ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ribavirin Mylan 200 mg hard capsules
2.
Each hard capsule contains 200 mg of ribavirin.
Excipient: each hard capsule contains 15 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White opaque body imprinted "riba/200" in green and a white opaque cap imprinted "riba/200" in
green.
4.
Ribavirin Mylan is indicated for the treatment of chronic hepatitis C and must only be used as part of a
combination regimen with interferon alfa-2b (adults, children (3 years of age and older) and
adolescents). Ribavirin monotherapy must not be used.
There is no safety or efficacy information on the use of Ribavirin with other forms of interferon (i.e.,
not alfa-2b).
Please refer also to the interferon alfa-2b Summary of Product Characteristics (SPC) for prescribing
information particular to that product.
Naïve patients
Adult Patients
: Ribavirin Mylan is indicated, in combination with interferon alfa-2b, for the treatment
of adult patients with chronic hepatitis C except genotype 1, not previously treated, without liver
decompensation, with elevated alanine aminotransferase (ALT), who are positive for serum HCV-
RNA (see section 4.4).
Children and adolescents:
Ribavirin Mylan is indicated, in a combination regimen with interferon
alfa-2b, for the treatment of children and adolescents 3 years of age and older, who have all types of
chronic hepatitis C except genotype 1, not previously treated, without liver decompensation, and who
are positive for serum 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 treatment failure patients
Adult patients:
Ribavirin Mylan 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 alpha monotherapy but who have subsequently relapsed. (see
section 5.1).
2
Treatment should be initiated, and monitored, by a physician experienced in the management of
chronic hepatitis C.
Dose to be administered
The dose of Ribavirin Mylan is based on patient body weight (
Table 1
). Ribavirin capsules are to be
administered orally each day in two divided doses (morning and evening) with food.
Adult patients: Ribavirin Mylan must be used in combination with interferon alfa-2b (3 million
international units [MIU] three times a week).
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
Ribavirin Mylan dose based on body weight
Patient weight (kg)
Daily Ribavirin Mylan 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
Ribavirin in combination with interferon alfa-2b:
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).
Duration 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).
Duration of treatment – Retreatment
•
Genotypes Non-1: The decision to extend therapy to one year in patients with negative
HCVRNA 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:
(For patients who weigh <47 kg, or are unable to
swallow capsules, ribavirin oral solution is available and should be used in appropriate):
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
).
Ribavirin Mylan is to be administered orally each day in two divided doses with food (morning and
evening).
3
Table 2
Ribavirin Mylan paediatric dose based on body weight
Patient weight (kg)
Daily Ribavirin 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 2 or 3:
The recommended duration of treatment is 24 weeks.
Dose modification for all patients
If severe adverse reactions or laboratory abnormalities develop during therapy with Ribavirin Mylan
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 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.
4
Table 3
Dosage modification guidelines
Laboratory Values
Reduce only Ribavirin Mylan
daily dose adult to 600
mg/day* , paediatric to
7.5 mg/kg, if:
Reduce only interferon
alfa2b dose (adult and
paediatric
) to one-half
dose
, if:
Discontinue
combination therapy if:
Haemoglobin
< 10 g/dl
-
< 8.5 g/dl
Adult: Haemoglobin in:
patients with history of
stable cardiac disease
Paediatric: 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
White blood cells
-
< 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
-
Adult < 50 x 10
9
/l
Paediatric < 80 x
10
9
/l
Adult < 25 x 10
9
/l
Paediatric
< 50 x 10
9
/l
Bilirubin – Direct
-
-
2.5 x ULN**
Bilirubin – Indirect
> 5 mg/dl
-
Adult > 4 mg/dl
Paediatric > 5 mg/dl
(for > 4 weeks)
Creatinine
-
-
> 2.0 mg/dl
Alanine
aminotransferase/
aspartate
aminotransferase
(ALT/AST)
-
-
2 x baseline and > 10 x
ULN**
*
Upper limit of normal
**
Refer to the SPC for interferon alfa-2b for dose modification and discontinuation
Note 1: In adult patients, 1
st
dose reduction of Ribavirin Mylan is by 200 mg/day (except in patients
receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2
nd
dose
reduction of Ribavirin Mylan is by an additional 200 mg/day. Patients whose dose of
Ribavirin Mylan 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 Ribavirin Mylan plus interferon alfa-2b,
reduce Ribavirin Mylan dose to 7.5 mg/kg/day.
Note 2: In adult patients and children and adolescent patients treated with Ribavirin Mylan 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
Ribavirin Mylan. Patients with creatinine clearance < 50 ml/minute must not be treated with Ribavirin
Mylan (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 mg/dl
(Table 3)
Ribavirin
Mylan and interferon alfa-2b must be discontinued.
5
Use in hepatic impairment:
No pharmacokinetic interaction appears between ribavirin and hepatic
function (see section 5.2). Therefore, no dose adjustment of Ribavirin Mylan is required in patients
with hepatic impairment.
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 Ribavirin Mylan (see section 5.2).
Use in patients under the age of 18 years
: Ribavirin Mylan may be used in combination with
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 (see section 4.1). Safety and effectiveness of
Ribavirin Mylan with pegylated or other forms of interferon (i.e. not alfa-2b) in these patients have not
been evaluated.
Patients co-infected with HCV/HIV:
Patients taking NRTI treatment in association with ribavirin and
interferon 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). Ribavirin Mylan 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).
Children and adolescents:
-
Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal
ideation, or suicide attempt.
Because of co-administration with 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 Ribavirin 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 Ribavirin 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
6
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal
ideation is identified, it is recommended that treatment with Ribavirin 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 Ribavirin 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 Ribavirin 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 Ribavirin
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.
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 Ribavirin in combination with peginterferon
alfa-2b or interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects,
anaemia associated with Ribavirin may result in deterioration of cardiac function, or exacerbation of
the symptoms of coronary disease, or both. Thus, Ribavirin Mylan 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
7
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, Ribavirin Mylan 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.
