Ribavirina teva

Overdose

In clinical trials with Ribavirina Teva used in combination with interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Ribavirina Teva (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.

Contraindications

- Pregnancy. In females of childbearing potential, Ribavirina Teva must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

- Breast-feeding.

- History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

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

Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirina Teva for contraindications specific to these products.

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

Summary of safety profile

The salient safety issue of Ribavirina Teva is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Ribavirina Teva therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients.

The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when Ribavirina Teva was used in combination with interferon alfa-2b or peginterferon alfa-2b.

Please refer to the corresponding SmPC of medicinal products that are used in combination with Ribavirina Teva for additional undesirable effects reported with these products.

Paediatric population

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 Ribavirina Teva, 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 Ribavirina Teva, growth inhibition was observed that resulted in reduced height in some patients. 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 (< 3rd 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 < 3rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy.

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

In combination with interferon alfa-2b

In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Ribavirina Teva, 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 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa-2b and Ribavirina Teva, growth inhibition was observed that resulted in reduced final adult height in some patients. 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.

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). 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.

Tabulated list of adverse reactions in paediatric population

Reported adverse reactions listed in Table 4 are based on experience from the two multicentre children and adolescents clinical trials using Ribavirina Teva 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.

Most of the changes in laboratory values in the Ribavirina Teva/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. While changes in laboratory values were observed in some patients treated with Ribavirina Teva 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.

Adults

Adverse reactions reported with a > 10 % incidence in adult patients treated with Ribavirina Teva capsules in combination with interferon alfa-2b or pegylated interferon alfa-2b for one year have also been reported in children and adolescents. The side effect profile was also similar at the lower incidences.

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 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 Ribavirina Teva) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Ribavirina Teva price

Preclinical safety data

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3-and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles.

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.

Therapeutic indications

Ribavirina Teva is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) for paediatric patients (children 3 years of age and older and adolescents) not previously treated and without liver decompensation.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B04.

Mechanism of action

Ribavirin (Ribavirina Teva) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Ribavirina Teva in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Ribavirina Teva monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Ribavirina Teva 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.

Clinical efficacy and safety

Only the description of the use of Ribavirina Teva from the original development with (peg)interferon alfa-2b is detailed in the current SmPC.

Paediatric population

Ribavirina Teva 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 Ribavirina Teva 15 mg/kg per day plus pegylated interferon alfa-2b 60 µg/m2 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 Ribavirina Teva and pegylated interferon alfa-2b needs to be carefully considered in this population.The study results are summarized in Table 6

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.

Ribavirina Teva 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 Ribavirina Teva 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 three times a week for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults (see Table 7). 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 Ribavirina Teva and interferon alfa-2b needs to be carefully considered in this population. The study results are summarized in Table 7.

*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

Ribavirina Teva in combination with peginterferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three 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 with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up.

Ribavirina Teva in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Ribavirina Teva 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).

Pharmacokinetic properties

In a single dose, crossover study of ribavirin in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 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 AUCtf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-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.

Biotransformation

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.

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 Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr. 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.

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

Food effect

The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax 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

Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUCtf was twofold greater compared with control subjects. 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) is similar to those of normal controls.

Paediatric population

Ribavirina Teva in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Ribavirina Teva 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/m2/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 Ribavirina Teva (dose-normalized) in this trial was similar to those reported in a prior study of Ribavirina Teva in combination with interferon alfa-2b in children and adolescent patients and in adult patients.

Ribavirina Teva in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Ribavirina Teva capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 8. The pharmacokinetics of Ribavirina Teva and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

*AUC12 (ng.hr/mL) for Ribavirina Teva; AUC0-24 (IU.hr/mL) for interferon alfa-2b

Qualitative and quantitative composition

Special warnings and precautions for use

Ribavirina Teva must be used in combination with other medicinal products.

Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa.

There are several serious adverse reactions associated with the combination therapy of Ribavirina Teva with (peg)interferon alfa. These include:

- Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.)

- Growth inhibition in children and adolescents that may be irreversible in some patients

- Increased thyroid stimulating hormone (TSH) in children and adolescents

- Severe ocular disorders

- Dental and periodontal disorders.

Paediatric population

When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case.

