Ребетол

Ребетол is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.

Ребетол 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.

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

Posology

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

Ребетол capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adults

The recommended dose and duration of Ребетол depends on patient's weight and on the medicinal product that is used in combination. Please refer to the corresponding SmPC of medicinal products used in combination with Ребетол

In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg.

Paediatric population

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

Note: For patients who weigh < 47 kg, or are unable to swallow capsules, please refer to the SmPC for Ребетол 40 mg/mL oral solution.

Dosing of Ребетол 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 is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with Ребетол as some combination regimens do not adhere to the Ребетол dosing guidance provided in Table 1.

a: 1 morning, 2 evening

b: 2 morning, 2 evening

Dose modification for adverse reactions

Dose modification for adults

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

If a patient has a serious adverse reaction potentially related to Ребетол, the Ребетол 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, cardiac status and indirect bilirubin concentration.

* For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, Ребетол dose should be reduced to 600 mg/day (administered as one 200 mg capsule in the morning and two 200 mg capsules in the evening). If the abnormality is reversed, Ребетол 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.

For patients receiving a 800 mg (< 65 kg)-1,000 mg (65-80 kg)-1,200 mg (81-105 kg) or 1,400 mg (> 105 kg) dose, 1st dose reduction of Ребетол is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Ребетол is by an additional 200 mg/day. Patients whose dose of Ребетол is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

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

Dose modification for paediatric patients

Dose reduction in paediatric patients without cardiac disease follows the same guidelines as adult patients without cardiac disease regarding haemoglobin levels (Table 2).

There are no data for paediatric patients with cardiac disease.

Table 3 provides guidelines for discontinuation based on the patient's indirect bilirubin concentration.

Special populations

Elderly (> 65 years of age)

There does not appear to be a significant age-related effect on the pharmacokinetics of Ребетол. However, as in younger patients, renal function must be determined prior to administration of Ребетол.

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

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

The safety and efficacy of Ребетол 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 Ребетол for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Ребетол are 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 Ребетол. Adult patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Ребетол 200 mg/day. Table 4 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 Ребетол and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with Ребетол.

Method of administration

Ребетол should be administered orally with food.

-

- Pregnacy. In females of childbearing potential, Ребетол 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).

Ребетол 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 Ребетол 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 7 % of children and adolescents treated with Ребетол in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Ребетол has no direct cardiovascular effects, anaemia associated with Ребетол may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Ребетол 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 Ребетол the physician must comprehensively inform both male and female patients of the teratogenic risk of Ребетол, 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 Ребетол. For laboratory monitoring of pregnancy, please refer to Laboratory tests.

Acute hypersensitivity:

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

Renal impairment

The pharmacokinetics of Ребетол 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 Ребетол. Due to substantial increases in Ребетол plasma concentrations in patients with moderate and severe renal impairment, Ребетол 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 Ребетол 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-2b/Ребетол 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 Ребетол 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 Ребетол and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Ребетол 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 respective 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.

Laboratory tests: Standard haematologic tests and 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 Ребетол therapy:

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 Ребетол due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.

Information on excipients

Each Ребетол capsule contains 40 mg of lactose.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ребетол 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.

Summary of the safety profile

The salient safety issue of Ребетол is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Ребетол 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 Ребетол 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 Ребетол for additional undesirable effects reported with these products.

Adults

Bitherapy with peginterferon alfa-2b or interferon alfa-2b

The safety of Ребетол capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Ребетол in combination with interferon alfa-2b, two trials studied Ребетол in combination with peginterferon alfa-2b.

Patients who are treated with interferon alfa-2b and Ребетол after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below.

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 Ребетол) 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 interferon monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Since Ребетол is always prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using Ребетол in combination with interferon alfa-2b (pegylated or non-pegylated).

Description of selected adverse reactions

A reduction in haemoglobin concentrations by > 4 g/dl was observed in 30 % of patients treated with Ребетол and peginterferon alfa-2b and 37 % of patients treated with Ребетол and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dl in up to 14 % of adult patients and 7 % of children and adolescents treated with Ребетол in combination with either peginterferon alfa-2b or interferon alfa-2b.

Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Ребетол capsules in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group.

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Ребетол used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials.

HCV/HIV co-infected patients:

For HCV/HIV co-infected patients receiving Ребетол in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-Ребетол for co-HCV infection.

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment. Haematological abnormalities were more frequently reported in patients receiving Ребетол in combination with peginterferon alfa-2b when compared to patients receiving Ребетол in combination with interferon alfa-2b. In Study 1 , decrease in absolute neutrophil count levels below 500 cells/mm³ was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm³ was observed in 4 % (8/194) of patients receiving Ребетол capsules in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Ребетол in combination with peginterferon alfa-2b.

