Ribavirin Mylan (previously Ribavirin Three Rivers) - summary of medicine characteristics

Ribavirin Mylan 200 mg hard capsules

Each hard capsule contains 200 mg of ribavirin.

Excipient with known effect: each hard capsule contains 15 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule.

a/200" in

White opaque body imprinted „riba/200“ in green and a white opaque cap green.

Ribavirin Mylan is indicated for the treatment of chroni a combination regimen with interferon alfa-2b (adults, c adolescents). Ribavirin monotherapy must not be used.

tis C and must only be used as part of (3 years of age and older) and

There is no safety or efficacy information not alfa-2b).

Please refer also to the interferon a information particular to that produ

e of Ribavirin with other forms of interferon (i.e.,

ummary of Product Characteristics (SPC) for prescribing

Naïve patients

Adult Patients(18 years

alfa-2b, for the treat previously treated, are positive for seru

nt

H

e or older) : Ribavirin Mylan is indicated, in combination with interferon dult patients with all types of chronic hepatitis C except genotype 1, not t liver decompensation, with elevated alanine aminotransferase (ALT), who -RNA (see section 4.4).

Paediatric patients (children 3 years of age and older and adolescents): Ribavirin Mylan is indicated, in a cnation regimen with interferon alfa-2b, for the treatment of children and adolescents 3 years older, who have all types of chronic hepatitis C except genotype 1, not previously treated, iver decompensation, and who are positive for serum HCV-RNA. When deciding not to treatment until adulthood, it is important to consider that the combination therapy can induce a th inhibition that may be irreversible in some patients. 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).

800 mg

1,000 mg

1,200 mg

1,400

Number of 200 mg capsules

4 a 5b

6 c

7 d

months. During those cl show a virological res were unlikely to beco six months after wit

, it is recommended that patients be treated for at least six trials in which patients were treated for one year, patients who failed to fter six months of treatment (HCV-RNA below lower limit of detection) tained virological responders (HCV-RNA below lower limit of detection of treatment).

Duration

uration of treatment – Retreatment

Paediatric population:

Note: For patients who weigh <47 kg, or are unable to swallow capsules, ribavirin oral solution is available and should be used if appropriate.

Dosing for children and adolescent patients is determined by body weight for Ribavirin Mylan and by body surface area for interferon alfa-2b.

Dose to be administered for the combination therapy with interferon alfa-2b in paediatric patients: In clinical studies performed in this population ribavirin and interferon alfa-2b were used in doses o 15 mg/kg/day and 3 million international units (MIU)/m2 three times a week respectively (Table 2 ).

Table 2 Ribavirin Mylan paediatric dose based on body weight when used in combination wit interferon alfa-2b in childen and adolescents

a1 morning, 2 evening b2 morning, 2 evening

Duration of treatment in children and adolescents

• • Genotype 2 or 3: The recommended duration^f^reatment is 24 weeks.

Dose modification for all patients

If severe adverse reactions or laborat and interferon alfa-2b, modify t abate. Guidelines were develop

guidelines,. As ad be kept as close as possib ribavirin dose reduction o

bnormalities develop during therapy with Ribavirin Mylan of each product if appropriate, until the adverse reactions inical trials for dose modification (see Dosage modification ight be of importance for outcome of therapy, the dose should

recommended standard dose. The potential negative impact of icacy results could not be ruled out.

nuation

Upper limit of normal

**

Refer to the SmPC for interferon alfa-2b for dose modification a

Note 1: In adult patients, 1st dose reduction of Ribavirin

patients receiving the 1,400 mg, dose reducti dose reduction of Ribavirin Mylan is by an a Ribavirin Mylan is reduced to 600 mg daily r and two 200 mg capsules in the evening.

y 200 mg/day (except in

y 400 mg/day). If needed, 2nd

dditional 200 mg/day. Patients whose dose of eceive one 200 mg capsule in the morning

In children and adolescent patients reduce Ribavirin Mylan dose t Note 2: In adult patients and children a interferon alfa-2b, reduce the i

ated with Ribavirin Mylan plus interferon alfa-2b,

lescent patients treated with Ribavirin Mylan plus eron alfa-2b dose by one-half dose.

