Order of Ministry of
Health of Ukraine
11.01.2019 № 81
for medical use
active substance: ribavirin;
1 capsule contains ribavirin 200 mg;
excipients: lactose monohydrate, сroscarmellose sodium, povidone, magnesium stearate, colloidal silicon dioxide anhydrous;
hard gelatin capsule: gelatin, purified water, Patent Blue V (E131), carmoisine (E 122), titanium dioxide (E 171), Ponceau 4R (E 124), Sunset Yellow FCF (E 110).
Pharmaceutical form: Capsules.
Basic physico-chemical properties: capsules with a pink body and a violet cap that contain white powder.
Direct acting antivirals. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. АТС Code J05А В04.
Ribavirin is a synthetic analogous of nucleoside with in vitro activity against RNA and DNA viruses. Mechanism of action of ribavirin combined with peginterferon α-2b or interferon α-2b acts against hepatitis C virus is unknown. Ribavirin monotherapy of chronic hepatitis C does not lead to elimination of the virus (RNA of hepatitis C virus) or improving the histologic pattern of liver after 6-12 months of therapy and during the 6 month follow-up period. However, the combination of ribavirin with peginterferon α-2b or interferon α-2b in clinical trials led to high levels of response to treatment compared to monotherapy with peginterferon α-2b or interferon α-2b.
Ribavitin is easily absorbed after oral administration of a single dose (Тmax = 1.5 hours) and is rapidly distributed in the body. The elimination phase is quite long lasting. Half-periods of absorption, distribution and elimination of a single dose are 0.05; 3.75; and 79 hours, respectively. Ribavirin is intensively absorbed; only 10% of the traced dose is excreted with the feces. However, absolute bioavailability is about 45-65% which is probably due with the first-pass metabolism. There is a linear dependence between dose and bioavailability index (AUCtf) when administering single doses of ribavirin in the amount from 200 mg to 1200 mg. The volume of distribution is approximately 5000 L. Ribavirin does not bind to plasma proteins.
The transfer of ribavirin by non-plasma route has been most extensively studied in erythrocytes; it has been shown that, in general, transport occurs with the equilibrium nucleoside carrier of the type es. This type of carrier is present in virtually all cell types and can be a factor that predetermines a large amount of ribavirin distribution. The ratio of ribavirin to whole blood is: plasma is about 60:1; the excess of ribavirin in whole blood exists in the form of ribavirin nucleotides isolated in erythrocytes.
Ribavirin is metabolised in two ways: a reversible phosphorylation and a degradative transformation involving deribosylation and amide hydrolysis to form a triazole carboxyacid metabolite. The ribavirin itself and its metabolites - triazolcarboxamide and triazolecarboxylic acid are excreted from the body with urine.
For ribavirin, after its single oral administration, high pharmacokinetic variability was demonstrated in both one patient and between different patients (the variability of AUC and Cmax in one patient is approximately 30%), which may be due to the intensive metabolism of the first pathway and significant transplantation in the circulatory system and beyond.
Upon multiple administrating, ribavirin accumulates extensively in plasma; the ratio of multiple-administration to single-administration bioavailability (AUC12h) at multiple administration and single administration is 6. At oral administration (600 mg 2 times per day), steady-state concentration was reached by the end of the 4th week; while it was about 2.2 ng / ml. After discontinuation of administration the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.
The ability to penetrate into the seminal fluid. The ability of ribavirin to penetrate into the seminal fluid has been studied. The concentrations of ribavirin in the seminal fluid is approximately 2-fold higher than in the blood serum. However, ribavirin systemic exposure in women after sexual contact with a person who receives treatment remains extremely limited compared to therapeutic plasma concentrations of ribavirin.
Food effect. The bioavailability of a single oral dose of ribavirin is 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 is due to delayed transit or modified pH.
Renal function. In patients with renal insufficiency, the pharmacokinetics of ribavirin in single-dose administration varies (AUCtf and Cmax are increased) compared to control (creatinine clearance> 90 ml/min). This change appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.
Hepatic function. The pharmacokinetics of ribavirin when administered at a single dose to patients with moderate to severe hepatic insufficiency (type A, B or C according to the Childe-Pugh’s Classification) is similar to the pharmacokinetics of ribavirin in healthy volunteers in the control group.
Elderly patients (≥65 years old). Specific pharmacokinetic analyses for elderly subjects have not been performed. However, in the conducted studies, age was not one of the main factors affecting the kinetics of ribavirin; the main factor of this is renal function.
The pharmacokinetics of ribavirin in combination with peginterferon α-2b or with interferon α-2b (normalized by dose) did not differ in adults and children aged 5 to 16 years.
Therapy with three drug
Virorib® in combination with boceprevir and peginterferon α-2b is indicated for treatment of chronic hepatitis C (genotype 1) in adult patients (aged 18 years and more) with compensated liver disease, who have not received treatment before, or if previous treatment had failed.
It is recommended to read the instruction for use of peginterferon α-2b and boceprevir, if the drug Virorib® is used in combination with such drugs.
Therapy with two drugs.
Virorib® is indicated for treatment of chronic hepatitis C in adults, adolescents and children aged 3 years and more; the drug should be used only in combination with peginterferon α-2b or interferon α-2b. The drug Virorib® must not be used as monotherapy.
It is recommended to read the instruction for use of peginterferon α-2b or interferon α-2b if the drug Virorib® is used in combination with such drugs.
There is no information on safety or efficacy of using the drug Virorib® with other forms of interferon (i.e. besides α-2b).
Adults (aged 18 years and older).