CD4 lymphocytes decrease

Treatment with Ребетол in combination with peginterferon alfa-2b was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of Ребетол in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected patients with CD4+ cell counts < 200/µl.

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 Ребетол in combination withother medicinal 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 Ребетол, 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 Ребетол, 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 (< 3^rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3^rd percentile). 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, weightfor- 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 followup 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 Ребетол, 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). 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 Ребетол, growth inhibition is 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 6 are based on experience from the two multicentre children and adolescents clinical trials using Ребетол with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10), and uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Ребетол in combination with interferon alfa-2b or peginterferon alfa-2b

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis

Uncommon

Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Thrombocytopenia, lymphadenopathy

Endocrine disorders

Very common:

Hypothyroidism

Common:

Hyperthyroidism, virilism

Metabolism and nutrition disorders

Very common:

Anorexia, increased appetite, decreased appetite

Common:

Hypertriglyceridemia, hyperuricemia

Psychiatric disorders

Very common:

Depression, insomnia, emotional lability

Common:

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

Uncommon:

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

Nervous system disorders

Very common:

Headache, dizziness

Common:

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

Uncommon:

Neuralgia, lethargy, psychomotor hyperactivity

Eye disorders

Common:

Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder

Uncommon:

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

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

Common:

Tachycardia, palpitations

Vascular disorders

Common:

Pallor, flushing

Uncommon:

Hypotension

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain

Uncommon:

Wheezing, nasal discomfort

Gastro-intestinal disorders

Very common:

Abdominal pain, abdominal pain upper, vomiting, diarrhoea, nausea

Overdose The information provided in Overdose of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Overdose in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... In clinical trials with Ребетол used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Ребетол (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. Pharmacodynamic properties The information provided in Pharmacodynamic properties of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04. Mechanism of action Ребетол is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Ребетол in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Ребетол monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Ребетол 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 Ребетол in combination with Direct Antiviral Agent (DAA): Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with such combination. Only the description of the use of Ребетол from the original development with interferon alfa-2b is detailed in the current SmPC: Bitherapy with interferon alfa-2b: The use of Ребетол in combination treatment with interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT. Naïve patients Three trials examined the use of interferon in naïve patients, two with Ребетол + interferon alfa-2b (C95-132 and I95-143) and one with Ребетол + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of Ребетол to interferon alfa-2b (41 % vs 16 %, p < 0.001). In clinical trials C95-132 and I95-143, Ребетол + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes. In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following combination regimens: - Ребетол (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511). - Ребетол (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514). - Ребетол (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505). In this trial, the combination of Ребетол and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of Ребетол and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of Ребетол administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg Ребетол (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received 10.6 mg/kg Ребетол (Table7), while response rates in patients that received > 13.2 mg/kg Ребетол were even higher. Table 7 Sustained response rates with Ребетол + peginterferon alfa-2b (by Ребетол dose [mg/kg], genotype and viral load) HCV Genotype Ребетол dose (mg/kg) P 1.5/R P 0.5/R I/R All Genotypes All ≤ 10.6 > 10.6 54 % 50 % 61 % 47 % 41 % 48 % 47 % 27 % 47 % Genotype 1 All ≤ 10.6 > 10.6 42 % 38 % 48 % 34 % 25 % 34 % 33 % 20 % 34 % Genotype 1 ≤ 600,000 IU/ml All ≤ 10.6 > 10.6 73 % 74 % 71 % 51 % 25 % 52 % 45 % 33 % 45 % Genotype 1 > 600,000 IU/ml All ≤ 10.6 > 10.6 30 % 27 % 37 % 27 % 25 % 27 % 29 % 17 % 29 % Genotype 2/3 All ≤ 10.6 > 10.6 82 % 79 % 88 % 80 % 73 % 80 % 79 % 50 % 80 % P1.5/R Ребетол (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg) P0.5/R Ребетол (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg) I/R Ребетол (1,000/1,200 mg) + interferon alfa-2b (3 MIU) HCV/HIV Co-infected patients Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 7. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Ребетол (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or Ребетол (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Ребетол (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Ребетол (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period. Table 7 Sustained virological response based on genotype after Ребетол in combination with peginterferon alfa-2b in HCV/HIV co-infected patients Study 11 Study 22 Ребетол (800 mg/day) + peginterferon alfa-2b (1.5 µg/kg/week) Ребетол (800 mg/day) + interferon alfa-2b (3 MIU TIW) p valuea Ребетол (800-1,200 mg/day)d + peginterferon alfa-2b (100 or 150cµg/week) Ребетол (800-1,200 mg/day)d + interferon alfa-2b (3 MIU TIW) p valueb All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017 Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007 Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730 MIU = million international units; TIW = three times a week. a: p value based on Cochran-Mantel Haenszel Chi square test. b: p value based on chi-square test. c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects > 75 kg received 150 µg/week peginterferon alfa-2b. d: Ребетол dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg. 1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36. Histological response Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Ребетол in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3. -Retreatment of relapse patients with Ребетол and interferon alfa-2b combination treatment Two trials examined the use of Ребетол and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with Ребетол and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging. Long-term efficacy data - Adults Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with non-pegylated interferon alfa-2b (with or without Ребетол) and pegylated interferon alfa-2b (with or without Ребетол), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies. The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Ребетол), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Ребетол). SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated,with or without Ребетол) 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). Paediatric population Clinical efficacy and safety Ребетол 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 Ребетол 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Ребетол and interferon alfa-2b needs to be carefully considered in this population. The study results are summarized in Table 9. Table 9 Sustained virological response in previously untreated children and adolescents Ребетол 15 mg/kg/day + interferon alfa-2b 3 MIU/m2 3 times a week Overall Responsea (n = 118) 54 (46 %)* Genotype 1 (n = 92) 33 (36 %)* Genotype 2/3/4 (n = 26) 21 (81 %)* * Number (%) of patients a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period. Long-term efficacy data Ребетол 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 Ребетол 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 Ребетол. 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 Ребетол. 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 Ребетол 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 The information provided in Pharmacokinetic properties of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... In a single dose, crossover study of Ребетол in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent. Absorption Ребетол 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 Ребетол. Volume of distribution is approximately 5,000 l. Ребетол does not bind to plasma proteins. Distribution Ребетол 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 Ребетол. The ratio of whole blood:plasma Ребетол concentrations is approximately 60:1; the excess of Ребетол in whole blood exists as Ребетол nucleotides sequestered in erythrocytes. Biotransformation Ребетол 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 Ребетол and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally. Ребетол 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, Ребетол 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 Ребетол has been studied. Ребетол concentration in seminal fluid is approximately two-fold higher compared to serum. However, Ребетол 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 Ребетол. Food effect The bioavailability of a single oral dose of Ребетол 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 Ребетол 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 Ребетол with food to achieve the maximal plasma concentration of Ребетол. Renal function Based on published data,Single-dose Ребетол 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. Ребетол concentrations are essentially unchanged by haemodialysis. Hepatic function Single-dose pharmacokinetics of Ребетол in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls. Elderly patients (> 65 years of age) Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of Ребетол; renal function is the determining factor. Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on Ребетол clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model. Paediatric population Ребетол in combination with interferon alfa-2b Multiple-dose pharmacokinetic properties for Ребетол capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The pharmacokinetics of Ребетол and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents. Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Ребетол when administered to children or adolescents with chronic hepatitis C Parameter Ребетол 15 mg/kg/day as 2 divided doses (n = 17) Interferon alfa-2b 3 MIU/m2 3 times a week (n = 54) Tmax (hr) 1.9 (83) 5.9 (36) Cmax (ng/ml) 3,275 (25) 51 (48) AUC* 29,774 (26) 622 (48) Apparent clearance l/hr/kg 0.27 (27) Not done *AUC12 (ng.hr/ml) for Ребетол; AUC0-24 (IU.hr/ml) for interferon alfa-2b Pharmacotherapeutic group The information provided in Pharmacotherapeutic group of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04. Preclinical safety data The information provided in Preclinical safety data of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... Ребетол Ребетол 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 Ребетол 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 Ребетол 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 Ребетол 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 Ребетол-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 Ребетол-induced testicular toxicity occurred within one or two spermatogenic cycles. Genotoxicity studies have demonstrated that Ребетол does exert some genotoxic activity. Ребетол 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 Ребетол. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, Ребетол 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 Ребетол in humans is unlikely. Ребетол plus interferon When used in combination with peginterferon alfa-2b or interferon alfa-2b, Ребетол 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. Incompatibilities The information provided in Incompatibilities of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... Not applicable Special precautions for disposal and other handling The information provided in Special precautions for disposal and other handling of Ребетол is based on data of another medicine with exactly the same composition as the Ребетол. . Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug Ребетол directly from the package or from the pharmacist at the pharmacy. more... No special requirements Ребетол price We have no data on the cost of the drug. However, we will provide data for each active ingredient The approximate cost of Ribavirin 200 mg per unit in online pharmacies is from 2.14$ to 3.2$, per package is from 128$ to 199$. References: https://www.drugs.com/search.php?searchterm=rebetol-rus https://pubmed.ncbi.nlm.nih.gov/?term=rebetol-rus Available in countries Russia Find in a country: A B C D E F G H I J K L M N O P Q R S T U V Y Z