ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Pegasys 135 micrograms solution for injection
2.
peginterferon alfa-2a*.....................................................................................135 micrograms
Each vial of 1 ml solution contains 135 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 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.
For a full list of excipients, see section 6.1.
Excipient:
Benzyl alcohol (10 mg/ 1 ml)
3.
Solution for injection (injection).
The solution is clear and colourless to light yellow.
4.
Chronic hepatitis B:
Pegasys is indicated for the treatment of HBeAg-positive or HBeAg-negative chronic hepatitis B in
adult patients with compensated liver disease and evidence of viral replication, increased ALT and
histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1).
Chronic hepatitis C:
Pegasys is indicated for the treatment of chronic hepatitis C in adult patients who are positive for
serum HCV-RNA, including patients with compensated cirrhosis and/or co-infected with clinically
stable
HIV (see section 4.4).
The optimal way to use Pegasys in patients with chronic hepatitis C is in combination with ribavirin.
The combination of Pegasys and ribavirin is indicated in naive patients and patients
who have failed
previous treatment with interferon alpha (pegylated or non-pegylated) alone or in combination therapy
with ribavirin.
Monotherapy is indicated mainly in case of intolerance or contraindication to ribavirin.
2
Treatment should be initiated only by a physician experienced in the treatment of patients with
hepatitis B or C.
Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be
used in combination with ribavirin.
Dose to be administered and duration of treatment
Chronic hepatitis B:
The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative
chronic hepatitis B is 180 micrograms once weekly for 48 weeks by subcutaneous administration in
the abdomen or thigh.
Chronic hepatitis C – treatment-naïve patients:
The recommended dose for Pegasys is 180 micrograms once weekly by subcutaneous administration
in the abdomen or thigh 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
The duration of combination therapy with ribavirin for chronic hepatitis C 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
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 1000/1200 mg of ribavirin for 48 weeks is recommended.
3
Table 1: Dosing Recommendations for Combination Therapy for HCV Patients
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 retreating non-responding and relapsing patients.
The recommended duration of Pegasys monotherapy is 48 weeks.
Chronic hepatitis C – treatment-experienced 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
PEG-IFN and ribavirin are considered for treatment, the recommended total duration of therapy is 72
weeks (see section 5.1).
HIV-HCV co-infection
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 that 48 weeks has not been adequately studied.
Predictability of response and non-response – 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 6).
4
Table 2: Predictive Value of Week 12 Virological Response at the Recommended Dosing
Regimen while on Pegasys Combination Therapy
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 – 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
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. However, 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)
Dose reduction is recommended if the neutrophil count is < 750/mm
3
. For patients with Absolute
Neutrophil Count (ANC) < 500/mm
3
treatment should be suspended until ANC values return to
> 1000/mm
3
. 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 < 50,000/mm
3
. Cessation of
therapy is recommended when platelet count decreases to levels < 25,000/mm
3
.
Specific recommendations for management of treatment-emergent anaemia 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 apply: (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.
5
Table 3: Dose Adjustment for Adverse Reaction (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
< 750/mm
3
< 500/mm
3
Platelet Count
< 50,000/mm
3
> 25,000/mm
3
< 25,000/mm
3
Haemoglobin
- nocardiac
disease
< 10 g/dl, and
≥ 8.5 g/dl
< 8.5 g/dl
Haemoglobin
- stablecardiac
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 chronic hepatitis C.
As with other alpha interferons, increases in ALT levels above baseline (BL) have been observed in
patients treated with Pegasys, including patients with a virological response.
In chronic hepatitis C clinical trials, isolated increases in ALT (≥ 10x 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 increase in ALT levels is progressive despite dose
reduction, or is accompanied by increased bilirubin or evidence of hepatic decompensation, therapy
should be discontinued (see section 4.4).
For chronic hepatitis B patients, transient flares of ALT levels sometimes exceeding 10 times the
upper limit of normal are not uncommon, and may reflect immune clearance. Treatment should
normally not be initiated if ALT is >10 times the upper limit of normal. 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).