The drug Virorib ® is indicated:
- within the treatment regimen with three drugs: in combination with peginterferon α-2b and boceprevir for the treatment of chronic hepatitis С (genotype 1) in adult patients with compensated liver disease;
- within the treatment regimen with two drugs: in combination with interferon α-2b or peginterferon α-2b for the treatment of chronic hepatitis С in naive adult patients (in the absence of decompensation of liver function, increased ALT level and positive test for RNA of hepatitis C virus (HCV RNA);
- within the treatment regimen with two drugs: in combination with peginterferon α-2b for the treatment of chronic hepatitis С in patients with compensated cirrhosis and/or clinically stable concomitant HIV infection.
Therapy with two drugs.
Children aged 3 years and more, adolescents.
Virorib® is indicated, in combination with peginterferon α-2b or interferon α-2b for the treatment of chronic hepatitis С in children aged 3 years and more, as well as adolescents, who have not been treated before, in the absence of decompensation of liver function and in the presence of RNA of hepatitis C virus.
If the question on postponing treatment until the adulthood is regarded, it should be kept in mind that combined therapy induces growth delay that can be irreversible in some patients. Decisions about the treatment should be taken individually for each patient.
Patients that have been treated before.
Virorib® is indicated:
- within the treatment regimen with three drugs: in combination with peginterferon α-2b and boceprevir for the treatment of chronic hepatitis С (genotype 1) in adult patients with compensated liver disease;
- within the treatment regimen with two drugs: in combination with peginterferon α-2b for the treatment of chronic hepatitis С in case if the previous treatment only with α-interferon (pegylated or non-pegylated) or its combination with ribavirin was ineffective;
- within the treatment regimen with two drugs: in combination with interferon α-2b for the treatment of chronic hepatitis С in case if the previous monotherapy with α- interferon was initially effective (normalization of ALT by the end of treatment course), but later a relapse occurred.
Hypersensitivity to ribavirin or to any of the drug components.
Pregnancy. The therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
Men, whose wives are pregnant.
Severe cardiac diseases, including unstable and uncontrolled forms that are observed within 6 months before initiation of treatment.
Severe, debilitating diseases.
Chronic renal failure or creatinine clearance < 50 ml/min and/or conditions that require haemodialysis.
Severe hepatic dysfunction (B or C degree according to Child-Pugh’s Classification) or decompensated cirrhosis of the liver.
Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia)
Prescription of peginterferon α-2b is contraindicated in patients coinfected with the virus of hepatitis C/HIV with cirrhosis of the liver Child-Pugh Score ≥ 6 points.
Anamnestic or clinical data on severe mental disorder, including severe depression, suicidal thoughts or attempted suicide in children and adolescents are present.
Autoimmune hepatitis or other autoimmune diseases in anamnesis (due to combination with peginterferon α-2b or interferon α-2b).
Interaction with other medicinal products and other forms of interaction.
Studies of interactions were conducted only with adult patients.
According to the results of in vitro studies using human liver microsome perparations, cytochrome P450 enzymes do not take part in metabolic transformations of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that ribavirin stimulates the enzymatic activity of the liver. Therefore, there is a minimal probability for interactions with cytochrome P450.
By inhibiting inosine monophosphate dehydrogenase, ribavirin may affect the metabolism of azathioprine with further accumulation of 6-methylthioinosine monophosphate, which is associated with myelotoxicity in patients receiving azathioprine treatment. It is recommended to avoid using pegylated α-interferon and ribavirin concomitantly with azathioprine. In individual cases, when the benefit of using ribavirin concomitantly with azathioprine overweighs the potential risk, frequent control of hematological parameters in the period of concomitant use of azathioprine is recommended to identify signs of myelotoxicity, and if they are present – the use of these drugs should be stopped.
No interaction studies have been conducted with ribavirin and other medicinal products, except for peginterferon α-2b, interferon α-2b and antacids.
Interferon α-2b. No pharmacokinetic interactions were noted between ribavirin and peginterferon α -2b or interferon α -2b in a multiple-dose.
Antacides. The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid drug containing magnesium compounds and aluminium or simethicone; AUCtf decreased to 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is not considered to be clinically relevant.
Nucleoside analogs. Use of nucleoside analogs, alone or in combination with other nucleosides, may lead to lactic acidosis. Ribavirin in vitro increases phosphorylated metabolites of purine nucleosides. This effect may potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Concomitant use of ribavirin and didanosine is not recommended. Cases of mitochondrial toxicity (lactic acidosis and pancreatitis) have been registered, some of them were fatal.
There have been reports of cases of exacerbation of anemia caused by ribavirin, when zidovudine was used as a part of a treatment regimen of HIV, although the exact mechanism is not yet been studied. Because of the increased risk of anemia ribavirin is not recommended for use in combination with zidovudine. The regimen of co-administration of zidovudine and ribavirin at the background of highly active antiretroviral therapy (HAART) should be reviewed in case of anemia. This is especially important for patients who have already had anemia when using zidovudine.
The possibility of interaction with ribavirin remains within 2 months (5 half-life periods of ribavirin) since discontinuation of use due to the long half-life.
No interaction has been observed between ribavirin and non-nucleoside reverse transcriptase inhibitors or protease inhibitors.
Controversial data have been published regarding coadministration of abacavir and ribavirin. Some data indicate a risk of a lower response to the treatment with pegylated interferon/ribavirin in patients with co-infection of hepatitis C and HIV receiving antiretroviral therapy with abacavir. Precautions should be taken when using these drugs concomitantly.
Mental illness and Central Nervous System (CNS). Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during ribavirin combination therapy with peginterferon alfa-2b or interferon alfa-2b and even during the 6-months’ period of observation after discontinuation of such treatment. Among children and adolescents who have been treated with ribavirin in combination with interferon α-2b, suicidal ideation or suicide attempts during treatment and 6-month follow-up period after treatment were observed more frequently than among adults (2.4% versus 1%). In children and adolescents, as well as in adults, there were other mental disorders (e.g., depression, emotional lability, and somnolence). When using α-interferons, other CNS disorders have been observed, including aggressive behavior (sometimes directed against others such as thoughts of murder), bipolar disorder, mania, confusion and disturbance of mental status.
