solution for injection in pre-filled syringe
Each syringe of 0.5 ml solution contains 90 micrograms peginterferon alfa-2a*. 

Pegasys 135 micrograms solution for injection in pre-filled syringe
Each syringe of 0.5 ml solution contains 135 micrograms peginterferon alfa-2a*. 

Pegasys 180 micrograms solution for injection in pre-filled syringe
Each syringe of 0.5 ml solution contains 180 micrograms peginterferon alfa-2a*. 

The strength indicates the quantity of the interferon alfa-2a moiety of peginterferon alfa-2a without 
consideration of the pegylation.

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

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

Excipient with known effect: Benzyl alcohol (10 mg/ 1 ml)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

The solution is clear and colourless to light yellow.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B

Adult patients

Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg-
negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of 
viral replication, increased alanine aminotransferase (ALT) and histologically verified liver 
inflammation and/or fibrosis (see sections 4.4 and 5.1).

Paediatric patients 3 years of age and older

Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and 
adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum 



39

ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 
and 5.1.

Chronic hepatitis C

Adult patients

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

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

Paediatric patients 5 years of age and older

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

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

4.2 Posology and method of administration

Treatment should be initiated only by a physician experienced in the treatment of patients with 
hepatitis B or C.

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

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

Posology

Chronic hepatitis B – adult patients

The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative 
CHB is 180 micrograms once weekly for 48 weeks. For information on predictive values for on-
treatment response, see section 5.1.

Chronic hepatitis C

Treatment-naïve adult patients

The recommended dose for Pegasys is 180 micrograms once weekly given in combination with oral 
ribavirin or as monotherapy.

The dose of ribavirin to be used in combination with Pegasys is given in Table 1.
The ribavirin dose should be administered with food.

Duration of treatment – dual therapy with Pegasys and ribavirin

The duration of combination therapy with ribavirin for CHC depends on viral genotype. Patients 
infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment 
viral load should receive 48 weeks of therapy. 
Treatment for 24 weeks may be considered in patients infected with
- genotype 1 with low viral load (LVL) ( 800,000 IU/ml) at baseline or



40

- genotype 4
who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. 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). In these patients, tolerability to combination therapy and 
additional prognostic factors such as degree of fibrosis should be taken into account when deciding on 
treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load 
(HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV 
RNA negative at week 24 should be considered with even more caution since the limited data 
available suggest that this may significantly negatively impact the sustained virologic response.

Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of 
pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be 
considered in selected patients infected with genotype 2 or 3 with LVL ( 800,000 IU/ml) at baseline 
who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 
16 weeks of treatment may be associated with a lower chance of response and is associated with a 
higher risk of relapse than a 24-week treatment duration (see section 5.1). In these patients, tolerability 
to combination therapy and the presence of additional clinical or prognostic factors such as degree of 
fibrosis should be taken into account when considering deviations from standard 24 weeks treatment 
duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL
(> 800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more 
caution as this may significantly negatively impact the sustained virological response (see Table 1).

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

Table 1: Dosing recommendations for combination therapy for adult patients with chronic 
hepatitis C
Genotype Pegasys dose Ribavirin dose Duration
Genotype 1 LVL 
with RVR* 

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

24 weeks or
48 weeks

Genotype 1 HVL 
with RVR* 

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

48 weeks 

Genotype 4 with 
RVR*

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

24 weeks or
48 weeks

Genotype 1 or 4 
without RVR*

180 micrograms <75 kg = 1000 mg
75 kg = 1200 mg

48 weeks

Genotype 2 or 3 
without RVR**

180 micrograms 800 mg 24 weeks

Genotype 2 or 3 
LVL with RVR**

180 micrograms 800 mg(a) 16 weeks(a) or 24 
weeks

Genotype 2 or 3 
HVL with RVR**

180 micrograms 800 mg 24 weeks

*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24; 
**RVR = rapid viral response (HCV RNA negative) by week 4
LVL = ≤ 800,000 IU/ml; HVL = > 800,000 IU/ml
(a) It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher 
SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is 
unknown, taking into account the need for re-treating non-responding and relapsing patients.



41

The recommended duration of Pegasys monotherapy is 48 weeks.

Treatment-experienced adult patients

The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by 
subcutaneous administration. For patients <75 kg and 75 kg, 1000 mg daily and 1200 mg daily of 
ribavirin, respectively, and regardless of genotype, should be administered.
Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of 
therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with 
peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 
72 weeks (see section 5.1).

HIV-HCV co-infected adult patients

The recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once 
weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and 75 kg, 
1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected 
with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration of 
therapy less than 48 weeks has not been adequately studied.

Duration of therapy when Pegasys is used in combination with other medicinal products

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

Predictability of response and non-response with Pegasys and ribavirin dual therapy – treatment-
naïve patients

Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of 
HCV RNA has been shown to be predictive for sustained response (see Tables 2 and 13).

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

Genotype Negative Positive
No 

response 
by week 

12

No 
sustained 
response

Predictive 
Value

Response 
by week 

12
Sustained 
response

Predictive 
Value

Genotype 1 
(N= 569)

102 97 95%
(97/102)

467 271 58% 
(271/467)

Genotype 2 and 3 
(N=96) 3 3

100%
(3/3) 93 81

87%
(81/93)

The negative predictive value for sustained response in patients treated with Pegasys in monotherapy 
was 98%.
A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with 
Pegasys monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). 
Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and 
genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.

Predictability of response and non-response with Pegasys and ribavirin dual therapy – treatment-
experienced patients

In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable 
HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. 
The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if 
viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), 



42

respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of 
treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100),
respectively.

Dose adjustment for adverse reactions in adult patients

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

Haematological (see also Table 3)
For adults, dose reduction is recommended if the absolute neutrophil count (ANC) is 500 to < 750
cells/mm3. For patients with ANC < 500 cells/mm3 treatment should be suspended until ANC values 
return to > 1000 cells/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys and the 
neutrophil count monitored. 

Dose reduction to 90 micrograms is recommended if the platelet count is 25,000 to < 50,000 cells/mm3. 
Treatment discontinuation is recommended when platelet count decreases to levels < 25,000 cells/mm3.

Specific recommendations for management of treatment-emergent anaemia in adults are as follows: 
ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams 
in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease 
experiences a fall in haemoglobin to < 10 g/dl and ≥ 8.5 g/dl, or (2) a patient with stable 
cardiovascular disease experiences a fall in haemoglobin by ≥ 2 g/dl during any 4 weeks of treatment. 
A return to original dosing is not recommended. Ribavirin should be discontinued if either of the 
following applies: (1) a patient without significant cardiovascular disease experiences a fall in 
haemoglobin confirmed to < 8.5 g/dl; (2) a patient with stable cardiovascular disease maintains a 
haemoglobin value < 12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, 
ribavirin may be restarted at 600 milligrams daily, and further increased to 800 milligrams daily at the 
discretion of the treating physician. A return to original dosing is not recommended.

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

Reduce 
ribavirin

to 600 mg

Withhold
ribavirin

Reduce Pegasys
to 135/90/45 
micrograms

Withhold
Pegasys

Discontinue 
combination

Absolute
Neutrophil 
Count 

500 to < 750
cells/mm3

< 500
cells/mm3

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

< 25,000
cells/mm3

Haemoglobin
- no cardiac 

disease

< 10 g/dl, and 
≥ 8.5 g/dl

< 8.5 g/dl

Haemoglobin
- stable cardiac 

disease

decrease 
≥ 2 g/dl during 
any 4 weeks

< 12 g/dl 
despite 4 weeks 
at reduced dose

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



43

Liver function
Fluctuations in abnormalities of liver function tests are common in patients with CHC. Increases in 
ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including 
patients with a virological response.
In CHC clinical trials with adult patients, isolated increases in ALT (≥ 10x upper limit of normal 
[ULN], or ≥ 2x BL for patients with a BL ALT ≥ 10x ULN) which resolved without dose-modification 
were observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive or 
persistent, the dose should be reduced initially to 135 micrograms. When increases in ALT levels are 
progressive despite dose reduction, or are accompanied by increased bilirubin or evidence of hepatic 
decompensation, therapy should be discontinued (see section 4.4).

For CHB patients, transient flares of ALT levels sometimes exceeding 10x ULN are not uncommon, 
and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10x ULN . 
Consideration should be given to continuing treatment with more frequent monitoring of liver function 
during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is 
subsiding (see section 4.4).

Special populations

Elderly
Adjustments in the recommended dosage of 180 micrograms once weekly are not necessary when 
instituting Pegasys therapy in elderly patients (see section 5.2).

Renal impairment
No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduced 
dose of 135 mcg once weekly is recommended in adult patients with severe renal impairment or end 
stage renal disease (see section 5.2). Regardless of the starting dose or degree of renal impairment, 
patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy 
should be made in the event of adverse reactions.

Hepatic impairment
In patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effective 
and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B 
or C or bleeding oesophageal varices) (see section 4.3).

The Child-Pugh classification divides patients into groups A, B, and C, or "Mild", "Moderate" and 
"Severe" corresponding to scores of 5-6, 7-9 and 10-15, respectively.



44

Modified Assessment

Assessment Degree of abnormality Score
Encephalopathy None

Grade 1-2
Grade 3-4*

1 
2 
3

Ascites Absent
Slight
Moderate

1 
2 
3

S-Bilirubin (mg/dl)

SI unit = mol/l)

<2
2.0-3 
>3

<34 
34-51 
>51

1 
2 
3

1 
2 
3

S-Albumin (g/dl) >3.5 
3.5-2.8 
<2.8

1 
2 
3

INR <1.7 
1.7-2.3
>2.3

1 
2 
3

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

Paediatric population

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

It is recommended that Pegasys pre-filled syringes be used for paediatric patients. The Pegasys pre-
filled pens do not allow for appropriate adjustment of dosing in these patients. Patients who initiate 
treatment prior to their 18th birthday should maintain paediatric dosing through the completion of 
therapy. 

The posology of Pegasys in paediatric patients is based on the Body Surface Area (BSA). To calculate 
BSA, it is recommended to use Mosteller’s equation:

The recommended duration of therapy is 48 weeks in patients with CHB.
Before initiating therapy for CHB, persistently elevated serum ALT levels should have been 
documented. The response rate was lower in patients with no to minimal increase in ALT level at 
baseline (see Section 5.1). 

The duration of treatment with Pegasys in combination with ribavirin in paediatric patients with CHC 
depends on viral genotype.  Patients infected with viral genotypes 2 or 3 should receive 24 weeks of 
treatment, while patients infected with any other genotype should receive 48 weeks of therapy. 
Patients who still have detectable levels of HCV-RNA despite an initial 24 weeks of therapy, should 
discontinue therapy, as it is unlikely they will be able to achieve a sustained virological response with 
continued therapy.

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



45

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

Body Surface Area (BSA) range (m2)
Weekly dose (mcg)

CHC CHB
0.71-0.74 0.54-0.74 65

0.75-1.08 90
1.09-1.51 135

>1.51 180

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

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

Starting dose
(mcg)

1 level reduction
(mcg)

2 level reduction
(mcg)

3 level reduction
(mcg)

65 45 30 20
90 65 45 20

135 90 65 30
180 135 90 45

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

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

Toxicity Pegasys Dose Modification
Neutropenia 500 to < 750 cells/mm3: Immediate 1 level adjustment.

250 to < 500 cells/mm3: interrupt dosing until ≥ 1000 cells/mm3, then 
resume dose with 2 level adjustments and monitor.

< 250 cells/mm3 (or febrile neutropenia): discontinue treatment.
Thrombocytopenia Platelet 25,000 to <50,000 cells/mm3: 2 level adjustment.

Platelet <25,000 cells/mm3: discontinue treatment.
Increased alanine 
aminotransferase 
(ALT)

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

For persistent ALT values ≥10 x ULN discontinue treatment.

Dose adjustement in paediatric patients – dual therapy with Pegasys and ribavirin

For children and adolescents aged 5 to 17 years with CHC, the recommended dose of ribavirin is 
based on the patient’s body weight, with a target dose of 15 mg/kg/day, divided in two daily doses. 
For children and adolescents 23 kg or greater, a dosing schedule using 200 mg ribavirin tablets is 
provided in Table 7. Patients and caregivers must not attempt to break the 200 mg tablets.



46

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

Body weight kg (lbs) Ribavirin daily dose
(Approx. 15 mg/kg/day)

Ribavirin number of tablets

23 – 33 (51-73) 400 mg/day 1 x 200 mg tablets A.M.
1 x 200 mg tablets P.M.

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

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

60 – 74 (132-163) 1000 mg/day 2 x 200 mg tablets A.M.
3 x 200 mg tablets P.M.

≥75 (>165) 1200 mg/day 3 x 200 mg tablets A.M.
3 x 200 mg tablets P.M.

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

In paediatric patients, ribavirin treatment-associated toxicities, such as treatment-emergent anaemia, 
will be managed by reduction of the full dose. The dose reduction levels are provided in Table 8. 

Table 8: Ribavirin dose modification recommendations in paediatric patients with chronic 
hepatitis C

Full dose
(Approx. 15 mg/kg/day)

One step dose modification
(Approx. 7.5 mg/kg/day)

Ribavirin number of tablets

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

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

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

1000 mg/day 600 mg/day
1 x 200 mg tablets A.M.
2 x 200 mg tablets P.M.

1200 mg/day 600 mg/day
1 x 200 mg tablets A.M.
2 x 200 mg tablets P.M.

