ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rebetol 200 mg hard capsules
2.
Each hard capsule contains 200 mg of ribavirin.
Excipient: each hard capsule contains 40 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White, opaque and imprinted with blue ink.
4.
Rebetol is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults, children
3 years of age and older and adolescents and must only be used as part of a combination regimen with
peginterferon alfa-2b or interferon alfa-2b. Rebetol monotherapy must not be used.
There is no safety or efficacy information on the use of Rebetol with other forms of interferon (i.e., not
alfa-2b).
Naïve patients
Adult patients:
Rebetol is indicated, in combination with interferon alfa-2b or peginterferon alfa-2b,
for the treatment of adult patients with chronic hepatitis C, not previously treated, without liver
decompensation, with elevated alanine aminotransferase (ALT), who are positive for hepatitis C viral
ribonucleic acid (HCV-RNA). In combination with peginterferon alfa-2b also patients with
compensated cirrhosis and/or clinically stable HIV co-infection are included (see section 4.4).
Children 3 years of age and older and adolescents
: Rebetol is indicated, in a combination regimen
with peginterferon alfa-2b or interferon alfa-2b, for the treatment of children 3 years of age and older
and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation,
and who are positive for HCV-RNA.
When deciding to not to defer treatment until adulthood, it is important to consider that the
combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain.
The decision to treat should be made on a case by case basis (see section 4.4).
Previously treated patients
Adult patients:
Rebetol is indicated, in combination with interferon alfa-2b, for the treatment of adult
patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the
end of treatment) to interferon alfa monotherapy but who have subsequently relapsed. Rebetol is
indicated, in combination with peginterferon alfa-2b, for the treatment of adult patients with chronic
hepatitis C who have failed previous treatment with interferon alpha (pegylated or non-pegylated)
alone or in combination with ribavirin (see section 5.1)
.
2
Treatment should be initiated, and monitored, by a physician experienced in the management of
chronic hepatitis C.
Rebetol must be used in combination with either peginterferon alfa-2b or interferon alfa-2b.
Please refer also to the peginterferon alfa-2b or interferon alfa-2b Summary of Product Characteristics
(SPC) for prescribing information particular to that product.
Dose to be administered
The dose of Rebetol is based on patient body weight. Rebetol capsules are to be administered orally
each day in two divided doses (morning and evening) with food.
Adult patients:
The dose of Rebetol is based on patient body weight (
Table 1
).
Rebetol must be used in combination with either peginterferon alfa-2b (1.5 micrograms/kg/week) or
interferon alfa-2b (3 million international units [MIU] three times a week). The choice of combination
regimen is based on the characteristics of the patient. The regimen administered should be selected
based on the anticipated efficacy and safety of the combination treatment for an individual patient (see
section 5.1).
Table 1.
Rebetol dose based on body weight for HCV monoinfected or HCV/HIV co-
infected patients and whatever the genotype
Patient weight (kg)
Daily Rebetol dose
Number of 200 mg capsules
< 65
800 mg
4
a
65 – 80
1,000 mg
5
b
81 - 105
1,200 mg
6
c
> 105
1,400 mg
7
d
a: 2 morning, 2 evening
b: 2 morning, 3 evening
c: 3 morning, 3 evening
d: 3 morning, 4 evening
Rebetol capsules in combination with peginterferon alfa-2b:
Duration of treatment – Naïve patients
Predictability of sustained virological response
:
Patients infected with virus genotype 1
who fail to
achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are
highly unlikely to become sustained virological responders and should be evaluated for
discontinuation (see also section
5.1).
•
Genotype 1:
-
Patients who have undetectable HCV-RNA at treatment week 12, treatment should be
continued for another nine month period (i.e., a total of 48 weeks).
-
Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment
week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they
should continue with full course of therapy (i.e., a total of 48 weeks). However, if HCV-RNA is
still detectable at treatment week 24, discontinuation of therapy should be considered.
-
In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who
become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24,
the treatment could either be stopped after this 24 week treatment course or pursued for an
additional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weeks
treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment
duration (see section 5.1).
•
Genotype 2 or 3
: It is recommended that all patients be treated for 24 weeks, except for
HCV/HIV co-infected patients who should receive 48 weeks of treatment.
3
•
Genotype 4
:
In general, patients infected with genotype 4 are considered harder to treat and
limited study data (n=66) indicate they are compatible with a duration of treatment as for
genotype 1.
Duration of treatment - HCV/HIV co-infected patients
The recommended duration of Rebetol weight-based dosing (see
Table 1
) for HCV/HIV co-infected
patients is 48 weeks, regardless of genotype.
Predictability of response and non-response in HCV/HIV Co-infection
Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of
HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for
sustained response in HCV/HIV co-infected patients treated with Rebetol in combination with
peginterferon alfa-2b was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value of 50 %
(52/104; Study 1) was observed for HCV/HIV co-infected patients receiving combination therapy.
Duration of treatment - Retreatment
Predictability of sustained virological response:
All patients, irrespective of genotype, who have
demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of
therapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of
detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of
therapy (see also section 5.1).
Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been
studied with pegylated interferon alfa-2b and ribavirin combination therapy.
Rebetol capsules in combination with interferon alfa-2b:
Duration of treatment
:
Based on the results of clinical trials, it is recommended that patients be treated for at least six months.
During those clinical trials in which patients were treated for one year, patients who failed to show a
virological response after six months of treatment (HCV-RNA below lower limit of detection) were
unlikely to become sustained virological responders (HCV-RNA below lower limit of detection six
months after withdrawal of treatment).
•
Genotype 1
: Treatment should be continued for another six month period (i.e., a total of one
year) in patients who exhibit negative HCV-RNA after six months of treatment.
•
Genotypes Non-1:
The decision to extend therapy to one year in patients with negative HCV-
RNA after six months of treatment should be based on other prognostic factors (e.g.,
age > 40 years, male gender, bridging fibrosis).
Children 3 years of age and older and adolescents:
Note: For patients who weigh < 47 kg, or are unable to swallow capsules, please refer to the SPC for
ribavirin 40 mg/ml oral solution.
Dosing for children and adolescent patients is determined by body weight for Rebetol and by body
surface area for peginterferon alfa-2b and interferon alfa-2b.
Dose to be administered for the combination therapy with peginterferon alfa-2b:
The recommended dose of peginterferon alfa-2b is 60 µg/m
2
/week subcutaneously in combination
with Rebetol 15 mg/kg/day (
Table 2
).
Dose to be administered for the combination therapy with interferon alfa-2b:
In clinical studies performed in this population ribavirin and interferon alfa-2b were used in doses of
15 mg/kg/day and 3 million international units (MIU)/m
2
three times a week respectively (
Table 2
).
4
Table 2 Rebetol dose based on body weight when used in combination with interferon
alfa-2b or peginterferon alfa-2b in children and adolescents
Patient weight (kg)
Daily Rebetol dose
Number of 200 mg capsules
47 - 49
600 mg
3 capsules
a
50 - 65
800 mg
4 capsules
b
> 65
Refer to adult dosing table (Table 1)
a
1 morning, 2 evening
b
2 morning, 2 evening
Duration of treatment in children and adolescents
•
Genotype 1:
The recommended duration of treatment is 1 year. By extrapolation from clinical
data on combination therapy with standard interferon in paediatric patients (negative
predictive value 96 % for interferon alfa-2b/Rebetol), patients who fail to achieve virological
response at 12 weeks are highly unlikely to become sustained virological responders.
Therefore, it is recommended that children and adolescent patients receiving interferon alfa-2b
(pegylated or non-pegylated)/Rebetol combination be discontinued from therapy if their
week 12 HCV-RNA dropped < 2 log
10
compared to pretreatment, or if they have detectable
HCV-RNA at treatment week 24.
•
Genotype 2 or 3:
The recommended duration of treatment is 24 weeks.
•
Genotype 4:
Only 5 children and adolescents with Genotype 4 were treated in the
peginterferon alfa-2b/Rebetol clinical trial. The recommended duration of treatment is 1 year.
It is recommended that children and adolescent patients receiving peginterferon alfa-
2b/Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped
< 2 log
10
compared to pretreatment, or if they have detectable HCV-RNA at treatment
week 24.
Dose modification for all patients
If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol and
peginterferon alfa-2b or interferon alfa-2b, modify the
dosages of each product if appropriate, until the
adverse reactions abate. Guidelines were developed in clinical trials for dose modification (see Dosage
modification guidelines,
Table 3
). As adherence might be of importance for outcome of therapy, the dose
should be kept as close as possible to the recommended standard dose. The potential negative impact of
ribavirin dose reduction on efficacy results could not be ruled out.
Table 3
Dosage modification guidelines based on laboratory parameter
s
Laboratory values
Reduce only Rebetol
daily dose
(see note 1) if:
Reduce only
peginterferon alfa-2b or
interferon alfa-2b dose
(see note 2) if:
Discontinue
combination therapy
when the below test
value is reported:**
Haemoglobin
< 10 g/dl
-
< 8.5 g/dl
Adults:
Haemoglobin in:
patients with history
of stable cardiac
disease
Children and
adolescents: not
applicable (see
section 4.4)
≥ 2 g/dl decrease in haemoglobin during any
4 week period during treatment
(permanent dose reduction)
< 12 g/dl after 4
weeks of dose
reduction
Leukocytes
-
< 1.5 x 10
9
/l
< 1.0 x 10
9
/l
Neutrophils
-
< 0.75 x 10
9
/l
< 0.5 x 10
9
/l
Platelets
-
< 50 x 10
9
/l (adults)
< 70 x 10
9
/l (children
and adolescents)
< 25 x 10
9
/l (adults)
< 50 x 10
9
/l
(children and
adolescents)
5
Bilirubin – Direct
-
-
2.5 x ULN
*
Bilirubin – Indirect
> 5 mg/dl
-
> 4 mg/dl (adults)
> 5 mg/dl
(for > 4 weeks)
(children and
adolescents treated
with interferon alfa-
2b),
or
> 4 mg/dl (for > 4
weeks) (children
and adolescents
treated with
peginterferon alfa-
2b))
Serum Creatinine
-
-
> 2.0 mg/dl
Creatinine
Clearance
-
-
Discontinue Rebetol
if
CrCl < 50 ml/minut
e
Alanine
aminotransferase
(ALT)
-
-
2 x baseline and
> 10 x ULN
*
or
2 x baseline and
> 10 x ULN
*
or
Aspartate
aminotransferase
(AST)
*
Upper limit of normal
** Refer to the SPC for pegylated interferon alfa-2b and interferon alfa-2b for dose modification and discontinuation.
Note 1: In adult patients, 1
st
dose reduction of Rebetol is by 200 mg/day (except in patients
receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2
nd
dose
reduction of Rebetol is by an additional 200 mg/day.Patients whose dose of Rebetol is
reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg
capsules in the evening.
In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1
st
dose
reduction of Rebetol is to 12 mg/kg/day, 2
nd
dose reduction of Rebetol is to 8 mg/kg/day.
In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce
Rebetol dose to 7.5 mg/kg/day.
Note 2: In adult patients treated with Rebetol plus peginterferon alfa-2b, 1
st
dose reduction of
peginterferon alfa-2b is to 1 µg/kg/week. If needed, 2
nd
dose reduction of peginterferon
alfa-2b is to 0.5 µg/kg/week.
In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1
st
dose
reduction of peginterferon alfa-2b is to 40 µg/m
2
/week, 2
nd
dose reduction of peginterferon
alfa-2b is to 20 µg/m
2
/week.
In adult patients and children and adolescent patients treated with Rebetol plus interferon
alfa-2b, reduce the interferon alfa-2b dose by one-half dose.
Special populations
Use in renal impairment
: The pharmacokinetics of ribavirin are altered in patients with renal
dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2).
Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of
Rebetol. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol (see
section 4.3). Subjects with impaired renal function should be more carefully monitored with respect to
the development of anaemia. If serum creatinine rises to > 2.0 mg/dl (
Table 3
), Rebetol and
peginterferon alfa-2b/interferon alfa-2b must be discontinued.
6
Use in hepatic impairment
: No pharmacokinetic interaction appears between ribavirin and hepatic
function (see section 5.2). Therefore, no dose adjustment of Rebetol is required in patients with hepatic
impairment. The use of ribavirin is contraindicated in patients with severe hepatic impairment or
decompensated cirrhosis (see section 4.3).
Use in the elderly (
≥
65 years of age):
There does not appear to be a significant age-related effect on
the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined
prior to administration of Rebetol
(see section 5.2).
Use in patients under the age of 18 years
: Rebetol may be used in combination with peginterferon
alfa-2b or interferon alfa-2b in children 3 years of age and older and adolescents. The selection of
formulation is based on individual characteristics of the patient. Safety and effectiveness of Rebetol
with other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.
Patients co-infected with HCV/HIV:
Patients taking nucleoside reverse transcriptase inhibitor (NRTI)
treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at
increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section 4.4).
Please refer also to the relevant product information for antiretroviral medicinal products.
-
Hypersensitivity to the active substance or to any of the excipients.