Patients should be closely monitored to identify any signs or symptoms of psychiatric disorders. In case of such symptoms, the prescribing physician has to evaluate potential severity of such adverse effects and the need for appropriate treatment. If psychiatric symptoms persist or worsen, as well as if suicidal thoughts or thoughts of murder appear, it is recommended to discontinue treatment with Virorib® in combination with peginterferon α-2b or interferon α-2b and, if necessary, provide patient appropriate psychiatric care.
Patients with a history of or clinical signs of severe mental states. If it is decided that combined therapy with the drug Virorib® and peginterferon α-2b or interferon α-2b is necessary for adult patients with clinical or anamnestic data on severe psychiatric conditions, it should be started after an appropriate individual diagnosis at the background of therapeutic monitoring of the mental state.
The use of the drug Virorib® and peginterferon α-2b or interferon α-2b for the treatment of children and adolescents with clinical or anamnestic data on severe psychiatric condition is contraindicated.
Patients who use/abuse psychoactive substances. The patients with viral hepatitis C who simultaneously consume psychoactive substances (alcohol, marijuana, etc.) have a high risk of psychiatric disorders or exacerbation of the existing psychiatric disorder when treatment with α-interferon. If treatment with α-interferon is necessary in such patients, the presence of concomitant psychiatric disorders and potential for use of other substances should be carefully evaluated, and appropriate measures should be taken before starting the therapy. If necessary (for assessment of treatment and follow-up), interdisciplinary approach should be considered, including a psychologist or a psychiatrist. The patient’s condition should be carefully monitored during the treatment and after its discontinuation. Early intervention is recommended for reappearance or development of mental disorders and psychoactive substances use.
Hemolysis. There are clinical data regarding the decrease in hemoglobin levels in adult patients (< 10 g/dl), as well as in children and adolescents that were treated with a combination of ribavirin and peginterferon α-2b or interferon α-2b. Although ribavirin has no direct effect on the cardio-vascular system, anemia associated with taking ribavirin may affect the cardiac function and/or exacerbate the symptoms of coronary disease. Therefore, Virorib® should be prescribed with caution in patients with cardiac diseases. It is recommended to evaluate the condition of the cardiovascular system before treatment and during the therapy. In case of any signs of deterioration of the cardiovascular system, the therapy should be stopped.
Cardiovascular system. Adult patients who have or had congestive heart failure, myocardial infarction and / or arrhythmia, should be under constant medical supervision. In patients with cardiac diseases, it is recommended to conduct electrocardiography before and during treatment. Arrhythmias (mainly supraventricular) are usually treated by the conventional therapy, but may require discontinuation of treatment. There are no data regarding the use of combined therapy in children and adolescents with the history of cardiovascular diseases.
Immediate hypersensitivity. In case of acute hypersensitivity (e.g., urticaria, angioedema, bronchospasm, anaphylaxis), the drug Virorib® should be discontinued immediately, and appropriate treatment should be prescribed. Transient rashes are not the reason for termination of treatment.
Ophthalmological changes. Ribavirin is used in combination with α-interferons. In rare cases, during the combination treatment with α-interferons, cases of retinopathy have been marked, including bleeding in the retina, retinal exudates, papillary edema, optic neuropathy and occlusion of arteries or veins of the retina that can cause vision loss. All patients should undergo ophthalmological examination before starting the treatment. Immediate full ophthalmological examination should be conducted for the patient who has signs of eye disease or deterioration of vision. Periodic ophthalmological examination should be conducted in patients with existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) during combination treatment with α-interferons. Patients who have new or deterioration of existing ophthalmic diseases, combined treatment with α-interferons should be stopped.
Liver function. All patients, who have shown signs of significant deterioration of liver function during the treatment, should be carefully monitored. The therapy should be stopped in patients, who have shown increased coagulation, which may indicate liver decompensation.
Potential for increased immunosuppression. A report has been published on pancytopenia and bone marrow suppression that occurred within 3-7 weeks after the use of peginterferon and ribavirin concomitantly with azathioprine. Such myelotoxicity disappeared in 4-6 weeks after discontinuation of antiviral therapy for hepatitis C and simultaneously azathioprine, and it did not appear again after repeated individual use of any of the drugs.
Co-infection with HIV and hepatitis C virus.
Mitochondrial toxicity and lactic acidosis. Caution is required for patients with HIV-infection and concomitant hepatitis C virus infection receiving treatment with Nucleoside Reverse Transcriptase Inhibitors (especially didanosine and stavudine) together with a combination of ribavirin and interferon α-2b. In HIV-infected patients who used nucleoside reverse transcriptase inhibitors, during the treatment with ribavirin, physicians much carefully monitor the markers of mitochondrial toxicity and lactic acidosis. In particular, ribavirin is not recommended for use together with didanosine and stavudine because of the risk of mitochondrial toxicity and to limit the risk of overlapping mitochondrial toxicity, respectively.
Decompensation of liver function in patients with co-infection of HIV and hepatitis C virus and advanced cirrhosis. Patients with concomitant HIV infection and advanced cirrhosis receiving HAART may have an increased risk of liver function decompensation and fatal outcome. Additional use of α-interferons separately or in combination with ribavirin increases the above risk in this category of patients. Other initial factors in patients with concomitant infection may increase the risk of decompensated liver function, including treatment with didanosine and increased concentration of bilirubin in the blood serum. The condition of patients with concomitant infection receiving both antiretroviral therapy and treatment for hepatitis should be closely monitored and the degree of liver dysfunction should be evaluated according to the Child-Pugh classification. In case of liver decompensation, the treatment of hepatitis should be stopped immediately and re-evaluation of antiretroviral treatment regimen.