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

Method of administration

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

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

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

4.3 Contraindications 

 Hypersensitivity to the active substance, to alfa interferons, or to any of the excipients listed in 
section 6.1

 Autoimmune hepatitis



47

 Severe hepatic dysfunction or decompensated cirrhosis of the liver
 A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac 

disease in the previous six months (see section 4.4)
 HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect 

hyperbilirubinemia caused by medicinal products such as atazanavir and indinavir
 Combination with telbivudine (see section 4.5) 
 Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see 

section 4.4 for benzyl alcohol)
 In paediatric patients, the presence of, or history of severe psychiatric condition, particularly 

severe depression, suicidal ideation or suicidal attempt

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 Pegasys 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 alfa interferons. All patients should be closely monitored for any signs or symptoms of 
psychiatric disorders. If symptoms of psychiatric disorders 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 Pegasys be discontinued, and the patient 
followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys 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 Pegasys in children and adolescents with existence of or history of severe psychiatric 
conditions is contraindicated (see section 4.3).

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 alfa interferon. If treatment 
with alfa 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.



48

Growth and development (children and adolescents):

During therapy with Pegasys +/- ribavirin lasting up to 48 weeks in patients aged 3 to 17 years, 
weight loss and growth inhibition were common (see sections 4.8 and 5.1). 

The expected benefit of treatment should be carefully weighed against the safety findings observed 
for children and adolescents in the clinical trials on a case by case basis (see sections 4.8 and 5.1). It 
is important to consider the treatment with Pegasys +/- ribavirin induced a growth inhibition during 
treatment, the reversibility of which is uncertain.

The risk of growth inhibition 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 (for HBV-
infection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotype and 
HCV-RNA levels) (see section 5.1).

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.

In order to improve the traceability of biological medicinal products, the trade name and the batch 
number of the administered product should be clearly recorded (or stated) in the patient file.

Laboratory tests prior to and during therapy
Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are 
recommended for all patients.

The following may be considered as baseline values for initiation of treatment:
- Platelet count  90,000 cells/mm3

- ANC  1500 cells/mm3

- Adequately controlled thyroid function (TSH and T4)

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

In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell 
(WBC) count and ANC, usually starting within the first 2 weeks of treatment (see section 4.8). 
Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible 
upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the 
majority of patients and returned to baseline in all patients after about 16 weeks.

Pegasys treatment has been associated with decreases in platelet count, which returned to pre-
treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose 
modification may be necessary (see section 4.2).

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

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

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 
weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This 
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and 



49

concomitant azathioprine and did not recur upon re-introduction of either treatment alone (see section 
4.5).

The use of Pegasys and ribavirin combination therapy in CHC patients who failed prior treatment has 
not been adequately studied in patients who discontinued prior therapy for haematological adverse 
reactions. Physicians considering treatment in these patients should carefully weigh the risks versus 
the benefits of re-treatment.

Endocrine system
Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with 
the use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels 
should be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintained 
in the normal range by pharmaceutical means. TSH levels should be determined during the course of 
therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (see 
section 4.8). Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys 
(see section 4.8). Patients with these conditions who cannot be effectively controlled by medication 
should not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients who 
develop these conditions during treatment and cannot be controlled with medication should 
discontinue Pegasys or Pegasys/ribavirin therapy.

Cardiovascular system
Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial 
infarction have been associated with alfa interferon therapies, including Pegasys. It is recommended 
that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation 
of Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspended 
or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or 
discontinuation of ribavirin (see section 4.2).

Liver function
In patients who develop evidence of hepatic decompensation during treatment, Pegasys should be 
discontinued. Increases in ALT levels above baseline have been observed in patients treated with 
Pegasys, including patients with a viral response. When the increase in ALT levels is progressive and 
clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy 
should be discontinued (see sections 4.2 and 4.8).

In CHB, unlike CHC, disease exacerbations during therapy are not uncommon and are characterised 
by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, 
marked transaminase flares have been accompanied by mild changes in other measures of hepatic 
function and without evidence of hepatic decompensation. In approximately half the cases of flares 
exceeding 10x ULN, Pegasys dosing was reduced or withheld until the transaminase elevations 
subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic 
function was recommended in all instances.

Hypersensitivity
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, 
anaphylaxis) have been rarely observed during alfa interferon therapy. If this occurs, therapy must be 
discontinued and appropriate medical therapy instituted immediately. Transient rashes do not 
necessitate interruption of treatment.

Autoimmune disease
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alfa 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 re-assessed (see also 
Endocrine system in sections 4.4 and 4.8).



50

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with CHC 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).

Fever/infections 
While fever may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must 
be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and 
sepsis have been reported during treatment with alfa interferons including Pegasys. Appropriate anti-
infective therapy should be started immediately and discontinuation of therapy should be considered.

Ocular changes
Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and 
retinal artery or vein obstruction which may result in loss of vision have been reported in rare 
instances with Pegasys. All patients should have a baseline eye examination. Any patient complaining of 
decrease or loss of vision must have a prompt and complete eye examination. Adult and paediatric 
patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should 
receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be 
discontinued in patients who develop new or worsening ophthalmologic disorders.

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

Skin disorder
Use of alfa interferons has been associated with exacerbation or provocation of psoriasis and 
sarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset or 
worsening of psoriatic lesions, discontinuation of therapy should be considered.

Transplantation
The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with 
liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, 
alone or in combination with ribavirin.

HIV-HCV co-infection
Please refer to the respective Summary of Product Characteristics of the antiretroviral 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 Pegasys with or 
without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon 
therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).

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

Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of 
hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, 
including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with 
hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline 
phosphatase or decreased platelet count, and treatment with didanosine (ddI).

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



51

During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic 
decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic 
function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors 
related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily 
attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately 
in patients with hepatic decompensation.

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

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving Pegasys 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 Pegasys 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.

Use of peginterferon as long term maintenance monotherapy (unapproved use)
In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees 
of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was 
studied, no significant reductions were observed in the rate of fibrosis progression or related clinical 
events.

Excipient
Pegasys contains benzyl alcohol. Must not be given to premature babies or neonates. May cause toxic 
reactions and anaphylactoid reactions in infants and children up to 3 years old.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not 
show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, 
suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 
2C19 and 2D6 isozymes.

In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 
activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. 
Serum concentrations of theophylline should be monitored and appropriate dose adjustments of 
theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction 
between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy.

HCV monoinfected patients and HBV monoinfected patients

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

Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere 
with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine 
monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with 
azathioprine. The use of peginterferon alfa-2a and ribavirin concomitantly with azathioprin should be 



52

avoided. In individual cases where the benefit of administering ribavirin concomitantly with 
azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be 
done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment 
with these medicinal products should be stopped (see section 4.4).

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

A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, 
indicates that the combination is associated with an increased risk for developing peripheral 
neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and
other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the 
combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.
Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).

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

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

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 therapy 
regimen if this is already established. This would be particularly important in patients with a known 
history of zidovudine induced anaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of peginterferon alfa-2a in pregnant women. 
Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and the 
potential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potential 
benefit justifies the potential risk to the foetus.

Breastfeeding

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

Fertility

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



53

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Chronic hepatitis B in adult patients

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

Chronic hepatitis C in adult patients

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar 
to those reported with interferon alfa-2a (see Table 9). The most frequently reported adverse reactions 
with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without 
the need for modification of doses or discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

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

In another clinical trial, non-responder patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 
6) and baseline platelet counts as low as 50,000 cells/mm3 were treated for 48 weeks. Haematologic 
laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of 
patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC 



54

<750 cells/mm3), and thrombocytopenia (13% experienced a platelet count <50,000 cells/mm3) (see 
section 4.4).

Chronic hepatitis C and HIV co-infection

In HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for Pegasys, alone or 
in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For 
HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have 
been reported in ≥ 1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, 
affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and 
chromaturia. Pegasys treatment 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 Pegasys had no observable negative 
impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available 
in co-infected patients with CD4+ cell counts <200/µl.

Tabulated list of adverse reactions

Table 9 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC adult 
patients and with Pegasys in combination with ribavirin in CHC patients. Undesirable effects reported 
in clinical studies are grouped according to frequency as follows: very common (≥ 1/10), common 
(≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare 
(< 1/10,000). For spontaneous reports of undesirable effects from post-marketing experience, the 
frequency is not known (cannot be estimated from the available data). Within each frequency grouping, 
adverse reactions are presented in decreasing order of seriousness.

Table 9: Undesirable effects reported with Pegasys monotherapy for CHB or CHC or in 
combination with ribavirin for CHC patients in clinical trials and post marketing
Body system Very 

common 
Common Uncommon Rare Very rare Frequency 

not known
Infections and 
infestations

Bronchitis, 
upper 
respiratory 
infection, oral 
candidiasis, 
herpes 
simplex, 
fungal, viral 
and bacterial 
infections

Pneumonia, 
skin infection

Endocarditis, 
otitis externa

Sepsis

Neoplasms 
benign and 
malignant

Hepatic 
neoplasm

Blood and 
lymphatic 
system disorders

Thrombocyto
penia, 
anaemia, 
lymphadenop
athy

Pancytopenia Aplastic 
anaemia

Pure red cell 
aplasia

Immune system 
disorders

Sarcoidosis, 
thyroiditis

Anaphylaxis, 
systemic 
lupus 
erythematosu
s rheumatoid 
arthritis

Idiopathic or 
thrombotic 
thrombocytop
enic purpura

Liver and 
renal graft 
rejection, 
Vogt-
Koyanagi-
Harada 
disease

Endocrine 
disorders

Hypothyroidis
m, 
hyperthyroidi
sm

Diabetes Diabetic 
ketoacidosis 



55

Body system Very 
common 

Common Uncommon Rare Very rare Frequency 
not known

Metabolism and 
nutrition 
disorders

Anorexia Dehydration

Psychiatric 
disorders

Depression*, 
anxiety, 
insomnia* 

Aggression, 
mood 
alteration, 
emotional 
disorders, 
nervousness, 
libido 
decreased

Suicidal 
ideation, 
hallucinations

Suicide, 
psychotic 
disorder 

Mania, 
bipolar 
disorders, 
homicidal 
ideation

Nervous system 
disorders

Headache, 
dizziness*, 
concentration 
impaired

Syncope, 
migraine, 
memory 
impairment, 
weakness, 
hypoaesthesia
, 
hyperaesthesi
a, 
paraesthesia, 
tremor, taste 
disturbance, 
nightmares, 
somnolence

Peripheral 
neuropathy

Coma, 
convulsions, 
facial palsy

Cerebral 
ischaemia

Eye disorders Vision 
blurred, eye 
pain, eye 
inflammation, 
xerophthalmia

Retinal 
haemorrhage

Optic 
neuropathy, 
papilloedema, 
retinal 
vascular 
disorder, 
retinopathy, 
corneal ulcer

Vision loss Serous retinal 
detachment

Ear and 
labyrinth 
disorders

Vertigo, 
earache

Hearing loss

Cardiac 
disorders

Tachycardia, 
oedema 
peripheral, 
palpitations

Myocardial 
infarction, 
congestive 
heart failure, 
cardiomyopat
hy, angina, 
arrhythmia, 
atrial 
fibrillation, 
pericarditis, 
supraventricu
lar 
tachycardia

Vascular 
disorders

Flushing Hypertension Cerebral 
haemorrhage, 
vasculitis

Peripheral 
ischaemia



56

Body system Very 
common 

Common Uncommon Rare Very rare Frequency 
not known

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea, 
cough

Dyspnoea 
exertional, 
epistaxis, 
nasopharyngit
is, sinus 
congestion, 
nasal 
congestion, 
rhinitis, sore 
throat

Wheezing Interstitial 
pneumonitis 
including 
fatal 
outcome, 
pulmonary 
embolism 

Pulmonary 
arterial 
hypertension§

Gastrointestinal 
disorders

Diarrhoea*, 
nausea*, 
abdominal 
pain*

Vomiting, 
dyspepsia, 
dysphagia, 
mouth 
ulceration, 
gingival 
bleeding, 
glossitis, 
stomatitis, 
flatulence, dry 
mouth

Gastrointestin
al bleeding

Peptic ulcer, 
pancreatitis

Ischaemic 
colitis, tongue 
pigmentation

Hepato-biliary 
disorders

Hepatic 
dysfunction

Hepatic 
failure, 
cholangitis, 
fatty liver

Skin and 
subcutaneous 
tissue disorders

Alopecia, 
dermatitis, 
pruritis, dry 
skin

Psoriasis, 
urticaria, 
eczema, rash, 
sweating 
increased, 
skin disorder, 
photosensitivi
ty reaction, 
night sweats

Stevens-
Johnson 
syndrome, 
toxic 
epidermal 
necrolysis,
angioedema, 
erythema 
multiforme

Musculoskeletal 
and connective 
tissue disorders

Myalgia, 
arthralgia

Back pain, 
arthritis, 
muscle 
weakness, 
bone pain, 
neck pain, 
musculoskelet
al pain, 
muscle 
cramps

Myositis Rhabdomyoly
sis

Renal and 
urinary 
disorders

Renal 
insufficiency

Reproductive 
system and 
breast disorders

Impotence

General 
disorders and 
administration 
site conditions

Pyrexia, 
rigors*, 
pain*, 
asthenia, 
fatigue, 
injection site 
reaction*, 
irritability*

Chest pain, 
influenza like 
illness, 
malaise, 
lethargy, hot 
flushes, thirst

Investigations Weight 
decreased



57

Body system Very 
common 

Common Uncommon Rare Very rare Frequency 
not known

Injury, 
poisoning and 
procedural 
complications

Substance 
overdose

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

Description of selected adverse reactions

Pulmonary arterial hypertension
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

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

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

Moderate (ANC: 0.749 - 0.5 x 109/l) and severe (ANC: < 0.5 x 109/l) neutropenia was observed 
respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and 
ribavirin 1000/1200 milligrams for 48 weeks.