Haemolysis

A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and in 7 % of children and adolescents treated with Ribavirina Teva in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Ribavirina Teva has no direct cardiovascular effects, anaemia associated with Ribavirina Teva may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both. Thus, Ribavirina Teva must be administered with caution to patients with pre-existing cardiac disease. Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped.

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.

Teratogenic risk

Prior to initiation of treatment with Ribavirina Teva the physician must comprehensively inform both male and female patients of the teratogenic risk of Ribavirina Teva, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with Ribavirina Teva. For laboratory monitoring of pregnancy, please refer to Laboratory tests.

Acute hypersensitivity

If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirina Teva must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.

Liver function

Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirina Teva for discontinuation or dose modification recommendations.

Renal impairment

The pharmacokinetics of Ribavirina Teva is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Ribavirina Teva. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Ribavirina Teva dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment.

Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary.

Potential to exacerbate immunosuppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and Ribavirina Teva concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone.

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/ribavirin treatment.

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. 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. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirina Teva for discontinuation or dose modification recommendations. 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

Patients treated with Ribavirina Teva and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Ribavirina Teva with zidovudine is not recommended.

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 corresponding SmPC 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 Ribavirina Teva.

Laboratory tests

Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Ribavirina Teva therapy in children and adolescents:

- Haemoglobin > 11 g/dL (females); > 12 g/dL (males)

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.

Uric acid may increase with Ribavirina Teva due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.

Information on excipients

This product contains sucrose and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltase insufficiency should not take this medicine.

Effects on ability to drive and use machines

Ribavirina Teva has no or negligible influence on the ability to drive and use machines; however, other medicinal products 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.

Dosage (Posology) and method of administration

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Posology

Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Ribavirina Teva for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirina Teva.

Ribavirina Teva oral solution is supplied in a concentration of 40 mg/mL.

Ribavirina Teva oral solution is administered orally in two divided doses (morning and evening) with food.

Paediatric population

No data are available in children below 3 years of age.

Dosing of Ribavirina Teva for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b or peginterferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirina Teva as some combination regimens do not adhere to the Ribavirina Teva dosing guidance provided in Table 1.

In clinical studies performed in this population, Ribavirina Teva was used in doses of 15 mg/kg/day (Table 1).

Patients who weigh > 47 kg and are able to swallow capsules may take the equivalent dose of ribavirin 200 mg capsules in two divided doses (Please see SmPC for Ribavirina Teva capsules).

Dose modification for adverse reactions

Dose reduction of Ribavirina Teva depends on the initial Ribavirina Teva posology which depends on the medicinal product that is used in combination with Ribavirina Teva.

If a patient has a serious adverse reaction potentially related to Ribavirina Teva, the Ribavirina Teva dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and indirect bilirubin concentration.

There are no data for paediatric patients with cardiac disease.

* In children and adolescent patients treated with Ribavirina Teva plus peginterferon alfa-2b, 1st dose reduction of Ribavirina Teva is to 12 mg/kg/day, 2nd dose reduction of Ribavirina Teva is to 8 mg/kg/day.

In children and adolescent patients treated with Ribavirina Teva plus interferon alfa-2b, reduce Ribavirina Teva dose to 7.5 mg/kg/day.

In case of serious adverse reaction potentially related to medicinal products used in combination with Ribavirina Teva, please refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Ribavirina Teva dose modification and/or discontinuation guidelines as described in Table 2.

Special populations

Paediatric patients (children 3 years of age and older and adolescents)

Ribavirina Teva may be used in combination with peginterferon alfa-2b or interferon alfa-2b. The selection of Ribavirina Teva formulation is based on individual characteristics of the patient.

The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available.

Please refer to the corresponding SmPC of medicinal products used in combination with Ribavirina Teva for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Ribavirina Teva is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Ribavirina Teva. Adult patients with moderate renal impairment (creatinine clearance 30- 50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Ribavirina Teva 200 mg/day. Table 3 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Hepatic impairment

No pharmacokinetic interaction appears between Ribavirina Teva and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of medicinal products used in combination with Ribavirina Teva.

Method of administration

Ribavirina Teva should be administered orally with food.

Special precautions for disposal and other handling

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