Hematological disorders in patients with co-infection of HIV and hepatitis C virus. The patients with concomitant HIV-infection receiving HAART and treatment with ribavirin in combination with peginterferon α-2b may have an increased risk of hematologic disorders (e.g., neutropenia, thrombocytopenia and anemia) compared with patients with hepatitis C virus. Most of these disorders disappear at lowering the doses, but it is necessary to closely monitor the hematological parameters in these patients. The patients treated with ribavirin and zidovudine have an increased risk of anemia, therefore, ribavirin is not recommended for use together with zidovudine.
Patients with low CD4 cell count. The data on the efficacy and safety of treatment of patients with HIV-infection and hepatitis C virus with CD4 cell count <200/µl are limited. The treatment of patients with low CD4 cell count should be conducted carefully.
You should follow the instructions for the medical use according to antivirus drugs which used together with drugs to treat hepatitis C (for getting the information about the toxicity of each drug and possible increasing the toxicity combined use of ribavirin and peginterferon α-2b).
Dental and periodontal disorders. There is an information that the development of dental and periodontal disorders (which can lead to tooth loss) in patients receiving combination therapy with ribavirin and peginterferon α-2b or interferon α-2b. In addition, dry mouth could have negatively affected on the teeth and the mucous membrane of the mouth during long-term combination therapy of ribavirin and peginterferon α-2b or interferon α-2b. Patients should thoroughly clean the teeth two times a day and regularly have dental examination. In addition, some patients may experience vomiting, after which they must thoroughly rinse mouth.
Laboratory assessment. All patients before treatment recommended complete blood count (a
complete blood count to determine leucogram) and biochemical analysis of blood (electrolytes, serum creatinine, liver function tests, uric acid). Prior to the combination therapy is appropriate following initial values of blood:
hematoglobulin: adults ³ 120 g / l (female) and ³ 130 g / l (male);
children and adolescents: ³ 110 g / l (girls) and ³120 g / l (boys);
platelets ³ 100 ´ 109/l;
neutrophil ³ 1,5 ´ 109/l.
Laboratory tests should be performed on the 2nd and 4th week of treatment, and later - according to clinical indications. Periodically during the treatment should determine the level of VHC RNA.
Female of reproductive age. Women who are under medical treatment, and female who is male’s sexual partner who are under medical treatment should conduct pregnancy tests every month throughout the period of treatment and for 4 months and 7 months, respectively, after completion of treatment, as ribavirin can not be used during pregnancy.
While using ribavirin there is possible increasing of concentration the uric acid through erythrocyte hemolysis, so you must carefully observe prone to this disease patients to identify potential indications of gout.
The drug contains lactose. If you have intolerance to some sugars, consult your doctor before taking the drug.
The product contains Ponceau 4R (E 124), sunset yellow FCF (E 110), carmoyizyn (E 122) and it may cause allergic reactions.
Administration during pregnancy and breast feeding.
Pregnancy. Using the drug Virorib® is contraindicated during pregnancy.
Breast feeding. There is no information whether ribavirin excreted in human breast milk. Because of the possible development of adverse effects in the child breastfeeding should be discontinued before treatment.
Women of childbearing age / contraception in men and women.
Female (patient). Virorib® can not be used during pregnancy. To prevent pregnancy, patients should use effective contraception. Therapy should not begin, until a negative pregnancy test result is obtained. Women of childbearing age and their sexual partners should use effective contraceptives during treatment and for 4 months after treatment; and during this period should do a standard monthly pregnancy test. If a woman becomes pregnant during treatment or within 4 months after treatment, then it needs to provide the information about significant risk of teratogens effects of ribavirin to the fetus.
Male (patient) and their female partners. It is necessary to follow the effective means of contraception to prevent pregnancy in male partners treated with the drug Virorib®. Ribavirin accumulates in cells and slowly excreted. There is unknown potential teratogenic or genotoxic effect of ribavirin contained in sperm, on the embryo / fetus.
Effect on reaction rate when driving motor transport or using other mechanisms.
Ribavirin does not influence nor has the insignificant influence on ability to drive motor transport or using other mechanisms, but when it’s combined with peginterferon α-2b or interferon α-2b there is some possible influence. Therefore, patients who have fatigue during treatment, somnolense or mental confusion, should avoid driving or operating other mechanisms.
Administration and dosage.
Therapy should be conducted by the doctor who has an experience of treating chronic hepatitis C.
Virorib® should be used in combination with peginterferon α-2b or interferon α-2b (two drugs regimen), or - adults with chronic hepatitis C (genotype 1) - in combination with boceprevir and peginterferon α-2b (three drugs scheme).
When administering combination therapy, instructions for the medical use of boceprevir, peginterferon α-2b or interferon α-2b should also be followed.
The dose of Virorib® drug depends on the patient's body weight. Virorib® capsules, should be taken oraly, with food, daily, for 2 administrations (morning and evening).
The dose of Virorib® drug depends on the patient's body weight (see. Table 1).
Virorib® should be used in combination with either peginterferon α-2b (1.5 μg / kg / week) or interferon α-2b (3 million CO 3 times a week). The regimen of combined therapy is determined by the physician individually, taking into account the expected effectiveness and safety of the selected combination.
Table 1. The dose of Virorib® (depending on patient body weight) for patients with virus monoinfection hepatitis C or co-infection virus hepatitis C virus and HIV, and regardless of genotype.
Body Weight (kg)
Virorib® daily dose
Quantity of capsules
4 (2 in the morning, 2 in the evening)
5 (2 in the morning, 3 in the evening)
6 (3 in the morning, 3 in the evening)
7 (3 in the morning, 4 in the evening)
Duration of therapy in patients who have not received the treatment before.
Treatment scheme three drugs.
Read the instructions for medical use of boceprevir and peginterferon α-2b.
Treatment scheme two drugs (with peginterferon α-2b).