Anti-interferon antibodies
1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other 
interferons, a higher incidence of neutralising antibodies was seen in CHB. However in neither disease 
was this correlated with lack of therapeutic response.

Thyroid function
Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values 
requiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving 
Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more 
frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of 
growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC 
levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving Pegasys monotherapy 
and combination therapy, respectively. Decrease in platelets below 50,000 cells/mm3 was observed in 
10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. 
Anaemia (haemoglobin < 10 g/dl) was reported in 7% and 14% of patients treated with Pegasys 
monotherapy or in combination therapy, respectively.



58

Paediatric population

Chronic hepatitis B 

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

The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment in 
study YV25718 were -0.07 and -0.21(n=108 and n= 106 respectively) for Pegasys-treated patients as 
compared to - 0.01 and -0.08 (n=47 each) in untreated patients. At Week 48 of Pegasys treatment, a 
height or weight percentile decrease of more than 15 percentiles on the normative growth curves was 
observed in 6% of patients for height and 11% of patient for weight, whereas in the untreated group it 
was 2% of patients for height and 9% for weight. No data is available on long-term follow-up post-
treatment in these patients (see section 4.4).

Chronic hepatitis C

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

Growth inhibition was observed in paediatric patients (see section 4.4). Paediatric patients treated with 
Pegasys plus ribavirin combination therapy showed a delay in weight and height increases after 48 
weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of 
the normative population decreased during treatment. At the end of 2 years follow-up after treatment, 
most patients had returned to baseline normative growth curve percentiles for weight and height (mean 
weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 
54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients 
experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced a 
height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-
treatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight 
curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.

55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up 
extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in 
growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who 
were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either 
returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related 
causative factor has been identified. The extent of available data is not sufficient to conclude that 
growth inhibition due to Pegasys exposure is always reversible.



59

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

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

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

4.9 Overdose

Overdoses involving between two injections on consecutive days (instead of weekly interval) up to 
daily injections for 1 week (i.e., 1260 micrograms/week) have been reported. None of these patients 

Body system Very common Common
Infections and infestations Infectious mononucleosis, 

pharyngitis streptococcal, influenza, 
gastroenteritis viral, candidiasis, 
gastroenteritis, tooth abscess, 
hordeolum, urinary tract infection, 
nasopharyngitis

Blood and lymphatic system 
disorders

Anaemia

Metabolism and nutrition disorders Decreased appetite Hyperglycaemia, type 1 diabetes 
mellitus 

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

Nervous system disorders Headache Dizziness, disturbance in attention, 
migraine

Eye disorders Blindness transient, retinal 
exudates, visual impairment eye 
irritation, eye pain, eye pruritis

Ear and labyrinth disorders Ear pain
Respiratory, thoracic and 
mediastinal disorders

Dyspnoea, epistaxis

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

Skin and subcutaneous tissue 
disorders

Rash, pruritus, alopecia Swollen face, drug eruption, 

Musculoskeletal and connective 
tissue disorders

Musculoskeletal pain Back pain, pain in extremity

Renal and urinary disorders Dysuria, incontinence, urinary tract 
disorder

Reproductive system and breast 
disorders

Vaginal discharge

Body system Very common Common

General disorders and 
administration site conditions

Influenza-like illness, injection site 
reaction, irritability, fatigue

Pyrexia, vessel puncture site 
haematoma, pain

Investigations Psychiatric evaluation abnormal

Surgical and medical procedures Tooth extraction, cholecystectomy

Social circumstances Educational problem

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


60

experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and 
630 micrograms have been administered in renal cell carcinoma and chronic myelogenous leukaemia 
clinical trials, respectively. Dose limiting toxicities were fatigue, elevated liver enzymes, neutropenia 
and thrombocytopenia, consistent with interferon therapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB11

Mechanism of action

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

Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of 
substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 
60,000 of which the protein moiety constitutes approximately 20,000.

Pharmacodynamic effects

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

Clinical efficacy and safety

Chronic hepatitis B

Predictability of response

A patient-level meta-analysis of 9 Pegasys clinical studies (n=1,423) in CHB HBeAg positive and 
HBeAg-negative patients demonstrated that HBsAg and HBV DNA levels at Week 12 of treatment, 
are predictive of final treatment outcome at Week 24 post-treatment in certain genotypes. Operating 
characteristics of these biomarkers are presented in Table 11. No single biomarker with a cut-off can 
be identified to optimize all the operating characteristics (negative predictive value [NPV], sensitivity, 
specificity) and practical characteristics (simplicity, convenience). Consideration for early treatment 
discontinuation should be evaluated in the context of a particular clinical situation.

For HBeAg-positive patients with HBV genotype B and C infection, HBsAg > 20,000 IU/mL or HBV 
DNA > 8 log10 IU/mL at Week 12 following commencement of treatment is associated with high 
likelihood of failure to achieve HBeAg seroconversion and HBV-DNA <2,000 IU/mL at 24 week 
post-treatment (NPV > 90%). For HBV genotype A and D, subgroup size was insufficient to be 
analyzed. 

For HBeAg-negative patients with HBV genotype D infection, HBsAg > 20,000 IU/mL or HBV DNA 
> 6.5 log10 IU/mL at Week 12 following commencement of treatment is associated with high 
likelihood of failure to achieve HBV-DNA <2,000 IU/mL and ALT normalization at Week 24 post 
treatment. HBV genotype A subgroup size was insufficient to be analyzed. No biomarker can be 
identified with acceptable performance for HBeAg-negative patients with HBV genotype B or C 
infection. 



61

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

Table 11: Performance of individual biomarkers at Week 12 of therapy in CHB HBeAg-positive 
and HBeAg-negative patients according to genotype

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

HBeAg-positive(a)

B
HBsAg > 20,000 0.93 0.96 0.23

HBV DNA > 8 log10 0.90 0.94 0.26

C
HBsAg > 20,000 0.96 0.97 0.22

HBV DNA > 8 log10 0.98 0.98 0.19

HBeAg-negative(a)

D
HBsAg > 20,000 0.91 0.94 0.16

HBV DNA > 6.5 log10 1.00 1.00 0.11
NPV= negative predictive value; Sensitivity = % of all responders not meeting the stopping rule; Specificity = % of 
all non-responders meeting stopping rule
(a) Treatment response for HBeAg-positive patients was defined as HBeAg seroconversion (defined as loss of 
HBeAg and presence of anti-HBe) + HBV DNA <2,000 IU/mL at 6 months post-treatment and treatment response 
for HBeAg-negative patients was defined as HBV DNA < 2,000 IU/mL + ALT normalization at 6 months post-
treatment.

All clinical trials recruited patients with CHB who had active viral replication measured by HBV 
DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 
recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were 
negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, 
with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys 
plus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in these 
clinical trials.

Response rates at the end of follow-up for the two studies are presented in Table 12. In study 
WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105

copies/ml. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-
DNA below 2 x 104 copies/ml. HBV-DNA was measured by the COBAS AMPLICOR HBV 
MONITOR Assay (limit of detection 200 copies/ml).

A total of 283/1351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1351 (6%) had cirrhosis. 
There was no difference in response rate between these patients and those without advanced fibrosis or 
cirrhosis.



62

Table 12: Serological, virological and biochemical responses in chronic hepatitis B
HBeAg positive
Study WV16240

HBeAg negative / anti-HBe positive
Study WV16241

Response 
Parameter

Pegasys
180 mcg

&
Placebo

(N=271)

Pegasys
180 mcg

&
Lamivudine

100 mg
(N=271)

Lamivudine
100 mg

(N=272)

Pegasys
180 mcg

&
Placebo

(N=177)

Pegasys
180 mcg

&
Lamivudine

100 mg
(N=179)

Lamivudine
100 mg

(N=181)
HBeAg Sero-
conversion

32% # 27% 19% N/A N/A N/A

HBV DNA 
response *

32% # 34% 22% 43% # 44% 29%

ALT Normal-
isation

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

HBsAg Sero-
conversion

3% # 3% 0% 3% 2% 0%

* For HBeAg-positive patients: HBV DNA < 105 copies/ml
For HBeAg-negative/anti-HBe-positive patients: HBV DNA < 2 x 104 copies/ml

# p-value (vs. lamivudine) < 0.01 (stratified Cochran-Mantel-Haenszel test)

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

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

Chronic hepatitis C

Predictability of response
Please refer to section 4.2, in Table 2.

Dose-response in monotherapy
In a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superior 
sustained virological response in patients with cirrhosis, but in a study in non-cirrhotic patients very 
similar results were obtained with doses of 135 micrograms and 180 micrograms.

Confirmatory clinical trials in adult treatment-naïve patients
All clinical trials recruited interferon-naïve patients with CHC confirmed by detectable levels of serum 
HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy 
consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological 
diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected 
patients were included in the study NR15961 (see Table 21). These patients had stable HIV disease 
and mean CD4 T-cell count was about 500 cells/µl. 
For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration 
of therapy and study outcome see Tables 13, 14, 15 and Table 21, respectively. Virological response 
was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, 
version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained 
response as one negative sample approximately 6 months after end of therapy.



63

Table 13: Virological response in CHC patients
Pegasys monotherapy Pegasys combination therapy

non-cirrhotic and 
cirrhotic

cirrhotic non-cirrhotic and cirrhotic

Study NV15496 + 
NV15497 + NV15801

Study NV15495 Study 
NV15942

Study NV15801

Pegasys

180 mcg

(N=701)
48 weeks

Interferon
alfa-2a

6 MIU/3 MIU
&

3 MIU

(N=478)
48 weeks

Pegasys
180 mcg

(N=87)
48 weeks

Interferon 
alfa-2a
3 MIU

(N=88)
48 weeks

Pegasys
180 mcg

&
Ribavirin
1000/1200

mg

(N=436)
48 weeks

Pegasys
180 mcg

&
Ribavirin
1000/1200

mg

(N=453)
48 weeks

Interferon
alfa-2b
3 MIU

&
Ribavirin
1000/1200

mg

(N=444)
48 weeks

Response 
at End of 
Treatment 

55 - 69% 22 - 28% 44% 14% 68% 69% 52%

Overall 
Sustained 
Response

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

* 95% CI for difference: 11% to 33% p-value (stratified Cochran-Mantel-Haenszel test) = 0.001
** 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Pegasys and ribavirin 
combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, 
pre-treatment viral load and rapid virological response at week 4 are summarised in Table 14 and 
Table 15, respectively. The results of study NV15942 provide the rationale for recommending 
treatment regimens based on genotype, baseline viral load and virological response at week 4 (see 
Tables 1, 14 and 15).
The difference between treatment regimens was in general not influenced by presence/absence of 
cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline 
characteristic.



64

Table 14: Sustained virological response based on genotype and pre-treatment viral load after 
Pegasys combination therapy with ribavirin in CHC patients

Study NV15942 Study NV15801
Pegasys
180 mcg

&
Ribavirin

800 mg

24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

24 weeks

Pegasys
180 mcg

&
Ribavirin

800 mg

48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg

48 weeks

Interferon
alfa-2b
3 MIU

&
Ribavirin

1000/1200 mg

48 weeks

Genotype 1
Low viral load
High viral load

29% 
(29/101)
41% (21/51)
16% (8/50)

42% (49/118)*
52% (37/71)
26% (12/47)

41% 
(102/250)*
55% (33/60)
36% (69/190)

52% (142/271)*
65% (55/85)
47% (87/186)

45% (134/298)
53% (61/115)
40% (73/182)

36% (103/285)
44% (41/94)
33% (62/189)

Genotype 2/3
Low viral load
High viral load

84% (81/96)
85% (29/34)
84% (52/62)

81% (117/144)
83% (39/47)
80% (78/97)

79% (78/99)
88% (29/33)
74% (49/66)

80% (123/153)
77% (37/48)
82% (86/105)

71% (100/140)
76% (28/37)
70% (72/103)

61% (88/145)
65% (34/52)
58% (54/93)

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

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
*Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 800 mg, 48 w: 
Odds Ratio (95% CI) = 1.52 (1.07 to 2.17), P-value (stratified Cochran-Mantel-Haenszel test) = 0.020
*Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 1000/1200 mg, 24 w: 
Odds Ratio (95% CI) = 2.12 (1.30 to 3.46), P-value (stratified Cochran-Mantel-Haenszel test) = 0.002.

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was 
examined based on a sustained rapid virological response observed in patients with rapid virological 
response at week 4 in studies NV15942 and ML17131 (see Table 15).

Table 15: Sustained virological response based on rapid viral response at week 4 for genotype 1 
and 4 after Pegasys combination therapy with ribavirin in CHC patients

                                         Study NV15942 Study ML17131
Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Genotype 1 RVR
Low viral load
High viral load

90% (28/31)
93% (25/27)

75% (3/4)

92% (47/51)
96% (26/27)
88% (21/24)

77% (59/77)
80% (52/65)
58% (7/12)

Genotype 1 non 
RVR
Low viral load
High viral load

24% (21/87)

27% (12/44)
21% (9/43)

43% (95/220)

50% (31/62)
41% (64/158)

-
-
-

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

Genotype 4 non 
RVR

(3/6) (4/6) -

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a 
higher risk of relapse (see Table 16).