Thyroid supplemental monitoring specific for children and adolescents:
Approximately 12% to 21% of
children treated with Ribavirin 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 Ribavirin
and interferon alfa-2b and during treatment with Ribavirin 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).
8
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 Ribavirin Mylan and didanosine is not recommended due to the risk of
mitochondrial toxicity (see section 4.5).
-
co-administration of Ribavirin Mylan 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 Ribavirin 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 Ribavirin 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 Ribavirin 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 Ribavirin Mylan therapy:
•
Haemoglobin
Adult: ≥ 12g/dl (females); ≥ 13g/dl (males)
9
Children and adolescents: ≥ 11g/dl (females); ≥ 12g/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 Ribavirin Mylan 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 Ribavirin Mylan hard capsule contains 15 mg of
lactose monohydrate. 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.
No interaction studies have been conducted with Ribavirin and other medicinal products, except for
peginterferon alfa-2b, interferon alfa-2b and antacids.
Interferon alfa-2b:
No pharmacokinetic interactions were noted between Ribavirin 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 Ribavirin Mylan 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
(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 Ribavirin Mylan 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.
10
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.
4.6 Fertility,
pregnancy and lactation
The use of Ribavirin Mylan 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:
Ribavirin Mylan 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). Ribavirin
Mylan 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 Ribavirin Mylan (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 Ribavirin Mylan 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.
Ribavirin Mylan have 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.
Adult patients:
The safety of Ribavirin is evaluated from data from four clinical trials in patients with no previous
exposure to interferon (interferon-naïve patients): two trials studied ribavirin capsules in combination
with interferon alfa-2b, two trials studied ribavirin capsules in combination with peginterferon alfa-2b.
11
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 interferon
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 Ribavirin 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*
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
12
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, 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
13
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 > 4g/dl was observed in 30% of patients treated with
Ribavirin and peginterferon alfa-2b and 37% of patients treated with Ribavirin + 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 Ribavirin 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 ribavirin capsules 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.
An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some
patients treated with Ribavirin 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 Ribavirin 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).
14
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 Ribavirin in combination with peginterferon alfa-
2b when compared to patients receiving Ribavirin 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 ribavirin capsules in combination with peginterferon alfa-2b. Anaemia
(haemoglobin < 9.4 g/dl) was reported in 12% (23/194) of patients treated with Ribavirin in
combination with peginterferon alfa-2b.
CD4 lymphocytes decrease:
Treatment with Ribavirin 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
Ribavirin 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 Ribavirin 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 Ribavirin, dose modifications were required in 25 %
of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions
profile in children and adolescents was similar to that observed in adults, although there is a paediatric-
specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with
pegylated interferon alfa-2b and Ribavirin, growth inhibition is observed, the reversibility of which is
uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment
(at the end of treatment, mean decrease from baseline in weight and 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 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.
15
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 Ribavirin, 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).
T
wenty (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
Ribavirin, 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 Ribavirin 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 5
Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in
children and adolescents with Ribavirin 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
16
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
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
:
17
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 Ribavirin /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 Ribavirin 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.
In clinical trials with Ribavirin used in combination with peginterferon alfa-2b or interferon alfa-2b,
the maximum overdose reported was a total dose of 10 g of Ribavirin (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: J05AB04.
Ribavirin (Ribavirin Mylan) is a synthetic nucleoside analogue which has shown
in vitro
activity
against some RNA and DNA viruses. The mechanism by which Ribavirin in combination with
peginterferon alfa-2b or interferon alfa-2b exerts its effects against HCV is unknown. Oral
formulations of Ribavirin monotherapy have been investigated as therapy for chronic hepatitis C in
several clinical trials. Results of these investigations showed that Ribavirin 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.
Ribavirin clinical trials in adults
The use of Ribavirin 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
18
Three trials examined the use of interferon in naïve patients, two with Ribavirin + interferon alfa-2b
(C95-132 and I95-143) and one with Ribavirin + 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 ribavirin capsules to interferon alfa-2b (41%
vs 16%, p < 0.001).
In clinical trials C95-132 and I95-143, Ribavirin + 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:
• Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n=511).
• Ribavirin (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).
• Ribavirin (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n=505).
In this trial, the combination of Ribavirin and peginterferon alfa-2b (1.5 micrograms/kg/week) was
significantly more effective than the combination of Ribavirin 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.
HCV genotype and baseline virus load are prognostic factors which are known to affect response rates.
However, response rates in this trial were shown to be dependent also on the dose of Ribavirin
administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that
received >10.6 mg/kg Ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral
load, response rates were significantly higher than in those patients that received ≤ 10.6 mg/kg
Ribavirin (
Table 6
), while response rates in patients that received > 13.2 mg/kg ribavirin were even
higher.
Table 6
Sustained response rates with Ribavirin + peginterferon alfa-2b (By Ribavirin [mg/kg],
genotype and viral load)
HCV Genotype
Ribavirin Dose
(mg/kg)
P 1.5/R
P 0.5/R
I/R
All Genotypes
All
54 %
47 %
47 %
≤ 10.6
50 %
41 %
27 %
> 10.6
61 %
48 %
47 %
Genotype 1
All
42 %
34 %
33 %
≤ 10.6
38 %
25 %
20 %
> 10.6
48 %
34 %
34 %
Genotype 1
≤ 600,000 IU/ml
All
73 %
51 %
45 %
≤ 10.6
74 %
25 %
33 %
> 10.6
71 %
52 %
45 %
Genotype 1
> 600,000 IU/ml
All
30 %
27 %
29 %
≤ 10.6
27 %
25 %
17 %
> 10.6
37 %
27 %
29 %
Genotype 2/3
All
82 %
80 %
79 %
≤ 10.6
79 %
73 %
50 %
> 10.6
88 %
80 %
80 %
P1.5/R Ribavirin (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)
P0.5/R Ribavirin (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)
I/R
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
19
Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU)
(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*
Ribavirin 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)
> 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 Ribavirin. The overall sustained response rate after a 24-week treatment duration was
50%. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4
and week 24 of therapy. In this subgroup, there was a 92% (89/97) sustained virological response
rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis
(n=49) and prospectively confirmed (n=48).