-
Pregnant women (see sections 4.4, 4.6 and 5.3). Rebetol must not be initiated until a report of a
negative pregnancy test has been obtained immediately prior to initiation of therapy.
-
Lactation.
-
A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease,
in the previous six months (see section 4.4).
-
Patients with severe, debilitating medical conditions.
-
Patients with chronic renal failure, patients with creatinine clearance < 50 ml/minute and/or on
haemodialysis.
-
Severe hepatic impairment (Child-Pugh Classification B or C)
or decompensated cirrhosis of the
liver.
-
Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).
-
Initiation of peginterferon alfa-2b is contraindicated in HCV/HIV patients with cirrhosis and a
Child-Pugh score ≥ 6.
Children and adolescents:
-
Because of co-administration with peginterferon alfa-2b or interferon alfa-2b:
-
Autoimmune hepatitis; or history of autoimmune disease.
7
Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal
ideation, or suicide attempt.
Psychiatric and Central Nervous System (CNS):
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been
observed in some patients during Rebetol combination therapy with peginterferon alfa-2b or interferon
alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up period. Among
children and adolescents, treated with Rebetol in combination with interferon alfa-2b, suicidal ideation or
attempts were reported more frequently compared to adult patients (2.4 % versus 1 %) during
treatment and during the 6-month follow-up after treatment. As in adult patients, children and
adolescents experienced other psychiatric adverse reactions (e.g., depression, emotional lability, and
somnolence). Other CNS effects including aggressive behaviour (sometimes directed against others such
as homicidal ideation), bipolar disorder, 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 Rebetol and peginterferon alfa-2b or interferon alfa-2b be
discontinued, and the patient followed, with psychiatric intervention as appropriate.
Patients with existence of or history of severe psychiatric conditions:
If treatment with
Rebetol in
combination with peginterferon alfa-2b or interferon alfa-2b is judged necessary in adult patients with
existence or history of severe psychiatric conditions, this should only be initiated after having ensured
appropriate individualised diagnostic and therapeutic management of the psychiatric condition.
The use of Rebetol and interferon alfa-2b or peginterferon alfa-2b in children and adolescents with
existence of or history of severe psychiatric conditions is contraindicated (see section 4.3).
Growth and development (children and adolescents):
During the course of interferon (standard and pegylated)/ribavirin therapy lasting up to 48 weeks in
patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and
5.1). The longer term data available in children treated with the combination therapy with standard
interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in
height percentile as compared to baseline) in 21 % of children despite being off treatment for more
than 5 years.
Case by case benefit/risk assessment in children:
The expected benefit of treatment should be carefully weighed against the safety findings observed for
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
−
It is important to consider that the combination therapy induced a growth inhibition, the
reversibility of which is uncertain.
−
This risk should be weighed against the disease characteristics of the child, such as evidence of
disease progression (notably fibrosis), co-morbidities that may negatively influence the disease
progression (such as HIV-co-infection), as well as prognostic factors of response (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the
risk of growth inhibition. There are no data on long term effects on sexual maturation.
Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Rebetol must not
be used alone. The safety and efficacy of this combination have been established only using ribavirin
capsules together with peginterferon alfa-2b or interferon alfa-2b solution for injection.
All patients in selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain
cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological
confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed
prior to commencing treatment.
8
Haemolysis:
A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14 % of adult patients
and 7 % of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b or
interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia
associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of
coronary disease, or both. Thus, Rebetol
must be administered with caution to patients with pre-existing
cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored
clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).
Cardiovascular:
Adult patients with a history of congestive heart failure, myocardial infarction and/or
previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients
who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course
of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but
may require discontinuation of therapy. There are no data in children or adolescents with a history of
cardiac disease.
Acute hypersensitivity
: If an acute hypersensitivity reaction (e.g., urticaria, angioedema,
bronchoconstriction, anaphylaxis) develops, Rebetol must be discontinued immediately and appropriate
medical therapy instituted. Transient rashes do not necessitate interruption of treatment.
Ocular changes:
Ribavirin is used in combination therapy with alpha interferons. Retinopathy
including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery or
vein occlusion which may result in loss of vision have been reported in rare instances with
combination therapy with alpha interferons. 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 (e.g., diabetic or hypertensive retinopathy) should
receive periodic ophthalmologic exams during combination therapy with alpha interferons. Combination
therapy with alpha interferons should be discontinued in patients who develop new or worsening
ophthalmologic disorders.
Liver function
: Any patient developing significant liver function abnormalities during treatment must
be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation
markers which might indicate liver decompensation.
Potential to exacerbate immunosuppression
: 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).
Thyroid supplemental monitoring specific for children and adolescents
:
Approximately 12 to 21 % of children treated with Rebetol and interferon alfa-2b (pegylated and non-
pegylated) developed increase in thyroid stimulating hormone (TSH). Another approximately 4 % had
a transient decrease below the lower limit of normal. Prior to initiation of interferon alfa-2b therapy,
TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with
conventional therapy. Interferon alfa-2b (pegylated and non-pegylated) therapy may be initiated if
TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during
treatment with Rebetol and interferon alfa-2b and during treatment with Rebetol and peginterferon
alfa-2b has been observed. If thyroid abnormalities are detected, the patient’s thyroid status should be
evaluated and treated as clinically appropriate. Children and adolescents should be monitored every
3 months for evidence of thyroid dysfunction (e.g. TSH).
9
HCV/HIV Co-infection
:
Mitochondrial toxicity and lactic acidosis:
Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside
reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon
alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians
should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is
administered. In particular:
-
co-administration of Rebetol and didanosine is not recommended due to the risk of
mitochondrial toxicity (see section 4.5).
-
co-administration of Rebetol and stavudine should be avoided to limit the risk of overlapping
mitochondrial toxicity.
Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis:
Co-infected patients with advanced cirrhosis receiving highly active anti-retroviral therapy (HAART)
may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons
alone or in combination with ribavirin may increase the risk in this patient subset. Other baseline
factors in co-infected patients that may be associated with a higher risk of hepatic decompensation
include treatment with didanosine and elevated bilirubin serum concentrations.
Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely
monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic
decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV
treatment reassessed.
Haematological abnormalities in HCV/HIV co-infected patients:
HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be
at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and
anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed
by dose reduction, close monitoring of haematological parameters should be undertaken in this
population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).
Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia; therefore,
the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5).
Patients with low CD4 counts:
In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in
subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of
patients with low CD4 counts.
Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal
products that are to be taken concurrently with HCV therapy for awareness and management of
toxicities specific for each product and the potential for overlapping toxicities with Rebetol and
peginterferon alfa-2b.
Dental and periodontal disorders
:
Dental and periodontal disorders, which may lead to loss of teeth,
have been reported in patients receiving Rebetol and peginterferon alfa-2b or interferon alfa-2b
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 Rebetol and
peginterferon alfa-2b or interferon alfa-2b. 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.
Laboratory tests
: Standard haematologic tests and blood chemistries (complete blood count [CBC] and
differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) must be conducted
in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline
prior to initiation of Rebetol therapy:
•
Haemoglobin
Adult: ≥ 12 g/dl (females); ≥ 13 g/dl (males)
10
Children and adolescents: ≥ 11 g/dl (females); ≥ 12 g/dl (males)
•
Platelets
≥ 100,000/mm
3
•
Neutrophil Count ≥ 1,500/mm
3
Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as
clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).
For females of childbearing potential
: Female patients must have a routine pregnancy test performed
monthly during treatment and for four months thereafter. Female partners of male patients must have a
routine pregnancy test performed monthly during treatment and for seven months thereafter (see
section 4.6).
Uric acid may increase with Rebetol due to haemolysis; therefore, the potential for development of gout
must be carefully monitored in pre-disposed patients.
Use in patients with rare hereditary disorders
: Each Rebetol capsule contains 40 mg of lactose.
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
Results of
in vitro
studies using both human and rat liver microsome preparations indicated no cytochrome
P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes.
There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a
minimal potential for P450 enzyme-based interactions.
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 pegylated alpha interferons and ribavirin concomitantly with azathioprine
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 medicines should be stopped (see section 4.4).
No interaction studies have been conducted with Rebetol and other medicinal products, except for
peginterferon alfa-2b, interferon alfa-2b and antacids.
Interferon alfa-2b
: No pharmacokinetic interactions were noted between Rebetol and peginterferon
alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic study.
Antacid:
The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid
containing magnesium aluminium and simethicone; AUC
tf
decreased 14 %. It is possible that the decreased
bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is not
considered to be clinically relevant.
Nucleoside analogs
: Use of nucleoside analogs, alone or in combination with other nucleosides, has
resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine
nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine
nucleoside analogs (e.g. didanosine or abacavir). Co-administration of Rebetol and didanosine is not
recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of
which some fatal, have been reported (see section 4.4).
The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of
ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).
Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment
11
(ART) regimen if this is already established. This would be particularly important in patients with a
known history of zidovudine induced anaemia.
Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after
cessation of Rebetol therapy due to the long half-life (see section 5.2).
There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or
protease inhibitors.
Conflicting findings are reported in literature on co-administration between abacavir and ribavirin.
Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at
risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised
when both medicines are co-administered.
The use of Rebetol is contraindicated during pregnancy.
Preclinical data:
-
Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see
section 5.3).
-
Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for
ribavirin in all animal species in which adequate studies have been conducted, occurring at doses as
low as one twentieth of the recommended human dose (see section 5.3).
-
Genotoxicity: Ribavirin induces genotoxicity (see section 5.3).
Female patients:
Rebetol must not be used by females who are pregnant (see sections 4.3 and 5.3).
Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must
not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation
of therapy. Females of childbearing potential and their partners must each use an effective contraceptive
during treatment and for four months after treatment has been concluded; routine monthly pregnancy tests
must be performed during this time. If pregnancy does occur during treatment or within four months from
stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to the foetus.
Male patients and their female partners:
Extreme care must be taken to avoid pregnancy in partners of
male patients taking Rebetol (see sections 4.3 and 5.3). Ribavirin accumulates intracellularly and is cleared
from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its
potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately
300 prospectively followed pregnancies with paternal exposure to ribavirin have not shown an
increased risk of malformation compared to the general population, nor any specific pattern of
malformation, male patients and their female partners of childbearing age must be advised to each use
an effective contraceptive during treatment with Rebetol and for seven months after treatment. Men
whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the
partner.
Breast-feeding:
It is not known whether ribavirin is excreted in human milk. Because of the potential for
adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.
Rebetol has no or negligible influence on the ability to drive and use machines; however, peginterferon
alfa-2b or interferon alfa-2b used in combination may have an effect. Thus, patients who develop fatigue,
somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.
12
Adult patients:
The safety of Rebetol capsules is evaluated from data from four clinical trials in patients with no
previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combination
with interferon alfa-2b, two trials studied Rebetol in combination with peginterferon alfa-2b.
Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon
therapy or who are treated for a shorter period are likely to have an improved safety profile than that
described below.
The adverse reactions listed in
Table 4
are based on experience from clinical trials in adult naïve
patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally
attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in
combination with ribavirin) are also listed for reference in
Table 4
. Also, refer to peginterferon alfa-2b
and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferons monotherapy.
Within the organ system classes, adverse reactions are listed under headings of frequency using the
following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness.