The prediction of sustained virological response. In patients infected with the hepatitis C virus genotype 1, which did not have a reduction in RNA-HCV levels below the level of detection, or which did not achieve an adequate virological response after 4 or 12 weeks of treatment, the probability of developing a stable virological response is very low, so this patients are advised to discontinue this treatment.
Patients who achieved the absence RNA virus for hepatitis C after 12 weeks of treatment, therapy should be continued next 9 months (48 weeks total).
For patients after 12 weeks of treatment, the level of RNA HCV decreased by ≥ 2 log compared with the initial period, it is necessary to conduct a second evaluation at 24 weeks of treatment and if the level of RNA HCV will be lower than the level of definition, it is necessary to have a full course of treatment (in general 48 weeks). However, if after 24 weeks of treatment, HCV RNA levels would still exceed the determination it is necessary to discontinue the treatment.
For the subgroup of patients with an infection of genotype 1 and low viral load (Genotype 2 or 3. The recommended duration of treatment is 24 weeks for all patients except for patients with concomitant HIV infection whose treatment should be carried out during 48 weeks.
Genotype 4. It is accepted that patients infected with genotype 4 is more difficult to treat; but limited clinical data (n = 66) is revealed similarities in the treatment of these patients and patients with genotype 1.
Duration of therapy in patients co-infected with hepatitis C and HIV who had not previously received treatment.
Treatment scheme two drugs. For patients with concomitant HIV infection is recommended duration of Virorib® treatment in dose, depending on body weight (see. Table 1) is 48 weeks, regardless of genotype.
Prediction of the development or lack of the response in patients with co-infection of the hepatitis C virus and HIV who had not received the treatment before.
Early virological response at 12 weeks of treatment (reduction of virological burden on or 2 log HCV RNA levels below the definition) is a prognostic factor about the development of sustained virological response. In the negative prediction group (patients who have not demonstrated an early virological response) 99% of patients (67 of 68 patients) did not receive sustained virological response while using ribavirin combination therapy with peginterferon α-2b. In the positive prediction group (patients who demonstrated an early virological response) 50% of patients (52 of 104 patients) got constant virological response while using combination therapy.
The duration of treatment with repeated treatment.
Treatment scheme three drugs. Read the instructions for medical use of boceprevir and peginterferon α-2b.
Treatment scheme two drugs (with peginterferon α-2b).
The prediction of sustained virological response. All patients, regardless of viral genotype, which after 12 weeks of treatment decreased HCV RNA levels to below definition, it is necessary to have a 48-week course of treatment. In conducting the re-treatment of patients after 12 weeks of treatment with no virological response (i.e. HCV RNA value is not reduced to a level below the definition), the probability of sustained virological response after 48 weeks of treatment is very low.
For patients with genotype 1 virus who have no reaction to treatment, the appropriateness of re-treatment longer than 48 weeks have not studied during combination therapy of pegylated interferon using α-2b and ribavirin.
Using the drug Virorib® caps in combination with interferon α-2b (only in the treatment scheme with two drugs).
The duration of therapy with the use of interferon α -2b.
Based on clinical studies the recommended duration of treatment is at least 6 months. During the clinical studies in which treatment lasted for 1 year in patients who have not achieved virological response after 6 months of treatment (RNA of hepatitis C virus below the level of detection), the probability of sustained virological response (RNA of hepatitis C virus below the level of detection within 6 months after completion of therapy) was very low.
Genotype 1. For patients who, after 6 months of treatment do not define HCV RNA, it is necessary to continue the treatment for the next 6 months (i.e., generally during 1 year).
Any other genotype. For patients who, after 6 months of treatment do not have HCV RNA, the decision to continue treatment up to 1 year based on other prognostic factors (e.g., patient age> 40 years, male gender, liver bridging fibrosis).
Children (treatment scheme two drugs).
The drug Virorib® applies to children whose weight at least 47 kg and who can swallow caps.
The dosage of the drug Virorib® for children and adolescents is determined by weight, and the dosage of peginterferon α-2b and interferon α-2b is determined by body surface area.
The dosage for children in the combined treatment with peginterferon α-2b.
Virorib® at a dose of 15 mg / kg per day is recommended for use in combination with peginterferon α-2b for subcutaneous introduction at a dose of 60 mcg / m2 per week (table 2).
The dosage for children in the combined treatment with interferon α-2b.
In clinical studies conducted for this group of patients, ribavirin and interferon α-2b used in accordance dosage of 15 mg / kg per day and 3 million CO / m2 3 times a week (table 2).
Table 2.The dosage of the drug Virorib® for children and adolescents based on body weight when used in combination with interferon α-2b or peginterferon α-2b
Patient’s Body Weight (kg)
Virorib® daily dose
Quantity of capsules
3 (1 in the morning, 2 in the evening)
4 (2 in the morning, 2 in the evening)
Corresponding to the dosage for adults ( table 1)
The duration of treatment for children and adolescents.
Genotype 1. The recommended duration of treatment is 1 year. Children and adolescents who are being treated with interferon α-2b (pegylated or nepehilovanym) in combination with the drug Virorib® recommended to discontinue this treatment if after 12 weeks of treatment, the level of RNA of hepatitis C virus reduced to < 2 log10 compared with initial indicator or if in 24 weeks of the treatment still be HCV RNA.
Genotype 2 or 3. The recommended duration of treatment is 24 weeks.
Genotype 4. The recommended duration of treatment is 1 year. Children and adolescents who are being treated peginterferon α-2b in combination with the drug Virorib® recommended to discontinue this treatment if after 12 weeks of treatment, HCV RNA levels decreased to Modification of dose for all patients.