65

Table 16: Relapse of virological response at the end of treatment for rapid virological response 
population

Study NV15942 Study NV15801
Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
24 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Pegasys
180 mcg

&
Ribavirin

1000/1200 mg
48 weeks

Genotype 1 RVR

Low viral load
High viral load

6.7% (2/30)

3.8% (1/26)
25% (1/4)

4.3% (2/47)

0% (0/25)
9.1% (2/22)

0% (0/24)

0% (0/17)
0% (0/7)

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

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined 
based on a sustained virological response observed in patients with rapid virological response by week 
4 in study NV17317 (see Table 17).

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

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was 
also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 
4 and had a LVL at baseline (see Table 17).

Table 17: Sustained virological response overall and based on rapid viral response by week 4 for 
genotype 2 or 3 after Pegasys combination therapy with ribavirin in CHC patients

Study NV17317
Pegasys 180 mcg

&
Ribavirin 800 mg

16 weeks

Pegasys 180 mcg
& 

Ribavirin 800 mg
24 weeks

Treatment difference 
[95%CI]

p value

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

82%  (378/461)

89%  (147/166)
78%  (231/295)

90%  (370/410)

94%  (141/150)
88%  (229/260)

-8.2% [-12.8% ; -3.7%]

-5.4% [-12% ; 0.9%]
-9.7% [-15.9% ;-3.6%]

P=0.0006

P=0.11
P=0.002

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4

It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body 
weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 
weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse 
(see Table 18).



66

Table 18: Relapse of virological response after the end of treatment in genotype 2 or 3 patients 
with a rapid viral response

Study NV17317
Pegasys
180 mcg

&
Ribavirin 

800 mg
16 weeks

Pegasys
180 mcg

& 
Ribavirin

800 mg
24 weeks

Treatment difference 
[95%CI]

p value

Genotype 2 or 3 RVR
Low viral load
High viral load

15%  (67/439)
6%  (10/155)
20%  (57/284)

6%  (23/386)
1%  (2/141)

9%  (21/245)

9.3% [5.2% ; 13.6%]
5% [0.6% ; 10.3%]

11.5% [5.6% ; 17.4%]

P<0.0001
P=0.04

P=0.0002

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4

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

Adult chronic hepatitis C prior treatment non-responder patients
In study MV17150, patients who were non-responders to previous therapy with pegylated interferon 
alfa-2b plus ribavirin were randomised to four different treatments:
 Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks
 Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks
 Pegasys 180 mcg/week for 72 weeks
 Pegasys 180 mcg/week for 48 weeks
All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment 
arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use 
of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for 
achieving a sustained virological response. Differences in sustained virological response (SVR) based 
on treatment duration, demographics and best responses to previous treatment are displayed in Table 
19.



67

Table 19: Week 12 virological response (VR) and sustained virological response (SVR) in 
patients with virological response at week 12 after treatment with Pegasys and ribavirin 
combination therapy in nonresponders to peginterferon alfa-2b plus ribavirin

Study MV17150
Pegasys 360/180 or 

180 mcg
&

Ribavirin 
1000/1200 mg

72 or 48 Weeks
(N = 942)
Pts with

VR at Wk 12 a

(N = 876)

Pegasys 360/180 or 
180 mcg

&
Ribavirin 

1000/1200 mg
72 Weeks
(N = 473)

SVR in Pts with 
VR at Wk 12 b

(N = 100)

Pegasys 360/180 or 
180 mcg 

&
Ribavirin 

1000/1200 mg
48 Weeks
(N = 469)

SVR in Pts with VR 
at Wk 12 b

(N = 57)
Overall
    Low viral load
    High viral load

   18% (157/876)
   35% (56/159)
   14% (97/686)

    57% (57/100)
    63% (22/35)
    54% (34/63)

     35% (20/57)
     38% (8/21)
     32% (11/34)

Genotype 1/4
   Low  viral load
   High viral load

   17% (140/846)
   35% (54/154)
   13% (84/663)

55% (52/94)
63% (22/35)
52% (30/58)

     35% (16/46)
     37% (7/19)
     35% (9/26)

Genotype 2/3
   Low  viral load
   High viral load

   58% (15/26)
           (2/5)
           (11/19)

             (4/5)
—
         (3/4)

             (3/10)
             (1/2)
             (1/7)

Cirrhosis Status
Cirrhosis
Noncirrhosis

     8% (19/239)
   22% (137/633)

             (6/13)
    59% (51/87)

              (3/6)
     34% (17/50)

Best Response during 
Previous Treatment
  2log10 decline in HCV RNA
   <2log10 decline in HCV RNA
Missing best previous response

   28% (34/121)
   12% (39/323)
   19% (84/432)

    68% (15/22)
    64% (16/25)
    49% (26/53)

              (6/12)
              (5/14)
     29% (9/31)

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

In the HALT-C study, patients with CHC and advanced fibrosis or cirrhosis who were non-responders 
to previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combination 
therapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. 
Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on 
Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 
weeks after the end of treatment. The probability for sustained virological response varied depending 
upon the previous treatment regimen; see Table 20. 

Table 20: Sustained virological response in HALT-C by previous treatment regimen in non-
responder population
Previous Treatment Pegasys 180 mcg

&
Ribavirin 1000/1200 mg

48 weeks

Interferon 27% (70/255)

Pegylated interferon 34% (13/38)

Interferon plus ribavirin 13% (90/692)

Pegylated interferon plus ribavirin 11% (7/61)



68

HIV-HCV co-infected patients
The virological responses of patients treated with Pegasys monotherapy and with Pegasys and 
ribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-
infected patients are summarised below in Table 21.

Table 21: Sustained virological response based on genotype and pre-treatment viral load after 
Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients

Study NR15961
Interferon alfa-2a

3 MIU 
&

Ribavirin 800 mg
48 weeks

Pegasys
180 mcg

&
Placebo
48 weeks

Pegasys
180 mcg

&
Ribavirin 800 mg

48 weeks

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

Genotype 1 7% (12/171) 14% (24/175) 29% (51/176)
Low viral load 19% (8/42) 38% (17/45) 61% (28/46)
High viral load 3% (4/129) 5% (7/130) 18% (23/130)

Genotype 2-3 20% (18/89) 36% (32/90) 62% (59/95)
Low viral load 27% (8/30) 38% (9/24) 61% (17/28)
High viral load 17% (10/59) 35% (23/66) 63% (42/67)

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml
* Pegasys 180 mcg & ribavirin 800 mg vs. Interferon alfa-2a 3 MIU & ribavirin 800 mg: 
Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001
* Pegasys 180 mcg & ribavirin 800 mg vs. Pegasys 180 mcg: 
Odds Ratio (95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001
* Interferon alfa-2a 3 MIU & ribavirin 800 mg vs. Pegasys 180 mcg: 
Odds Ratio (95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared 
treatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1000 mg (<75 kg)/1200 mg 
(75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety 
profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus 
ribavirin combination treatment and not indicative of any relevant differences, with the exception of a 
slight increase in anaemia in the high dose ribavirin arm.

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

Paediatric population

Chronic hepatitis B

Study YV25718 was conducted in previously untreated paediatric patients aged 3 to 17 years (51% < 
12 years old) with HBeAg positive CHB and ALT > ULN but < 10 x ULN in two blood samples 
taken ≥ 14 days apart during the 6 months before the first dose of study drug. Patients with cirrhosis 
were not enrolled in this study. A total of 151 patients without advanced fibrosis were 2:1 randomized 
to Pegasys (group A, n=101) or untreated control (group B, n=50), respectively. Patients with 
advanced fibrosis were assigned to Pegasys treatment (group C, n=10). Patients in groups A and C 
(n=111) were treated with Pegasys once weekly for 48 weeks according to BSA categories, whereas 
patients in group B were observed for a period of 48 weeks (principal observation period). Patients in 
group B had the choice to switch to treatment with Pegasys after Week 48 of the principal observation 
period. All patients were followed up for 24 weeks post-treatment (groups A and C), or post-principal 
observation period (group B). After the Week 24 follow-up visit, patients from group A, B and C 
entered a long-term follow-up period (lasting for 5 years after end of treatment). Response rates in 



69

groups A and B at the end of 24 weeks follow-up are presented in Table 22. Efficacy response in 
group C to Pegasys treatment was in line with that seen in group A. For paediatric patients, efficacy 
has not been established in HBV genotypes other than genotypes A-D.

Table 22: Serological, virological and biochemical responses in paediatric patients with chronic 
hepatitis B

Group A
(Pegasys 

treatment)
(N=101)

Group B**
Untreated

(N=50)
Odds Ratio

(95% CI)
p-value

HBeAg Seroconversion 25.7% 6.0% 5.4
(1.5 – 19.2)

0.0043 1

HBV DNA < 20,000 IU/mL* 33.7% 4.0% 12.2
(2.9 – 108.3)

<0.0001 2

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

<0.0001 2

ALT Normalization 51.5% 12.0% 7.8
(2.9 – 24.1)

<0.0001 2

HBsAg Seroconversion 7.9% 0.0% - 0.0528 2

Loss of HBsAg 8.9% 0.0% - 0.0300 2

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

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

The response rate of HBeAg seroconversion was lower in patients with HBV genotype D, also in 
patients with no to minimal increase in ALT level at baseline (see Table 23).

Table 23: HBeAg seroconversion rates (%) by HBV genotype and baseline ALT levels

Group A
(Pegasys treatment)

(N=101)

Group B**
Untreated

(N=50)

Odds Ratio
(95% CI)

HBV genotype A 3/9 (33.3%) 1/3 (33.3%) 1.0   (0.04,78.4)
  B 7/21 (33.3%) 0/6 (0.0%) -
  C 13/34 (38.2%) 1/23 (4.3%) 13.62 (1.7,604.5)
  D* 3/31 (9.7%) 1/18 (5.6%) 1.8   (0.1,101.2)
  Other 0/6 (0.0%) 0/0 -

ALT <1xULN 0/7 (0.0%) 0/5 (0.0%) -
>=1xULN -
<1.5xULN

2/22 (9.1%) 0/8 (0.0%) -

>=1.5xULN -
<2xULN

7/19 (36.8%) 0/11 (0.0%) -

>=2xULN -
<5xULN

15/43 (34.9%) 1/17 (5.9%) 8.6   (1.1,383.0)

>=5xULN -
<10xULN

2/8 (25.0%) 2/9 (22.2%) 1.2   (0.06,20.7)

>=10xULN 0/2 (0.0%) 0/0 -
* Subgroup of patients with genotype D had a higher proportion with baseline ALT < 1.5x ULN (13/31) compared to other genotype groups 

(16/70).
** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.

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



70

Table 24: HBeAg seroconversion rates (%) by HBV-DNA decline from baseline to week 12 of 

Pegasys treatment in paediatric patients

HBeAg 

seroconversion 

rates 

By HBV-DNA (IU/mL) decline from baseline to 

week 12

<1 log10

decline

1 - <2 log10

decline

2 log10

decline

All genotypes (N=101)

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

(50.0 %)

Genotype-A (N=9)

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

Genotype-B (N=21)

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

Genotype-C (N=34)

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

Genotype-D (N=31)

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

Chronic hepatitis C

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

In the NV17424 (PEDS-C) study, previously untreated paediatric patients 5 to 17 years of age (55% 
<12 years old) with compensated CHC and detectable HCV RNA were treated with Pegasys 180 mcg 
x BSA/1.73 m2 once weekly for 48 weeks with or without ribavirin 15 mg/kg/day. All patients were 
followed for 24 weeks post-treatment. A total of 55 patients received initial combination treatment of 
Pegasys plus ribavirin, of whom 51% were female, 82% were Caucasian, and 82% were infected with 
HCV genotype 1. The study efficacy results for these patients are summarised in Table 25.

Table 25: Sustained virological response in the NV17424 study

Pegasys

180 mcg x BSA/1.73 m² + 

Ribavirin 15 mg/kg (N=55)*

All HCV genotypes** 29 (53%)

HCV genotype 1 21/45 (47%)

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

*Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/ml at 24 weeks post-treatment using the 
AMPLICOR HCV test v2.
**Scheduled treatment duration was 48 weeks regardless of the genotype



71

5.2 Pharmacokinetic properties

Absorption
Following a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serum 
concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 
80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peak 
serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is 
84% and is similar to that seen with interferon alfa-2a.

Distribution
Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the 
volume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration. 
From mass balance, tissue distribution and whole body autoradioluminography studies performed in 
rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being 
highly concentrated in the blood.

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

Elimination
In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the 
native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa-
2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard 
interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean 
value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase 
of the compound, but may also reflect the sustained absorption of Pegasys.

Linearity/non-linearity
Dose-proportional increases in exposure of Pegasys are seen in healthy subjects and in patients with 
chronic hepatitis B or C after once-weekly dosing.

In CHB or CHC patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 
8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 
8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. 
Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).

Patients with renal impairment
A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) 
or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease 
(ESRD) requiring chronic hemodialysis (HD). Patients with moderate renal impairment receiving 
Pegasys 180 mcg once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to 
patients with normal renal function. Patients with severe renal impairment receiving Pegasys 180 mcg 
once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal 
function, therefore a reduced dose of Pegasys 135 mcg once weekly is recommended in patients with 
severe renal impairment. In 13 patients with ESRD requiring chronic HD, administration of Pegasys 
135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with 
normal renal function. However, several independent studies have demonstrated the 135mcg dose to 
be safe, efficacious and well tolerated, in patients with ESRD (see section 4.2).

Gender
The pharmacokinetics of Pegasys after single subcutaneous injections was comparable between male 
and female healthy subjects.