Table 4
Adverse reactions reported during clinical trials or following the marketing use of
Rebetol with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class
Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Bacterial infection (including sepsis), fungal infection,
influenza, respiratory tract infection, bronchitis, herpes
simplex, sinusitis, otitis media, rhinitis, urinary tract
infection
Uncommon Injection site infection, lower respiratory tract infection
Rare: Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:
Neoplasm unspecified
Blood and lymphatic system disorders
Very common:
Anaemia, neutropenia
Common:
Haemolitic anaemia, leukopenia, thrombocytopenia,
lymphadenopathy, lymphopenia
Very rare:
Aplastic anaemia*
Not known:
Pure red cell aplasia, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:
Drug hypersensitivity
Rare:
Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known:
Vogt-Koyanagi-Harada syndrome, systemic lupus
erythematosus, vasculitis, acute hypersensitivity reactions
including urticaria, angioedema, bronchoconstriction,
anaphylaxis
Endocrine disorders
Common:
Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:
Anorexia
Common:
Hyperglycaemia, hyperuricaemia, hypocalcaemia,
dehydration, increased appetite
Uncommon:
Diabetes mellitus, hypertriglyceridemia*
13
Psychiatric disorders
Very common:
Depression, anxiety, emotional lability, insomnia
Common:
Suicidal ideation, psychosis, aggressive behaviour,
confusion, agitation, anger, mood altered, abnormal
behaviour, nervousness, sleep disorder, decreased libido
apathy, abnormal dreams, crying
Uncommon:
Suicide attempts, panic attack, hallucination
Rare:
Bipolar disorder*
Very rare:
Suicide*
Not known:
Homicidal ideation*, mania*, mental status change
Nervous system disorders
Very common:
Headache, dizziness, dry mouth, concentration impaired
Common:
Amnesia, memory impairment, syncope, migraine, ataxia,
paraesthaesia, dysphonia, taste loss, hypoaesthesia,
hyperaesthesia, hypertonia, somnolence, disturbance in
attention, tremor, dysgeusia
Uncommon:
Neuropathy, peripheral neuropathy
Rare:
Seizure (convulsion)*
Very rare:
Cerebrovascular haemorrhage*, cerebrovascular ischaemia*,
encephalopathy*, polyneuropathy*
Not known:
Facial palsy, mononeuropathies
Eye disorders
Common:
Visual disturbance, blurred vision, conjunctivitis, eye
irritation, eye pain, abnormal vision, lacrimal gland disorder,
dry eye
Rare:
Retinal haemorrhages*, retinopathies (including macular
oedema)*, retinal artery occlusion*, retinal vein occlusion*,
optic neuritis*, papilloedema*, loss of visual acuity or visual
field*, retinal exudates
Ear and labyrinth disorders
Common:
Vertigo, hearing impaired/loss, tinnitus, ear pain
Cardiac disorders
Common:
Palpitation, tachycardia
Uncommon:
Myocardial infarction
Rare:
Cardiomyopathy, arrhythmia*
Very rare:
Cardiac ischaemia*
Not known:
Pericardial effusion*, pericarditis*
Vascular disorders
Common: Hypotension, hypertension, flushing
Rare: Vasculitis
Very rare: Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:
Dyspnoea, coughing
Common:
Epistaxis, respiratory disorder, respiratory tract congestion,
sinus congestion, nasal congestion, rhinorrhea, increased
upper airway secretion, pharyngolaryngeal pain,
nonproductive cough
Very rare:
Pulmonary infiltrates*, pneumonitis*, interstitial
pneumonitis*
Gastro-intestinal disorders
Very common:
Diarrhoea, vomiting, nausea, abdominal pain
Common:
Ulcerative stomatitis, stomatitis, mouth ulceration, colitis,
upper right quadrant pain, dyspepsia, gastroesophoageal
reflux*, glossitis, cheilitis, abdominal distension, gingival
bleeding, gingivitis, loose stools, tooth disorder,
14
constipation, flatulence
Uncommon:
Pancreatitis, oral pain
Rare:
Ischaemic colitis
Very rare:
Ulcerative colitis*
Not Known:
Periodontal disorder, dental disorder
Hepatobiliary disorders
Common:
Hepatomegaly, jaundice, hyperbilirubinemia*
Very rare:
Hepatotoxicity (including fatalities)*
Skin and subcutaneous tissue disorders
Very common: Alopecia, pruritus, skin dry, rash
Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity
reaction, maculopapular rash, erythematous rash, night
sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema,
urticaria, skin disorder, bruise, sweating increased, abnormal
hair texture, nail disorder*
Rare: Cutaneous sarcoidosis
Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*,
erythema multiforme*
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Common:
Arthritis, back pain, muscle spasms, pain in extremity
Uncommon:
Bone pain, muscle weakness
Rare:
Rhabdomyolysis*, myositis*
Renal and urinary disorders
Common:
Micturition frequency, polyuria, urine abnormality
Rare:
Renal failure, renal insufficiency*
Very rare:
Nephrotic syndrome*
Reproductive system and breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder,
dysmenorrhea, breast pain, ovarian disorder, vaginal
disorder.
Male:
impotence, prostatitis, erectile dysfunction.
Sexual dysfunction (not specified)*
General disorders and administration site conditions
Very common:
Injection site inflammation, injection site reaction, fatigue,
rigors, pyrexia, influenza like illness, asthenia, irritability
Common:
Chest pain, chest discomfort, peripheral oedema, malaise,
injection site pain, feeling abnormal, thirst
Uncommon:
Face oedema
Rare:
Injection site necrosis
Investigations
Very common: Weight decrease
Common: Cardiac murmur
* Since ribavirin is always prescribed with an alpha interferon product, and the listed adverse drug reactions included
reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from
clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or non-pegylated).
A reduction in haemoglobin concentrations by > 4 g/dl was observed in 30 % of patients treated with
Rebetol and peginterferon alfa-2b and 37 % of patients treated with Rebetol and interferon alfa-2b.
Haemoglobin levels dropped below 10 g/dl in up to 14 % of adult patients and 7 % of children and
adolescents treated with Rebetol in combination with either peginterferon alfa-2b or interferon alfa-2b.
Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There
were some cases of more severe neutropenia in patients treated with Rebetol in combination with
peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO
grade 3 leukopenia was also reported in 7 % of this treatment group.
15
An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some
patients treated with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b in
clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among
those patients with elevated uric acid levels, very few patients treated with the combination developed
clinical gout, none of which required treatment modification or discontinuation from the clinical trials.
HCV/HIV co-infected patients:
For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other
adverse reactions (that were not reported in mono-infected patients) which have been reported in the
studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4
lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %),
back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis
(6 %), lipase increased (6 %) and pain in limb (6 %).
Mitochondrial toxicity:
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI
regimen and associated-ribavirin for co-HCV infection (see section 4.4).
Laboratory values for HCV/HIV co-infected patients:
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more
frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and
rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities
were more frequently reported in patients receiving Rebetol in combination with peginterferon alfa-2b
when compared to patients receiving Rebetol in combination with interferon alfa-2b. In Study 1 (see
section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm
3
was observed in 4 %
(8/194) of patients and decrease in platelets below 50,000/mm
3
was observed in 4 % (8/194) of
patients receiving Rebetol in combination with peginterferon alfa-2b. Anaemia (haemoglobin
< 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Rebetol in combination with
peginterferon alfa-2b.
CD4 lymphocytes decrease:
Treatment with Rebetol in combination with peginterferon alfa-2b 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
Rebetol in combination with peginterferon alfa-2b had no observable negative impact on the control of
HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected
patients with CD4+ cell counts < 200/µl (see section 4.4).
Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products
that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific
for each product and the potential for overlapping toxicities with Rebetol in combination with
peginterferon alfa-2b.
Children and adolescents:
In combination with peginterferon alfa-2b
In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with
combination therapy of peginterferon alfa-2b and Rebetol, dose modifications were required in 25 %
of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions
profile in children and adolescents was similar to that observed in adults, although there is a paediatric-
specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with
pegylated interferon alfa-2b and Rebetol, growth inhibition is observed, the reversibility of which is
uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment
(at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15
percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3
rd
percentile in 70 %
of the patients).
16
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height
percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued
to have inhibited growth (growth velocity < 3
rd
percentile). Based on interim data from the long-term
follow-up portion of this study, 22 % (16/74) of children had a > 15 percentile decrease in height
percentile, of whom 3 (4 %) children had a > 30 percentile decrease despite being off treatment for
more than 1 year. In particular, decrease in mean height percentile at year 1 of long term follow-up
was most prominent in prepubertal age children (see section 4.4).
In this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache
(62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only
1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of
adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions
were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity
(1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse
reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger
(2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received
levothyroxine treatment for hypothyroidism/elevated TSH.
In combination with interferon alfa-2b
In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy
of interferon alfa-2b and Rebetol, 6 % discontinued therapy due to adverse reactions. In general, the
adverse reaction profile in the limited children and adolescent population studied was similar to that
observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as
decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean
percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up
post-treatment period, the children had a mean height of 44
th
percentile, which was below the median
of the normative population and less than their mean baseline height (48
th
percentile). Twenty (21 %)
of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a
> 30 percentile decrease in their height percentile from the start of treatment to the end of long-term
follow-up (up to 5 years). During combination therapy for up to 48 weeks with interferon alfa-2b and
Rebetol, growth inhibition is observed, the reversibility of which is uncertain. In particular, decrease in
mean height percentile from baseline to the end of the long-term follow-up was most prominent in
prepubertal age children (see section 4.4).
Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients
(2.4 % vs. 1 %) during treatment and during the 6 month follow-up after treatment. As in adult
patients, children and adolescents also experienced other psychiatric adverse reactions (e.g.,
depression, emotional lability, and somnolence) (see
section 4.4). In addition, injection site disorders,
pyrexia, anorexia, vomiting and emotional lability occurred more frequently in children and
adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most
commonly for anaemia and neutropenia.
Reported adverse reactions listed in
Table 5
are based on experience from the two multicentre children
and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b. Within
the organ system classes, adverse reactions are listed under headings of frequency using the following
categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to
< 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
17
Table 5
Adverse reactions very commonly, commonly and uncommonly reported during clinical
trials in children and adolescents with Rebetol in combination with interferon alfa-2b or
peginterferon alfa-2b
System Organ Class
Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Fungal infection, bacterial infection, pulmonary infection,
nasopharyngitis, pharyngitis streptococcal, otitis media,
sinusitis, tooth abscess, influenza, oral herpes, herpes
simplex, urinary tract infection, vaginitis, gastroenteritis
Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:
Neoplasm unspecified
Blood and lymphatic system disorders
Very common:
Anaemia, neutropenia
Common:
Thrombocytopenia, lymphadenopathy
Endocrine disorders
Very common:
Hypothyroidism
Common:
Hyperthyroidism, virilism
Metabolism and nutrition disorders
Very common:
Anorexia, increased appetite, decreased appetite
Common:
Hypertriglyceridemia, hyperuricemia
Psychiatric disorders
Very common:
Depression, insomnia, emotional lability
Common:
Suicidal ideation, aggression, confusion, affect liability,
behaviour disorder, agitation, somnambulism, anxiety, mood
altered, restlessness, nervousness, sleep disorder, abnormal
dreaming, apathy
Uncommon:
Abnormal behaviour, depressed mood, emotional disorder,
fear, nightmare
Nervous system disorders
Very common:
Headache, dizziness
Common:
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia,
hyperaesthesia, concentration impaired, somnolence,
disturbance in attention, poor quality of sleep
Uncommon:
Neuralgia, lethargy, psychomotor hyperactivity
Eye disorders
Common:
Conjunctivitis, eye pain, abnormal vision, lacrimal gland
disorder
Uncommon:
Conjunctival haemorrhage, eye pruritus, keratitis, vision
blurred, photophobia
Ear and labyrinth disorders
Common:
Vertigo
Cardiac disorders
Common:
Tachycardia, palpitations
Vascular disorders
Common: Pallor, flushing
Uncommon: Hypotension
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion,
nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal
pain
Uncommon:
Wheezing, nasal discomfort
Gastro-intestinal disorders
18
Very common:
Abdominal pain, abdominal pain upper, vomiting , diarrhoea,
nausea
Common:
Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous
stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal
reflux, rectal disorder, gastrointestinal disorder, constipation,
loose stools, toothache, tooth disorder, stomach discomfort,
oral pain
Uncommon:
Gingivitis
Hepatobiliary disorders
Common:
Hepatic function abnormal
Uncommon:
Hepatomegaly
Skin and subcutaneous tissue disorders
Very common: Alopecia, rash
Common: Pruritus, photosensitivity reaction, maculopapular rash,
eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin
discolouration, dry skin, erythema, bruise
Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Common:
Pain in extremity, back pain, muscle contracture
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence,
proteinuria
Reproductive system and breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder,
vaginal disorder,
Male
: testicular pain
Uncommon:
Female: dysmenorrhoea
General disorders and administration site conditions
Very common:
Injection site inflammation, injection site reaction, injection
site erythema, injection site pain, fatigue, rigors, pyrexia,
influenza-like illness, asthenia, malaise, irritability
Common:
Chest pain, oedema, pain, injection site pruritus, injection site
rash, injection site dryness, feeling cold
Uncommon:
Chest discomfort, facial pain, injection site induration
Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)
Common: Blood thyroid stimulating hormone increased, thyroglobulin
increased
Uncommon: Anti-thyroid antibody positive
Injury, poisoning and procedural complications
Common:
Skin laceration
Uncommon:
Contusion
Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b clinical trial were mild
or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in
bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2).
While changes in laboratory values were observed in some patients treated with Rebetol used in
combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a
few weeks after the end of therapy.
19
In clinical trials with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b, the
maximum overdose reported was a total dose of 10 g of Rebetol (50 x 200 mg capsules) and 39 MIU of
interferon alfa-2b
(13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at
suicide. The patient was observed for two days in the emergency room, during which time no adverse
reaction from the overdose was noted.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides (excl. reverse
transcriptase inhibitors), ATC code: J05A B04.
Ribavirin (Rebetol) is a synthetic nucleoside analogue which has shown
in vitro
activity against some
RNA and DNA viruses. The mechanism by which Rebetol in combination with peginterferon alfa-2b or
interferon alfa-2b exerts its effects against HCV is unknown. Oral formulations of Rebetol monotherapy
have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these
investigations
showed that Rebetol monotherapy had no effect on eliminating hepatitis virus (HCV-RNA)
or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.
Rebetol clinical trials in adults
The use of Rebetol in combination treatment with peginterferon alfa-2b or interferon alfa-2b was
evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver
biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic
hepatitis, and abnormal serum ALT.
Naïve patients
Three trials examined the use of interferon in naïve patients, two with Rebetol + interferon alfa-2b
(C95-132 and I95-143) and one with Rebetol + peginterferon alfa-2b (C/I98-580). In all cases the
treatment was for one year with a follow-up of six months. The sustained response at the end of
follow-up was significantly increased by the addition of Rebetol to interferon alfa-2b (41 % vs 16 %,
p < 0.001).