In case of the appearance severe adverse reactions or pathological abnormalities in laboratory values during combination therapy with Virorib® and peginterferon α-2b or interferon α-2b or drug Virorib® peginterferon α-2b and boceprevir dose should be modified (as indicated in table 3) to the disappearance of adverse reactions. Dosage reduction is not recommended. Since compliance with the treatment regimen may be important for the result of the therapy, the dose should be kept as close to the recommended standard dose as possible. The potential negative effect of reducing the dose of ribavirin on efficacy results can not be excluded.
Table 3. Recommendations about the dosage adjustments based on laboratory parameters
Reducing the daily dosage of the drug only Virorib® (see. note 1) if:
Reducing the dosage of peginterferon α-2b or interferon α-2b only (see. note 2) if:
Termination of combined treatment in case of values indicated below: **
Hemaglobulin (adult patients without heart disease)
< 100 GM/DL
< 85 GM/DL
Hemaglobulin (adult patients with a history of heart disease with a stable course).
Hemaglobulin decreased by 20 GM/DL during any 4 weeks during treatment (permanent application of reduced dosage)
< 1,5 × 109/l
< 1,0 × 109/l
< 0,75 × 109/l
< 0,5 ×109/l
< 50 × 109/l (adults)
< 70 × 109/l (children and adolescents)
< 25 × 109/l (adults)
< 50 × 109/l (children and adolescents)
2,5 × ULN *
> 5 mgm
> 4 mgm (adults)
> 5 mgm
(more than 4 weeks) (children and adolescents who are being treated with interferon α-2b) or
> 4 mgm
(more than 4 weeks) (children and adolescents who are being treated peginterferon α-2b)
Creatinin (blood serum)
> 2,0 mgm
Discontinuation of the use of drug Virorib® if creatinine clearance
2 × initial value
> 10 × ULN**
* ULN – upper limit of normal.
** Follow the instructions for medical use of peginterferon α-2b or interferon α-2b concerning the recommendations for changing the dosage and discontinuation using of interferon α-2b and pegylated interferon α-2b.
Note 1. For adult patients, the first time Virorib® reduce the dosage to 200 mg daily (except for patients receiving a dose of 1400 mg; for them the dose should be reduced to 400 mg per day). If it is necessary, the dose should be reduced further to 200 mg per day. Patients who reduced Virorib® dose to 600 mg per day should take 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening.
For children and adolescents who are being treated by drug Virorib® in combination with peginterferon α-2b, for the first time Virorib® reduce the dose to 12 mg / kg per day, and the second time - up to 8 mg / kg per day. For children and adolescents who are being treated by drug Virorib® in combination with interferon α-2b, Virorib® dose should be reduced to 7.5 mg / kg per day.
Note 2. For adult patients who are treated by drug Virorib® in combination with peginterferon α-2b, for the first time dose peginterferon α-2b is reduced to 1 mcg / kg per week. If it is necessary, the dose peginterferon α-2b is reduced to 0.5 mcg / kg per week.
For children and adolescents who are being treated by the drug Virorib® in combination with peginterferon α-2b, for the first time dose peginterferon α-2b is reduced to 40 mcg / m2 per week, and the second time dose peginterferon α-2b is reduced to 20 mcg / m2 per week.
For adults and for children and adolescents who are being treated by the drug Virorib® in combination with interferon α-2b, the dosage interferon α-2b reduced by half.
Special groups of patients.
Use in renal impairment. Due to the decrease in apparent creatinine clearance in patients with renal impairment, the pharmacokinetics of ribavirin in this group of patients varies. Therefore it is recommended to evaluate renal function in all patients before beginning the therapy with Virorib® . Patients with creatinine clearance below 50 ml / min should not be treated by drug Virorib®. Patients with impaired renal function should be thorough overview of anemia. If the concentration of creatinine in blood serum increased to > 2.0 mg / dl (table 3), should discontinue the use of the drug Virorib® and peginterferon α-2b or interferon α-2b.
Use in case of liver dysfunction. Pharmacokinetic impact of ribavirin on liver function were not found. So, for patients with hepatic impairment dose Virorib® modification is not required. The use of ribavirin is contraindicated in severe hepatic dysfunction or decompensated liver cirrhosis.
Use in the elderly patients ( 65 років). There is no obviously addiction ribavirin pharmacokinetics depending on age. However, as in younger patients, it is recommended to evaluate kidney function before beginning the therapy with Virorib® .
Use in age under 18. Virorib® in combination with peginterferon α-2b or interferon α-2b administered to children aged 3 years and adolescents. The choice of treatment scheme depends on the individual characteristics of the patient. Safety and efficacy Virorib® in combination with other forms of interferon (i.e. except α-2b) for this category of patients was not evaluated.
Use in HIV-infection. In patients receiving therapy with nucleoside reverse transcriptase inhibitors in ribavirin combination with peginterferon α-2b or interferon α-2b, may increase the risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation. When prescribing such therapy it is necessary to follow the instructions for medical use of appropriate antiretroviral drugs.
Growth and development (children and adolescents).
During the course of combined treatment with interferon (standard and pegylated) / ribavirin duration of 48 weeks in patients ages 3 to 17 years are often observed weight loss and slowing growth. There is some information about the treatment of long period combination of pegylated interferon / ribavirin confirms a significant slowdown, despite the fact that after treatment discontinuation passed 5 or more years.
Individual assessment of the benefit / risk in children.
The expected benefits in the treatment should be carefully compared with data safety obtained in clinical studies involving children and adolescents.
It is important to consider that the combination therapy induced
growth inhibition, leading to reduced growth rate in some patients.
The risk should be compared with the characteristics of the disease in the child as signs of disease progression (especially fibrosis), concurrent disease that may have negative influence on the disease progression (such as concomitant HIV infection), as well as prognostic factors with respect to virological response (genotype of hepatitis C virus and viral load).
If possible, the child should be the treatment after the adolescence, to reduce the risk of growth retardation. Although the results are limited, no signs of long-term effects on puberty over 5 years of follow-up were observed.