Children and adolescents
Only limited safety and efficacy data are available in children and adolescents (6-18 years) (see
section 5.1). Pegasys is contraindicated in neonates and young children up to 3 years old because of
the excipient benzyl alcohol (see sections 4.3 and 4.4).
Patients with renal impairment
In patients with end stage renal disease, a starting dose of 135 micrograms should be used (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.
6
Patients with hepatic impairment
In patients with compensated cirrhosis (eg, Child-Pugh A), Pegasys has been shown to be effective
and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (eg, 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)
<2
2.0-3
>3
1
2
3
SI unit = μmol/l)
<34
34-51
>51
1
2
3
S-Albumin (g/dl)
>3.5
3.5-2.8
<2.8
1
2
3
1
2
3
*Grading according to Trey, Burns and Saunders (1966)
<1.7
1.7-2.3
>2.3
•
Hypersensitivity to the active substance, to alpha interferons, or to any of the excipients
•
Autoimmune hepatitis
•
Severe hepatic dysfunction or decompensated cirrhosis of the liver
•
Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see
section 4.4 for benzyl alcohol)
•
A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac
disease in the previous six months (see section 4.4)
•
Initiation of Pegasys is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh
score ≥ 6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir
and indinavir
For contraindications to ribavirin, please refer also to the ribavirin Summary of Product Characteristics
(SPC) when Pegasys is to be used in combination with ribavirin.
7
INR
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 alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric
disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be
borne in mind by the prescribing physician and the need for adequate therapeutic management should
be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is
recommended that treatment with 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.
Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be
used in combination with ribavirin.
All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases
(ie, patients with genotype 2 or 3), treatment may be possible without histological confirmation.
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to
commencing treatment.
In patients with normal ALT, progression of fibrosis occurs on average at a slower rate than in patients
with elevated ALT. This should be considered in conjunction with other factors, such as HCV
genotype, age, extrahepatic manifestations, risk of transmission, etc. which influence the decision to
treat or not.
Excipient: Benzyl alcohol. Pegasys is contraindicated in infants or young children up to 3 years old
because of the excipient benzyl alcohol.
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/mm
3
-
Absolute neutrophil counts ≥ 1500/mm
3
-
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.
In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell
(WBC) count and absolute neutrophil count (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).
8
The occurrence of anaemia (haemoglobin <10 g/dl) has been observed in up to 15% of chronic
hepatitis C 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.
As with other interferons, 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 reintroduction of either treatment alone (see section
4.5).
The use of Pegasys and ribavirin combination therapy in chronic hepatitis C patients who failed prior
treatment has not been adequately studied in patients who discontinued prior therapy for
hematological adverse events. 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 alpha 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 medication. 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). As with other interferons, 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 nor 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 alpha 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. As with other alpha interferons, 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 chronic hepatitis B, unlike chronic hepatitis C, 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 case of flares exceeding 10 times the upper limit of normal, 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.
9
Hypersensitivity
Serious, acute hypersensitivity reaction (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis)
have been rarely observed during alpha 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 alpha interferons. Patients predisposed to the development of autoimmune disorders may be at
increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also
Endocrine System
in sections 4.4 and 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment
should be withdrawn and corticosteroid therapy discussed (see section 4.8).
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 alpha interferons including Pegasys. Appropriate anti-
infective therapy should be started immediately and discontinuation of therapy should be considered.
Ocular changes
As with other interferons 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.
Patients with preexisting ophthalmologic disorders (eg, 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
As with other alpha interferons, 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 alpha 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 coinfection
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).
10
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 SPC).
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 subjects with
CD4 counts less than 200 cells/uL. 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.
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
11
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 hematologic monitoring be done
during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with
these drugs 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.
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 ART regimen if this is
already established. This would be particularly important in patients with a known history of
zidovudine induced anaemia.
