Ribavirin teva pharma bv

Overdose

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

No cases of overdose of Ribavirin Teva Pharma BV have been reported in clinical trials. Hypocalcaemia and hypomagnesaemia have been observed in persons administered dosages greater than four times the maximal recommended dosages. In many of these instances ribavirin was administered intravenously. Due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed by haemodialysis.

Contraindications

- Pregnancy. In females of childbearing potential, Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV for contraindications specific to these products.

- pregnant women. Ribavirin Teva Pharma BV must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

- women who are breast-feeding.

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

- haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).

Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Teva Pharma BV for contraindications related to those products.

Incompatibilities

Not applicable.

Not applicable

Pharmaceutical form

Undesirable effects

Summary of safety profile

The salient safety issue of Ribavirin Teva Pharma BV is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV, 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 Teva Pharma BV, 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 Ribavirin Teva Pharma BV, 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 Ribavirin Teva Pharma BV, 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV/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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV) 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.

The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy.).

The adverse events listed in this section are reported in clinical trials and/or as adverse drug reactions from spontaneous reports primarily when Ribavirin Teva Pharma BV was used in combination with interferon alfa-2a or peginterferon alfa-2a.

Adverse events reported in patients receiving Ribavirin Teva Pharma BV in combination with interferon alfa-2a are essentially the same as for those reported for Ribavirin Teva Pharma BV in combination with peginterferon alfa-2a.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Teva Pharma BV for additional undesirable effects reported with these products.

Chronic hepatitis C

The most frequently reported adverse events with Ribavirin Teva Pharma BV in combination with peginterferon alfa-2a 180 µg were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Ribavirin Teva Pharma BV in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and Ribavirin Teva Pharma BV treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and Ribavirin Teva Pharma BV treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.

In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm3), and thrombocytopenia (13% experienced a platelet count <50,000/mm3).

Chronic hepatitis C and Human Immunodeficiency Virus Co-infection

In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Ribavirin Teva Pharma BV and peginterferon alfa-2a combination therapy other undesirable effects have been reported in >1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/µl (see peginterferon alfa-2a SmPC).

Table 4 shows the undesirable effects reported in patients who have received Ribavirin Teva Pharma BV primarily in combination with peginterferon alfa-2a or interferon alfa-2a.

* Identified in postmarketing experience

Laboratory values: In clinical trials of Ribavirin Teva Pharma BV in combination with peginterferon alfa-2a or interferon alfa-2a, the majority of cases of abnormal laboratory values were managed with dose modifications. With peginterferon alfa-2a and Ribavirin Teva Pharma BV combination treatment, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of treatment.

Haemolysis is the dose limiting toxicity of ribavirin therapy. A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Ribavirin Teva Pharma BV 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Ribavirin Teva Pharma BV 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. In most cases the decrease in haemoglobin occurred early in the treatment period and stabilised concurrently with a compensatory increase in reticulocytes.

Most cases of anaemia, leucopenia and thrombocytopenia were mild (WHO grade 1). WHO grade 2 laboratory changes were reported for haemoglobin (4% of patients), leucocytes (24% of patients) and thrombocytes (2% of patients). Moderate (absolute neutrophil count (ANC): 0.749-0.5x109/l) and severe (ANC: <0.5x109/l) neutropenia was observed in 24% (216/887) and 5% (41/887) of patients receiving 48 weeks of Ribavirin Teva Pharma BV 1000/1200 mg in combination with peginterferon alfa-2a.

An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated with Ribavirin Teva Pharma BV used in combination with peginterferon alfa-2a or interferon alfa-2a and values returned to baseline levels within 4 weeks after the end of therapy. In rare cases (2/755) this was associated with clinical manifestation (acute gout).

Laboratory values for HIV-HCV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3 was observed in 10% and 8% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

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.

Ribavirin is embryotoxic and/or teratogenic at doses well below the recommended human dose in all animal species in which adequate 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 is reduced.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies, including studies in dogs and monkeys. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment. Hypoplastic anaemia was observed only in rats at the high dose of 160 mg/kg/day in the subchronic study.

Reduced leucocyte and/or lymphocyte counts were consistently noted in the repeat-dose rodent and dog toxicity studies with ribavirin and transiently in monkeys administered ribavirin in the subchronic study. Repeat-dose rat toxicity studies showed thymic lymphoid depletion and/or depletion of thymus-dependent areas of the spleen (periarteriolar lymphoid sheaths, white pulp) and mesenteric lymph node. Following repeat-dosing of dogs with ribavirin, increased dilatation/necrosis of the intestinal crypts of the duodenum was noted, as well as chronic inflammation of the small intestine and erosion of the ileum.

In repeat dose studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses in animals well below 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 an in vitro Transformation Assay. Genotoxic activity was observed in in vivo mouse micronucleus assays. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Ribavirin is a possible human carcinogen.

Administration of ribavirin and peginterferon alfa-2a in combination did not produce any unexpected toxicity in monkeys. The major treatment-related change was reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Therapeutic indications

Ribavirin Teva Pharma BV 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.

Ribavirin Teva Pharma BV is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC).

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 (Ribavirin Teva Pharma BV) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Ribavirin Teva Pharma BV in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Ribavirin Teva Pharma BV monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV from the original development with (peg)interferon alfa-2b is detailed in the current SmPC.

Paediatric population

Ribavirin Teva Pharma BV 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 Teva Pharma BV 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 Ribavirin Teva Pharma BV 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.

Ribavirin Teva Pharma BV 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 Teva Pharma BV 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 Ribavirin Teva Pharma BV 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

Ribavirin Teva Pharma BV 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.

Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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).

Pharmacotherapeutic group: Nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

Mechanism of Action: Ribavirin is a synthetic nucleoside analog that shows in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin exerts its effects against HCV is unknown.

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 µg peginterferon alfa-2a. The first phase of decline occurs 24 to 36 hours after the first dose of peginterferon alfa-2a and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Ribavirin Teva Pharma BV had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of Ribavirin Teva Pharma BV and pegylated interferon alfa-2a or interferon alfa.

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.

Clinical efficacy and safety

Ribavirin Teva Pharma BV in combination with DAA

Please refer to the SmPC of the corresponding direct antiviral agent for a full description of the clinical data with such combination. Only the description of the use of Ribavirin Teva Pharma BV with (peg)interferon are detailed in the current SmPC

Ribavirin Teva Pharma BV in combination with peginterferon alfa-2a

Predictability of response

Please refer to the peginterferon alfa-2a SmPC.

Study results in treatment-naive patients

Efficacy and safety of the combination of Ribavirin Teva Pharma BV and peginterferon alfa-2a were established in two pivotal studies (NV15801 + NV15942), including a total of 2405 patients. The study population comprised interferon-naive patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT, and a liver biopsy consistent with chronic hepatitis C infection. Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 13). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.

Study NV15801 (1121 patients treated) compared the efficacy of 48 weeks of treatment with peginterferon alfa-2a (180 µg once weekly) and Ribavirin Teva Pharma BV (1000/1200 mg daily) with either peginterferon alfa-2a monotherapy or combination therapy with interferon-alfa-2b and ribavirin. The combination of peginterferon alfa-2a and Ribavirin Teva Pharma BV was significantly more efficacious than either the combination of interferon alfa-2b and ribavirin or peginterferon alfa-2a monotherapy.

Study NV15942 (1284 patients treated) compared the efficacy of two durations of treatment (24 weeks with 48 weeks) and two dosages of Ribavirin Teva Pharma BV (800 mg with 1000/1200 mg).

For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see tables 5, 6, 7 and 13 respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICORâ„¢ HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after the end of therapy.

* 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Ribavirin Teva Pharma BV and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, pre-treatment viral load and rapid virological response at week 4 are summarised in Table 6 and Table 7 respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 1, 6 and 7).

The difference between treatment regimens was in general not influenced by presence/absence of cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline characteristic.

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml

*Ribavirin Teva Pharma BV 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Ribavirin Teva Pharma BV 800 mg + peginterferon alfa-2a 180 µg, 48 w: Odds Ratio (95% CI) = 1.52 (1.07 to 2.17) P-value (stratified Cochran-Mantel-Haenszel test) = 0.020

†Ribavirin Teva Pharma BV 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Ribavirin Teva Pharma BV 1000/1200 mg + peginterferon alfa-2a 180 µg, 24 w: Odds Ratio (95% CI) = 2.12 (1.30 to 3.46) P-value (stratified Cochran-Mantel-Haenszel test) = 0.002

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 7).

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml

RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 8).

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 9).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received peginterferon alfa-2a 180 µg sc qw and a Ribavirin Teva Pharma BV dose of 800 mg and were randomised to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 9).

Low viral load= ≤800,000 IU/ml at baseline; High viral load= >800,000 IU/ml at baseline

RVR = rapid viral response (HCV RNA negative) by week 4

It is presently not clear whether a higher dose of Ribavirin Teva Pharma BV (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 10)

Chronic hepatitis C prior treatment non-responder patients

In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments:

- peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 60 weeks

- peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 36 weeks

- peginterferon alfa-2a 180 µg/week for 72 weeks

- peginterferon alfa-2a 180 µg/week for 48 weeks

All patients received Ribavirin Teva Pharma BV (1000 or 1200 mg/day) in combination with peginterferon alfa-2a. All treatment arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 11.

High viral load = >800,000 IU/ml, low viral load = ≤800,000 IU/ml.

a Patients who achieved viral suppression (undetectable HCV RNA, <50 IU/ml) at week 12 were considered to have a virological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.

b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were considered to be non-responders

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 µg/week and Ribavirin Teva Pharma BV 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Ribavirin Teva Pharma BV combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 12).

HCV patients with normal ALT

In study NR16071, HCV patients with normal ALT values were randomised to receive peginterferon alfa-2a 180 µg/week with a Ribavirin Teva Pharma BV dose of 800 mg/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or an untreated control group for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.

Children and adolescents

In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with peginterferon alfa-2a 100 µg/m2 sc once weekly and Ribavirin Teva Pharma BV 15 mg/kg/day, for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.

HIV-HCV co-infected patients

The virological responses of patients treated with Ribavirin Teva Pharma BV and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 13.

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml

* peginterferon alfa-2a 180 µg + Ribavirin Teva Pharma BV 800 mg vs. Interferon alfa-2a 3 MIU + Ribavirin Teva Pharma BV 800 mg: Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001; peginterferon alfa-2a 180 µg + Ribavirin Teva Pharma BV 800 mg vs. peginterferon alfa-2a 180 μg: Odds Ratio ( 95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001; Interferon alfa-2a 3 MIU + Ribavirin Teva Pharma BV 800 mg vs. peginterferon alfa-2a 180 µg: Odds Ratio ( 95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using peginterferon alfa-2a 180 µg/week and either Ribavirin Teva Pharma BV 800 mg or 1000 mg (<75 kg)/1200 mg (>75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety profiles in both Ribavirin Teva Pharma BV groups were consistent with the known safety profile of peginterferon alfa-2a plus Ribavirin Teva Pharma BV combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Ribavirin Teva Pharma BV arm.

Ribavirin in combination with interferon alfa-2a

The therapeutic efficacy of interferon alfa-2a alone and in combination with oral ribavirin was compared in clinical trials in naive (previously untreated) and relapsed patients who had virologically, biochemically and histologically documented chronic hepatitis C. Six months after end of treatment sustained biochemical and virological response as well as histological improvement were assessed.

A statistically significant 10-fold increase (from 4% to 43%; p

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

Ribavirin Teva Pharma BV in combination with peginterferon alfa-2b

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

Ribavirin Teva Pharma BV in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

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

Ribavirin is absorbed rapidly following oral administration of a single dose of Ribavirin Teva Pharma BV (median Tmax = 1-2 hours). The mean terminal phase half-life of ribavirin following single doses of Ribavirin Teva Pharma BV range from 140 to 160 hours. Ribavirin data from the literature demonstrates 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 an approximately linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Mean apparent oral clearance of ribavirin following single 600 mg doses of Ribavirin Teva Pharma BV ranges from 22 to 29 litres/hour. Volume of distribution is approximately 4,500 1itres following administration of Ribavirin Teva Pharma BV. Ribavirin does not bind to plasma proteins.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses of Ribavirin Teva Pharma BV (intra-subject variability of ≤25% for both AUC and Cmax), 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 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.

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. Ribavirin and both its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally.

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr based on literature data. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady state plasma concentrations of approximately 2,200 ng/ml. Upon discontinuation of dosing the half-life was approximately 300 hours, which probably reflects slow elimination from non-plasma compartments.

Food effect: The bioavailability of a single oral 600 mg dose Ribavirin Teva Pharma BV was increased by coadministration of a high fat meal. The ribavirin exposure parameters of AUC(0-192h) and Cmax increased by 42% and 66%, respectively, when Ribavirin Teva Pharma BV was taken with a high fat breakfast compared to being taken in the fasted state. The clinical relevance of results from this single dose study is unknown. Ribavirin exposure after multiple dosing when taken with food was comparable in patients receiving peginterferon alfa-2a and Ribavirin Teva Pharma BV and interferon alfa-2b and ribavirin. In order to achieve optimal ribavirin plasma concentrations, it is recommended to take ribavirin with food.

Renal function: The apparent clearance of ribavirin is reduced in patients with creatinine clearance ≤50 ml/min, including patients with ESRD on chronic haemodialysis, exhibiting approximately 30% of the value found in patients with normal renal function. Based on a small study in patients with moderate or severe renal impairment (creatinine clearance ≤50 ml/min) receiving reduced daily doses of 600 mg and 400 mg of Ribavirin Teva Pharma BV, respectively ribavirin plasma exposure (AUC) was found to be 20 to 30% higher compared to patients with normal renal function (creatinine clearance >80 ml/min) receiving the standard Ribavirin Teva Pharma BV dose. In patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Ribavirin Teva Pharma BV, mean ribavirin exposure (AUC) was found to be approximately 20% lower compared to patients with normal renal function receiving the standard 1000/1200 mg Ribavirin Teva Pharma BV daily dose. Plasma ribavirin is removed by haemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed from the body by haemodialysis. Increased rates of adverse drug reactions were observed in patients with moderate and severe renal impairment receiving the doses evaluated in this study.

Based on pharmacokinetic modelling and simulation, dose adjustments are recommended in patients with significant renal impairment. These adjusted doses are expected to provide ribavirin plasma exposures comparable to those achieved in patients with normal renal function receiving the standard Ribavirin Teva Pharma BV dose. Most of the recommended doses were derived from PK modelling and simulation and have not been studied in clinical trials.

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.

Use in elderly patients over the age of 65: Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a published population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.

Patients under the age of 18 years: Refer to the SmPC of the medicinal products that are indicated in combination with Ribavirin Teva Pharma BV for this population.

No Ribavirin Teva Pharma BV pharmacokinetic analysis has been performed in patients under the age of 18 years

Population Pharmacokinetics: A population pharmacokinetic analysis was performed using plasma concentration values from five clinical trials. While body weight and race were statistically significant covariates in the clearance model, only the effect of body weight was clinically significant. Clearance increased as a function of body weight and was predicted to vary from 17.7 to 24.8 L/h over a weight range of 44 to 155 kg. Creatinine clearance (as low as 34 ml/min) did not affect ribavirin clearance.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentrations in seminal fluid are 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 concentrations of ribavirin.

Name of the medicinal product

Ribavirin Teva Pharma BV price

Qualitative and quantitative composition

Special warnings and precautions for use

Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Ribavirin Teva Pharma BV has no direct cardiovascular effects, anaemia associated with Ribavirin Teva Pharma BV may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both. Thus, Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV the physician must comprehensively inform both male and female patients of the teratogenic risk of Ribavirin Teva Pharma BV, 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 Ribavirin Teva Pharma BV. For laboratory monitoring of pregnancy, please refer to Laboratory tests.

Acute hypersensitivity

If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV for discontinuation or dose modification recommendations.

Renal impairment

The pharmacokinetics of Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV.

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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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.

Ribavirin Teva Pharma BV monotherapy must not be used

Combination therapy of ribavirin with (peg)interferon alfa.

There are several severe adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa.

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

Carcinogenicity: Ribavirin is mutagenic in some in vivo and in vitro genotoxicity assays. A potential carcinogenic effect of ribavirin cannot be excluded.

Haemolysis and Cardiovascular system: A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Ribavirin Teva Pharma BV 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Ribavirin Teva Pharma BV 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. The risk of developing anaemia is higher in the female population. Although ribavirin has no direct cardiovascular effects, anaemia associated with Ribavirin Teva Pharma BV may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Ribavirin Teva Pharma BV must be administered with caution to patients with pre-existing cardiac disease. Cardiac status must be assessed before the start of therapy and monitored clinically during therapy; if any deterioration occurs, stop therapy. 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.

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of ribavirin and a peginterferon 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.

The use of Ribavirin Teva Pharma BV and peginterferon alfa-2a combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse events. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.

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

Liver function: In patients who develop evidence of hepatic decompensation during treatment, Ribavirin Teva Pharma BV in combination with other medicinal products should be discontinued. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued.

Renal impairment: The pharmacokinetics of ribavirin are 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 Ribavirin Teva Pharma BV, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute, therefore Ribavirin Teva Pharma BV dose adjustments are recommended in these patients.

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

Transplantation: The safety and efficacy of peginterferon-alfa-2a and Ribavirin Teva Pharma BV treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with peginterferon-alfa-2a, alone or in combination with Ribavirin Teva Pharma BV.

HIV/HCV Co-infection: 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 the other medicinal products. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).

Chronic hepatitis C patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of serious adverse effects (e.g. lactic acidosis; peripheral neuropathy; pancreatitis).

Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with Ribavirin Teva Pharma BV in combination with interferons. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI). Caution should therefore be exercised when adding peginterferon alfa-2a and Ribavirin Teva Pharma BV to HAART.

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia.

During treatment co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Ribavirin Teva Pharma BV in combination with other medicinal products should be discontinued immediately in patients with hepatic decompensation.

Co-administration of Ribavirin Teva Pharma BV and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-administration of Ribavirin Teva Pharma BV and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.

Laboratory tests: Standard haematologic tests and blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, glucose, 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 Teva Pharma BV:

Haemoglobin >12 g/dl (females); >13 g/dl (males)

In patients co-infected with HIV-HCV, limited efficacy and safety data 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.

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate.

For women of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for 4 months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for 7 months thereafter.

Uric acid may increase with Ribavirin Teva Pharma BV due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.

Effects on ability to drive and use machines

Ribavirin Teva Pharma BV 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.

Ribavirin Teva Pharma BV has no or negligible influence on the ability to drive and use machines. However peginterferon alfa or interferon alfa or other medicinal products used in combination with Ribavirin Teva Pharma BV may have an effect. Refer to the SmPC of the medicinal products that are used in combination with Ribavirin Teva Pharma BV for further information.

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 Ribavirin Teva Pharma BV for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirin Teva Pharma BV.

Ribavirin Teva Pharma BV oral solution is supplied in a concentration of 40 mg/mL.

Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV as some combination regimens do not adhere to the Ribavirin Teva Pharma BV dosing guidance provided in Table 1.

In clinical studies performed in this population, Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV capsules).

Dose modification for adverse reactions

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

If a patient has a serious adverse reaction potentially related to Ribavirin Teva Pharma BV, the Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV plus peginterferon alfa-2b, 1st dose reduction of Ribavirin Teva Pharma BV is to 12 mg/kg/day, 2nd dose reduction of Ribavirin Teva Pharma BV is to 8 mg/kg/day.

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

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

Special populations

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

Ribavirin Teva Pharma BV may be used in combination with peginterferon alfa-2b or interferon alfa-2b. The selection of Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV. 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 Ribavirin Teva Pharma BV 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 Ribavirin Teva Pharma BV and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of medicinal products used in combination with Ribavirin Teva Pharma BV.

Method of administration

Ribavirin Teva Pharma BV should be administered orally with food.

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

Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Teva Pharma BV for the treatment of hepatitis C.

Method of Administration

Ribavirin Teva Pharma BV film-coated tablets are administered orally in two divided doses with food (morning and evening). Due to the teratogenic potential of ribavirin, the tablets should not be broken or crushed.

Posology

Dose to be administered

The dose of Ribavirin Teva Pharma BV is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1). Ribavirin Teva Pharma BV tablets are to be administered orally each day in two divided doses (morning and evening) with food.

Duration of treatment

Duration of treatment depends on medicinal products that it is being combined with and may depend on several patients or virus characteristics including genotype, co-infection status, previous history of treatment, on-treatment response.

Refer to the SPC of the medicinal product that is used in combination with Ribavirin Teva Pharma BV.

Dosage modification for adverse reactions

Dose modification of Ribavirin Teva Pharma BV depends on medicinal products that it is being combined with.

If a patient has a severe adverse reaction potentially related to ribavirin, the ribavirin 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 cardiac status.

[1] For patients receiving a 1000mg (<75kg) or 1200mg (>75kg) dose, Ribavirin Teva Pharma BV dose should be reduced to 600mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening). If the abnormality is reversed, Ribavirin Teva Pharma BV may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.

[2]For patients receiving an 800mg (<65kg)-1000mg (65-80kg)-1200mg (81-105kg) or 1400mg (>105kg) dose, 1st dose reduction of Ribavirin Teva Pharma BV is by 200 mg/day (except in patients receiving the 1400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Ribavirin Teva Pharma BV is by an additional 200 mg/day. Patients whose dose of Ribavirin Teva Pharma BV is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

Refer to the SmPCs of peginterferon alfa or interferon alfa for dose modification and/or discontinuation in case of serious adverse reaction potentially related to these drugs.”

Special populations

Use in renal impairment: The recommended dose regimens (adjusted by the body weight cutoff of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment.).

Therapy should be initiated (or continued if renal impairment develops while on therapy) with extreme caution and intensive monitoring of haemoglobin concentrations, with corrective action as may be necessary, should be employed throughout the treatment period.

If severe adverse reactions or laboratory abnormalities develop, Ribavirin Teva Pharma BV should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Ribavirin Teva Pharma BV, Ribavirin Teva Pharma BV therapy should be discontinued. No data are available for pediatric subjects with renal impairment.

Use in hepatic impairment: Hepatic function does not affect the pharmacokinetics of ribavirin. Therefore, no dose adjustment of Ribavirin Teva Pharma BV is required in patients with hepatic impairment. Use in elderly patients over the age of 65: 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 Teva Pharma BV.

Use in patients under the age of 18 years: Treatment with Ribavirin Teva Pharma BV is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with other medicinal products for the treatment of hepatitis C. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a. A case by case benefit/risk assessment with respect to the use of Ribavirin Teva Pharma BV in children is needed .

Special precautions for disposal and other handling

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

No special requirements.

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