Additional monitoring of thyroid function in children and adolescents.
There is an information, that some children treated by ribavirin and interferon α-2b (pegylated and non-pegylated), there was an increase of TSH and transient decrease in hormone levels (below the lower limit of normal). Before the use of interferon α-2b should determine the level of TSH. If you find any pathology of the thyroid gland it is recommended to be treated with a standard treatment. If the TSH level is able to maintain drug therapy normaly, it is liable to start the treatment with interferon α-2b (pegylated and non-pegylated). There was thyroid dysfunction during treatment with ribavirin and interferon α-2b, as also ribavirin and peginterferon α-2b. Upon detection of pathology of the thyroid gland should determine thyroid status and conduct appropriate treatment. Children and adolescents should monitor thyroid gland function every 3 months (in particular determining TSH level).
Treatment scheme three drugs. (See the instruction for medical use of boceprevir).
Treatment scheme two drugs. The known maximum overdose of ribavirin was 10 g (50 capsules of 200 mg), together with 39 million IU of interferon α-2b in the form of a solution for injection (13 subcutaneous injections of 3 million IU). This amount the patient had for the purpose of suicide during the day. The patient was observed two days in the emergency treatment; during this time, no adverse reactions related to overdose have been noted.
Treatment: withdrawal of the drug, symptomatic therapy.
Infections and infestations: virus infection, influenza, herpes simplex, fungal infection, bacterial infection (including sepsis), respiratory tract infection, lower respiratory tract infection, pharyngitis, bronchitis, pneumonia, rhinitis, sinusitis, otitis media, urinary tract infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): neoplasms uncertain.
Blood and lymphatic system: anemia, hemolytic anemia, aplastic anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia, real erythrocytic aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, lymphadenopathy.
Immune system: drug hypersensitivity, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis, sarcoidosis, rheumatoid arthritis (for the first time or exacerbation) syndrome Vogt-Harada-Koyanahi, systemic lupus erythematosus, vasculitis.
Endocrine system: hypothyroidism, hyperthyroidism.
Metabolic disorders: anorexia, increased appetite, hyperglycemia, diabetes, hyperuricemia, hypocalcemia, dehydration, hypertriglyceridemia.
Psychiatric disorders: depression, apathy, tearfulness, anxiety, emotional lability, aggressive behavior, agitation, anger, mood changes, unusual behavior, nervousness, panic attack, confusion, insomnia, sleep disturbances, unusual dreams, suicidal ideation, suicide, thoughts about murder, suicide attempt, psychosis, hallucinations, mania, bipolar disorder, decreased libido, changes in mental status.
Nervous system: headache, migraine, dizziness, dry mouth, loss of taste, dysgeusia, dysphonia, decreased concentration, amnesia, memory impairment, ataxia, paresthesia, hypesthesia, hyperesthesia, somnolence, deterioration of attention, tremor, neuropathy, peripheral neuropathy, seizures, cerebrovascular hemorrhage, cerebrovascular ischemia, encephalopathy, polyneuropathy, facial palsy, mononeyropatiya.
Visual organ disorders: visual impairment, blurred vision, disturbance of visual acuity, decreased visual acuity or visual field constriction, conjunctivitis, eye irritation, eye pain, disorders of the lacrimal glands, dry eye, hemorrhage in the retina, retinopathy (including macular edema), retinal artery occlusion, retinal vein occlusion, optic neuritis, papillary edema, retinal exudates, serious retinal detachment.
Ear and vestibular apparatus disorders: vertigo, weakening / hearing loss, tinnitus, ear pain.
Cardiac disorders: palpitatsiya, tachycardia, arrhythmia, myocardial infarction, cardiomyopathy, ischemic heart disease, pericardial effusion, pericarditis, hypotension, hypertension, hot flushes, vasculitis, peripheral ischemia.
Respiratory disorders: shortness of breath, nasal congestion, rhinorrhea, nasal bleeding, respiratory failure, cough, stagnation in the respiratory tract, congestion in the sinuses, increased secretion of the upper respiratory tract, sore throat and into the throat, pulmonary infiltrates, pneumonitis, interstitial pneumonitis.
Gastrointestinal disorders: stomatitis, ulcerative stomatitis, sores in the mouth, sore throat, glossitis, cheilitis, gingivitis, bleeding gums, pigmentation of the tongue, dental disorders, disorders of the periodontal, dental disorders, nausea, vomiting, dyspepsia, abdominal pain, pain in the upper quadrant, gastroesophageal reflux, bloating, flatulence, colitis, diarrhea, frequent liquid bowel movements, constipation, colitis, ischemic colitis, ulcerative colitis, pancreatitis.
Hepatobiliary disorders: hepatomegaly, jaundice, hyperbilirubinemia, hepatotoxicity (including fatalities).
Skin and subcutaneous tissue disorders: hair loss, abnormal hair structure, disorders of the nails, itching, dry skin, rash, maculopapular rash, erythematous rash, psoriasis, strengthening psoriasis, eczema, reaction photosensitivity, night sweats, excessive sweating (hyperhidrosis), dermatitis, acne, boil, erythema, urticaria, disorders of the skin, bruising, skin sarcoidosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Musculoskeletal and connective tissue disorders: arthralgia, arthritis, back pain, pain in extremity, bone pain, musculoskeletal pain, myalgia, muscle weakness, rhabdomyolysis, myositis, muscle cramps.
Urinary system disorders: frequent urination, polyuria, abnormal discoloration of urine, renal failure, renal impairment, nephrotic syndrome.
Reproductive system and breast disorders: female: amenorrhea, menorrhagia, irregular menstruation, dysmenorrhea, chest pain, disorders of the ovary, vaginal violations; male: impotence, prostatitis, erectile dysfunction, sexual dysfunction (without adjustment).