In clinical trials C95-132 and I95-143, Rebetol + interferon alfa-2b combination therapy proved to be
significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response).
Combination therapy also decreased the relapse rate. This was true for all HCV genotypes, particularly
Genotype 1, in which the relapse rate was reduced by 30 % compared with interferon alfa-2b
monotherapy.
In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following
combination regimens:
•
Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).
•
Rebetol (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month
followed by 0.5 microgram/kg/week for 11 months) (n = 514).
•
Rebetol (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).
In this trial, the combination of Rebetol and peginterferon alfa-2b (1.5 micrograms/kg/week) was
significantly more effective than the combination of Rebetol and interferon alfa-2b, particularly in
patients infected with Genotype 1. Sustained response was assessed by the response rate six months
after the cessation of treatment.
20
HCV genotype and baseline virus load are prognostic factors which are known to affect response rates.
However, response rates in this trial were shown to be dependent also on the dose of Rebetol
administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that
received > 10.6 mg/kg Rebetol (800 mg dose in typical 75 kg patient), regardless of genotype or viral
load, response rates were significantly higher than in those patients that received ≤ 10.6 mg/kg Rebetol
(
Table 6
), while response rates in patients that received > 13.2 mg/kg Rebetol were even higher.
Table 6
Sustained response rates with Rebetol + peginterferon alfa-2b
(by Rebetol dose [mg/kg], genotype and viral load)
HCV Genotype
Rebetol dose
(mg/kg)
P 1.5/R
P 0.5/R
I/R
All Genotypes
All
54 %
47 %
47 %
≤ 10.6
50 %
41 %
27 %
> 10.6
61 %
48 %
47 %
Genotype 1
All
42 %
34 %
33 %
≤ 10.6
38 %
25 %
20 %
> 10.6
48 %
34 %
34 %
Genotype 1
≤ 600,000 IU/ml
All
73 %
51 %
45 %
≤ 10.6
74 %
25 %
33 %
> 10.6
71 %
52 %
45 %
Genotype 1
> 600,000 IU/ml
All
30 %
27 %
29 %
≤ 10.6
27 %
25 %
17 %
> 10.6
37 %
27 %
29 %
Genotype 2/3
All
82 %
80 %
79 %
≤ 10.6
79 %
73 %
50 %
> 10.6
88 %
80 %
80 %
P1.5/R
Rebetol (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)
P0.5/R
Rebetol (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)
I/R
Rebetol (1,000/1,200 mg) + interferon alfa-2b (3 MIU)
In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b, 1.5 microgram/kg
subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months
(based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (
Table 7
).
Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).
Table 7
Virologic Response at End of Treatment, Sustained Virologic Response and Relapse
by HCV Genotype and Viral Load*
Rebetol 800-1,400 mg/day plus peginterferon alfa-2b 1.5 μg/kg once
weekly
End of Treatment
Response
Sustained Virologic Response
Relapse
All Subjects
94 % (211/224)
81 % (182/224)
12 %
(27/224)
HCV 2
100 % (42/42)
93 % (39/42)
7 % (3/42)
≤
600,000
IU/ml
100 % (20/20)
95 % (19/20)
5 % (1/20)
> 600,000
IU/ml
100 % (22/22)
91 % (20/22)
9 % (2/22)
HCV 3
93 % (169/182)
79 % (143/182)
14 %
(24/166)
≤
600,000
IU/ml
93 % (92/99)
86 % (85/99)
8 % (7/91)
21
> 600,000
IU/ml
93 % (77/83)
70 % (58/83)
23 % (17/75)
* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-
up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up
week 12 window was considered to be a non-responder at week 24 of follow-up.
The 6 month treatment duration in this trial was better tolerated than one year of treatment in the
pivotal combination trial; for discontinuation 5 % vs.
14 %, for dose modification 18 % vs
.
49 %.
In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received
peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight
adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration was 50 %.
Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and
week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate.
The high sustained response rate in this subgroup of patients was identified in an interim analysis
(n=49) and prospectively confirmed (n=48).
Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained
response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of
treatment).
A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two
peginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 µg/kg and 1 µg/kg subcutaneously
once weekly both in combination with Rebetol 800 to 1,400 mg p.o. daily (in two divided doses)] and
peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily
(in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response
to the treatment was measured by Sustained Virologic Response (SVR) which is defined as
undetectable HCV-RNA at 24 weeks post-treatment (see
Table 8
).
Table 8 Virologic response at treatment week 12, end of treatment response, relapse rate* and
Sustained Virologic Response (SVR)
Treatment group
% (number) of patients
peginterferon alfa-2b
1.5 µg/kg
+ Rebetol
peginterferon alfa-2b
1 µg/kg
+ Rebetol
peginterferon alfa-2a
180 µg
+ ribavirin
Undetectable HCV-
RNA at treatment
week 12
40 (407/1,019)
36 (366/1,016)
45 (466/1,035)
End of treatment
response
*
53 (542/1,019)
49 (500/1,016)
64 (667/1,035)
Relapse
*
24 (123/523)
20 (95/475)
32 (193/612)
SVR
*
40 (406/1,019)
38 (386/1,016)
41 (423/1,035)
SVR in patients with
undetectable HCV-
RNA at treatment week
12
81 (328/407)
83 (303/366)
74 (344/466)
*
HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml
Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log
10
reduction from
baseline) was a criterion for discontinuation of treatment.
In all three treatment groups, sustained virologic response rates were similar. In patients of African
American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with
peginterferon alfa-2b (1.5 µg/kg)/Rebetol combination therapy resulted in a higher sustained virologic
response rate compared to peginterferon alfa-2b 1 µg/kg dose. At the peginterferon alfa-2b 1.5 µg/kg
plus Rebetol dose, sustained virologic response rates were lower in patients with cirrhosis, in patients
22
with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml and in patients
> 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the
African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse
rate was 24 %.
Predictability of sustained virological response in naïve patients
Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels
of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or
undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have
been shown to be predictive for sustained response (
Table 9
).
Table 9
Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b 1.5
µg/kg/Rebetol 800-1,400 mg Combination Therapy
Negative
Positive
No
response
at
Treatment
Week
No
sustained
Response
Predictive
Value
Response
at
Treatment
Week
Sustained
Response
Predictive
Value
Genotype 1*
By Week 4
***
(n= 950)
HCV-RNA negative
834
539
65%
(539/834)
116
107
92%
(107/116)
HCV-RNA negative
or
≥ 1 log decrease in
viral load
220
210
95%
(210/220)
730
392
54%
(392/730)
By Week 12
***
(n= 915)
HCV-RNA negative
508
433
85%
(433/508)
407
328
81%
(328/407)
HCV-RNA negative
or
≥ 2 log decrease in
viral load
206
205
N/A
†
709
402
57%
(402/709)
Genotype 2, 3**
By Week 12
(n=215)
HCV-RNA negative
or
≥ 2 log decrease in
viral load
2
1
50%
(1/2)
213
177
83%
(177/213)
*Genotype 1 receive 48 weeks treatment
**Genotype 2, 3 receive 24 weeks treatment
***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4
or week 12.
†
These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 log
10
decrease from baseline, patients to
stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2 log
10
from baseline, then retest HCV-RNA at week 24
and if positive, patients to stop therapy.
HCV/HIV Co-infected patients
Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment
in both of these trials is presented in
Table 10
. Study 1 (RIBAVIC; P01017) was a randomized,
multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who
were co-infected with HIV. Patients were randomized to receive either Rebetol (800 mg/day) plus
23
peginterferon alfa-2b (1.5 µg/kg/week) or Rebetol (800 mg/day) plus interferon alfa-2b (3 MIU TIW)
for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre
study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-
infected with HIV. Patients were randomized to receive either Rebetol (800-1,200 mg/day based on
weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Rebetol (800-
1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was
48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and
viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up
period.
Table 10
Sustained virological response based on genotype after Rebetol in combination with
peginterferon alfa-2b in HCV/HIV co-infected patients
Study 1
1
Study 2
2
Rebetol
(800 mg/day)
+
peginterferon
alfa-2b
(1.5 µg/kg/
week)
Rebetol
(800 mg/day) +
interferon alfa-
2b (3 MIU
TIW)
p
value
a
Rebetol
(800-
1,200 mg/da
y)
d
+
peginterfero
n alfa-2b
(100 or 150
c
µg/week)
Rebetol (800-
1,200 mg/day)
d
+
interferon
alfa-2b
(3 MIU TIW)
p
value
b
All
27 % (56/205) 20 % (41/205) 0.047 44 % (23/52)
21 % (9/43)
0.017
Genotype 1, 4 17 % (21/125)
6 % (8/129)
0.006 38 % (12/32)
7 % (2/27)
0.007
Genotype 2, 3 44 % (35/80)
43 % (33/76)
0.88 53 % (10/19)
47 % (7/15)
0.730
MIU = million international units; TIW = three times a week.
a: p value based on Cochran-Mantel Haenszel Chi square test.
b: p value based on chi-square test.
c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferon
alfa-2b .
d: Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.
1
Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2
Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.
Histological response
Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the
412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with
Rebetol in combination with peginterferon alfa-2b. This decline was significant among responders
(-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-
responders. In terms of activity, about one-third of sustained responders showed improvement and
none showed worsening. There was no improvement in terms of fibrosis observed in this study.
Steatosis was significantly improved in patients infected with HCV Genotype 3.
24
Previously treated patients
- Retreatment of prior treatment failures (relapse and non-responder patients) with peginterferon alfa-2b
in combination with Rebetol:
In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous
treatment with combination alpha interferon/ribavirin were retreated with peginterferon alfa-2b,
1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol. Failure
to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum
of 12 weeks of treatment).
Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks and
were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-
RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable
HCV-RNA at 24 weeks post-treatment (
Table 11
)
.
Table 11
Rates of Response to retreatment in prior treatment failures
Patients with undetectable HCV–RNA
at treatment week 12 and SVR upon retreatement
interferon alpha/ribavirin
peginterferon alpha/ribavirin
Overall
Population*
Response
week 12 %
(n/N)
SVR % (n/N)
99% CI
Response
week 12 %
(n/N)
SVR % (n/N)
99% CI
SVR % (n/N)
99 % CI
Overall
38.6 (549/1,423) 59.4 (326/549)
54.0,64.8
31.5 (272/863) 50.4 (137/272)
42.6, 58.2
21.7 (497/2,293)
19.5, 23.9
Prior Response
Relapse
67.7 (203/300)
59.6 (121/203)
50.7, 68.5
58.1 (200/344) 52.5 (105/200)
43.4, 61.6
37.7 (243/645)
32.8, 42.6
Genotype 1/4 59.7 (129/216)
51.2 (66/129)
39.8, 62.5
48.6 (122/251) 44.3 (54/122)
32.7, 55.8
28.6 (134/468)
23.3, 34.0
Genotype 2/3 88.9 (72/81)
73.6 (53/72)
(60.2, 87.0)
83.7 (77/92)
64.9 (50/77)
50.9, 78.9
61.3 (106/173)
51.7, 70.8
NR
28.6 (258/903)
57.0 (147/258)
49.0, 64.9
12.4 (59/476) 44.1 (26/59)
27.4, 60.7
13.6 (188/1,385)
11.2, 15.9
Genotype 1/4 23.0 (182/790)
51.6 (94/182)
42.1, 61.2
9.9 (44/446)
38.6 (17/44)
19.7, 57.5
9.9 (123/1,242)
7.7, 12.1
Genotype 2/3 67.9 (74/109)
70.3 (52/74)
56.6, 84.0
53.6 (15/28)
60.0 (9/15)
27.4, 92.6
46.0 (63/137)
35.0, 57.0
Genotype
1
30.2 (343/1,135) 51.3 (176/343)
44.4, 58.3
23.0 (162/704) 42.6 (69/162)
32.6, 52.6
14.6 (270/1,846)
12.5, 16.7
2/3
77.1 (185/240)
73.0 (135/185)
64.6, 81.4
75.6 (96/127) 63.5 (61/96)
50.9, 76.2
55.3 (203/367)
48.6, 62.0
4
42.5 (17/40)
70.6 (12/17)
42.1, 99.1
44.4 (12/27)
50.0 (6/12)
12.8, 87.2
28.4 (19/67)
14.2, 42.5
METAVIR
Fibrosis score
F2
46.0 (193/420)
66.8 (129/193)
58.1, 75.6
33.6 (78/232) 57.7 (45/78)
43.3, 72.1
29.2 (191/653)
24.7, 33.8
F3
38.0 (163/429)
62.6 (102/163)
52.8, 72.3
32.4 (78/241) 51.3 (40/78)
36.7, 65.9
21.9 (147/672)
17.8, 26.0
F4
33.6 (192/572)
49.5 (95/192)
29.7 (116/390)
44.8 (52/116) 16.5 (159/966)
25
40.2, 58.8
32.9, 56.7
13.4, 19.5
Baseline Viral
Load
HVL (>600,000
IU/ml)
32.4 (280/864)
56.1 (157/280)
48.4, 63.7
26.5 (152/573) 41.4 (63/152)
31.2, 51.7
16.6 (239/1,441)
14.1, 19.1
30.2 (256/848)
26.1, 34.2
NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.
Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central
laboratory
*Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed
.
48.3 (269/557)
62.8 (169/269)
55.2, 70.4
41.0 (118/288) 61.0 (72/118)
49.5, 72.6
Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at
week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this
subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior
failure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12, the
sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral
reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients
the SVR was 12 %.
Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a
week 12 response to retreatment than non-responders to non-pegylated interferon alpha/ribavirin
(12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR
regardless of prior treatment or prior response.
- Retreatment of relapse patients with Rebetol and interferon alfa-2b combination treatment
Two trials examined the use of Rebetol and interferon alfa-2b combination treatment in relapse
patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous
interferon treatment were treated for six months with a six month follow-up. Combination therapy with
Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than
that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective
of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and
histological staging.
Long-term efficacy data - Adults
Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior
studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon alfa-
2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate the durability of
sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical
outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and
327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained
responders relapsed, respectively, in the studies.
The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %)
for patients receiving non-pegylated interferon alfa-2b (with or without Rebetol), and is 99 % (95 %
CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated,with or
without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic
infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of
hepatic events in patients with cirrhosis (including hepatocarcinoma).
Rebetol clinical trials in children and adolescents:
Rebetol in combination with peginterferon alfa-2b
Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable
HCV-RNA were enrolled in a multicentre trial and treated with Rebetol 15 mg/kg per day plus
pegylated interferon alfa-2b 60 µg/m
2
once weekly for 24 or 48 weeks, based on HCV genotype and
baseline viral load. All patients were to be followed for 24 weeks post-treatment.
A total of
107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV
26
LVL
(≤600,000
IU/ml)
Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with
mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease,
and the potential for undesirable effects, the benefit/risk of the combination of Rebetol and pegylated
interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
The study results are summarized in
Table
12
.
Table 12
Sustained virological response rates (n
a,b
(%)) in previously untreated children
and adolescents by genotype and treatment duration – All subjects
n = 107
24 weeks
48 weeks
All Genotypes
26/27 (96 %)
44/80 (55 %)
Genotype 1
-
38/72 (53 %)
Genotype 2
14/15 (93 %)
-
12/12 (100 %) 2/3 (67 %)
Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment,
lower limit of
detection = 125 IU/ml.
b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while
those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment
.
Rebetol in combination with interferon alfa-2b
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in
two multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m
2
3 times
a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were
enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population
enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials,
sustained virological response rates in children and adolescents were similar to those in adults. Due to
the lack of data in these two multicentre trials for children with severe progression of the disease, and
the potential for undesirable effects, the benefit/risk of the combination of Rebetol and interferon alfa-
2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).The study results
are summarized in
Table 13
.
Table 13
Sustained virological response in previously untreated children and adolescents
Rebetol 15 mg/kg/day
+
interferon alfa-2b 3 MIU/m
2
3 times a week
Overall Response
a
(n = 118)
54 (46 %)*
Genotype 1 (n = 92)
33 (36 %)*
Genotype 2/3/4 (n = 26)
21 (81 %)*
* Number (%) of patients
a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during
follow-up period.
Long-term efficacy data - Children and adolescents
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C
patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all
enrolled subjects completed this study of which 75 % (42/56) were sustained
responders. The purpose
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess
the impact of continued viral negativity on clinical outcomes for patients who were sustained
27
Genotype 3
c
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but
one of the paediatric subjects remained sustained virologic responders during long-term follow-up
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Rebetol results in
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with
cirrhosis (including hepatocarcinoma).
5.2
Pharmacokinetic properties
Ribavirin is absorbed rapidly following oral administration of a single dose (mean T
max
= 1.5 hours),
followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption,
distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with
approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is
approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship
between dose and AUC
tf
following single doses of 200-1,200 mg ribavirin. Volume of distribution is
approximately 5,000 l. Ribavirin does not bind to plasma proteins.
Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following
single oral doses (intrasubject variability of approximately 30 % for both AUC and C
max
), which may be
due to extensive first pass metabolism and transfer within and beyond the blood compartment.
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has
been identified to be primarily via an e
s
-type equilibrative nucleoside transporter. This type of transporter is
present on virtually all cell types and may account for the high volume of distribution of ribavirin. The
ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in
whole blood exists as ribavirin nucleotides sequestered in erythrocytes.
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative
pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both
ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.
Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to
single-dose AUC
12hr
. Following oral dosing with 600 mg BID, steady-state was reached by approximately
four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml. Upon
discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow
elimination from non-plasma compartments.
Food effect
: The bioavailability of a single oral dose of ribavirin was increased by co-administration of a
high fat meal (AUC
tf
and C
max
both increased by 70 %). It is possible that the increased bioavailability in
this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this
single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin
with food to achieve the maximal plasma concentration of ribavirin.
Renal function
: Single-dose ribavirin pharmacokinetics were altered (increased AUC
tf
and C
max
) in patients
with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). This appears
to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially
unchanged by haemodialysis.
Hepatic function
: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe
hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.
28
Elderly patients (≥ 65 years of age):
Specific pharmacokinetic evaluations for elderly subjects have not
been performed.
However, in a population pharmacokinetic study, age was not a key factor in the kinetics
of ribavirin; renal function is the determining factor.
Population pharmacokinetic analysis
was performed using sparsely sampled serum concentration values
from four controlled clinical trials. The clearance model developed showed that body weight, gender, age,
and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than
for females. Clearance increased as a function of body weight and was reduced at ages greater than
40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due
to the substantial residual variability not accounted for by the model.
Children and adolescents
:
Rebetol in combination with peginterferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children and
adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children
and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at
60 µg/m
2
/week, the log transformed ratio estimate of exposure during the dosing interval is predicted
to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 µg/kg/week. The
pharmacokinetics of Rebetol (dose-normalized) in this trial were similar to those reported in a prior
study of Rebetol in combination with interferon alfa-2b in children and adolescent patients and in adult
patients.
Rebetol in combination with interferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and
adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in
Table 14
. The
pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and
children or adolescents.
Table 14
Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and
Rebetol capsules when administered to children or adolescents with chronic
hepatitis C
Parameter
Rebetol
15 mg/kg/day as 2 divided
doses
(n = 17)
Interferon alfa-2b
3 MIU/m
2
3 times a week
(n = 54)
T
max
(hr)
1.9 (83)
5.9 (36)
C
max
(ng/ml)
3,275 (25)
51 (48)
AUC*
29,774 (26)
622 (48)
Apparent clearance l/hr/kg
0.27 (27)
Not done
*AUC
12
(ng.hr/ml) for Rebetol; AUC
0-24
(IU.hr/ml) for interferon alfa-2b
5.3 Preclinical safety data
Ribavirin
: Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human
dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye,
jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects
increased with escalation of the dose. Survival of foetuses and offspring was reduced.
In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of
ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as
slight decreases in body weight, crown-rump length and bone length. At the end of the recovery
period, tibial and femoral changes were minimal although generally statistically significant compared
to controls in males at all dose levels and in females dosed with the two highest doses compared to
controls.
No histopathological effects on bone were observed. No ribavirin effects were observed
regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were
below human plasma concentrations at the therapeutic dose.
29
Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after
initiation of dosing, but is rapidly reversible upon cessation of treatment.
In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects,
abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce
systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of
treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two
spermatogenic cycles (see section 4.6).
Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was
active in the Balb/3T3
in vitro
Transformation Assay. Genotoxic activity was observed in the mouse
lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in
rats was negative, indicating that if mutations occurred in rats they were not transmitted through male
gametes.
Conventional carcinogenicity rodent studies with low exposures compared to human exposure under
therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In
addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin
did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor
approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential
of ribavirin in humans is unlikely.
Ribavirin plus interferon: When used in combination with peginterferon alfa-2b or interferon alfa-2b,
ribavirin did not cause any effects not previously seen with either active substance alone. The major
treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater
than that produced by either active substance alone.
6.
6.1
List of excipients
Capsule contents:
Microcrystalline cellulose,
Lactose monohydrate,
Croscarmellose sodium,
Magnesium stearate.
Capsule shell:
Gelatine,
Titanium dioxide.
Capsule imprint:
Propylene glycol,
Ammonium hydroxide,
Colouring agent (E 132).
6.2
Incompatibilities
Not applicable.
30
Shellac,
6.3
Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5
Nature and contents of container
Ribavirin capsules are packaged in blisters consisting of polyvinyl chloride (PVC)/polyethylene
(PE)/polyvinylidene chloride (PVdC).
Packs of 84, 112, 140 and 168 capsules
.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
8.
MARKETING AUTHORISATION
NUMBER(S)
EU/1/99/107/001
84 hard capsules
EU/1/99/107/005
140 hard capsules
EU/1/99/107/003
168 hard capsules
9.
Date of first authorisation: 07 May 1999
Date of last renewal: 08 May 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
31
EU/1/99/107/002
112 hard capsules
1.
Rebetol 40 mg/ml oral solution
2.
Each ml of oral solution contains 40 mg of ribavirin.
Rebetol contains 142 mg of sorbitol and 300 mg of sucrose per ml.
For a full list of excipients, see section 6.1.
Oral solution
Clear, colourless to pale or light yellow oral solution
4.1 Therapeuticindications
Rebetol is indicated, in a combination regimen with peginterferon alfa-2b or interferon alfa-2b, for the
treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C virus
(HCV) infection, not previously treated, without liver decompensation, and who are positive for
hepatitis C viral ribonucleic acid (HCV-RNA).
When deciding not to defer treatment until adulthood, it is important to consider that the combination
therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain. The decision
to treat should be made on a case by case basis (see section 4.4).
Rebetol monotherapy must not be used.
There is no safety or efficacy information in children or adolescents on the use of Rebetol with other forms
of interferon (i.e., not alfa-2b).
Treatment should be initiated, and monitored, by a physician experienced in the management of
chronic hepatitis C.
Please refer also to the pegylated interferon alfa-2b or interferon alfa-2b Summary of Product
Characteristics (SPC) for prescribing information particular to that product.
Dose to be administered
Rebetol oral solution is supplied in a concentration of 40 mg/ml.
32
Children 3 years of age and older and adolescents:
Rebetol oral solution is administered orally in two divided doses (morning and evening) with food
Dosing for children and adolescent patients is determined by body weight for Rebetol and by body
surface area for peginterferon alfa-2b and interferon alfa-2b.
The recommended dose of peginterferon alfa-2b is 60 µg/m
2
/week subcutaneously in combination
with Rebetol 15 mg/kg/day (
Table 1
).
In clinical studies performed in this population, ribavirin and interferon alfa-2b were used in doses of
15 mg/kg/day (
Table 1
) and 3 million international units (MIU)/m
2
three times a week, respectively.
Table 1
Rebetol oral solution - Children and
adolescents dosage
Body Weight (kg)
Measured Dose
(Morning / Evening)
10-12
2 ml / 2 ml
13-14
3 ml / 2 ml
15-17
3 ml / 3 ml
18-20
4 ml / 3 ml
21-22
4 ml / 4 ml
23-25
5 ml / 4 ml
26-28
5 ml / 5 ml
29-31
6 ml / 5 ml
32-33
6 ml / 6 ml
34-36
7 ml / 6 ml
37-39
7 ml / 7 ml
40-41
8 ml / 7 ml
42-44
8 ml / 8 ml
45-47
9 ml / 8 ml
Patients who weigh > 47 kg and are able to swallow capsules may take the equivalent dose of ribavirin
200 mg capsules in two divided doses (Please see SPC for ribavirin capsules).
Duration of treatment
•
Genotype 1.
The recommended duration of treatment is one year. By extrapolation from
clinical data on combination therapy with standard interferon in paediatric patients (negative
predictive value 96 % for interferon alfa-2b/Rebetol), patients who fail to achieve virological
response at 12 weeks are highly unlikely to become sustained virological responders.
Therefore, it is recommended that children and adolescent patients receiving interferon alfa-2b
(pegylated and non-pegylated)/Rebetol combination be discontinued from therapy if their
week 12 HCV-RNA dropped < 2 log
10
compared to pretreatment, or if they have detectable
HCV-RNA at treatment week 24.
•
Genotype 2 or 3
: The recommended duration of treatment is 24 weeks.
•
Genotype 4
: Only 5 children and adolescents with Genotype 4 were treated in the
peginterferon alfa-2b/Rebetol clinical trial. The recommended duration of treatment is 1 year.
It is recommended that children and adolescent patients receiving peginterferon alfa-
2b/Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped
< 2 log
10
compared to pretreatment, or if they have detectable HCV-RNA at treatment
week 24.
Dose modification
If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol oral solution
and interferon alfa-2b, modify the dosages of each product if appropriate, until the adverse reactions abate.
Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines,
Table 2
). As adherence might be of importance for outcome of therapy, the dose should be kept as close as
33
possible to the recommended standard dose. The potential negative impact of ribavirin dose reduction on
efficacy results could not be ruled out.
Table 2.
Dosage modification guidelines for children and adolescents based on laboratory
parameters
Laboratory values
Reduce only Rebetol
dose (see note 1) if:
Reduce only
peginterferon alfa-2b or
interferon alfa-2b dose
(see note 2) if:
Discontinue
combination therapy
when the below test
value is reported: **
Haemoglobin
< 10 g/dl
-
< 8.5 g/dl
Leukocytes
-
< 1.5 x 10
9
/l
< 1.0 x 10
9
/l
Neutrophils
-
< 0.75 x 10
9
/l
< 0.5 x 10
9
/l
Platelets
-
< 70 x 10
9
/l
< 50 x 10
9
/l
Bilirubin – Direct
-
-
2.5 x ULN
*
Bilirubin – Indirect
> 5 mg/dl
-
> 5 mg/dl
(for > 4 weeks)
treated with
interferon alfa-2b),
or
> 4 mg/dl
(for > 4 weeks
treated with
peginterferon alfa-
2b)
Serum Creatinine
-
-
> 2.0 mg/dl
Creatinine
Clearance
Discontinue Rebetol
if
CrCl < 50 ml/minute
Alanine
aminotransferase
(ALT)
-
-
2 x baseline and
> 10 x ULN
*
or
2 x baseline and
> 10 x ULN
*
or
Aspartate
aminotransferase
(AST)
*
Upper limit of normal
**
Refer to the SPC for pegylated interferon alfa-2b and interferon alfa-2b for dose modification and discontinuation.
Note 1: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1
st
dose
reduction of Rebetol is to 12 mg/kg/day, 2
nd
dose reduction of Rebetol is to 8 mg/kg/day.
In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce
Rebetol dose to 7.5 mg/kg/day.
Note 2: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1
st
dose
reduction of peginterferon alfa-2b is to 40 µg/m
2
/week, 2
nd
dose reduction of
peginterferon alfa-2b is to 20 µg/m
2
/week.
In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce the
interferon alfa-2b dose by one-half dose.
Special populations
Use in renal impairment
: The pharmacokinetics of ribavirin are altered in patients with renal
dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2).
Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of
Rebetol. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol (see
section 4.3). Subjects with impaired renal function should be more carefully monitored with respect to
34
the development of anaemia. If serum creatinine rises to > 2.0 mg/dl (see
Table 2
), Rebetol and
interferon alfa-2b must be discontinued.
Use in hepatic impairment
: No pharmacokinetic interaction appears between ribavirin and hepatic
function (see section 5.2). Therefore, no dose adjustment of Rebetol is required in patients with hepatic
impairment. The use of ribavirin is contraindicated in patients with severe hepatic impairment or
decompensated cirrhosis (see section 4.3).
Use in patients under the age of 18 years
: Rebetol may be used in combination with peginterferon
alfa-2b or interferon alfa-2b in children 3 years of age and older and adolescents. The selection of
formulation is based on individual characteristics of the patient. Safety and effectiveness of Rebetol
with other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.
Patients co-infected with HCV/HIV
:
Patients taking nucleoside reverse transcriptase inhibitor (NRTI)
treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at
increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section 4.4).
Please refer also to the relevant product information for antiretroviral medicinal products.
-
Hypersensitivity to the active substance or to any of the excipients.
-
Pregnant women (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Rebetol must
not be initiated until a report of a negative pregnancy test has been obtained immediately prior to
initiation of therapy.
-
Lactation.
-
A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease,
in the previous six months (see section 4.4).
-
Patients with chronic renal failure, patients with creatinine clearance < 50 ml/minute and/or on
haemodialysis.
-
Severe hepatic impairment (Child-Pugh Classification B or C) or decompensated cirrhosis of the
liver.
-
Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).
Children and adolescents:
-
Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal
ideation, or suicide attempt.
Because of co-administration with peginterferon alfa-2b or interferon alfa-2b:
-
Autoimmune hepatitis; or history of autoimmune disease.
Psychiatric and Central Nervous System (CNS):
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been
observed in some patients during Rebetol combination therapy with peginterferon alfa-2b or interferon
alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up period. Among
children and adolescents, treated with Rebetol in combination with interferon alfa-2b, suicidal ideation or
attempts were reported more frequently compared to adult patients (2.4 % versus 1 %) during
treatment and during the 6-month follow-up after treatment. As in adult patients, children and
adolescents experienced other psychiatric adverse reactions (e.g., depression, emotional lability, and
somnolence). Other CNS effects including aggressive behaviour (sometimes directed against others such
as homicidal ideation), bipolar disorder, 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
35
-
Patients with severe, debilitating medical conditions.
should be considered.
If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is
recommended that treatment with Rebetol and peginterferon alfa-2b or interferon alfa-2b be
discontinued, and the patient followed, with psychiatric intervention as appropriate.
Patients with existence of or history of severe psychiatric conditions:
The use of Rebetol and interferon alfa-2b or peginterferon alfa-2b in children and adolescents with
existence of or history of severe psychiatric conditions is contraindicated (see section 4.3).
Growth and development (children and adolescents):
During the course of interferon (standard and pegylated)/ribavirin therapy lasting up to 48 weeks in
patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and
5.1). The longer term data available in children treated with the combination therapy with standard
interferon/ribavirin are also indicative of substantial growth retardation (>15 percentile decrease in
height percentile as compared to baseline) in 21 % of children despite being off treatment for more
than 5 years.
Case by case benefit/risk assessment in children:
The expected benefit of treatment should be carefully weighed against the safety findings observed for
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
−
It is important to consider that the combination therapy induced a growth inhibition, the
reversibility of which is uncertain.
−
This risk should be weighed against the disease characteristics of the child, such as evidence of
disease progression (notably fibrosis), co-morbidities that may negatively influence the disease
progression (such as HIV-co-infection), as well as prognostic factors of response (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the
risk of growth inhibition. There are no data on long term effects on sexual maturation.
Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Rebetol must
not be used alone. The safety and efficacy of this combination have been established only using
ribavirin together with peginterferon alfa-2b or with interferon alfa-2b solution for injection.
Haemolysis:
A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14 % of adult patients
and in 7 % of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b or
interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia
associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of
coronary disease or both. Thus, Rebetol must be administered with caution to patients with pre-existing
cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored
clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).
Cardiovascular:
Adult patients with a history of congestive heart failure, myocardial infarction and/or
previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients
who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course
of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but
may require discontinuation of therapy. There are no data in children and adolescents with a history of
cardiac disease.
Acute hypersensitivity
: If an acute hypersensitivity reaction (e.g., urticaria, angioedema,
bronchoconstriction, anaphylaxis) develops, Rebetol must be discontinued immediately and appropriate
medical therapy instituted. Transient rashes do not necessitate interruption of treatment.
Ocular changes:
Ribavirin is used in combination therapy with alpha interferons. Retinopathy
including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery or
vein occlusion which may result in loss of vision have been reported in rare instances with
combination therapy with alpha interferons. All patients should have a baseline eye examination. Any
36
patient complaining of decrease or loss of vision must have a prompt and complete eye examination.
Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should
receive periodic ophthalmologic exams during combination therapy with alpha interferons. Combination
therapy with alpha interferons should be discontinued in patients who develop new or worsening
ophthalmologic disorders.
Liver function
: Any patient developing significant liver function abnormalities during treatment must
be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation
markers which might indicate liver decompensation.
Potential to exacerbate immunosuppression
: 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).
Thyroid supplemental monitoring for children and adolescents
:
Approximately 12 to 21 % of children treated with Rebetol and interferon alfa-2b (pegylated and non-
pegylated) developed increase in thyroid stimulating hormone (TSH). Another approximately 4 % had
a transient decrease below the lower limit of normal. Prior to initiation of interferon alfa-2b therapy,
TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with
conventional therapy. Interferon alfa-2b (pegylated and non-pegylated) therapy may be initiated if
TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during
treatment with Rebetol and interferon alfa-2b and during treatment with Rebetol and peginterferon
alfa-2b has been observed. If thyroid abnormalities are detected,
the patient’s
thyroid status should be
evaluated and treated as clinically appropriate. Children and
adolescents patients should be monitored
every 3 months for evidence of thyroid dysfunction (e.g. TSH).
HCV/HIV Co-infection
:
Mitochondrial toxicity and lactic acidosis:
Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside
reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon
alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians
should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is
administered. In particular:
-
co-administration of Rebetol and didanosine is not recommended due to the risk of
mitochondrial toxicity (see section 4.5).
-
co-administration of Rebetol and stavudine should be avoided to limit the risk of overlapping
mitochondrial toxicity.
Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis:
Co-infected patients with advanced cirrhosis receiving highly active anti-retroviral therapy (HAART)
may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons
alone or in combination with ribavirin may increase the risk in this patient subset.
Haematological abnormalities in HCV/HIV co-infected patients:
Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia; therefore, the
concomitant use of ribavirin with zidovudine is not recommended (see section 4.5).
Dental and periodontal disorders
:
Dental and periodontal disorders, which may lead to loss of teeth,
have been reported in patients receiving Rebetol and peginterferon alfa-2b or interferon alfa-2b
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 Rebetol and
peginterferon alfa-2b or interferon alfa-2b. 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.
37
Laboratory tests
: Standard haematological tests and blood chemistries (complete blood count [CBC]
and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) must be
conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered
as a guideline prior to initiation of Rebetol therapy in children and adolescents:
Haemoglobin
≥ 11 g/dl (females); ≥ 12 g/dl (males)
Platelets
≥ 100,000/mm
3
Neutrophil Count
≥ 1,500/mm
3
Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as
clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).
For females of childbearing potential:
Female patients must have a routine pregnancy test performed
monthly during treatment and for four months thereafter. Female partners of male patients must have a
routine pregnancy test performed monthly during treatment and for seven months thereafter (see
section 4.6).
Uric acid may increase with Rebetol due to haemolysis; therefore, the potential for development of gout
must be carefully monitored in pre-disposed patients.
Use in patients with rare hereditary disorders
: This product contains sucrose and sorbitol. Patients with
rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-
isomaltase insufficiency should not take this medicine.
Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome
P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes.
There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a
minimal potential for P450 enzyme-based interactions.
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 pegylated alpha interferons and ribavirin concomitantly with azathioprine
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 medicines should be stopped (see section 4.4).
No interaction studies have been conducted with Rebetol and other medicinal products, except for
interferon alfa-2b and antacids.
Interferon alfa-2b:
No pharmacokinetic interactions were noted between Rebetol and interferon alfa-2b
in a multiple-dose pharmacokinetic study.
Antacid:
The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid
containing magnesium, aluminium and simethicone; AUC
tf
decreased 14 %. It is possible that the
decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This
interaction is not considered to be clinically relevant.
Nucleoside analogues
: Use of nucleoside analogs, alone or in combination with other nucleosides, has
resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine
nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine
nucleoside analogs (e.g. didanosine or abacavir). Co-administration of Rebetol and didanosine is not
recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of
which some fatal, have been reported (see section 4.4).
38
The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin
with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration
should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is
already established. This would be particularly important in patients with a known history of zidovudine
induced anaemia.
Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after
cessation of Rebetol therapy due to the long half-life (see section 5.2).
There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or
protease inhibitors.
The use of Rebetol is contraindicated during pregnancy.
Preclinical data:
-
Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see
section 5.3).
-
Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for
ribavirin in all animal species in which adequate studies have been conducted, occurring at doses as
low as one twentieth of the recommended human dose (see section 5.3).
-
Genotoxicity: Ribavirin induces genotoxicity (see section 5.3).
Female patients:
Rebetol must not be used by females who are pregnant (see sections 4.3, and 5.3).
Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must
not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation
of therapy. Females of childbearing potential and their partners must each use an effective contraceptive
during treatment and for four months after treatment has been concluded; routine monthly pregnancy tests
must be performed during this time. If pregnancy does occur during treatment or within four months from
stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to the foetus.
Male patients and their female partners:
Extreme care must be taken to avoid pregnancy in partners of
male patients taking Rebetol (see sections 4.3, and 5.3). Ribavirin accumulates intracellularly and is cleared
from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its
potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately
300 prospectively followed pregnancies with paternal exposure to ribavirin have not shown an
increased risk of malformation compared to the general population, nor any specific pattern of
malformation, male patients and their female partners of childbearing age must be advised to each use
an effective contraceptive during treatment with Rebetol and for seven months after treatment. Men
whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the
partner.
Breast-feeding:
It is not known whether ribavirin is excreted in human milk. Because of the potential for
adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.
39
Rebetol has no or negligible influence on the ability to drive or use machines; however, interferon alfa-2b
used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion
during treatment must be cautioned to avoid driving or operating machinery.
4.8
Children and adolescents:
In combination with peginterferon alfa-2b
In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with
combination therapy of peginterferon alfa-2b and Rebetol, dose modifications were required in 25 %
of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions
profile in children and adolescents was similar to that observed in adults, although there is a paediatric-
specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with
pegylated interferon alfa-2b and Rebetol, growth inhibition is observed, the reversibility of which is
uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment
(at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15
percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3
rd
percentile in 70 %
of the patients).
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height
percentiles were still of 3 percentiles and 7 percentiles, respectively, and 20 % of the children
continued to have inhibited growth (growth velocity < 3
rd
percentile). Based on interim data from the
long-term follow-up portion of this study, 22 % (16/74) of children had a > 15 percentile decrease in
height percentile, of whom 3 (4 %) children had a > 30 percentile decrease despite being off treatment
for more than 1 year. In particular, decrease in mean height percentile at year 1 of long-term follow-up
was most prominent in prepubertal age children (see section 4.4).
In this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache
(62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection site erythema (29 %). Only
1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of
adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions
were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity
(1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse
reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger
(2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received
levothyroxine treatment for hypothyroidism/elevated TSH.
In combination with interferon alfa-2b
In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy
of interferon alfa-2b and Rebetol, 6 % discontinued therapy due to adverse reactions. In general, the
adverse reaction profile in the limited children and adolescent population studied was similar to that
observed in adults, although there is a paediatric-specific concern regarding growth inhibition as
decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean
percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up
post-treatment period, the children had a mean height of 44
th
percentile, which was below the median
of the normative population and less than their mean baseline height (48
th
percentile). Twenty (21 %)
of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a
> 30 percentile decrease in their height percentile from the start of treatment to the end of long-term
follow-up (up to 5 years). During combination therapy for up to 48 weeks with interferon alfa-2b and
Rebetol, growth inhibition is observed, the reversibility of which is uncertain. In particular, decrease in
mean height percentile from baseline to the end of the long-term follow-up was most prominent in
prepubertal age children (see section 4.4).
Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients
(2.4 % vs. 1 %) during treatment and during the 6 month follow-up after treatment. As in adult
40
patients, children and adolescents also experienced other psychiatric adverse reactions (e.g.,
depression, emotional lability, and somnolence) (see
section 4.4). In addition, injection site disorders,
pyrexia, anorexia, vomiting and emotional lability occurred more frequently in children and
adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most
commonly for anaemia and neutropenia.
Reported adverse reactions listed in
Table 3
are based on experience from the two multicentre children
and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b. Within
the organ system classes, adverse reactions are listed under headings of frequency using the following
categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to
< 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Table 3
Adverse reactions very commonly, commonly and uncommonly reported during clinical
trials in children and adolescents with Rebetol in combination with interferon alfa-2b or
peginterferon alfa-2b
System Organ Class
Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Fungal infection, bacterial infection, pulmonary infection,
nasopharyngitis, pharyngitis streptococcal, otitis media,
sinusitis, tooth abscess, influenza, oral herpes, herpes
simplex, urinary tract infection, vaginitis, gastroenteritis
Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:
Neoplasm unspecified
Blood and lymphatic system disorders
Very common:
Anaemia, neutropenia
Common:
Thrombocytopenia, lymphadenopathy
Endocrine disorders
Very common:
Hypothyroidism
Common:
Hyperthyroidism, virilism
Metabolism and nutrition disorders
Very common:
Anorexia, increased appetite, decreased appetite
Common:
Hypertriglyceridemia, hyperuricemia
Psychiatric disorders
Very common:
Depression, insomnia, emotional lability
Common:
Suicidal ideation, aggression, confusion, affect liability,
behaviour disorder, agitation, somnambulism, anxiety, mood
altered, restlessness, nervousness, sleep disorder, abnormal
dreaming, apathy
Uncommon:
Abnormal behaviour, depressed mood, emotional disorder,
fear, nightmare
Nervous system disorders
Very common:
Headache, dizziness
Common:
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia,
hyperaesthesia, concentration impaired, somnolence,
disturbance in attention, poor quality of sleep
Uncommon:
Neuralgia, lethargy, psychomotor hyperactivity
Eye disorders
Common:
Conjunctivitis, eye pain, abnormal vision, lacrimal gland
disorder
Uncommon:
Conjunctival haemorrhage, eye pruritus, keratitis, vision
blurred, photophobia
Ear and labyrinth disorders
41
Common:
Vertigo
Cardiac disorders
Common:
Tachycardia, palpitations
Vascular disorders
Common: Pallor, flushing
Uncommon: Hypotension
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion,
nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal
pain
Uncommon:
Wheezing, nasal discomfort
Gastro-intestinal disorders
Very common:
Abdominal pain, abdominal pain upper, vomiting , diarrhoea,
nausea
Common:
Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous
stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal
reflux, rectal disorder, gastrointestinal disorder, constipation,
loose stools, toothache, tooth disorder, stomach discomfort,
oral pain
Uncommon:
Gingivitis
Hepatobiliary disorders
Common:
Hepatic function abnormal
Uncommon:
Hepatomegaly
Skin and subcutaneous tissue disorders
Very common: Alopecia, rash
Common: Pruritus, photosensitivity reaction, maculopapular rash,
eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin
discolouration, dry skin, erythema, bruise
Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Common:
Pain in extremity, back pain, muscle contracture
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence,
proteinuria
Reproductive system and breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder,
vaginal disorder,
Male
: testicular pain
Uncommon:
Female: dysmenorrhoea
General disorders and administration site conditions
Very common:
Injection site inflammation, injection site reaction, injection
site erythema, injection site pain, fatigue, rigors, pyrexia,
influenza-like illness, asthenia, malaise, irritability
Common:
Chest pain, oedema, pain, injection site pruritus, injection site
rash, injection site dryness, feeling cold
Uncommon:
Chest discomfort, facial pain, injection site induration
Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)
Common: Blood thyroid stimulating hormone increased, thyroglobulin
increased
Uncommon: Anti-thyroid antibody positive
Injury, poisoning and procedural complications
Common:
Skin laceration
Uncommon:
Contusion
42
Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b clinical trial were mild
or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in
bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2).
While changes in laboratory values were observed in some patients treated with Rebetol used in
combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a
few weeks after the end of therapy.
Adult patients:
Adverse reactions reported with a > 10 % incidence in adult patients treated with ribavirin capsules in
combination with interferon alfa-2b or pegylated interferon alfa-2b for one year have also been
reported in children and adolescents. The side effect profile was also similar at the lower incidences.
The adverse reactions listed in
Table 4
are based on experience from clinical trials in adult naïve
patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally
attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in
combination with ribavirin) are also listed for reference in
Table 4
. Also, refer to peginterferon alfa-2b
and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferons monotherapy.
Within the organ system classes, adverse reactions are listed under headings of frequency using the
following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥ 1/10,000 to <1/1,000); very rare (< 1/10,000); not known. Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness.
Table 4
Adverse reactions reported during clinical trials or following the marketing use of
Rebetol with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class
Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Bacterial infection (including sepsis), fungal infection,
influenza, respiratory tract infection, bronchitis, herpes
simplex, sinusitis, otitis media, rhinitis, urinary tract
infection
Uncommon Injection site infection, lower respiratory tract infection
Rare: Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:
Neoplasm unspecified
Blood and lymphatic system disorders
Very common:
Anaemia, neutropenia
Common:
Haemolitic anaemia, leukopenia, thrombocytopenia,
lymphadenopathy, lymphopenia
Very rare:
Aplastic anaemia*
Not known:
Pure red cell aplasia, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:
Drug hypersensitivity
Rare:
Sarcoidosis* rheumatoid arthritis (new or aggravated)
Not known:
Vogt-Koyanagi-Harada syndrome, systemic lupus
erythematosus, vasculitis, acute hypersensitivity reactions
including urticaria, angioedema, bronchoconstriction,
anaphylaxis
Endocrine disorders
Common:
Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:
Anorexia
Common:
Hyperglycaemia, hyperuricaemia, hypocalcaemia,
43
dehydration, increased appetite
Uncommon:
Diabetes mellitus, hypertriglyceridemia*
Psychiatric disorders
Very common:
Depression, anxiety, emotional lability, insomnia
Common:
Suicidal ideation, psychosis, aggressive behaviour,
confusion, agitation, anger, mood altered, abnormal
behaviour,nervousness, sleep disorder, decreased libido,
apathy, abnormal dreams, crying
Uncommon:
Suicide attempts, panic attack, hallucination
Rare:
Bipolar disporder*
Very rare:
Suicide*
Not known:
Homicidal ideation*, mania*, mental status change
Nervous system disorders
Very common:
Headache, dizziness, dry mouth, concentration impaired
Common:
Amnesia, memory impairment, syncope, migraine, ataxia,
paresthaesia, dysphonia, taste loss, hypoaesthesia,
hyperaesthesia, hypertonia, somnolence, disturbance in
attention, tremor, dysgeusia
Uncommon:
Neuropathy, peripheral neuropathy
Rare:
Seizure (convulsion)
Very rare:
Cerebrovascular haemorrhage*, cerebrovascular ischaemia*,
encephalopathy*, polyneuropathy*
Not known:
Facial palsy, mononeuropathies
Eye disorders
Common:
Visual disturbance, blurred vision, conjunctivitis, eye
irritiation, eye pain, abnormal vision, lacrimal gland
disorder, dry eye
Rare:
Retinal haemorrhages*, retinopathies (including macular
oedema)*, retinal artery occlusion*, retinal vein occlusion*,
optic neuritis*, papilloedema*, loss of visual acuity or visual
field*, retinal exudates
Ear and labyrinth disorders
Common:
Vertigo, hearing impaired/loss, tinnitus, ear pain
Cardiac disorders
Common:
Palpitation, tachycardia
Uncommon:
Myocardial infarction
Rare:
Cardiomyopathy, arrhythmia*
Very rare:
Cardiac ischaemia*
Not known:
Pericardial effusion*, pericarditis*
Vascular disorders
Common: Hypotension, hypertension, flushing
Rare: Vasculitis
Very rare: Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:
Dyspnoea, coughing
Common:
Epistaxis, respiratory disorder, respiratory tract congestion,
sinus congestion, nasal congestion, rhinorrhea, increased
upper airway secretion, pharyngolaryngeal pain,
nonproductive cough
Very rare:
Pulmonary infiltrates*, pneumonitis*, interstitial
pneumonitis*
Gastro-intestinal disorders
Very common:
Diarrhoea, vomiting, nausea, abdominal pain
Common:
Ulcerative stomatitis, stomatitis, mouth ulceration, colitis,
upper right quadrant pain, dyspepsia, gastroesophoageal
44
reflux*, glossitis, cheilitis, abdominal distension, gingival
bleeding, gingivitis, loose stools, tooth disorder,
constipation, flatulence
Uncommon:
Pancreatitis, oral pain
Rare:
Ischaemic colitis
Very rare:
ulcerative colitis*
Not known:
Periodontal disorder, dental disorder
Hepatobiliary disorders
Common:
Hepatomegaly, jaundice, hyperbilirubinemia*
Very rare:
Hepatotoxicity (including fatalities)*
Skin and subcutaneous tissue disorders
Very common: Alopecia, pruritus, skin dry, rash
Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity
reaction, maculopapular rash, erythematous rash, night
sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema,
urticaria, skin disorder, bruise, sweating increased, abnormal
hair texture, nail disorder*
Rare: Cutaneous sarcoidosis
Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*,
erythema multiforme*
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Common:
Arthritis, back pain, muscle spasms, pain in extremity
Uncommon:
Bone pain, muscle weakness
Rare:
Rhabdomyolysis*, myositis*
Renal and urinary disorders
Common:
Micturition frequency, polyuria, urine abnormality
Rare:
Renal failure*, renal insufficiency*
Very rare:
Nephrotic syndrome*
Reproductive system and breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder,
dysmenorrhea, breast pain, ovarian disorder, vaginal
disorder.
Male:
impotence, prostatitis, erectile dysfunction.
Sexual dysfunction (not specified)*
General disorders and administration site conditions
Very common:
Injection site inflammation, injection site reaction, fatigue,
rigors, pyrexia, influenza like illness, asthenia, irritability
Common:
Chest pain, chest discomfort, peripheral oedema, malaise,
injection site pain, feeling abnormal, thirst
Uncommon:
Face oedema
Rare:
Injection site necrosis
Investigations
Very common: Weight decrease
Common: Cardiac murmur
* Since ribavirin is always prescribed with an alpha interferon product, and the listed adverse drug reactions included
reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from
clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or non-pegylated).
An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some
patients treated with Rebetol used in combination with interferon alfa-2b in clinical trials, but values
returned to baseline levels by four weeks after the end of therapy.
In clinical trials with Rebetol used in combination with interferon alfa-2b, the maximum overdose reported
was a total dose of 10 g of Rebetol (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b
45
(13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The
patient was observed for two days in the emergency room, during which time no adverse reaction from the
overdose was noted.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides (excl. reverse
transcriptase inhibitors), ATC code: J05A B04.
Ribavirin (Rebetol) is a synthetic nucleoside analogue which has shown
in vitro
activity against some
RNA and DNA viruses. The mechanism by which Rebetol in combination with peginterferon alfa-2b or
interferon alfa-2b exerts its effects against HCV is unknown. Oral formulations of Rebetol monotherapy
have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these
investigations
showed that Rebetol monotherapy had no effect on eliminating hepatitis virus (HCV-RNA)
or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.
Rebetol clinical trials in children and adolescents:
Rebetol in combination with peginterferon alfa-2b
Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable
HCV-RNA were enrolled in a multicentre trial and treated with Rebetol 15 mg/kg per day plus
pegylated interferon alfa-2b 60 µg/m
2
once weekly for 24 or 48 weeks, based on HCV genotype and
baseline viral load. All patients were to be followed for 24 weeks post-treatment.
A total of
107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV
Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with
mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease,
and the potential for undesirable effects
,
the benefit/risk of the combination of Rebetol and pegylated
interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and
4.8).The study results are summarized in
Table
5
.
Table 5
Sustained virological response rates (n
a,b
(%)) in previously untreated children
and adolescents by genotype and treatment duration –All subjects
n = 107
24 weeks
48 weeks
All Genotypes
26/27 (96 %)
44/80 (55 %)
Genotype 1
-
38/72 (53 %)
Genotype 2
14/15 (93 %)
-
12/12 (100 %) 2/3 (67 %)
Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment,
lower limit of
detection = 125 IU/ml.
b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while those
with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.
Genotype 3
c
Rebetol in combination with interferon alfa-2b
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in
two multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m
2
three
times a week for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were
enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population
enrolled mainly consisted in children with mild to moderate hepatitis C. The population enrolled
mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained
46
virological response rates in children and adolescents were similar to those in adults (see
Table 6
).
Due to the lack of data in these two multicentre trials for children with severe progression of the
disease, and the potential for undesirable effects, the benefit/risk of the combination of Rebetol and
interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
The study results are summarized in
Table
6
.
Table 6
Sustained virological response: previously untreated children and adolescents
Rebetol 15 mg/kg/day
+
interferon alfa-2b 3 MIU/m
2
3 times a week
Overall Response
a
(n = 118)
54 (46 %)*
Genotype 1 (n = 92)
33 (36 %)*
Genotype 2/3/4 (n = 26)
21 (81 %)*
*Number (%) of patients
a. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during
follow-up period
Long-term efficacy data - Children and adolescents
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C
patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all
enrolled subjects completed this study of which 75 % (42/56) were sustained
responders. The purpose
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess
the impact of continued viral negativity on clinical outcomes for patients who were sustained
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but
one of the paediatric subjects remained sustained virologic responders during long-term follow-up
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Rebetol results in
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with
cirrhosis (including hepatocarcinoma).
5.2 Pharmacokinetic properties
Ribavirin is absorbed rapidly following oral administration of a single dose (mean T
max
= 1.5 hours),
followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption,
distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with
approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is
approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship
between dose and AUC
tf
following single doses of 200-1,200 mg ribavirin. Volume of distribution is
approximately 5,000 l. Ribavirin does not bind to plasma proteins.
Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following
single oral doses (intrasubject variability of approximately 30 % for both AUC and C
max
), which may be
due to extensive first pass metabolism and transfer within and beyond the blood compartment.
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has
been identified to be primarily via an e
s
-type equilibrative nucleoside transporter. This type of transporter is
present on virtually all cell types and may account for the high volume of distribution of ribavirin. The
47
ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in
whole blood exists as ribavirin nucleotides sequestered in erythrocytes.
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative
pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both
ribavirin and its triazole, carboxamide and triazole carboxylic acid metabolites are also excreted renally.
Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to
single-dose AUC
12hr
. Following oral dosing with 600 mg BID, steady-state was reached by approximately
four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml. Upon
discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow
elimination from non-plasma compartments.
Food effect
: The bioavailability of a single oral dose of ribavirin was increased by co-administration of a
high fat meal (AUC
tf
and C
max
both increased by 70 %). It is possible that the increased bioavailability in
this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this
single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin
with food to achieve the maximal plasma concentration of ribavirin.
Renal function
: Single-dose ribavirin pharmacokinetics were altered (increased AUC
tf
and C
max
) in patients
with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). This appears
to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially
unchanged by haemodialysis.
Hepatic function
: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe
hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.
Children and adolescents:
Rebetol in combination with peginterferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children and
adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children
and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at
60 µg/m
2
/week, the log transformed ratio estimate of exposure during the dosing interval is predicted
to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 µg/kg/week. The
pharmacokinetics of Rebetol (dose-normalized) in this trial were similar to those reported in a prior
study of Rebetol in combination with interferon alfa-2b in children and adolescent patients and in adult
patients.
Rebetol in combination with interferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and
adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in
Table 7
. The
pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and
children or adolescents.
48
Table 7
.
Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and
Rebetol capsules when administered to children or adolescents with chronic hepatitis C
PARAMETER
Rebetol
15 mg/kg/day as 2 divided
doses
(n = 17)
Interferon alfa-2b
3 MIU/m
2
3 times a week
(n = 54)
T
max
(hr)
1.9 (83)
5.9 (36)
C
max
(ng/ml)
3,275 (25)
51 (48)
AUC*
29,774 (26)
622 (48)
Apparent clearance l/hr/kg
0.27 (27)
Not done
*AUC
12
(ng.hr/ml) for Rebetol; AUC
0-24
(IU.hr/ml) for interferon alfa-2b
5.3 Preclinical safety data
Ribavirin:
Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human
dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye,
jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects
increased with escalation of the dose. Survival of foetuses and offspring was reduced.
In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of
ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as
slight decreases in body weight, crown-rump length and bone length. At the end of the recovery
period, tibial and femoral changes were minimal although generally statistically significant compared
to controls in males at all dose levels and in females dosed with the two highest doses compared to
controls.
No histopathological effects on bone were observed. No ribavirin effects were observed
regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were
below human plasma concentrations at the therapeutic dose.
Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after
initiation of dosing, but is rapidly reversible upon cessation of treatment.
In 3-and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects,
abnormalities in sperm occurred at doses of 15 mg/kg and above. These doses in animals produce systemic
exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment,
essentially total recovery from ribavirin-induced testicular toxicity occurred within one or
two spermatogenic cycles (see section 4.6).
Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was
active in the Balb/3T3
in vitro
Transformation Assay. Genotoxic activity was observed in the mouse
lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in
rats was negative, indicating that if mutations occurred in rats they were not transmitted through male
gametes.
Conventional carcinogenicity rodent studies with low exposures compared to human exposure under
therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In
addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin
did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor
approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential
of ribavirin in humans is unlikely.
Ribavirin plus interferon
: When used in combination with peginterferon alfa-2b or interferon alfa-2b,
ribavirin did not cause any effects not previously seen with either active substance alone. The major
treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater
than that produced by either active substance alone.
49
6.
6.1 List of excipients
Oral solution contents:
Citric acid, anhydrous
Sodium benzoate
Glycerol
Sucrose
Sorbitol liquid (crystallising)
Propylene glycol
Purified Water
Natural and artificial bubble gum flavouring.
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
3 years
In use: After first opening the medicinal product should be used within one month.
6.4 Special precautions for storage
Do not store above 30°C.
6.5
Nature and contents of container
Rebetol oral solution 100 ml is packaged in 118 ml amber glass bottles (coloured EP Type IV glass, Ph
Eur.).
The child-resistant cap has inner and outer polypropylene shells.
The 10 ml oral dosing syringe consists of a natural polyethylene barrel, with a white polystyrene
plunger rod. Calibrations are marked at 0.5 m1 increments from 1.5 ml to 10 ml.
6.6 Special precautions for disposal
No special requirements.
7.
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
50
Sodium citrate
8.
MARKETING AUTHORISATION
NUMBER(S)
EU/1/99/107/004
9.
Date of first authorisation: 25 January 2005
Date of last renewal: 08 May 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
51
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
52
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release for the hard capsules
SP Labo N.V.
Industriepark 30
2220 Heist op den Berg
Belgium
Name and address of the manufacturer responsible for batch release for the oral solution
SP S.A.
2, rue Louis Pasteur
14200 Hérouville St Clair
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The holder of this marketing authorisation must submit yearly PSURs for the medicinal product
authorised by this decision until further review by CHMP.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by
the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
* When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
* Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
* At the request of the European Medicines Agency
53
ANNEX III
LABELLING AND PACKAGE LEAFLET
54
A. LABELLING
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
REBETOL – 84, 112, 140, 168 hard capsules
1.
Rebetol 200 mg hard capsules
ribavirin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 200 mg of ribavirin.
3.
LIST OF EXCIPIENTS
Contains lactose
See leaflet for further information
4.
84 hard capsules
112 hard capsules
140 hard capsules
168 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
56
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
EU/1/99/107/001 (84 hard capsules)
EU/1/99/107/005 (112 hard capsules)
EU/1/99/107/002 (140 hard capsules)
EU/1/99/107/003 (168 hard capsules)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Rebetol
57
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Immediate packaging (blister foil)
1.
FURTHER INFORMATION
What Rebetol contains
-
The other ingredients are: Sodium citrate, citric acid, anhydrous, sodium benzoate, glycerol,
sucrose, sorbitol liquid (crystallising), propylene glycol, purified water, natural and artificial
bubble gum flavouring
84
-
The active substance is ribavirin 40 mg/ml.
What Rebetol looks like and contents of the pack
Rebetol 40 mg/ml oral solution is packaged in 118 ml size amber glass bottles containing 100 ml of
oral solution.
A 10 ml oral dosing syringe is provided to measure the dose.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
:
Manufacturer
:
73, rue de Stalle
2, rue Louis Pasteur
B-1180 Bruxelles
F-14200 Hérouville St Clair
Belgium
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Rue de Stalle/Stallestraat 73
B-1180 Bruxelles/Brussel/Brüssel
Tél/Tel: + 32-(0)2 370 92 11
Luxembourg/Luxemburg
Rue de Stalle 73
B-1180 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: + 32-(0)2 370 92 11
България
Ийст Парк Трейд Център
Бул. „Н.Й.Вапцаров” 53А, ет. 2
BG-София 1407
Тел.: +359 2 806 3030
Magyarország
Alkotás u. 53.
H-1123 Budapest
Tel.: +36 1 457-8500
Česká republika
Ke Štvanici 3
CZ-186 00 Praha 8
Tel: +420 221771250
Malta
168 Christopher Street
MT-VLT02 Valletta
Tel: + 356-21 23 21 75
Danmark
Lautrupbjerg 2
DK-2750 Ballerup
Tlf: + 45-44 39 50 00
Nederland
Walmolen 1
NL-3994 DL Houten
Tel: + 31-(0)800 9999000
Deutschland
Thomas-Dehler-Straße 27
D-81737 München
Tel: + 49-(0)89 627 31-0
Norge
Pb. 398
N-1326 Lysaker
Tlf: + 47 67 16 64 50
Eesti
Järvevana tee 9
EE-11314 Tallinn
Tel: + 372 654 96 86
Österreich
Am Euro Platz 2
A-1120 Wien
Tel: + 43-(0) 1 813 12 31
Ελλάδα
Αγίου Δημητρίου 63
GR-174 55 Άλιμος
Tηλ.: + 30-210 98 97 300
Polska
Ul. Taśmowa 7
PL-02-677 Warszawa
Tel.: + 48-(0)22 478 41 50
España
Josefa Valcárcel, 38
E-28027 Madrid
Portugal
Rua Agualva dos Açores 16
P-2735-557 Agualva-Cacém
85
SP Europe
SP S.A.
Tel: + 34-91 321 06 00
Tel: +351-21 433 93 00
France
34 avenue Léonard de Vinci
F-92400 Courbevoie
Tél: + 33-(0)1 80 46 40 40
România
Şos. Bucureşti-Ploieşti, nr. 17-21,
Băneasa Center, et. 8, sector 1
RO-013682 Bucureşti
Tel. + 40 21 233 35 30
Ireland
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
Tel: +44-(0)1 707 363 636
Slovenija
Dunajska 22
SI-1000 Ljubljana
Tel: + 386 01 3001070
Ísland
Hörgatún 2
IS-210 Garðabær
Sími: + 354 535 70 00
Slovenská republika
Strakova 5
SK-811 01 Bratislava
Tel: + 421 (2) 5920 2712
Italia
Via fratelli Cervi snc,
Centro Direzionale Milano Due
Palazzo Borromini
I-20090 Segrate (Milano)
Tel: + 39-02 21018.1
Suomi/Finland
PL 46/PB 46
FIN-02151 Espoo/Esbo
Puh/Tel: + 358 (0)9 804 650
Κύπρος
Οδός Αγίου Νικολάου, 8
CY-1055 Λευκωσία
Τηλ: +357-22 757188
Sverige
Box 7152
S-192 07 Sollentuna
Tel: + 46-(0)8 522 21 500
Latvija
Bauskas 58a -401
Rīga, LV-1004
Tel: + 371-7 21 38 25
United Kingdom
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW - UK
Tel: + 44-(0)1 707 363 636
Lietuva
Kęstučio g. 65/40
LT-08124 Vilnius
Tel. + 370 52 101868
This leaflet was last approved on
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
86
Source: European Medicines Agency
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