Special populations

and/or on

Severe hepatic impairment (Child-Pugh Classification B or C) or decompens the liver.

Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia

ed cirrhosis of

Initiation of peginterferon alfa-2b is contraindicated in HCV/HIV Pugh score > 6.

Children and adolescents:

–     Existence of, or history of severe psychiatric conditi

ideation, or suicide attempt.

ith cirrhosis and a Child-

rticularly severe depression, suicidal

Because of co-administration with interferon a –     Autoimmune hepatitis; or history o

ne disease.

Psychiatric and Central Nerv

use

m (CNS):

4.4 Special warnings and precautio

Severe CNS effects, particul observed in some patients interferon alfa-2b, and eve period. Among children a 2b, suicidal ideation or att

ession, suicidal ideation and attempted suicide have been ing Ribavirin combination therapy with peginterferon alfa-2b or after treatment discontinuation mainly during the 6-month follow-up adolescents, treated with Ribavirin in combination with interferon alfa-pts were reported more frequently compared to adult patients (2.4%

versus 1%) d children and

drionlgest

reatment and during the 6-month follow-up after treatment. As in adult patients, cents 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

status have been observed with alpha interferons. Patients should be closely monitored for any r symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of ndesirable effects must be borne in mind by the prescribing physician and the need for

Patients with substance use/abuse:

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an interdisciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or develop of psychiatric disorders and substance use is recommended.

Paediatric population: Growth and development:

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. Long-term data available in children treated with the combination therapy of pegylated interferon/ri­bavirin are

indicative of substantial growth retardation. Thirty two percent (30/94) percentile decrease in height-for-age percentile 5 years after completio and 5.1).

The longer term data available in children treated with the combination

ects demonstrated > 15 rapy (see sections 4.8

interferon/ri­bavirin are also indicative of substantial growth retardation

height percentile as compared to baseline) in 21 % (n more than 5 years. Final adult height was available fo continued to have height deficits > 15 percentiles, 10

e children and show that 12 after the end of treatment.

erapy with standard

15 percentile decrease in pite being off treatment for

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 clinicals (see sections 4.8 and 5.1).

ombination therapy induced a growth inhibition that

It is important to consider that th resulted in reduced height in so

ients.

inst the disease characteristics of the child, such as evidence of

This risk should be weigh

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 poss risk of growth i maturation was

hild should be treated after the pubertal growth spurt, in order to reduce the. Although data are limited, no evidence of long-term effects on sexual the 5 year observational follow-up study.

Base

results of clinical trials, the use of ribavirin as monotherapy is not effective and Ribavirin be used alone. The safety and efficacy of this combination have been established only using capsules together with peginterferon alfa-2b or interferon alfa-2b solution for injection.

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 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 immediat appropriate medical therapy instituted. Transient rashes do not necessitate interruption of trea

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 inst combination therapy with alpha interferons. All patients should have a baseline

ith amination.

Any patient complaining of decrease or loss of vision must have a prom examination. Patients with preexisting ophthalmologic disorders (e.g., retinopathy) should receive periodic ophthalmologic exams during interferons. Combination therapy with alpha interferons should be develop new or worsening ophthalmologic disorders.

d complete eye

ic or hypertensive

ion therapy with alpha inued in patients who

Liver function : Any patient developing significant liver fui      abnormalities during treatment must

be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation markers which might indicate liver decompensation.

Potential to exacerbate immunosuppression reported in the literature to occur within 3 ribavirin concomitantly with azathioprine.

upon withdrawal of HCV antiviral ther reintroduction of either treatment alone

^Pancytopenia and bone marrow suppression have been o 7 weeks after the administration of a peginterferon and This myelotoxicity was reversible within 4 to 6 weeks and concomitant azathioprine and did not recur upon

see section 4.5).

o roi

increase in thyroid stimu

below the lowe evaluated and a therapy. Interfe

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 ris

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 th may be at increased risk of hepatic decompensation and death. Adding treatment with alone or in combination with ribavirin may increase the risk in this patient subset. Ot

factors in co-infected patients that may be associated with a higher risk of h include treatment with didanosine and elevated bilirubin serum concentrati Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis monitored, assessing their Child-Pugh score during treatment. Patients pr decompensation should have their anti-hepatitis treatment immedia treatment reassessed.