There are no adequate data on 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.
It is not known whether the components of this medicinal product are excreted in human milk.
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior
to initiation of treatment.
12
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 and their partners must each use
an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male
patients and their female partners must each use an effective contraceptive during treatment and for 7
months after treatment has been concluded. Please refer to the ribavirin SPC.
Pegasys has a 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.
Experience from clinical trials
Chronic hepatitis C
The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar
to those reported with interferon alfa-2a (see Table 4). 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 B
In clinical trials of 48 week treatment and 24 weeks follow-up, the safety profile for Pegasys in
chronic hepatitis B was similar to that seen in chronic hepatitis C. 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 HCV patients treated with Pegasys monotherapy (see Table
4) 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 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 hematological 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/mm
3
were treated for 48 weeks. Haematologic
laboratory abnormalities observed during the first 20 weeks of the trial included anemia (26% of
13
patients experienced a hemoglobin level of <10 g/dL), neutropenia (30% experienced an ANC
<750/mm
3
), and thrombocytopenia (13% experienced a platelet count <50,000/ mm
3
) (see section 4.4).
Chronic hepatitis C and HIV co-infection
In HIV-HCV co-infected patients, the clinical adverse event 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.
Table 4 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC
patients and with Pegasys in combination with ribavirin in CHC patients.
Table 4: Undesirable Effects Reported with Pegasys Monotherapy for HBV or HCV or In
Combination with Ribavirin for HCV Patients
Body system
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
Infections and
infestations
Upper respiratory
infection,
bronchitis, oral
candidiasis, herpes
simplex, fungal,
viral and bacterial
infections
Pneumonia,
skin infection
Endocarditis,
otitis externa
Neoplasms
benign and
malignant
Hepatic
neoplasm
Blood and
lymphatic system
disorders
Thrombocytopenia,
anaemia,
lymphadenopathy
Pancytopenia
Aplastic anemia
Immune system
disorders
Sarcoidosis,
thyroiditis
Anaphylaxis,
systemic lupus
erythematosus,
rheumatoid
arthritis
Idiopathic or
thrombotic
thrombocytopenic
purpura
Endocrine
disorders
Hypothyroidism,
hyperthyroidism
Diabetes
Diabetic
ketoacidosis
Metabolism and
Nutrition
Disorders
Anorexia
Dehydration
Psychiatric
disorders
Depression*,
anxiety,
insomnia*
Emotional
disorders, mood
alteration
Aggression,
nervousness, libido
decreased
Suicidal
ideation,
hallucinations
Suicide, psychotic
disorder
14
Body system
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
Nervous system
disorders
Headache,
dizziness*,
concentration
impaired
Memory
impairment,
syncope, weakness,
migraine,
hypoaesthesia,
hyperaesthesia,
paraesthesia,
tremor, taste
disturbance,
nightmares,
somnolence
Peripheral
neuropathy
Coma,
convulsions, ,
facial palsy
Eye disorders
Vision blurred, eye
pain, eye
inflammation,
xerophthalmia
Retinal
hemorrhage
Optic neuropathy,
papilledema,
retinal vascular
disorder,
retinopathy,
corneal ulcer
Vision loss ,
Ear and labyrinth
disorders
Vertigo, earache
Hearing loss
Cardiac disorders
Tachycardia,
palpitations,
oedema peripheral
Myocardial
infarction,
congestive heart
failure, angina,
supraventricular
tachycardia,
arrhythmia, atrial
fibrillation,
pericarditis,
cardiomyopathy
Vascular
disorders
Flushing
Hypertension Cerebral
haemorrhage,
vasculitis
Respiratory,
thoracic and
mediastinal
disorders
Dyspnoea,
cough
Dyspnoea
exertional,
epistaxis,
nasopharyngitis,
sinus congestion,
nasal congestion,
rhinitis, sore throat
Wheezing
Interstitial
pneumonitis
including fatal
outcome,
pulmonary
embolism
Gastrointestinal
disorders
Diarrhoea*,
nausea*,
abdominal
pain*
Vomiting,
dyspepsia,
dysphagia, mouth
ulceration, gingival
bleeding, glossitis,
stomatitis,
flatulence,
dry mouth
Gastrointestinal
bleeding
Peptic ulcer,