Paediatric population
Pegasys pharmacokinetics have been characterized in paediatric patients with CHB (YV25718), as 
well as in paediatric patients with CHC (NR16141), using population pharmacokinetics.  In both 



72

studies, Pegasys apparent clearance and apparent volume of distribution were related linearly to body 
size ie. either BSA (NR16141) or body weight (YV25718).

From the YV25718 study, 31 paediatric patients 3 to 17 years of age with CHB participated in the PK 
sub-study and received Pegasys according to a BSA category dosing regimen. Based on the population 
pharmacokinetic model, the mean exposure (AUC) during the dosing interval for each BSA category 
was comparable with that observed in adults receiving 180 mcg fixed dosing. 

From the NR16141study, 14 children 2 to 8 years of age with CHC received Pegasys monotherapy at a 
dose of: 180 mcg x BSA of the child/1.73 m2. The PK model developed from this study shows a linear 
influence of BSA on the apparent clearance of the drug over the age range studied. Thus, the lower the 
BSA of the child, the lower the clearance of the drug and the higher the resultant exposure. The mean 
exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in 
adults receiving 180 mcg fixed dosing.

Elderly
In subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of 
180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hours 
vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 
1295 ng·h/ml) but peak concentrations (9.1 vs. 10.3 ng/ml) were similar in subjects older than 62 
years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys is 
not needed in the geriatric patient (see section 4.2).

Hepatic impairment
The pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis B 
or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) 
and non-cirrhotic patients.

Site of administration
Subcutaneous administration of Pegasys should be limited to the abdomen and thigh, as the extent of 
absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. 
Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm 
compared to administration in the abdomen and thigh.

5.3 Preclinical safety data

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

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

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



73

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride
Polysorbate 80
Benzyl alcohol
Sodium acetate 
Acetic acid
Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Pegasys 90 micrograms solution for injection in pre-filled syringe
3 years.

Pegasys 135 micrograms solution for injection in pre-filled syringe
4 years

Pegasys 180 micrograms solution for injection in pre-filled syringe
4 years

6.4 Special precautions for storage

Store in a refrigerator (2C-8C). Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.

6.5 Nature and contents of container

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

Pegasys 90 micrograms solution for injection in pre-filled syringe 
The syringe is labeled with graduations corresponding to doses of 90 mcg, 65 mcg, 45 mcg, 30 mcg, 
20 mcg and 10 mcg. Available in packs of 1 pre-filled syringe.

Pegasys 135 micrograms solution for injection in pre-filled syringe
The syringe is labeled with graduations corresponding to doses of 135 mcg, 90 mcg and 45 mcg. 
Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes. Not all pack-sizes 
may be marketed.

Pegasys 180 micrograms solution for injection in pre-filled syringe
The syringe is labeled with graduations corresponding to doses of 180 mcg, 135 mcg and 90 mcg. 
Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes. Not all pack-sizes 
may be marketed.

6.6 Special precautions for disposal

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



74

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

7. MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

8. MARKETING AUTHORISATION NUMBERS

Pegasys 90 micrograms solution for injection in pre-filled syringe
EU/1/02/221/017

Pegasys 135 micrograms solution for injection in pre-filled syringe
EU/1/02/221/005
EU/1/02/221/006
EU/1/02/221/009

Pegasys 180 micrograms solution for injection in pre-filled syringe
EU/1/02/221/007
EU/1/02/221/008
EU/1/02/221/010

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 June 2002 
Date of latest renewal: 20 June 2007

10. DATE OF REVISION OF THE TEXT

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



75

ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER(S) RESPONSIBLE FOR 
BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT



76

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) of the biological active substance

Roche Diagnostics GmbH
Nonnenwald 2
D-82377 Penzberg
Germany

Name and address of the manufacturer(s) responsible for batch release

Roche Pharma AG
Emil-Barell-Str. 1
D-79639 Grenzach- Wyhlen
Germany

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and  published on the European medicines web-
portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time.



77

ANNEX III

LABELLING AND PACKAGE LEAFLET



78

A. LABELLING



79

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 1 x 180 g VIAL

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial of 1 ml solution contains 180 micrograms peginterferon alfa-2a.

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
1 vial
180 micrograms/1 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze
Keep the vial in the outer carton in order to protect from light



80

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/003

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



81

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 4 x 180 g VIALS

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial of 1 ml solution contains 180 micrograms peginterferon alfa-2a.

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
4 vials
180 micrograms/1 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze
Keep the vial in the outer carton in order to protect from light



82

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/004

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



83

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

180 g VIAL 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pegasys 180 mcg injection
Peginterferon alfa-2a
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

180 mcg/1 ml

6. OTHER



84

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 1 x 90 g PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 90 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
1 pre-filled syringe + 1 injection needle
90 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light



85

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/017

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 90 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



86

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

90 g PRE-FILLED SYRINGE 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pegasys 90 mcg injection
Peginterferon alfa-2a
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

90 mcg/0.5 ml

6. OTHER



87

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 1 x 135 g PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 135 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
1 pre-filled syringe + 1 injection needle
135 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light



88

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/005

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 135 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



89

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 4 x 135 g PRE-FILLED SYRINGES

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 135 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for futher information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
4 pre-filled syringes + 4 injection needles
135 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze
Keep the pre-filled syringe in the outer carton in order to protect from light



90

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/006

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 135 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



91

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 6 x 135 g PRE-FILLED SYRINGES (WITHOUT BLUE BOX) -
Multipack

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 135 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for futher information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
6 pre-filled syringes + 6 injection needles
135 micrograms/0.5 ml
Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



92

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze
Keep the pre-filled syringe in the outer carton in order to protect from light

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/009

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 135 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



93

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 12 x 135 g PRE-FILLED SYRINGES (WITH BLUE BOX) - Multipack

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 135 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
Multipack: 12 (2 packs of 6) pre-filled syringes + 12 injection needles
135 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light 



94

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/009

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 135 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



95

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

135 g PRE-FILLED SYRINGE 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pegasys 135 mcg injection
Peginterferon alfa-2a
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

135 mcg/0.5 ml

6. OTHER



96

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 1 x 180 g PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
1 pre-filled syringe + 1 injection needle
180 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light



97

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/007

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



98

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 4 x 180 g PRE-FILLED SYRINGES

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
4 pre-filled syringes + 4 injection needles
180 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light



99

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/008

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



100

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 6 x 180 g PRE-FILLED SYRINGES (WITHOUT BLUE BOX) -
Multipack

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
6 pre-filled syringes + 6 injection needles
180 micrograms/0.5 ml
Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



101

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/010

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



102

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON – 12 x 180 g PRE-FILLED SYRINGES (WITH BLUE BOX) - Multipack

1. NAME OF THE MEDICINAL PRODUCT

Pegasys 180 micrograms solution for injection in pre-filled syringe
Peginterferon alfa-2a

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Also contains sodium chloride, polysorbate 80, benzyl alcohol (see leaflet for further information), 
sodium acetate, acetic acid and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

solution for injection
Multipack: 12 (2 packs of 6) pre-filled syringes + 12 injection needles
180 micrograms/0.5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator 
Do not freeze 
Keep the pre-filled syringe in the outer carton in order to protect from light



103

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/221/010

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

pegasys 180 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



104

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

180 g PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Pegasys 180 mcg injection
Peginterferon alfa-2a
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

180 mcg/0.5 ml

6. OTHER



105

B. PACKAGE LEAFLET



106

Package leaflet: Information for the user

Pegasys 180 micrograms solution for injection
Peginterferon alfa-2a

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
● Keep this leaflet. You may need to read it again.
● If you have any further questions, ask your doctor, pharmacist or nurse.
● This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
● If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Pegasys is and what it is used for
2. What you need to know before you use Pegasys
3. How to use Pegasys
4. Possible side effects
5. How to store Pegasys
6. Contents of the pack and other information

1. What Pegasys is and what it is used for

Pegasys contains the active substance peginterferon alfa-2a, which is a long-acting interferon. 
Interferon is a protein that modifies the response of the body's immune system to help fight infections 
and severe diseases. Pegasys is used to treat chronic hepatitis B or chronic hepatitis C in adults. It is 
also used to treat chronic hepatitis B in children and adolescents aged 3 years and older and chronic 
hepatitis C in children and adolescents aged 5 years and older, who have not been treated before. Both 
chronic hepatitis B and C are viral infections of the liver.

Chronic Hepatitis B: Pegasys is usually used alone.
Chronic Hepatitis C: Pegasys is used in combination with other medicines, for the treatment of 
chronic hepatitis C (CHC). 

Refer also to the package leaflets of any other medicines that are used in combination with Pegasys.

2. What you need to know before you use Pegasys

Do not use Pegasys
● if you are allergic to peginterferon alfa-2a, to any interferon or any of the other ingredients of 

this medicine (listed in section 6).
● if you have ever had a heart attack or have been hospitalised for serious chest pains in the last 

six months.
● if you have, so called autoimmune hepatitis.
● if you have advanced liver disease and your liver does not work properly (e.g. your skin has 

become yellow).
● if the patient is a child less than 3 years old.
● if the patient is a child who has ever had serious psychiatric conditions such as severe 

depression or thoughts of committing suicide.
● if you are infected with both the hepatitis C virus and the human immunodeficiency virus, and 

your liver does not work properly (e.g. your skin has become yellow).
● if you are being treated with telbivudine, a medicine for hepatitis B infection (see “Other 

medicines and Pegasys”).



107

Warnings and precautions
Talk to your doctor, or pharmacist or nurse before using Pegasys
● if you have had a severe nervous or mental disorder.
● if you have ever had depression or symptoms associated with depression (e.g. feelings of 

sadness, dejection, etc.).
● if you are an adult who has or had a  history of substance abuse (e.g. alcohol or drugs)
● if you have psoriasis, it may get worse during treatment with Pegasys.
● if you have a problem with your liver other than hepatitis B or C.
● if you have diabetes or high blood pressure, your doctor may ask you to have an eye 

examination.
● if you have been told you have VKH syndrome.
● if you have thyroid disease that is not well controlled with medicines.
● if you have ever had anaemia.
● if you have had an organ transplant (liver or kidney) or have one planned in the near future.
● if you are coinfected with HIV and treated with anti HIV medicinal products.
● if you have been withdrawn from previous therapy for Hepatitis C because of anaemia or low 

blood count.

Once you have started Pegasys treatment, talk to your doctor, nurse or pharmacist:
● if you develop symptoms associated with depression (e.g. feelings of sadness, dejection, etc.) 

(see section 4).
● if you notice a change in your vision.
● if you develop symptoms associated with a cold or other respiratory infection (such as cough, 

fever or any difficulty in breathing).
● if you think you are getting an infection (such as pneumonia) as when receiving Pegasys you 

may temporarily have a greater risk of getting an infection.
● if you develop any signs of bleeding or unusual bruising, check with your doctor immediately.
● if you develop signs of a severe allergic reaction (such as difficulty in breathing, wheezing or 

hives) while on this medication, seek medical help immediately.
● if you develop symptoms of Vogt-Koyanagi-Harada syndrome; combination of complaints of 

neck stiffness, headache, loss of colour in skin or hair, eye disorders (such as blurred vision), 
and/or hearing abnormality (such as ringing in the ears).

During treatment your doctor will take blood samples regularly to check for changes in your white 
blood cells (cells that fight infection), red blood cells (cells that carry oxygen), platelets (blood clotting 
cells), liver function, glucose (blood sugar levels) or changes in other laboratory values.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of Pegasys with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Children and adolescents
Pegasys use is restricted to children and adolescents with chronic hepatitis C aged 5 years and above
or children and adolescents with chronic hepatitis B aged 3 years and above.  Pegasys must not be 
given to children below the age of 3 years because it contains benzyl alcohol and may cause toxic 
reactions and allergic reactions in these children. 
 If your child has or has ever had a psychiatric disorder, talk to your doctor, who will 

monitor your child for signs or symptoms of depression (see section 4).
 When receiving Pegasys, your child may have slower growth and development (see section 4).

Other medicines and Pegasys
Do not use Pegasys if you are taking telbivudine (see “Do not use Pegasys”) because the combination 
of these medicines increases the risk of developing peripheral neuropathy (numbness, tingling, and/or 



108

burning sensations in the arms and/or legs). Therefore, the combination of Pegasys with telbivudine is 
contraindicated. Tell your doctor or pharmacist if you are being treated with telbivudine.
Tell your doctor if you are taking medicines for asthma, because the dose for your asthma medicine 
may need to be changed.

Patients who also have HIV infection: Tell your doctor if you are taking anti-HIV therapy. Lactic 
acidosis and worsening liver function are side effects associated with Highly Active Anti-Retroviral 
Therapy (HAART), an HIV treatment. If you are receiving HAART, the addition of Pegasys + 
ribavirin may increase your risk of lactic acidosis or liver failure. Your doctor will monitor you for 
signs and symptoms of these conditions. Patients receiving zidovudine in combination with ribavirin 
and alfa interferons are at increased risk of developing anaemia. Patients receiving azathioprin in 
combination with ribavirin and peginterferon are at increased risk of developing severe blood 
disorders. Please be sure to read the ribavirin package leaflet also.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.
When Pegasys is used in combination with ribavirin, both male and female patients must take special 
precautions in their sexual activity if there is any chance for pregnancy to occur, as ribavirin can be 
very damaging to an unborn baby:
● if you are a woman of childbearing potential who is taking Pegasys in combination with ribavirin, 
you must have a negative pregnancy test before treatment, each month during therapy and for the 4 
months after treatment is stopped. You must use an effective contraceptive during the time you are 
taking the treatment and for 4 months after stopping treatment. This can be discussed with your doctor.
● if you are a man who is taking Pegasys in combination with ribavirin, do not have sex with a 
pregnant woman unless you use a condom. This will lessen the chance for ribavirin to be left in the 
woman’s body. If your female partner is not pregnant now, but is of childbearing potential, she must 
be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. 
You or your partner must use an effective contraceptive during the time you are taking the treatment 
and for 7 months after stopping treatment. This can be discussed with your doctor.