ART) interferons er baseline ompensation

Haematological abnormalities in HCV/HIV co-infected HCV/HIV co-infected patients receiving peginterferon

be at increased risk to develop haematological abno anaemia) compared to HCV mono-infected patients.

atment should be closely ssing to hepatic

ntinued and the ARV

bavirin treatment and HAART may (as neutropenia, thrombocytope­nia and

managed by dose reduction, close monitoring this population of patients (see section 4 Patients treated with ribavirin and zidov the concomitant use of ribavirin with zid

lthough, the majority of them could be atological parameters should be undertaken in

elow “Laboratory tests” and section 4.8).

e at increased risk of developing anaemia; therefore, e is not recommended (see section 4.5).

ective Summary of Product Characteristics of the antiretroviral medicinal

taken concurrently with HCV therapy for awareness and management of c for each product and the potential for overlapping toxicities with Ribavirin and a-2b.

Haemoglobin

Platelets

Neutrophil Count

Adult: > 12g/dl (females); > 13g/dl (males)

Children and adolescents: > 11g/dl (females); > 12g/dl (males)

> 100,000/mm3

> 1,500/mm3

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 section 4.6).

Uric acid may increase with Ribavirin Mylan due to haemolysis; therefore, the potential f 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.

Interaction studies have only been performed in adults.

Results of in vitro studies using both human and rat liver        me preparations indicated no

cytochrome P450 enzyme mediated metabolism of ribaviavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions.

Ribavirin, by having an inhibitory effect with azathioprine metabolism possibly le monophosphate (6-MTIMP), which has

azathioprine. The use of pegylat should be avoided. In individua azathioprine warrants the po

on inosine monophosphate dehydrogenase, may interfere

ading to an accumulation of 6-methylthioinosine

een associated with myelotoxicity in patients treated with interferons and ribavirin concomitantly with azathioprine

where the benefit of administering ribavirin concomitantly with , it is recommended that close hematologic monitoring be done

ine use to identify signs of myelotoxicity, at which time treatment with

during concomitant azathiopr

these medicines should be stoed (see section 4.4).

No interaction studies have been conducted with Ribavirin and other medicinal products, except for peginterferon      b, interferon alfa-2b and antacids.

Interfere        : No pharmacokinetic interactions were noted between Ribavirin and peginterferon

alfa-2b orferon alfa-2b in a multiple-dose pharmacokinetic stu­dy.

ay be at cised

Female patients: Ribavirin Mylan must not be used by females and 5.3). Extreme care must be taken to avoid pregnancy in fem Ribavirin Mylan therapy must not be initiated until a report of a

obtained immediately prior to initiation o effective contraceptive during treatment routine monthly pregnancy tests must be treatment or within four months from sto significant teratogenic risk of ribavirin to

ho are pregnant (see sections 4.3 le patients (see section 5.3).

egative pregnancy test has been ildbearing potential must use an

nths after treatment has been concluded;

ng this time. If pregnancy does occur during , the patient must be advised of the

Male patients and their female partners :

of male patients taking Ribaviri intracellularly and is cleared fro contained in sperm will exert i embryo/foetus. Although data paternal exposure to ribavirin general population, nor any sp

xtreme care must be taken to avoid pregnancy in partners ee sections 4.3 and 5.3). Ribavirin accumulates

partners of chil Ribavirin Myla instructed to us

ar

dy very slowly. It is unknown whether the ribavirin that is tial teratogenic or genotoxic effects on the human

n approximately 300 prospectively followed pregnancies with

ve not shown an increased risk of malformation compared to the ific pattern of malformation, either male patients or their female st be advised to use an effective contraceptive during treatment with

d for seven months after treatment. Men whose partners are pregnant must be ondom to minimise delivery of ribavirin to the partner.