pancreatitis
Hepato-biliary
disorders
Hepatic
dysfunction
Hepatic failure,
cholangitis,
fatty liver
15
Body system
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
Skin and
subcutaneous
tissue disorders
Alopecia,
dermatitis,
pruritis, dry
skin
Rash, sweating
increased,
psoriasis, urticaria,
eczema, skin
disorder,
photosensitivity
reaction, night
sweats
Toxic epidermal
necrolysis,
Stevens-Johnson
syndrome,
angioedema,
erythema
multiforme
Musculoskeletal
connective tissue
and bone
disorders
Myalgia,
arthralgia
Back pain,
arthritis, muscle
weakness, bone
pain, neck pain,
musculoskeletal
pain, muscle
cramps
Myositis
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 and
poisoning
Substance
overdose
*These adverse reactions were common (
≥1
/100
to < 1
/10)
in CHB patients treated with Pegasys monotherapy
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 10
9
/l) and severe (ANC: < 0.5 x 10
9
/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 chronic hepatitis B. However in
neither disease was this correlated with lack of therapeutic response.
16
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/mm
3
was observed in 13% and 11% of patients receiving Pegasys monotherapy
and combination therapy, respectively. Decrease in platelets below 50,000/mm
3
was observed in 10%
and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anaemia
(haemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or
in combination therapy, respectively.
Post marketing adverse events
Infections and infestations:
Sepsis: frequency unknown.
As with other alpha interferons, sepsis has been reported with Pegasys.
Blood and lymphatic system disorders:
Pure red cell aplasia: frequency unknown.
As with other alpha interferons, pure red cell aplasia has been reported with Pegasys.
Immune system disorders:
Liver and renal graft rejection: frequency unknown.
Liver and renal graft rejections have been reported with Pegasys, alone or in combination with
ribavirin.
A wide variety of autoimmune and immune-mediated disorders have been reported with alpha
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or
aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including
mononeuropathies and Vogt-Koyanagi-Harada disease (see also section 4.4, Autoimmune disease).
Psychiatric disorders:
Mania, bipolar disorders: frequency unknown.
As with other alpha interferons, mania and bipolar disorders have been reported with Pegasys.
Homicidal ideation: frequency unknown.
Nervous System Disorders:
Cerebral ischemia: frequency unknown.
Eye Disorders:
Serous retinal detachment: frequency unknown.
As with other alpha interferons, serous retinal detachment has been reported with Pegasys.
Vascular disorders:
Peripheral ischaemia: frequency unknown.
As with other alpha interferons, peripheral ischaemia has been reported with Pegasys.
Gastrointestinal disorders:
Ischaemic colitis: frequency unknown.
As with other alpha interferons, ischaemic colitis has been reported with Pegasys.
Musculoskeletal connective tissue and bone disorders:
Rhabdomyolysis: frequency unknown.
17
daily injections for1 week (ie, 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulating Agent/Cytokine, ATC code: L03A B11
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.
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.
Chronic hepatitis B:
Clinical trial results
All clinical trials recruited patients with chronic hepatitis B 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 5. In study WV16240,
the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 10
5
copies/ml. In
study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-DNA below 2 x
10
4
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.
18
Table 5: 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
Pegasys
180 mcg
&
Placebo
(N=177)
Pegasys
180 mcg
&
Lamivudine
100 mg
(N=179)
Lamivudine
100 mg
(N=272)
(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 < 10
5
copies/ml
For HBeAg-negative /anti-HBe-positive patients: HBV DNA < 2 x 10
4
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 treatment-naïve patients
All clinical trials recruited interferon-naïve patients with chronic hepatitis C 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 14). 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 6, 7, 8 and Table 14, 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.