Ask your doctor or pharmacist for advice before taking any medicine. It is not known whether this 
product is present in human milk. Therefore, do not breast-feed an infant if you are taking Pegasys. In 
combination therapy with ribavirin, take notice of the respective informing texts of ribavirin 
containing medicinal products.

Refer also to the package leaflets of any other medicines that are used in combination with Pegasys.

Driving and using machines
Do not drive or use machines if you feel drowsy, tired, or confused while taking Pegasys. 

Pegasys contains benzyl alcohol 
Must not be given to premature babies, neonates or children up to 3 years old. May cause toxic 
reactions and allergic reactions in infants and children up to 3 years old.

3. How to use Pegasys

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

Pegasys dosing
Your doctor has determined the exact dose of Pegasys, and will tell you how often to use it. If 
necessary, the dose may be changed during treatment. Do not exceed the recommended dose.



109

Pegasys is used alone only if you cannot take ribavirin for any reason.

Pegasys given alone or in combination with ribavirin is usually given at a dose of 
180 micrograms once a week.
The duration of combination treatment varies from 4 to 18 months depending on the type of 
virus you are infected with, on treatment response and whether you have been treated before. 
Please check with your doctor and follow the recommended duration of treatment.
Pegasys injection is normally taken at bedtime.

Use in children and adolescents
Your doctor has determined the exact dose of Pegasys for your child and will tell you how often to use 
it. The usual dose of Pegasysis based on your child’s height and weight. If necessary, the dose may be 
changed during treatment. It is recommended that Pegasys pre-filled syringes be used for children and 
adolescents, as they allow for dose adjustments.  Do not exceed the recommended dose.

The duration of combination treatment in children with chronic hepatitis C varies from 6 to 12 months 
depending on the type of virus your child is infected with and their response to therapy. In chronic 
hepatitis B the duration of Pegasys treatment is 48 weeks. Please check with your doctor and follow 
the recommended duration of treatment. Pegasys injection is normally taken at bedtime.

Pegasys is intended for subcutaneous use (under the skin). This means that Pegasys is injected with a 
short needle into the fatty tissue under the skin in the abdomen or thigh. If you are injecting this 
medicine yourself, you will be instructed how to give the injection. Detailed instructions are provided 
at the end of this leaflet (see “How to inject Pegasys”).

Use Pegasys exactly as described by your doctor, for as long as prescribed by your doctor.
If you have the impression that the effect of Pegasys is too strong or too weak, talk to your doctor or 
pharmacist.

Combination therapy with ribavirin in chronic hepatitis C
In the case of combination therapy with Pegasys and ribavirin, please follow the dosing regimen 
recommended by your doctor.

Combination therapy with other medicines in chronic hepatitis C
In the case of combination therapy with Pegasys, please follow the dosing regimen recommended 
by your doctor and refer also to the package leaflets of any other medicines that are used in 
combination with Pegasys.

If you use more Pegasys than you should
Contact your doctor or pharmacist as soon as possible.

If you forget to take Pegasys
If you realise you missed your injection 1 or 2 days after it was scheduled, you should inject your 
recommended dose as soon as possible. Take your next injection on the regularly scheduled day.
If you realise you missed your injection 3 to 5 days after it was scheduled, you should take your 
injection at the recommended dose as soon as possible. Take your next doses at 5 day intervals until 
you return to your regularly scheduled day of the week.

As an example: Your regular weekly Pegasys injection is on Monday. You remember on 
Friday that you forgot to take your injection on Monday (4 days late). You should inject your 
regularly scheduled dose immediately on Friday and take your next injection on Wednesday 
(5 days after your Friday dose). Your next injection will be on the Monday, 5 days later after 
the Wednesday injection. You are now back on your regularly scheduled day and should 
continue your injections every Monday.

If you realise you missed your injection 6 days after it was scheduled, you should wait and take your 
dose on the next day, your regularly scheduled day.
Contact your doctor or pharmacist if you need any help determining how to manage a missed dose of 
Pegasys.



110

Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some people get depressed when taking Pegasys alone or in combination treatment with ribavirin, and 
in some cases people have had suicidal thoughts or aggressive behaviour (sometimes directed against 
others such as thoughts about threatening the life of the others). Some patients have actually 
committed suicide. Be sure to seek emergency care if you notice that you are becoming depressed or 
have suicidal thoughts or change in your behaviour. You may want to consider asking a family 
member or close friend to help you stay alert to signs of depression or changes in your behaviour.

Growth and development (children and adolescents):
Some children and adolescents treated with Pegasys for chronic hepatitis B for 48 weeks did not grow 
or gain weight as much as expected for their age. It is not yet known whether they will return to their 
projected height and weight after completing treatment.

With up to one year of treatment with Pegasys in combination with ribavirin, some children and 
adolescents with chronic hepatitis C did not grow or gain weight as much as expected. While most 
children returned to their projected height within two years after completing treatment, and the 
majority of the remaining children within six years after completing treatment, it remains possible that 
Pegasys may affect the final adult height.

Tell your doctor immediately if you notice any of the following side effects: severe chest pain; 
persistent cough; irregular heartbeat; trouble breathing; confusion; depression; severe stomach pain; 
blood in stool (or black, tarry stools); severe nosebleed; fever or chills; problems with your eyesight. 
These side effects can be serious and you may need urgent medical attention.

Very common side effects with the combination of Pegasys and ribavirin (may effect more than 1 in 
10 people) are:

Metabolic disorders: Loss of appetite
Psychiatric and nervous system disorders: Feeling depressed (feeling low, feeling bad about yourself 
or feeling hopeless), anxiety, inability to sleep, headache, difficulty concentrating and dizziness
Breathing disorders: Cough, shortness of breath
Digestive system disorders: Diarrhoea, nausea, abdominal pain
Skin disorders: Loss of hair, and skin reactions (including itching, dermatitis and dry skin)
Muscle and bone disorders: Pain in joints and muscles
General disorders: Fever, weakness, tiredness, shaking, chills, pain, injection site irritation and 
irritability (getting easily upset)

Common side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 10 people) 
are:

Infections: Fungal, viral and bacterial infections. Upper respiratory infection, bronchitis, fungal 
infection of the mouth and herpes (a common recurring viral infection affecting the lips, mouth)
Blood disorders: Low platelet count (affecting the clotting ability), anaemia (low red cell count) and
enlarged lymph glands
Hormone system disorders: Overactive and underactive thyroid gland
Psychiatric and nervous system disorders: Mood /emotion changes, aggression, nervousness, 
decreased sexual desire, poor memory, fainting, decreased muscle strength, migraine, numbness, 
tingling, burning sensation, tremor, changes in the sense of taste, nightmares, sleepiness
Eye disorders: Blurry vision, eye pain, eye inflammation and dry eyes



111

Ear disorders: ear pain
Heart and blood vessel disorders: Rapid heart rate, pulsation of the heart beats, swelling in the 
extremities, flushing
Breathing disorders: Shortness  of breath with activity, nose bleeds, nose and throat inflammation, 
infections of the nose and sinuses (air-filled spaces found in the bones of the head and face), runny 
nose, sore throat
Digestive system disorders: Vomiting, indigestion, difficulty swallowing, mouth ulceration, bleeding 
gums, inflammation of tongue and mouth, flatulence (excess amount of air or gases), dry mouth and 
loss of weight
Skin disorders: Rash, increased sweating, psoriasis, hives, eczema, sensitivity to sunlight, night sweats
Muscle and bone disorders: Back pain, joint inflammation, muscle weakness, bone pain, neck pain, 
muscle pain, muscle cramps
Reproductive system disorders: Impotence (inability to maintain an erection)
General disorders: Chest pain, flu-like illness, malaise (not feeling well), lethargy, hot flushes, thirst

Uncommon side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 100 
people) are:

Infections: Lung infection, skin infections
Neoplasms benign and malignant disorders: Liver tumour
Immune system disorders: Sarcoidosis (areas of inflamed tissue occurring throughout the body), 
inflammation of the thyroid
Hormone system disorders: Diabetes (high blood sugar)
Metabolic disorders: Dehydration
Psychiatric and nervous system disorders: Thoughts of suicide, hallucinations (severe problems with 
personality and deterioration in normal social functioning),peripheral neuropathy (disorder of the 
nerves affecting the extremities)
Eye disorders: Bleeding in the retina (back of the eye)
Ear disorders: Hearing loss
Heart and blood vessel disorders: High blood pressure
Breathing disorders: Wheezing
Digestive system disorders: Gastrointestinal bleeding
Liver disorders: Poor functioning of the liver

Rare side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 1000 people) 
are:

Infections: Infection of the heart, infection of the external ear
Blood disorders: Severe reduction in red blood cells, white blood cells and platelets
Immune system disorders: Severe allergic reaction, systemic lupus erythematosus (an illness where the 
body attacks its own cells), rheumatoid arthritis (an autoimmune disease)
Hormone system disorders: Diabetic ketoacidosis, a complication of uncontrolled diabetes
Psychiatric and nervous system disorders: Suicide, psychotic disorders (severe problems with 
personality and deterioration in normal social functioning), coma (a deep prolonged unconsciousness), 
seizures, facial palsy (weakness of the facial muscle)
Eye disorders: Inflammation and swelling of the optic nerve, inflammation of the retina, ulceration of 
the cornea
Heart and blood vessel disorders: Heart attack, heart failure, heart pain, rapid heart rhythm, rhythm 
disorders or inflammation of the lining of the heart and cardiac muscle, bleeding in the brain and 
inflammation in the vessels
Breathing disorders: Interstitial pneumonia (inflammation of the lungs including fatal outcome), blood 
clots in the lung
Digestive system disorders: Stomach ulcer, inflammation of the pancreas
Liver disorders: Liver failure, bile duct inflammation, fatty liver
Muscle and bone disorders: Inflammation of the muscles
Kidney disorders: Kidney failure
Injury or poisoning: Substance overdose



112

Very rare side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 10,000 
people) are:

Blood disorders: Aplastic anaemia (failure of the bone marrow to produce red blood cells, white blood 
cells and platelets)
Immune system disorders: Idiopathic (or thrombotic) thrombocytopenic purpura (increased bruising, 
bleeding, decreased platelets, anaemia and extreme weakness)
Eye disorders: Loss of vision
Skin disorders: Toxic epidermal necrolysis/Stevens Johnson Syndrome/erythema multiforme (a 
spectrum of rashes with varying degrees of severity including death which may be associated with 
blisters in the mouth, nose, eyes and other mucosal membranes and sloughing of the affected area of 
the skin), angioedema (swelling in the skin and mucosa)

Side effects with unknown frequency:

Blood disorders: Pure red cell aplasia (a severe form of anaemia where red blood cell production is 
decreased or stopped); it can result in symptoms such as feeling very tired with no energy
Immune system disorders: Vogt Koyanagi Harada disease – a rare disease characterised by loss of 
vision, hearing and skin pigmentation; liver and kidney transplant rejections
Psychiatric and nervous system disorders: Mania (episodes of exaggerated elevation of mood) and 
bipolar disorders (episodes of exaggerated elevation of mood alternating with sadness and 
hopelessness); thoughts about threatening the life of others, stroke
Eye disorders: Rare form of retinal detachment with fluid in the retina
Heart and blood vessel disorders: Peripheral ischaemia (insufficient blood supply to the extremities)
Digestive system disorders: Ischaemic colitis (insufficient blood supply to the bowels), changes in the 
colour of the tongue
Muscle and bone disorders: Serious muscle damage and pain
Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with Pegasys.

When Pegasys is used alone in hepatitis B or C patients, some of these effects are less likely to occur.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Pegasys

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the 
last day of that month.

Store in a refrigerator (2C - 8C). Do not freeze. Keep the vial in the outer carton in order to protect 
from light.

Do not use this medicine if you notice the vial or packaging is damaged, if the solution is cloudy or if 
it has floating particles or if the medicine is any colour besides colourless to light yellow.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


113

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information

What Pegasys contains

● The active substance is peginterferon alfa-2a. Each vial of 1.0 ml solution contains 180 
micrograms peginterferon alfa-2a.

● The other ingredients are sodium chloride, polysorbate 80, benzyl alcohol, sodium acetate, 
acetic acid and water for injections.

What Pegasys looks like and contents of the pack

Pegasys is presented as a solution for injection in a vial (1 ml). It is available in packs containing 1 or 
4 single dose vials. Not all pack-sizes may be marketed.

Marketing Authorisation Holder
Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer

Roche Pharma AG
Emil-Barell-Str.1
D-79639 Grenzach-Wyhlen
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11

Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799

България
Рош България ЕООД
Тел: +359 2 818 44 44

Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)

Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111

Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800

Danmark
Roche a/s
Tlf: +45 - 36 39 99 99

Malta
(See Ireland)

Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140

Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050



114

Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380

Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00

Ελλάδα
Roche (Hellas) A.E. 
Τηλ: +30 210 61 66 100

Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739

España
Roche Farma S.A.
Tel: +34 - 91 324 81 00

Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88

France
Roche
Tél: +33 (0) 1 47 61 40 00

Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00

Hrvatska
Roche d.o.o.
Tel: +385 1 47 22 333

România
Roche România S.R.L.
Tel: +40 21 206 47 01

Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700

Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00

Ísland 
Roche a/s
c/o Icepharma hf
Simi: +354 540 8000

Slovenská republika 
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201

Italia
Roche S.p.A.
Tel: +39 - 039 2471

Suomi/Finland
Roche Oy 
Puh/Tel: +358 (0) 10 554 500

Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76

Sverige
Roche AB
Tel: +46 (0) 8 726 1200

Latvija
Roche Latvija SIA
Tel: +371 - 6 7 039831

United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000

This leaflet was last revised in 

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.