Pre

System Organ

Class

Infections and infestations

Very common:

Common:

Uncommon:

Viral infection, pharyngitis

Fungal infection, bacterial infection, pulmonary infection, nasopharyngiti streptococcal, otitis media, sinusitis, tooth abscess, influenza, or simplex, urinary tract infection, vaginitis, gastroenteritis

Neoplasms benign, malignant and unspecified (including cysts and poly

Common:

Blood and lymphatic system disorders

Very common:

Common:

Endocrine disorders

Very common:

Common:

Metabolism and nutrition disorders

Very common:

Common:

aryngitis , herpes

appetite, decreased appetite ia, hyperuricemia

Anorexia, in

Hypertri

Psychiatric disorders

Very common:

Common:

Uncomm

Nerv

ncommon:

Uncommon:

Eye disorders

Common:

ion, insomnia, emotional lability

idal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy

Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

sorders

Headache, dizziness

Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep

Neuralgia, lethargy, psychomotor hyperactivity

Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder

Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia

Common:

Cardiac disorders

Common:

Vertigo

Vascular disorders

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.

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 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 treat 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 a89/97) sustained virological

response rate. The high sustained response rate in this sub interim analysis (n=49) and prospectively confirmed (n=48 Limited historical data indicate that treatment for 48 weeks

f patients was identified in an

ght be associated with a higher

sustained response rate (11/11) and with a lower ris 24 weeks of treatment).

elapse (0/11 as compared to 7/96 following

A large randomized trial compared the sa peginterferon alfa-2b/ Ribavirin regime subcutaneously once weekly both in

divided doses)] and peginterfero 1,200 mg p.o. daily (in two divide genotype 1. Response to the is defined as undetectabl

and efficacy of treatment for 48 weeks with two peginterferon alfa-2b 1.5 pg/kg and 1 pg/kg

ination with Ribavirin 800 to 1,400 mg p.o. daily (in two

–2¹⁸⁰ pg subcutaneously once weekly with ribavirin 1,000 to ses) in 3,070 treatment-naive adults with chronic hepatitis C t was measured by Sustained Virologic Response (SVR) which

A at 24 weeks post-treatment (see.

Ise at treatment week 12, end of treatment response, relapse rate* and onse (SVR)

Table 8 Virolog Sustained Virol

HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml

Genotype 1 receive 48 weeks treatme

Genotype 2, 3 receive 24 weeks

***The presented results are from

e point of time. A patient may be missing or have had a different result for week 4 or

week 12.

t These criteria wereused inthejprotocol: If week 12 HCV-RNA is positive and < 2 log10 decrease from baseline, patients to stop therapy. If weekJ2 HCV-RNA is positive and decreased > 2 log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

o-infected patients

ave been conducted in patients co-infected with HIV and HCV. The response to nt in both of these trials is presented in Study 1 (RIBAVIC; P01017) was a ndomized, multicentre study which enrolled 412 previously untreated adult patients with chronic epatitis C who were co-infected with HIV. Patients were randomized to receive either Ribavirin (800 mg/day) plus peginterferon alfa-2b (1.5 gg/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 gg/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

Table 10 Sustained virological response based on genotype after Ribavirin in combination with peginterferon

__________alfa-2b in HCV/HIV co-infected patients _____________­________________________­_________________

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 gg/week peginterferon alfa-2b and sul peginterferon alfa-2b.

d: Ribavirin dosing was 800mg for patients < 60 kg, 1,000 mg for patie > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839–2848.

2Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36

Histological response

Liver biopsies were obtained before and after tr

412 subjects (51 %). Both the Metavir sc Ribavirin in combination with peginte (-0.3 for Metavir and –1.2 for Ishak

received 150 gg/week

g, and 1,200 mg for patients

1 and were available for 210 of the

d Ishak grade decreased among subjects treated with

a-2b. This decline was significant among responders le (-0.1 for Metavir and

–0.2 for Ishak) among non-respondterms 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

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).

atients 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.

-responder- defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.

CV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory o treat population includes 7 patients for whom at least 12 weeks prior therapy could not be confirmed.

verall, 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 maintain irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genot and histological staging.

Long-term efficacy data – Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after

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 ov for patients receiving non-pegylated interferon alfa-2b (with o

CI: 98–100 %) for patients receiving pegylated interferon alfa SVR after treatment of chronic HCV with interferon alfa-2b (

is 97 % (95 % CI: 95–99 %) ibavirin), and is 99 % (95 % ith or without Ribavirin).

gylated and non-pegylated, with or

without Ribavirin) results in long-term clearance ofvirus 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 (includingato­carcinoma).

Paediatric population

Ribavirin in combination with peginte

Children and adolescents 3 to

HCV-RNA were enrolled in a

s

ie

on alfa-2b

age with compensated chronic hepatitis C and detectable tre trial and treated with Ribavirin 15 mg/kg per day plus once weekly for 24 or 48 weeks, based on HCV genotype and were to be followed for 24 weeks post-treatment. A total of

pegylated interferon alfa-2b baseline viral load. All p 107 patients received treatt 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 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.

stained virological response rates (na,b(%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects

n= 107

Due

ase, interferon he study

Table 13

Sustained virological response in previously untreated children and adolescents

Overall Responsea(n = 118)

Genotype 1 (n = 92)

Genotype 2/3/4 (n = 26)

• Number (%) of patients

• a. Defined as HCV-RNA below limit of detectio follow-up period.

Ribavirin 15

ay

interferon alfa-2

3 times a week

33 (36 %)

21 (81 %)*

a research based RT-PCR assay at end of treatment and during

Long-term efficacy data- Paed

A five-year lo patients after t purpose of the and assess the sustained r ribavirin

Ribavirin in combination

icJPopulation

peginterferon alfa-2b

onal, follow-up study enrolled 94 paediatric chronic hepatitis C multicentre trial. Of these, sixty-three were sustained responders. The annually evaluate the durability of sustained virologic response (SVR)

of continued viral negativity on clinical outcomes for patients who were

24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and nt. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of

sustainedesponders completed the study. No paediatric subjects with SVR relapsed during the of follow-up.

ibavirin in combination with interferon alfa-2b

ive-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients

olume of

vailability

Distribution

Ribavirin transport in non-plasma compartments has been most ext has been identified to be primarily via an es-type equilibrative n transporter is present on virtually all cell types and may account

studied in red cells, and

transporter. This type of igh volume of distribution of

ribavirin. The ratio of whole blood:plasma ribavirin con of ribavirin in whole blood exists as ribavirin nucleotide

ns is approximately 60:1; the excess ered in erythrocytes.

Paediatric population :

Ribavirin in combination with peginterferon alfa-2b Multiple-dose pharmacokinetic properties for Ribaviri adolescent patients with chronic hepatitis C have been e

and adolescent patients receiving body surface area-adju 60 pg/m2/week, the log transformed ratio estimate dtcX

to be 58 % (90% CI: 141–177 %) higher pharmacokinetics of Ribavirin (dose-nor study of Ribavirin in combination with i adult patients.

peginterferon alfa-2b in children and during a clinical study. In children sted dosing of peginterferon alfa-2b at osure during the dosing interval is predicted in adults receiving 1.5 pg/kg/week. The

) in this trial were similar to those reported in a prior n alfa-2b in children and adolescent patients and in

Ribavirin in combination with in Multiple-dose pharmacokinet adolescents with chronic pharmacokinetics of Ri children or adolesce

rties for Ribavirin and interferon alfa-2b in children and

C between 5 and 16 years of age are summarized in Table 14. The nd interferon alfa-2b (dose-normalized) are similar in adults and

Table 14

(% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and ibavirin when administered to children or adolescents with chronic hepatitis C

*AUC12 (ng.hr/ml) for Ribavirin; AUC0–24 (IU.hr/ml) for interferon alfa-2b

Genotoxicity studies have demonstrated that ribavirin doessome genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro Transformation Assay.      toxic 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 thaations occurred in rats they were not transmitted through male gametes.

s with low exposures compared to human exposure under d 1 in mice) did not reveal tumorigenicity of ribavirin. In y using the heterozygous p53(+/-) mouse model, ribavirin y tolerated dose of 300 mg/kg (plasma exposure factor

Conventional carcinogenicity rodent stu therapeutic conditions (factor 0.1 in r

addition, in a 26 week carcinog did not produce tumours at the approximately 2.5 compared of ribavirin in humans is

Ribavirin plus interferOn :

ribavirin did no treatment-relate than that

MACEUTICAL PARTICULARS

exposure). These studies suggest that a carcinogenic potential

en used in combination with peginterferon alfa-2b or interferon alfa-2b, effects not previously seen with either active substance alone. The major

ge was a reversible mild to moderate anaemia, the severity of which was greater y either active substance alone.

Date of first authorisation: 10 June 2010