19
Table 6: Virological Response in HCV 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
Interferon
alfa-2a
6 MIU/3 MIU
&
3 MIU
Pegasys
180 mcg
Interferon
alfa-2a
3 MIU
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
(N=701)
48 weeks
(N=478)
48 weeks
(N=87)
48 weeks
(N=88)
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 monotherapy and 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 7 and Table 8, 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, 7 and 8).
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.
20
Table 7: Sustained Virological Response Based on Genotype and Pre-treatment Viral Load after
Pegasys Combination Therapy with Ribavirin in HCV 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 8).
Table 8: Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype
1 and 4 after Pegasys Combination Therapy with Ribavirin in HCV 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
21
Although limited, data indicated that shortening treatment to 24 weeks might be associated with a
higher risk of relapse (see Table 9).
Table 9: 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
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)
Low viral load
High viral load
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 10).
In study NV17317 in patients infected with viral genotype 2 or 3, all patients received Pegasys 180 μg
sc qw and a ribavirin dose of 800 mg and were randomized 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 10).
Table 10: 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 HCV
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.
22
The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse
(see Table 11).
Table 11: 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.
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 randomized 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
12.
23
Table 12: 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.
Pegasys
360/180 or
180 μg
&
Ribavirin
1000/1200
mg
72 or 48 Weeks
(N = 942)
Pts with
VR at Wk 12
a
(N = 876)
Pegasys
360/180 or
180 μg
&
Ribavirin
1000/1200 mg
72 Weeks
(N = 473)
SVR in Pts with
VR at Wk 12
b
(N = 100)
Pegasys
360/180 or
180 μg
&
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
≥2log
10
decline in HCV RNA
<2log
10
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 nonresponders
In the HALT-C study, patients with chronic hepatitis C 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 13.
Table 13 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)
24
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 14.
Table 14: 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 3MIU 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 180μg: Odds Ratio ( 95% CI) = 2.89 (1.93 to 4.32), ….P-value (stratified
Cochran-Mantel-Haenszel test) = < 0.0001
* Interferon alfa-2a 3MIU 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.
Children and adolescents
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 PEG-IFN alfa 2a
100 mcg/m
2
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.
5.2 Pharmacokinetic properties
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.
25
Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the
volume of distribution at steady-state (V
d
) 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.
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. 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.
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 chronic hepatitis B or C 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
Renal impairment is associated with slightly decreased CL/F and prolonged half-life. In patients (n=3)
with CL
crea
between 20 and 40 ml/min, the average CL/F is reduced by 25% compared with patients
with normal renal function. In patients with end stage renal disease undergoing haemodialysis, there is
a 25% to 45% reduction in the clearance, and doses of 135 micrograms result in similar exposure as
180 micrograms doses in patients with normal renal function (see section 4.2).
Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be
used in combination with ribavirin.
Gender
The pharmacokinetics of Pegasys after single subcutaneous injections were comparable between male
and female healthy subjects.
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 (t
max
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.
26
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 alpha 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.
6.
6.1 List of excipients
sodium chloride
polysorbate 80
benzyl alcohol (10 mg/ 1 ml)
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
3 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. 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.
27
Any unused product or waste material should be disposed of in accordance with local
requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/02/221/001
EU/1/02/221/002
9.
20 June 2002/ 20 June 2007
28
1.
Marketing Authorisation Holder and Manufacturer
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
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
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: +372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
175
France
Roche
Tél: +33 (0) 1 46 40 50 00
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
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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
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in
HOW TO SELF-INJECT PEGASYS
The following instructions explain how to use Pegasys pre-filled syringes to inject yourself. 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
-
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
).
176
-
an adhesive bandage
●
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.
●
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
).
177
●
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.
178
Source: European Medicines Agency
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