115

How to inject Pegasys

The following instructions explain how to use Pegasys single dose vials to inject yourself or your child. 
Please read the instructions carefully and follow them step by step. Your doctor or his/her assistant 
will instruct you on how to give the injections.

Getting ready

Wash your hand carefully before handling any of the items.

Collect the necessary items before beginning:
Included in the pack:
● a vial of Pegasys solution for injection
Not included in the pack:
● a 1 ml syringe
● a long needle to withdraw Pegasys from the vial
● a short needle for the subcutaneous injection
● a cleansing swab
● small bandage or sterile gauze
● an adhesive bandage
● a container for the waste material

Measuring the dose of Pegasys

● Remove the protective cap from the Pegasys vial (1).

● Clean the rubber top of the vial with a cleansing swab.
You can save the swab to clean the skin area where you will inject Pegasys.

● Remove the syringe from the wrapping. Do not touch the tip of the syringe. 
● Take the long needle and place it firmly on to the tip of the syringe (2). 

● Remove the needle guard without touching the needle and keep the syringe with the needle in 
your hand.



116

● Insert the needle through the rubber top of the Pegasys vial (3).

● Hold the vial and syringe in one hand and turn the vial and the syringe upside down (4).

4

With the syringe pointing up, make certain that the tip of the needle is in the Pegasys solution. Your 
other hand will be free to move the plunger of the syringe.
● Slowly pull back the plunger to withdraw a bit more than the dose prescribed by your doctor 

into the syringe.
● Hold the syringe with the needle in the vial pointing up, remove the syringe from the long 

needle while keeping the needle in the vial and without touching the tip of the syringe.
● Take the short needle and place it firmly on to the tip of the syringe (5).

● Remove the needle guard from the syringe needle.
● Check for air bubbles in the syringe. If you see any bubbles, pull the plunger slightly back. To 

remove air bubbles from the syringe, hold the syringe with the needle pointing up. Tap the 
syringe gently to bring the bubbles to the top. Push the plunger up slowly to the correct dose. 
Replace the needle guard and place the syringe in a horizontal position until ready for use.

● Allow the solution to reach room temperature before injection or warm the syringe between 
your palms.

● Visually inspect the solution prior to administration: do not use if it is discoloured or if particles 
are present. You are now ready to inject the dose.



117

Injecting the solution

● Select the injection site in the abdomen or thigh (except your navel or waistline). Change your 
injection site each time.

● Clean and disinfect the skin where the injection is to be made with a cleansing swab.
● Wait for the area to dry.
● Remove the needle guard.
● With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you would a 

pencil.
● Insert the needle all the way into the pinched skin at an angle of 45 to 90 (6).

● Inject the solution by gently pushing the plunger all the way down.
● Pull the needle straight out of the skin.
● Press the injection site with a small bandage or sterile gauze if necessary for several seconds.

Do not massage the injection site. If there is bleeding, cover with an adhesive bandage.

Disposal of the injection materials

The syringe, needle and all injection materials are intended for single use and must be discarded after 
the injection. Dispose of the syringe and needle safely in a closed container. Ask your doctor, hospital 
or pharmacist for an appropriate container.



118

Package leaflet: Information for the user

Pegasys 90 micrograms solution for injection in pre-filled syringe
Pegasys 135 micrograms solution for injection in pre-filled syringe
Pegasys 180 micrograms solution for injection in pre-filled syringe

Peginterferon alfa-2a

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
● Keep this leaflet. You may need to read it again.
● If you have any further questions, ask your doctor, pharmacist or nurse.
● This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
● If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet 
1. What Pegasys is and what it is used for
2. What you need to know before you use Pegasys
3. How to use Pegasys
4. Possible side effects
5. How to store Pegasys
6. Contents of the pack and other information

1. What Pegasys is and what it is used for

Pegasys contains the active substance peginterferon alfa-2a, which is a long-acting interferon. 
Interferon is a protein that modifies the response of the body's immune system to help fight infections 
and severe diseases. Pegasys is used to treat chronic hepatitis B or chronic hepatitis C in adults. It is 
also used to treat chronic hepatitis B in children and adolescents aged 3 years and older and chronic 
hepatitis C in children and adolescents aged 5 years and older, who have not been treated before. Both 
chronic hepatitis B and C are viral infections of the liver.

Chronic Hepatitis B: Pegasys is usually used alone.
Chronic Hepatitis C: Pegasys is used in combination with other medicines, for the treatment of 
chronic hepatitis C (CHC). 

Refer also to the package leaflets of any other medicines that are used in combination with Pegasys.

2. What you need to know before you use Pegasys

Do not use Pegasys
● if you are allergic to peginterferon-alfa-2a, to any interferon or any of the other ingredients of 

this medicine (listed in section 6).
● if you have ever had a heart attack or have been hospitalised for serious chest pains in the last 

six months.
● if you have, so called autoimmune hepatitis.
● if you have advanced liver disease and your liver does not work properly (e.g. your skin has 

become yellow).
● if the patient is a child less than 3 years old.
● if the patient is a child who has ever had serious psychiatric conditions such as severe 

depression or thoughts of committing suicide.
● if you are infected with both the hepatitis C virus and the human immunodeficiency virus, and 

your liver does not work properly (e.g. your skin has become yellow).



119

● if you are being treated with telbivudine, a medicine for hepatitis B infection (see “Other 
medicines and Pegasys”).

Warnings and precautions
Talk to your doctor , pharmacist or nurse before using Pegasys
● if you have had a severe nervous or mental disorder.
● if you have ever had depression or symptoms associated with depression (e.g. feelings of 

sadness, dejection, etc.).
● if you are an adult who has or had a  history of substance abuse (e.g. alcohol or drugs)
● if you have psoriasis, it may get worse during treatment with Pegasys.
● if you have a problem with your liver other than hepatitis B or C.
● if you have diabetes or high blood pressure, your doctor may ask you to have an eye 

examination.
● if you have been told you have VKH syndrome.
● if you have thyroid disease that is not well controlled with medicines.
● if you have ever had anaemia.
● if you have had an organ transplant (liver or kidney) or have one planned in the near future.
● if you are coinfected with HIV and treated with anti HIV medicinal products.
● if you have been withdrawn from previous therapy for Hepatitis C because of anaemia or low 

blood count.

Once you have started Pegasys treatment, talk to your doctor, nurse or pharmacist:
● if you develop symptoms associated with depression (e.g. feelings of sadness, dejection, etc.) 

(see section 4).
● if you notice a change in your vision.
● if you develop symptoms associated with a cold or other respiratory infection (such as cough, 

fever or any difficulty in breathing).
● if you think you are getting an infection (such as pneumonia) as when receiving Pegasys you 

may temporarily have a greater risk of getting an infection.
● if you develop any signs of bleeding or unusual bruising, check with your doctor immediately.
● if you develop signs of a severe allergic reaction (such as difficulty in breathing, wheezing or 

hives) while on this medication, seek medical help immediately.
● if you develop symptoms of Vogt-Koyanagi-Harada syndrome; combination of complaints of 

neck stiffness, headache, loss of colour in skin or hair, eye disorders (such as blurred vision), 
and/or hearing abnormality (such as ringing in the ears).

During treatment your doctor will take blood samples regularly to check for changes in your white 
blood cells (cells that fight infection), red blood cells (cells that carry oxygen), platelets (blood clotting 
cells), liver function, glucose (blood sugar levels) or changes in other laboratory values.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of Pegasys with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Children and adolescents
Pegasys use is restricted to children and adolescents with chronic hepatitis C aged 5 years and above 
or children and adolescents with chronic hepatitis B aged 3 years and above. Pegasys must not be 
given to children below the age of 3 years because it contains benzyl alcohol and may cause toxic 
reactions and allergic reactions in these children.
 If your child has or has ever had a psychiatric disorder, talk to your doctor, who will 

monitor your child for signs or symptoms of depression (see section 4).
 When receiving Pegasys, your child may have slower growth and development (see section 4).



120

Other medicines and Pegasys
Do not use Pegasys if you are taking telbivudine (see “Do not use Pegasys”) because the combination 
of these medicines increases the risk of developing peripheral neuropathy (numbness, tingling, and/or 
burning sensations in the arms and/or legs). Therefore, the combination of Pegasys with telbivudine is 
contraindicated. Tell your doctor or pharmacist if you are being treated with telbivudine.
Tell your doctor if you are taking medicines for asthma, because the dose for your asthma medicine 
may need to be changed.
Patients who also have HIV infection: Tell your doctor if you are taking anti-HIV therapy. Lactic 
acidosis and worsening liver function are side effects associated with Highly Active Anti-Retroviral 
Therapy (HAART), an HIV treatment. If you are receiving HAART, the addition of Pegasys + 
ribavirin may increase your risk of lactic acidosis or liver failure. Your doctor will monitor you for 
signs and symptoms of these conditions. Patients receiving zidovudine in combination with ribavirin 
and alfa interferons are at increased risk of developing anaemia. Patients receiving azathioprin in 
combination with ribavirin and peginterferon are at increased risk of developing severe blood 
disorders. Please be sure to read the ribavirin package leaflet also.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.
When Pegasys is used in combination with ribavirin, both male and female patients must take special 
precautions in their sexual activity if there is any chance for pregnancy to occur, as ribavirin can be 
very damaging to an unborn baby:
● if you are a woman of childbearing potential who is taking Pegasys in combination with ribavirin, 
you must have a negative pregnancy test before treatment, each month during therapy and for the 4 
months after treatment is stopped. You must use an effective contraceptive during the time you are 
taking the treatment and for 4 months after stopping treatment. This can be discussed with your doctor.
● if you are a man who is taking Pegasys in combination with ribavirin, do not have sex with a 
pregnant woman unless you use a condom. This will lessen the chance for ribavirin to be left in the 
woman’s body. If your female partner is not pregnant now, but is of childbearing potential, she must 
be tested for pregnancy each month during treatment and for the 7 months after treatment has stopped. 
You or your partner must use an effective contraceptive during the time you are taking the treatment 
and for 7 months after stopping treatment. This can be discussed with your doctor.

Ask your doctor or pharmacist for advice before taking any medicine. It is not known whether this 
product is present in human milk. Therefore, do not breast-feed an infant if you are taking Pegasys. In 
combination therapy with ribavirin, take notice of the respective informing texts of ribavirin 
containing medicinal products.

Refer also to the package leaflets of any other medicines that are used in combination with Pegasys.

Driving and using machines
Do not drive or use machinery if you feel drowsy, tired, or confused while taking Pegasys.

Pegasys contains benzyl alcohol
Must not be given to premature babies, neonates or children up to 3 years old. May cause toxic 
reactions and allergic reactions in infants and children up to 3 years old.

3. How to use Pegasys

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.



121

Pegasys dosing
Your doctor has determined the exact dose of Pegasys, and will tell you how often to use it. If 
necessary, the dose may be changed during treatment. Do not exceed the recommended dose.

Pegasys is used alone only if you cannot take ribavirin for any reason

Pegasys given alone or in combination with ribavirin is usually given at a dose of 
180 micrograms once a week.
The duration of combination treatment varies from 4 to 18 months depending on the type of 
virus you are infected with, on treatment response and whether you have been treated before. 
Please check with your doctor and follow the recommended duration of treatment.
Pegasys injection is normally taken at bedtime.

Use in children  and adolescents
Your doctor has determined the exact dose of Pegasys for your child and will tell you how often to use 
it. The usual dose of Pegasys is based on your child’s height and weight. If necessary, the dose may be 
changed during treatment. It is recommended that Pegasys pre-filled syringes be used for children and 
adolescents, as they allow for dose adjustments. Do not exceed the recommended dose.

The duration of combination treatment in children with chronic hepatitis C varies from 6 to 12 months 
depending on the type of virus your child is infected with and their response to therapy. In chronic 
hepatitis B the duration of Pegasys treatment is 48 weeks. Please check with your doctor and follow 
the recommended duration of treatment. Pegasys injection is normally taken at bedtime.

Pegasys is intended for subcutaneous use (under the skin). This means that Pegasys is injected with a 
short needle into the fatty tissue under the skin in the abdomen or thigh. If you are injecting this 
medicine yourself, you will be instructed how to give the injection. Detailed instructions are provided 
at the end of this leaflet (see “How to inject Pegasys”).

Use Pegasys exactly as described by your doctor, for as long as prescribed by your doctor.
If you have the impression that the effect of Pegasys is too strong or too weak, talk to your doctor or 
pharmacist.

Combination therapy with ribavirin in chronic hepatitis C
In the case of combination therapy with Pegasys and ribavirin, please follow the dosing regimen 
recommended by your doctor.

Combination therapy with other medicines in chronic hepatitis C
In the case of combination therapy with Pegasys, please follow the dosing regimen recommended 
by your doctor and refer also to the package leaflets of any other medicines that are used in 
combination with Pegasys.

If you use more Pegasys than you should
Contact your doctor or pharmacist as soon as possible.

If you forget to take Pegasys
If you realise you missed your injection 1 or 2 days after it was scheduled, you should inject your 
recommended dose as soon as possible. Take your next injection on the regularly scheduled day.
If you realise you missed your injection 3 to 5 days after it was scheduled, you should take your 
injection at the recommended dose as soon as possible. Take your next doses at 5 day intervals until 
you return to your regularly scheduled day of the week. 