General disorders: fatigue, chills, pirexia, flu-like symptoms, asthenia, irritability, chest pain, chest discomfort, peripheral edema, malaise, unusual feeling, thirst, swelling of face.
Test results: weight loss, heart murmur.
Patients with concomitant HIV infection.
In patients with concomitant HIV infection treated with ribavirin in combination with peginterferon α-2b, other adverse reactions (that were not observed in patients with monoinfection hepatitis C) were: oral candidiasis, acquired lipodystrophy, reducing the number of lymphocytes CD4, decrease of appetite, increased levels of gamma glutamyl transferase, back pain, increased amylase levels in the blood, increased levels of lactic acid in the blood, cytolytic hepatitis, increased lipase and pain in the limbs.
In HIV-infected patients who received high-level antiretroviral therapy and complex treatment with ribavirin to eliminate the concomitant infection caused by the hepatitis C virus, cases of mitochondrial toxicity and lactic acidosis were noted.
Laboratory findings in patients with concomitant HIV infection.
In patients with concomitant HIV infection there are often signs of hematologic toxicity as neutropenia, thrombocytopenia and anemia, but in most cases these violations disappeared when changing the dose, and did not require early termination of treatment. Hematologic abuse often occurred in patients receiving ribavirin in combination with peginterferon α-2b, compared to patients receiving ribavirin in combination with interferon α-2b.
Reducing the quantity of lymphocytes CD4.
Ribavirin treatment in combination with peginterferon α-2b for the first 4 weeks was accompanied by a decrease in the absolute number of cells CD4 +, but the percentage of CD4 + cells were not changed. This decrease in the absolute number of CD4 + cells was reversible after dose reduction or discontinuation. The use of ribavirin in combination with peginterferon α-2b was not accompanied by a noticeable negative impact on the control of HIV viremia during the treatment period or follow-up observations Safety data for patients with concomitant HIV infection with CD4 Children.
The profile of adverse reactions in children is basically similar to that in adult patients, but some side effects are child-specific and are related to weight loss and growth retardation, the reversibility of which is unknown. The degree of decline in growth was greatest in prepubertal children.
Infections and invasions: viral infection, influenza, oral herpes, herpes simplex, shingles, bacterial infection, fungal infection, pulmonary infection, nasopharyngitis, pharyngitis, streptococcal pharyngitis, otitis media, pneumonia, sinusitis, abscess tooth, urinary tract infection, vaginitis, cellulite, ascariasis, enterobiosis.
Neoplasms benign, malignant and unspecified (including cysts and polyps): neoplasms uncertain.
Blood and lymphatic system disorders: anemia, neutropenia, thrombocytopenia, lymphadenopathy.
Endocrine system: hypothyroidism, hyperthyroidism, virilism.
Metabolic disorder: anorexia, increased appetite, decreased appetite, hypertriglyceridemia, hyperuricemia.
Psychiatric disorders: depression, insomnia, emotional lability, suicidal ideation, suicidal thoughts, suicide attempts, aggression, confusion, a tendency to affect, changes in behavior, agitation, somnambulism, anxiety, mood swings, anxiety, nervousness, insomnia, unusual dreams, apathy, unusual behavior, depressive mood, emotional frustration, fear, nightmares, anger.
Nervous system: headache, dizziness, hyperkinesia, tremor, dysphonia, paresthesia, hypesthesia, hyperesthesia, decreased concentration, drowsiness, deterioration of attention, poor quality sleep, neuralgia, lethargy, psychomotor hyperactivity.
Sense of vision disorders: conjunctivitis, eye pain, abnormal vision, disorders of the lacrimal glands, hemorrhages in the conjunctiva, eye pruritus, keratitis, blurred vision, photophobia, serous retinal detachment.
Auditory organ disorders: vertigo.
Cardiovascular system disorders: tachycardia, palpitation, pale, hot flashes, hypotension.
Respiratory system disorders: shortness of breath, tachypnea, nose bleeding, cough, nasal congestion, nasal irritation, rhinorrhea, sneezing, sore pharynx and sore throat, difficult breathing, nasal discomfort.
Digestive tract disorders: abdominal pain, pain in the upper abdomen, vomiting, diarrhea, nausea, ulcers in the mouth, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorders, gastrointestinal disorders, constipation, frequent liquid stools, toothache, disorders of the teeth, stomach discomfort, sore mouth, gingivitis, gastroenteritis.
Hepatobiliary system disorders: liver dysfunction, hepatomegaly.
Skin disorders: alopecia, rash, pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, disorders of the skin, disorders of the nails, skin discoloration, dry skin, erythema, bruise, pigmentation, atopic dermatitis, skin exfoliation.
Musculoskeletal system disorders: arthralgia, myalgia, musculoskeletal pain, pain in extremity, back pain, muscle contracture.
Urinary system disorders: enuresis, urination disorders, urinary incontinence, proteinuria.
Reproductive system disorders: female: amenorrhea, menorrhagia, menstrual disorders, vaginal disorders, dysmenorrhea; male: pain in the testes (testicles).
Systemic disturbance: fatigue, increased fatigue, chills, pyrexia, flu-like symptoms, fatigue, asthenia, malaise, irritability, chest pain, swelling, feeling cold, chest discomfort, pain face.
Test results: reducing the growth rate (educed growth and / or body weight for a given age), an increase of TSG (thyroid stimulating hormone hormone) in the blood, increased level of thyroglobulin, presence of antithyroid antibodies.
Injuries, poisoning and procedural complications: slaughter, scratches on the skin.
Store in the original pack at a temperature NMT 25°C.
Keep it out of reach of children.
10 capsules are in a blister or strip; 10 blisters or strips are in a carton pack № 100 (10 x 10).
Conditions of supply.
“KUSUM PHARM” LLC.
54 Skryabina St., Sumy 40020, Ukraine.
Last revision date.