Limited historical data indicate that treatment for 48 weeks might be associated with a higher
sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following
24 weeks of treatment).
A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two
peginterferon alfa-2b/ Ribavirin regimens [peginterferon alfa-2b 1.5 µg/kg and 1 µg/kg
subcutaneously once weekly both in combination with Ribavirin 800 to 1,400 mg p.o. daily (in two
divided doses)] and peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to
1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C
genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is
defined as undetectable HCV-RNA at 24 weeks post-treatment (see
Table 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
+ Ribavirin
peginterferon alfa-2b
1 µg/kg
+ Ribavirin
peginterferon alfa-2a
180 µg
+ ribavirin
Undetectable HCV-RNA
at treatment week 12
40 (407/1,019)
36 (366/1,016)
45 (466/1,035)
End of treatment
response
*
53 (542/1,019)
49 (500/1,016)
64 (667/1,035)
Relapse
*
24 (123/523)
20 (95/475)
32 (193/612)
20
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)/ Ribavirin 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 Ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis,
in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml and in
patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to
the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the
relapse rate was 24 %.
Predictability of sustained virological response 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
).
21
Table 9
Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b 1.5 µg/kg/
Ribavirin
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.
.
22
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 Ribavirin (800 mg/day) plus
peginterferon alfa-2b (1.5 µg/kg/week) or Ribavirin (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 Ribavirin (800-1,200 mg/day based on
weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Ribavirin
(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 Ribavirin in combination with peginterferon
alfa-2b in HCV/HIV co-infected patients
Study 1
1
Study 2
2
Ribavirin
(800 mg/day) +
peginterferon
alfa-2b (1.5 µg
/kg/
week)
Ribavirin
(800 mg/day) +
interferon alfa-
2b (3 MIU
TIW)
p
Value
a
Ribavirin
(800-1,200 mg/da
y)
d
+
peginterferon
alfa-2b (100 or
150
c
µg/week)
Ribavirin
(800-1,200 mg/da
y)
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: Ribavirin dosing was 800mg 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
Ribavirin 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.
23
Previously treated patients
-
Retreatment of prior treatment failures (relapse and non-responder patients) with peginterferon alfa-
2b in combination with Ribavirin:
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 Ribavirin. Failure
to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum
of 12 weeks of treatment).
Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks and
were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-
RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable
HCV-RNA at 24 weeks post-treatment (
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
retreatment
Overall
Population*
interferon alfa/ribavirin
peginterferon alfa/ribavirin
Response week 12
% (n/N)
SVR% (n/N)
99% CI
Response week
12 % (n/N)
SVR% (n/N)
99% CI
SVR% (n/N)
99% CI
Overall
38.6(549/1,423)
59.4 (326/549)
54.0, 64.8
31.5(272/863)
50.4 (137/272)
42.6, 58.2
21.7 (497-
2,293)
19.5, 23.9
Prior Response
Relapse
67.7 (203/300)
59.6 (121/203)
50.7, 68.5
58.1 (200/344)
52.5 (105/200)
43.4, 61.6
37.7 (243/645)
32.8, 42.6
Genotype 1/4
59.7 (129/216)
51.2 (66/129)
39.8, 62.5
48.6 (122/251)
44.3 (54/122)
32.7, 55.8
28.6 (134/468)
23.3, 34.0
Genotype 2/3
88.9 (72/81)
73.6 (53/72)
(60.2, 87.0)
83.7 (77/92)
64.9 (50/77)
50.9, 78.9
61.3 (106/173)
51.7, 70.8
NR
28.6 (258/903)
57.0 (147/258)
49.0, 64.9
12.4 (59/476)
44.1 (26/59)
27.4, 60.7
13.6
(188/1,385)
11.2, 15.9
Genotype 1/4
23.0 (182/790)
51.6 (94/182)
42.1, 61.2
9.9 (44/446)
38.6 (17/44)
19.7, 57.5
9.9 (123/1,242)
7.7, 12.1
Genotype 2/3
67.9 (74/109)
70.3 (52/74)
56.6, 84.0
53.6 (15/28)
60.0 (9/15)
27.4, 92.6
46.0 (63/137)
35.0, 57.0
Genotype
1
30.2 (343/1,135) 51.3 (176/343)
44.4, 58.3
23.0 (162/704)
42.6 (69/162)
32.6, 52.6
14.6
(270/1,846)
12.5, 16.7
2/3
77.1 (185/240)
73.0 (135/185)
64.6, 81.4
75.6 (96/127)
63.5 (61/96)
50.9, 76.2
55.3 (203/367)
48.6, 62.0
4
42.5 (17/40)
70.6 (12/17)
42.1, 99.1
44.4 (12/27)
50.0 (6/12)
12.8, 87.2
28.4 (19/67)
14.2, 42.5
METAVIR
Fibrosis Score
F2
46.0 (193/420)
66.8 (129/193)
58.1, 75.6
33.6 (78/232)
57.7 (45/78)
43.3, 72.1
29.2 (191/653)
24.7, 33.8
F3
38.0 (163/429)
62.6 (102/163)
52.8, 72.3
32.4 (78/241)
51.3 (40/78)
36.7, 65.9
21.9 (147/672)
17.8, 26.0
F4
33.6 (192/572)
49.5 (95/192)
40.2, 58.8
29.7 (116/390)
44.8 (52/116)
32.9, 56.7
16.5 (159/966)
13.4, 19.5
Baseline Viral
Load
HVL
32.4 (280/864)
56.1 (157/280)
26.5 (152/573)
41.4 (63/152)
16.6
24
(>600,000
IU/ml)
48.4, 63.7
31.2, 51.7
(239/1,441)
14.1, 19.1
LVL
(≤600,000
IU/ml)
48.3 (269/557)
62.8 (169/269)
55.2, 70.4
41.0 (118/288)
61.0 (72/118)
49.5, 72.6
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 prior therapy could not be confirmed.
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 Ribavirin and interferon alfa-2b combination treatment
Two trials examined the use of Ribavirin 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 Ribavirin 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 Ribavirin) and pegylated interferon
alfa-2b (with or without Ribavirin), 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 Ribavirin), and is 99 % (95 %
CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Ribavirin).
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated, with or
without Ribavirin) results in long-term clearance of the virus providing resolution of the hepatic
infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of
hepatic events in patients with cirrhosis (including hepatocarcinoma).
Ribavirin clinical trials in children and adolescents:
Ribavirin 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 Ribavirin 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 Ribavirin and pegylated
25
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
.
Ribavirin 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 Ribavirin 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 ribavirin 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
Ribavirin 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
26
Genotype 3
c
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 Ribavirin results in
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with
cirrhosis (including hepatocarcinoma).
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.
27
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
:
Ribavirin in combination with peginterferon alfa-2b
Multiple-dose pharmacokinetic properties for Ribavirin 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 Ribavirin (dose-normalized) in this trial were similar to those reported in a prior
study of Ribavirin in combination with interferon alfa-2b in children and adolescent patients and in
adult patients.
Ribavirin in combination with interferon alfa-2b
Multiple-dose pharmacokinetic properties for Ribavirin 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 Ribavirin 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
Ribavirin when administered to children or adolescents with chronic hepatitis C
Parameter
Ribavirin
15 mg/kg/day as 2 divided doses
(n = 17)
Interferon alfa-2b
3 MIU/m
2
3 times a week
(n = 54)
Parameter
Ribavirin
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 Ribavirin; 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
28
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.
6.
6.1 List of excipients
Capsule contents:
Microcrystalline cellulose,
Lactose monohydrate,
Croscarmellose sodium,
Povidone.
Capsule shell:
Gelatin,
Titanium dioxide..
Capsule imprint:
Shellac,
Propylene glycol,
Ammonia solution, concentrated,
Yellow iron oxide (E172),
Indigotine (E132),
Titanium dioxide (E171).
29
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
Ribavirin Mylan are packaged in high-density polyethylene (HDPE) bottle, closed with a child-
resistant (CR) polypropylene (PP) screw cap.
Pack sizes of 84, 112, 140 and 168 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Generics [UK] Limited,
Station Close,
Potters Bar,
Hertfordshire,
EN6 1TL,
United Kingdom.
8.
EU/1/10/634/001
EU/1/10/634/002
EU/1/10/634/003
EU/1/10/634/004
9.
Date of first authorisation:10 June 2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
30
ANNEX II
A. Manufacturing authorisation holder responsible for batch release
B. Conditions of the marketing authorisation
31
A. Manufacturing authorisation holder responsible for batch release
Name and address of the manufacturer responsible for batch release
Penn Pharmaceutical Services Ltd.
23-24 Tafarnaubach Industrial Estate
Tredegar, Gwent NP2 3AA
United Kingdom
B.
Conditions of the marketing authorisation
•
Conditions or restrictions regarding supply and use imposed on the marketing
authorisation holder
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 use of the medicinal
product
Not applicable
•
Other conditions
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
32
ANNEX III
LABELLING AND PACKAGE LEAFLET
33
A. LABELLING
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Ribavirin Mylan 200 mg hard capsules
Ribavirin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains 200 mg 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.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
35
Generics [UK] Limited,
Station Close,
Potters Bar,
Hertfordshire,
EN6 1TL,
United Kingdom.
EU/1/10/634/001
EU/1/10/634/002
EU/1/10/634/003
EU/1/10/634/004
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ribavirin Mylan hard capsules
36
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Bottle
1.
Ribavirin Mylan 200 mg hard capsules
Ribavirin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 200 mg 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.
37
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Generics [UK] Limited,
Station Close,
Potters Bar,
Hertfordshire,
EN6 1TL,
United Kingdom.
EU/1/10/634/001
EU/1/10/634/002
EU/1/10/634/003
EU/1/10/634/004
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ribavirin Mylan 200 mg hard capsules
ribavirin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Ribavirin Mylan is and what it is used for
2.
Before you take Ribavirin Mylan
3.
How to take Ribavirin Mylan
4.
Possible side effects
5.
How to store Ribavirin Mylan
6.
Further information
1.
WHAT RIBAVIRIN MYLAN IS AND WHAT IT IS USED FOR
Ribavirin Mylan contain the active ingredient ribavirin. Ribavirin Mylan stops the multiplication of
many types of viruses, including hepatitis C virus. Ribavirin Mylan must not be used without
interferon alfa-2b, i.e. Ribavirin Mylan must not be used alone.
Previously untreated patients
:
The combination of Ribavirin Mylan with interferon alfa-2b is used to treat patients 3 years of age and
older who have chronic hepatitis C (HCV) infection. For children and adolescents weighing less than
47 kg a solution formulation is available.
Previously treated adult patients
:
The combination of Ribavirin Mylan with interferon alfa-2b is used to treat adult patients with chronic
hepatitis C, who have previously responded to treatment with an alpha interferon alone, but whose
condition has recurred.
There is no safety or efficacy information on the use of Ribavirin Mylan with pegylated or other forms of
interferon (i.e., not alfa-2b).
40
2.
BEFORE YOU TAKE RIBAVIRIN MYLAN
Ribavirin Mylan is not recommended for use in patients under the age of 3 years.
Do not take Ribavirin Mylan:
If any of the following apply to you or the child you are caring for,
do not take
Ribavirin Mylan, and
tell your doctor
if you:
-
are
allergic
(hypersensitive) to ribavirin or any of the other ingredients of Ribavirin Mylan
-
are
pregnant or planning to become pregnant
. (see section “Pregnancy and breast-feeding”)
-
are
breast-feeding
.
-
had a problem with your
heart
during the past 6 months
-
have severe medical conditions that leave you very weak
-
have severe
kidney
disease and/or are on haemodialysis
-
have a serious problem with your
liver
other than chronic hepatitis C.
-
have any
blood disorders
, such as anaemia (low blood count), thalassemia , sickle-cell
anaemia.
-
have autoimmune hepatitis or any other problem with your
immune system
;
-
are taking medicine that suppresses your immune system (that protects you against infection and
some diseases).
Children and adolescents must not take combination therapy with Ribavirin Mylan and alpha
interferon when there is existence or history of serious nervous or mental problems, such as severe
depression, thoughts of suicide or attempted suicide.
Reminder: Please read the “Do not use” section of the Package Leaflet for interferon alfa-2b before
you begin combination treatment with Ribavirin Mylan.
Take special care with Ribavirin Mylan
Seek medical help
immediately
if you develop symptoms of a severe allergic reaction (such as
difficulty in breathing, wheezing or hives) while taking this treatment.
Children and adolescents weighing less than 47 kg:
The use of Ribavirin Mylan is not recommended. An oral solution of ribavirin is available for children
3 years of age and older and adolescents weighing less than 47 kg.
You should
tell your doctor
if you or the child you are caring for:
• are an adult who has or had a severe
nervous or mental disorder
, confusion, unconsciousness,
or have had
thoughts of suicide
or
have attempted suicide
.
• have ever had
depression
or develop symptoms associated with depression (e.g. feeling of
sadness, dejection, etc.) while on treatment with Ribavirin Mylan
• are a woman of
childbearing
age (see section “Pregnancy and breast-feeding”)
• are a
male
and your female partner is of childbearing age (see section “Pregnancy and breast-
feeding”)
• had a previous serious
heart
condition or have cardiac disease
• are older than
65 years
or if you have problems with your
kidneys
• have or have had any
serious illness
• have
thyroid
problems
During treatment with Ribavirin Mylan in combination therapy with an alfa interferon,
dental and
gum disorders
, which may lead to loss of teeth, have been reported. In addition,
dry mouth
that
could have a damaging effect on teeth and membranes of the mouth has been reported during long-
term treatment with Ribavirin Mylan in combination therapy with an alpha interferon. You should
brush your teeth thoroughly twice daily and have regular dental examinations. In addition some
41
patients may experience
vomiting
. If you have this reaction, be sure to rinse your mouth thoroughly
afterwards.
During treatment with Ribavirin Mylan in combination therapy with an alpha interferon, patients may
experience
eye problems,
or loss of vision in rare instances. If you receive ribavirin in combination
with an alpha interferon, you 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 pre-
existing eye disorders (e.g. diabetic or hypertensive retinopathy) should receive periodic eye exams
during combination therapy with ribavirin and an alpha interferon. Combination therapy with
ribavirin and an alpha interferon should be discontinued in patients who develop new or worsening
eye disorders.
Reminder: Please read the “Take special care” section of the Package Leaflet for interferon alfa-2b
before you begin combination treatment.
Taking other medicines
Please tell your doctor or pharmacist if you or the child you are caring for:
-
are taking or have recently taken any other medicines, including medicines obtained without a
prescription.
-
are infected with both
Human Immunodeficiency Virus
(HIV-positive) and
Hepatitis C
Virus
(HCV) and are being treated with an anti-HIV medicinal product(s) – [nucleoside reverse
transcriptase inhibitor (
NRTI
), and/or highly active anti-retroviral therapy (
HAART
)]:
-
Taking Ribavirin Mylan in combination with an alpha interferon and an anti-HIV
medicinal product(s) may increase the risk of lactic acidosis, liver failure, and blood
abnormalities development (reduction in number of red blood cells which carry oxygen,
certain white blood cells that fight infection, and blood clotting cells called platelets).
-
With
zidovudine
or
stavudine
, it is not certain if Ribavirin Mylan will change the way
these medicines work. Therefore, your blood will be checked regularly to be sure that the
HIV infection is not getting worse. If it gets worse, your doctor will decide whether or not
your Ribavirin Mylan treatment needs to be changed. Additionally, patients receiving
zidovudine
with
ribavirin
in combination
with alpha interferons
could be at increased
risk of developing anaemia (low number of red blood cells). Therefore the use of
zidovudine and ribavirin in combination with alpha interferons is not recommended.
-
Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis,
the use of
ribavirin and didanosine
is not recommended and the use of
ribavirin and
stavudine
should be avoided.
-
Co-infected patients with advanced liver disease receiving (HAART) may be at increased
risk of worsening liver function. Adding treatment with alfa interferons alone or in
combination with ribavirin may increase the risk in this patient subset.
Reminder: Please read the “Taking other medicines” section of the Package Leaflet for interferon alfa-
2b before you begin combination treatment.
Taking Ribavirin Mylan with food and drink
Ribavirin Mylan must be taken with food.
Pregnancy and breast-feeding
If you are
pregnant
you must not take Ribavirin Mylan. Ribavirin Mylan can be very damaging to
your unborn baby (embryo).
Both female and male patients must take
special precautions
in their sexual activity if there is any
possibility for pregnancy to occur:
•
Girl
or
woman
of childbearing age:
42
You must have a negative pregnancy test before treatment, each month during treatment, and
for the 4 months after treatment is stopped. This should be discussed with your doctor.
•
Men
Do not have sex with a pregnant woman unless you
use a condom
. This will lessen the
possibility for ribavirin to be left in the woman’s body.
If your female partner is not pregnant now but is of childbearing age, she must be tested for
pregnancy each month during treatment and for the 7 months after treatment has stopped. You
and your female partner must each use an effective contraceptive during the time you are taking
ribavirin and for 7 months after stopping treatment. This should be discussed with your doctor
(see “Do not take Ribavirin Mylan”).
If you are a woman who is
breast-feeding
, you must not take Ribavirin Mylan. Discontinue breast-
feeding before starting to take Ribavirin Mylan.
Driving and using machines
Ribavirin Mylan does not affect your ability to drive or use machines; however, interferon alfa-2b may
affect your ability to drive or use machines. Therefore, do not drive or use machines if you become
tired, sleepy, or confused from this treatment.
Important information about some of the ingredients of Ribavirin Mylan
Each Ribavirin Mylan hard capsule contains a small amount of
lactose
. If you have been told by your
doctor that you have
an intolerance to some sugars
, discuss with your doctor before taking this
medicinal product.
3.
HOW TO TAKE RIBAVIRIN MYLAN
General information about taking Ribavirin Mylan
If the child you are caring for is
under the age of 3 years
, do not administer.
Always take Ribavirin Mylan exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure.
Do not take more than the recommended dosage and take the medicine for as long as prescribed.
Your doctor has determined the correct dose of Ribavirin Mylan based on how much you or the child
you are caring for weighs.
Standard blood tests
will be taken to check your blood, kidney and liver function.
- Blood tests will be done regularly to help your doctor to know if this treatment is working.
- Depending upon the results of these tests, your doctor may change/adjust the number of hard
capsules you or the child you are caring for take, prescribe a different pack size of Ribavirin
Mylan, and/or change the length of time to take this treatment.
- If you have or develop severe kidney or liver problems, this treatment will be stopped.
The
usual dose
, according to how much the patient weighs, is shown in the table below:
1. Look for the line that shows how much the adult or child/adolescent weighs.
Reminder: If the child is under the age of 3 years, do not administer.
2. Read across on the same line to see how many hard capsules to take.
Reminder: If your doctor’s instructions are different from the amounts in the below table,
follow your doctor’s instructions.
3. If you have any questions about the dose, ask your doctor.
43
Ribavirin Mylan for oral use - dose based on body weight
If the
adult
weighs
(kg)
Usual
daily Ribavirin
Mylan dose
Number of 200 mg capsules
< 65
800 mg
2 capsules in the morning and 2 capsules in the evening
65 – 80
1,000 mg
2 capsules in the morning and 3 capsules in the evening
81 - 105
1,200 mg
3 capsules in the morning and 3 capsules in the evening
> 105
1,400 mg
3 capsules in the morning and 4 capsules in the evening
If the
child/adolescent
weighs (kg)
Usual
daily Ribavirin
Mylan dose
Number of 200 mg capsules
47 – 49
600 mg
1 capsule in the morning and 2 capsules in the evening
50 – 65
800 mg
2 capsules in the morning and 2 capsules in the evening
> 65
see adult dose and corresponding number of hard capsules
Take your prescribed dose by mouth with water and during your meal. Do not chew the hard capsules.
For children or adolescents who cannot swallow a hard capsule, an oral solution of ribavirin is
available.
Reminder: Ribavirin Mylan is only to be used in combination with interferon alfa-2b for hepatitis C
virus infection. For complete information be sure to read the “How to use” section of the
Package Leaflet for interferon alfa-2b.
Interferon medicine that is used in combination with Ribavirin Mylan may cause unusual tiredness; if
you are injecting this medicine yourself or giving it to a child, use it at bedtime.
If you take more Ribavirin Mylan than you should
Tell your doctor or pharmacist as soon as possible.
If you forget to take Ribavirin Mylan
If you are self-administering treatment, or if you are the caregiver of a child taking Ribavirin Mylan in
combination with interferon alfa-2b, take/administer the missed dose as soon as possible during the
same day. If an entire day has gone by, check with your doctor. Do not take a double dose to make up
for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Please read the “Possible side effects” section of the Package Leaflet for interferon alfa-2b.
Like all medicines, Ribavirin Mylan used in combination with an alpha interferon product can cause
side effects, although not everybody gets them. Although not all of these unwanted effects may occur,
they may need medical attention if they do occur.
Psychiatric and Central Nervous System:
Some people get depressed when taking Ribavirin in combination treatment with an interferon, and in
some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or
change in your behaviour. You may want to consider asking a family member or close friend to help
you stay alert to signs of depression or changes in your behaviour.
44
Children and adolescents
are particularly prone to develop depression when being treated with
ribavirin and interferon alpha. Immediately contact the doctor or seek emergency treatment if they
display any unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or
others.
Growth and development
(children and adolescents):
During the one year of treatment with Ribavirin in combination with interferon alfa-2b, some children
and adolescents did not grow or gain weight as much as expected. Some children did not reach their
projected height within 1-5 years after completing treatment.
Contact your doctor immediately
if you notice any of the following side effects occuring during
combination treatment with an alpha interferon product:
- chest pain or persistent cough; changes in the way your heart beats, fainting,
- confusion, feeling depressed; suicidal thoughts or aggressive behaviour, attempt suicide,
thoughts about threatening the life of others,
- feelings of numbness or tingling,
- trouble sleeping, thinking or concentrating,
- severe stomach pain; black or tar-like stools; blood in stool or urine, lower back or side pain,
- painful or difficult urination,
- severe bleeding from your nose,
- fever or chills beginning after a few weeks of treatment,;
- problems with your eyesight or hearing
,
- severe skin rash or redness.
Possible side effects listed below are grouped by frequency of occurrence:
Very common
(affects more than 1 user in 10)
Common
(affects 1 to 10 users in 100)
Uncommon
(affects 1 to 10 users in 1,000)
Rare
(affects 1 to 10 users in 10,000)
Very rare
(affects less than 1 user in 10,000)
Not known
(frequency cannot be estimated from the available data).
The following side effects have been reported with the combination of Ribavirin Mylan and an alpha
interferon product
in adults
:
Very commonly reported side effects:
− decreases in the number of red blood cells (that may cause fatigue, shortness of breath,
dizziness), decrease in neutrophils (that make you more susceptible to different infections).
− difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or
irritable, tired feeling, trouble falling asleep or staying asleep,
− cough, dry mouth, pharyngitis (sore throat)
− diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus
infection, vomiting, weakness,
− loss of appetite, loss of weight, stomach pain,
− dry skin, irritation, pain or redness at the site of injection, hair loss, itching, muscle pain,
muscle aches, pain in joints and muscles, rash.
Commonly reported side effects:
− decrease in blood clotting cells called platelets that may result in easy bruising and
spontaneous bleeding, decrease in certain white blood cells called lymphocytes that help fight
infection, decrease in thyroid gland activity (which may make you feel tired, depressed,
increase your sensitivity to cold and other symptoms) excess of sugar or uric acid (as in gout)
in the blood, low calcium level in the blood, severe anaemia
− fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness,
abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental
45
disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble
sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling)
− blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in
your hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex),
change in taste, taste loss, bleeding gums or sores in mouth, burning sensation on tongue, sore
tongue, inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose bleed,
nonproductive cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth disorder,
− cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling
unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high
blood pressure, palpitations (pounding heart beat), rapid heart rate.
− bloating, constipation, indigestion intestinal gas (flatus), increased appetite, irritated colon,
irritation of prostate gland, jaundice (yellow skin), loose stools, pain on the right side around
your ribs, enlarged liver, stomach upset, frequent need to urinate, passing more urine than
usual, urinary tract infection, abnormal urine,
− difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual
periods, painful menstruation, disorder of ovary or vagina, breast pain, erectile problem,
− abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of the
skin with possible oozing lesions),hives, increased or decreased sensitivity to touch, nail
disorder, muscle spasms, numbness or tingling feeling, limb pain, pain at the site of injection,
pain in joints, shaky hands, psoriasis, puffy or swollen hands and ankles, sensitivity to
sunlight, rash with raised spotted lesions, , redness of skin or skin disorder, swollen face,
swollen glands (swollen lymph nodes), tense muscles, tumour (unspecified), unsteady when
walking, water impairment.
Uncommonly reported side effects:
− hearing or seeing images that are not present,
− heart attack, panic attack,
− hypersensitivity reaction to the medication,
− inflammation of pancreas, pain in bone, diabetes mellitus,
− muscle weakness.
Rarely reported side effects:
− seizure (convulsions)
− pneumonia,
− diabetes, rheumatoid arthritis, kidney problems,
− dark or bloody stools, intense abdominal pain
− sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling,
skin lesions and swollen glands),
− vasculitis.
Very rarely reported side effects
:
− suicide.
Not known side effects:
− thoughts about threatening the life of others,
− mania (excessive or unreasonable enthusiasm),
− pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection
that develops between the pericardium (the lining of the heart) and the heart itself.
The following side effects have been reported with the combination of Ribavirin Mylan and interferon
alfa-2b product
in children and adolescents:
46
Very commonly reported side effects:
− decreases in the number of red blood cells (that may cause fatigue, shortness of breath,
dizziness) decrease in neutrophils (that make you more susceptible to different infections),
− decrease in thyroid gland activity (which may make you feel tired, depressed, increase your
sensitivity to cold and other symptoms),
− feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired
feeling, trouble falling asleep or staying asleep, virus infection, weakness,
− diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss of
weight, decrease in the rate of growth (height and weight), pain on right side of ribs,
pharyngitis (sore throat), shaking chills, stomach pain, vomiting,
− dry skin, hair loss, irritation, pain or redness at the site of injection, itching, muscle pain,
muscle aches, pain in joints and muscles, rash.
Commonly reported side effects:
− decrease in blood clotting cells called platelets (that may result in easy bruising and
spontaneous bleeding),
− excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in
thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating,
weight loss, palpitation, tremors),
− agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional
instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of
restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality
sleep, sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm
yourself,
− bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear
infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores,
coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore throat), rapid
breathing, respiratory infections, scaling lips and clefts in the corner of the mouth, shortness of
breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny nose, throat pain,
toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), weakness
− chest pain, flushing, palpitations (pounding heart beat), rapid heart rate,
−
abnormal liver function,
− acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder,
incontinence, increased appetite, inflammation of the membrane of the stomach and intestine,
stomach upset, loose stools,
− urination disorders, urinary tract infection,
− difficult, irregular or no menstrual period, abnormally heavy and prolonged menstrual periods,
disorder of vagina, inflammation of the vagina, testis pain, development of male body traits,
− acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing
lesions), increased or decreased sensitivity to touch, increased sweating, increase in muscle
movement, tense muscle, irritation or itching at the site of injection, limb pain, nail disorder,
numbness or tingling feeling, pale skin, rash with raised spotted lesions, shaky hands, redness
of skin or skin disorder, skin discolouration, skin sensitive to sunlight, skin wound, swelling
due to a build-up of excess water, ,swollen glands (swollen lymph nodes), tremor, tumour
(unspecified).
Uncommonly reported side effects
− abnormal behaviour, emotional disorder, fear, nightmare,
− bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision,
drowsiness, intolerance to light, itchy eyes, facial pain, inflamed gums,
− chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia, wheezing,
− low blood pressure,
− enlarged liver,
− painful menstruation,
47
− itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to touch,
muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling.
The attempt to harm yourself has also been reported in adults, children, and adolescents.
Ribavirin Mylan in combination with an alpha interferon product may also cause:
− aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the
production of red blood cells); this causes severe anaemia, symptoms of which would include
unusual tiredness and a lack of energy,
−
delusions
− upper and lower respiratory tract infection,
− inflammation of the pancreas,
− severe rashes which may be associated with blisters in the mouth, nose, eyes and other
mucosal membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal
necrolysis (blistering and peeling of the top layer of skin),
The following other side effects have also been reported with the combination of Ribavirin Mylan and
an alpha interferon product:
− abnormal thoughts, hearing or seeing images that are not present, altered mental status,
disorientation,
− angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause
difficulty in swallowing or breathing), stroke (cerebrovascular events)
− Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes,
skin and the membranes of the ears, brain and spinal cord)
− bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,
− eye problems including damage to the retina, obstruction of the retinal artery, inflammation of
the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),
− enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel
movement,
− acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg
or thigh pain, loss of range of motion, stiffness, sarcoidosis, (a disease characterised by
persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands)
Ribavirin Mylan in combination with interferon alfa-2b may also cause:
− dark, cloudy or abnormally coloured urine.
− difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw
pain,
− loss of consciousness,
− loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,
− loss of vision,
You or your caregiver should call your doctor immediately if you have any of these symptoms.
For HCV/HIV co-infected patients receiving Ribavirin Mylan in combination with peginterferon alfa-
2b, there is an increased risk of lactic acidosis, liver failure and blood abnormalities (reduction in red
or white blood cells that fight infection, and blood clotting cells called platelets).
The following additional side effects have occurred in HCV/HIV co-infected patients receiving
Ribavirin in combination with peginterferon alfa-2b: oral thrush, changes in the amount and
distribution of body fat, reduction in the amount of white blood cells, decreased appetite, increase in
gamma-glutamyltransferase (an enzyme produced by the liver, associated with early liver cell
damage), back pain, increase amounts of amylase (an enzyme present in the blood) and lactic acid,
hepatitis, increased lipase (the enzyme necessary for the absorption and digestion of nutrients in the
intestines) and limb pain.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
48
5.
HOW TO STORE RIBAVIRIN MYLAN
Keep out of the reach and sight of children.
Do not use Ribavirin Mylan after the expiry date which is stated on the bottle.
Do not store above 30°C.
Do not use Ribavirin Mylan without advice of your doctor or pharmacist if you notice any change in
the appearance of the capsules.
6.
FURTHER INFORMATION
What Ribavirin Mylan contains
-
The active substance is ribavirin. Each hard capsule contains 200 mg ribavirin.
-
The other ingredients are croscarmellose sodium, lactose monohydrate, microcrystalline
cellulose, povidone. The capsule shell contains gelatine and titanium dioxide (E171). The
capsule shell imprint contains shellac, propylene glycol, strong ammonia solution, colouring
agents (E172, E132, E171).
What Ribavirin Mylan looks like and contents of the pack
The Ribavirin Mylan hard capsule is a white, opaque, hard capsule imprinted with green ink.
The Ribavirin Mylan hard capsule is available in different pack sizes containing 84, 112, 140 or 168
capsules of 200 mg to be swallowed.
Not all pack sizes may be marketed.
Your physician will prescribe the pack size which is best for you.
Marketing Authorisation Holder
Generics [UK] Limited,
Station Close,
Potters Bar,
Hertfordshire,
EN6 1TL,
United Kingdom.
Manufacturer
Penn Pharmaceutical Services Ltd
23-24 Tafarnaubach Industrial Estate,
Tredegar,
Gwent, NP22 3AA
United Kingom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
49
België/Belgique/Belgien
Mylan bvba/sprl
Tél/Tel: + 0032 02
658 61 00
Luxembourg/Luxemburg
Generics [UK] Ltd
Tél/Tel: +44 1707 853000
(United Kingdom)
България
Generics [UK] Ltd
Teл.: +44 1707 853000
(United Kingdom)
Magyarország
Generics [UK] Ltd
Tel: +44 1707 853000
(United Kingdom)
Ceská republika
Mylan Pharmaceuticals s.r.o.
Tel: +420 274 770 201
Malta
George Borg Barthet Ltd
Tel: +356 21244205
Danmark
Mylan ApS
Tlf: + 45 3694 4568
Nederland
Mylan B.V
Tel: + +31 (0)33 2997080
Norge
Mylan AB
Tlf: + 46 8-555 227 50
(Sweden)
Deutschland
Mylan dura GmbH
Tel: + 49-(0) 6151 9512 0
Eesti
Generics [UK] Ltd
Tel: +44 1707 853000
(United Kingdom)
Österreich
Arcana Arzneimittel GmbH
Tel: ++43 1 416 24 18
Ελλάδα
Generics Pharma Hellas ΕΠΕ
Τηλ: +30 210 9936410
Polska
Mylan Sp. z o.o.
Tel: +48 22 5466400
España
Mylan Pharmaceuticals, S.L
tel: +34 93 378 6400
Portugal
Mylan Lda.
Tel: + 351 21 412 72 00
France
Mylan SAS
Tel:
+33 4 37 25 75 00
România
Generics [UK]Limited
Tel: + 44 1707 853000
(United Kingdom)
Ireland
Mc Dermott Laboratories Ltd
t/a Gerard
Laboratories
Tel: 1800 272 272
or +353 (0)1 832 2250
Slovenija
Generics [UK] Ltd
Tél: +44 1707 853000
(United Kingdom)
Ísland
Mylan AB
Sími: + 46 8-555 227 50
(Sweden)
Slovenská republika
Mylan s r. o
Tel: + 421 2 32 604 901
Italia
Mylan S.p.A
Tel: + +39/02-61246921
Suomi/Finland
Mylan OY
Puh/Tel: + 358 9-46 60 03
Κύπρος
Pharmaceutical Trading Co Ltd
Τηλ: +357 24656165
Sverige
Mylan AB
Tel: + 46 8-555 227 50
Latvija
Generics [UK] Ltd
Tel: +44 1707 853000
(United Kingdom)
United Kingdom
Generics [UK] Ltd
Tel: +44 1707 853000
Lietuva
Generics [UK] Ltd
Tel: +44 1707 853000
50
(United Kingdom)
This Leaflet was Last Approved In
.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
51
Source: European Medicines Agency
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