As an example: Your regular weekly Pegasys injection is on Monday. You remember on 
Friday that you forgot to take your injection on Monday (4 days late). You should inject your 
regularly scheduled dose immediately on Friday and take your next injection on Wednesday 
(5 days after your Friday dose). Your next injection will be on the Monday, 5 days later after 
the Wednesday injection. You are now back on your regularly scheduled day and should 
continue your injections every Monday.



122

If you realise you missed your injection 6 days after it was scheduled, you should wait and take your 
dose on the next day, your regularly scheduled day.
Contact your doctor or pharmacist if you need any help determining how to manage a missed dose of 
Pegasys.

Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some people get depressed when taking Pegasys alone or in combination treatment with ribavirin, and 
in some cases people have had suicidal thoughts or aggressive behaviour (sometimes directed against 
others such as thoughts about threatening the life of the others). Some patients have actually 
committed suicide. Be sure to seek emergency care if you notice that you are becoming depressed or 
have suicidal thoughts or change in your behaviour. You may want to consider asking a family 
member or close friend to help you stay alert to signs of depression or changes in your behaviour.

Growth and development (children and adolescents):
Some children and adolescents treated with Pegasys for chronic hepatitis B for 48 weeks did not grow 
or gain weight as much as expected for their age. It is not yet known whether they will return to their 
projected height and weight after completing treatment.

With up to one year of treatment with Pegasys in combination with ribavirin, some children and 
adolescents with chronic hepatitis C did not grow or gain weight as much as expected. While most 
children returned to their projected height within two years after completing treatment, and the 
majority of the remaining children within six years after completing treatment, it remains possible that 
Pegasys may affect the final adult height.

Tell your doctor immediately if you notice any of the following side effects: severe chest pain; 
persistent cough; irregular heartbeat; trouble breathing; confusion; depression; severe stomach pain; 
blood in stool (or black, tarry stools); severe nosebleed; fever or chills; problems with your eyesight. 
These side effects can be serious and you may need urgent medical attention.

Very common side effects with the combination of Pegasys and ribavirin (may affect more than 1 in 
10 people) are:

Metabolic disorders: Loss of appetite
Psychiatric and nervous system disorders: Feeling depressed (feeling low, feeling bad about yourself 
or feeling hopeless), anxiety, inability to sleep, headache, difficulty concentrating and dizziness
Breathing disorders: Cough, shortness of breath
Digestive system disorders: Diarrhoea, nausea, abdominal pain
Skin disorders: Loss of hair, and skin reactions (including itching, dermatitis and dry skin)
Muscle and bone disorders: Pain in joints and muscles
General disorders: Fever, weakness, tiredness, shaking, chills, pain, injection site irritation and 
irritability (getting easily upset)

Common side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 10 people) 
are:

Infections: Fungal, viral and bacterial infections. Upper respiratory infection, bronchitis, fungal 
infection of the mouth and herpes (a common recurring viral infection affecting the lips, mouth)
Blood disorders: Low platelet count (affecting the clotting ability), anaemia (low red cell count) and 
enlarged lymph glands
Hormone system disorders: Overactive and underactive thyroid gland



123

Psychiatric and nervous system disorders: Mood /emotion changes, aggression, nervousness, 
decreased sexual desire, poor memory, fainting, decreased muscle strength, migraine, numbness, 
tingling, burning sensation, tremor, changes in the sense of taste, nightmares, sleepiness 
Eye disorders: Blurry vision, eye pain, eye inflammation and dry eyes
Ear disorders: ear pain
Heart and blood vessel disorders: Rapid heart rate, pulsation of the heart beats, swelling in the 
extremities, flushing
Breathing disorders: Shortness of breath with activity, nose bleeds, nose and throat inflammation, 
infections of the nose and sinuses (air-filled spaces found in the bones of the head and face), runny 
nose, sore throat
Digestive system disorders: Vomiting, indigestion, difficulty swallowing, mouth ulceration, bleeding 
gums, inflammation of tongue and mouth, flatulence (excess amount of air or gases), dry mouth and 
loss of weight
Skin disorders: Rash, increased sweating, psoriasis, hives, eczema, sensitivity to sunlight, night sweats
Muscle and bone disorders: Back pain, joint inflammation, muscle weakness, bone pain, neck pain, 
muscle pain, muscle cramps
Reproductive system disorders: Impotence (inability to maintain an erection)
General disorders: Chest pain, flu-like illness, malaise (not feeling well), lethargy, hot flushes, thirst

Uncommon side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 100 
people) are:

Infections: Lung infection, skin infections
Neoplasms benign and malignant disorders: Liver tumour
Immune system disorders: Sarcoidosis (areas of inflamed tissue occurring throughout the body), 
inflammation of the thyroid
Hormone system disorders: Diabetes (high blood sugar)
Metabolic disorders: Dehydration
Psychiatric and nervous system disorders: Thoughts of suicide, hallucinations (severe problems with 
personality and deterioration in normal social functioning), peripheral neuropathy (disorder of the 
nerves affecting the extremities)
Eye disorders: Bleeding in the retina (back of the eye)
Ear disorders: Hearing loss
Heart and blood vessel disorders: High blood pressure
Breathing disorders: Wheezing
Digestive system disorders: Gastrointestinal bleeding
Liver disorders: Poor functioning of the liver

Rare side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 1000 people) 
are:

Infections: Infection of the heart, infection of the external ear
Blood disorders: Severe reduction in red blood cells, white blood cells and platelets
Immune system disorders: Severe allergic reaction, systemic lupus erythematosus (an illness where the 
body attacks its own cells), rheumatoid arthritis (an autoimmune disease)
Hormone system disorders: Diabetic ketoacidosis, a complication of uncontrolled diabetes
Psychiatric and nervous system disorders: Suicide, psychotic disorders (severe problems with 
personality and deterioration in normal social functioning), coma (a deep prolonged unconsciousness), 
seizures, facial palsy (weakness of the facial muscle)
Eye disorders: Inflammation and swelling of the optic nerve, inflammation of the retina, ulceration of 
the cornea
Heart and blood vessel disorders: Heart attack, heart failure, heart pain, rapid heart rhythm, rhythm 
disorders or inflammation of the lining of the heart and cardiac muscle, bleeding in the brain and 
inflammation in the vessels
Breathing disorders: Interstitial pneumonia (inflammation of the lungs including fatal outcome), blood 
clots in the lung
Digestive system disorders: Stomach ulcer, inflammation of the pancreas



124

Liver disorders: Liver failure, bile duct inflammation, fatty liver
Muscle and bone disorders: Inflammation of the muscles
Kidney disorders: Kidney failure
Injury or poisoning: Substance overdose

Very rare side effects with the combination of Pegasys and ribavirin (may affect up to 1 in 10,000 
people) are:

Blood disorders: Aplastic anaemia (failure of the bone marrow to produce red blood cells, white blood 
cells and platelets)
Immune system disorders: Idiopathic (or thrombotic) thrombocytopenic purpura (increased bruising, 
bleeding, decreased platelets, anaemia and extreme weakness)
Eye disorders: Loss of vision
Skin disorders: Toxic epidermal necrolysis/Stevens Johnson Syndrome/erythema multiforme (a 
spectrum of rashes with varying degrees of severity including death which may be associated with 
blisters in the mouth, nose, eyes and other mucosal membranes and sloughing of the affected area of 
the skin), angioedema (swelling in the skin and mucosa)

Side effects with unknown frequency:

Blood disorders: Pure red cell aplasia (a severe form of anemia where red blood cell production is 
decreased or stopped); it can result in symptoms such as feeling very tired with no energy
Immune system disorders: Vogt Koyanagi Harada disease – a rare disease characterised by loss of 
vision, hearing and skin pigmentation; liver and kidney transplant rejections
Psychiatric and nervous system disorders: Mania (episodes of exaggerated elevation of mood) and 
bipolar disorders (episodes of exaggerated elevation of mood alternating with sadness and 
hopelessness); thoughts about threatening the life of others, stroke
Eye disorders: Rare form of retinal detachment with fluid in the retina
Heart and blood vessel disorders: Peripheral ischaemia (insufficient blood supply to the extremities)
Digestive system disorders: Ischaemic colitis (insufficient blood supply to the bowels), changes in the 
colour of the tongue
Muscle and bone disorders: Serious muscle damage and pain
Pulmonary arterial hypertension - a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with Pegasys.

When Pegasys is used alone in hepatitis B or C patients, some of these effects are less likely to occur

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Pegasys

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the 
last day of that month.

Store in a refrigerator (2C - 8C). Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


125

Do not use this medicine if you notice the syringe or needle packaging is damaged, if the solution is 
cloudy or if it has floating particles or if the medicine is any colour besides colourless to light yellow.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Pegasys contains

● The active substance is peginterferon alfa-2a. Each pre-filled syringe of 0.5 ml solution contains 
90, 135 or 180 micrograms peginterferon alfa-2a.

● The other ingredients are sodium chloride, polysorbate 80, benzyl alcohol, sodium acetate, 
acetic acid and water for injections.

What Pegasys looks like and contents of the pack

Pegasys is presented as a solution for injection in a pre-filled syringe (0.5 ml) with a separate injection 
needle. 

Pegasys 90 micrograms solution for injection in pre-filled syringe
The syringe contains graduation marks corresponding to 90 micrograms (mcg), 65 mcg, 45 mcg, 
30 mcg, 20 mcg and 10 mcg. It is available in packs containing 1 pre-filled syringe.

Pegasys 135 micrograms solution for injection in pre-filled syringe
The syringe contains graduation marks corresponding to 135 micrograms (mcg), 90 mcg and 45 mcg. 
It is available in packs containing containing 1, 4 or a multipack of 12 (2 packs of 6) pre-filled 
syringes. Not all pack-sizes may be marketed.

Pegasys 180 micrograms solution for injection in pre-filled syringe
The syringe contains graduation marks corresponding to 180 micrograms (mcg), 135 mcg and 90 mcg. 
It is available in packs containing containing 1, 4 or a multipack of 12 (2 packs of 6) pre-filled 
syringes. Not all pack-sizes may be marketed.

Marketing Authorisation Holder
Roche Registration GmbH 
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer

Roche Pharma AG
Emil-Barell-Str.1
D-79639 Grenzach-Wyhlen
Germany



126

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11

Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799

България
Рош България ЕООД
Тел: +359 2 818 44 44

Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)

Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111

Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800

Danmark
Roche a/s
Tlf: +45 - 36 39 99 99

Malta
(See Ireland)

Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140

Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050

Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380

Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00

Ελλάδα
Roche (Hellas) A.E. 
Τηλ: +30 210 61 66 100

Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739

España
Roche Farma S.A.
Tel: +34 - 91 324 81 00

Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88

France
Roche
Tél: +33 (0) 1 47 61 40 00

Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00

Hrvatska
Roche d.o.o.
Tel: +385 1 47 22 333

România
Roche România S.R.L.
Tel: +40 21 206 47 01

Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700

Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00

Ísland 
Roche a/s
c/o Icepharma hf
Simi: +354 540 8000

Slovenská republika 
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201

Italia
Roche S.p.A.
Tel: +39 - 039 2471

Suomi/Finland
Roche Oy 
Puh/Tel: +358 (0) 10 554 500



127

Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76

Sverige
Roche AB
Tel: +46 (0) 8 726 1200

Latvija
Roche Latvija SIA
Tel: +371 - 6 7 039831

United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.



128

How to inject Pegasys
The following instructions explain how to use Pegasys pre-filled syringes to inject yourself or your 
child. Please read the instructions carefully and follow them step by step. Your doctor or his/her 
assistant will instruct you on how to give the injections.

Getting ready

Wash your hands carefully before handling any of the items.

Collect the necessary items before beginning:
Included in the pack:
● a pre-filled syringe of Pegasys
● an injection needle
Not included in the pack:
● a cleansing swab 
● small bandage or sterile gauze 
● an adhesive bandage 
● a container for the waste material

Preparing the syringe and needle for injection

● Remove the protective cap that covers the back of the needle (1-2).

● Remove the rubber cap from the syringe (3). Do not touch the tip of the syringe.

● Place the needle firmly on the tip of the syringe (4).

● Remove the needle guard from the syringe needle (5).

● To remove air bubbles from the syringe, hold the syringe with the needle pointing up. Tap the 
syringe gently to bring the bubbles to the top. Push the plunger up slowly to the correct dose. 
Replace the needle guard and place the syringe in a horizontal position until ready for use.

● Allow the solution to reach room temperature before injection or warm the syringe between 
your palms.

● Visually inspect the solution prior to administration: do not use if it is discoloured or if particles 
are present.



129

You are now ready to inject the dose.

Injecting the solution

● Select the injection site in the abdomen or thigh (except your navel or waistline). Change your 
injection site each time.

● Clean and disinfect the skin where the injection is to be made with a cleansing swab.
● Wait for the area to dry.
● Remove the needle guard.
● With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you would a 

pencil.
● Insert the needle all the way into the pinched skin at an angle of 45 to 90 (6).

● Inject the solution by gently pushing the plunger all the way down to the appropriate graduation.
● Pull the needle straight out of the skin.
● Press the injection site with a small bandage or sterile gauze if necessary for several seconds.

Do not massage the injection site. If there is bleeding, cover with an adhesive bandage.

Disposal of the injection materials

The syringe, needle and all injection materials are intended for single use and must be discarded after 
the injection. Dispose of the syringe and needle safely in a closed container. Ask your doctor, hospital 
or pharmacist for an appropriate container.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET