Virorib

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VİRORİBÒ (VIRORIBÒ)

Composition:

Active substance: ribavirin;

1 capsule contains ribavirin 200 mg;

Excipients: lactose monohydrate, sodium croscarmellose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide;

hard gelatin capsule: gelatin, purified water, patent blue V (E 131), carmoisine (E 122), titanium dioxide (E 171), ponceau 4R (E 124), yellow FCF (E 110).

Pharmaceutical form. Capsules.

Main physicochemical properties: capsules with pink-colored body and violet-colored cap, containing white powder.

Pharmacotherapeutic group.

Direct-acting antiviral agents. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. ATC code J05AB04.

Pharmacological Properties

Pharmacodynamics

Ribavirin is a synthetic nucleoside analogue with in vitro activity against certain RNA and DNA viruses. The mechanism by which ribavirin in combination with peginterferon α-2b or interferon α-2b affects hepatitis C virus is unknown. Monotherapy with ribavirin for chronic hepatitis C does not lead to viral elimination (hepatitis C virus RNA) or improvement in liver histology after 6–12 months of treatment and during the subsequent 6-month follow-up period. However, in clinical trials, the combination of ribavirin with peginterferon α-2b or interferon α-2b resulted in an increased treatment response rate compared to monotherapy with peginterferon α-2b or interferon α-2b.

Pharmacokinetics

Ribavirin is readily absorbed after single oral administration (Tmax = 1.5 hours) and rapidly distributed throughout the body. The elimination phase is relatively prolonged. The half-lives of absorption, distribution, and elimination after a single dose are 0.05, 3.73, and 79 hours, respectively. Ribavirin is extensively absorbed; only about 10% of a radiolabeled dose is excreted in feces. However, absolute bioavailability is approximately 45–65%, possibly due to first-pass metabolism. There is a linear relationship between dose and bioavailability index (AUCtf) following single doses of ribavirin ranging from 200 mg to 1,200 mg. The volume of distribution is approximately 5000 L. Ribavirin does not bind to plasma proteins.

Non-plasma-mediated transport of ribavirin has been studied in detail with respect to erythrocytes; it has been shown that transport generally occurs via an equilibrative nucleoside transporter of the es type. This transporter type is present in almost all cell types and may contribute to the large volume of distribution of ribavirin. The ratio of ribavirin concentration in whole blood to plasma is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides isolated within erythrocytes.

Ribavirin is metabolized via two pathways: reversible phosphorylation and degradative transformation involving de-ribosylation and amide hydrolysis, resulting in the formation of a triazole carboxylic acid metabolite. Ribavirin itself and its metabolites—triazolecarboxamide and triazolecarboxylic acid—are excreted in urine.

High pharmacokinetic variability of ribavirin has been demonstrated after single oral administration both within an individual patient and among different patients (intra-individual variability of AUC and Cmax values is approximately 30%), which may be explained by extensive first-pass metabolism and significant transport within and beyond the bloodstream.

With repeated administration, ribavirin extensively accumulates in plasma; the ratio of bioavailability indices (AUC12h) after repeated versus single dosing is 6. With oral administration (600 mg twice daily), steady-state plasma concentrations of ribavirin are reached by the end of week 4, amounting to approximately 2.2 ng/mL. After discontinuation, the elimination half-life is approximately 298 hours, suggesting slow elimination from extraplasma compartments.

Ability to penetrate seminal fluid. The ability of ribavirin to penetrate into seminal fluid has been studied. Ribavirin concentrations in seminal fluid are approximately twice higher than in blood serum. However, systemic exposure of ribavirin in a female partner after sexual contact with a man receiving treatment remains extremely limited compared to therapeutic plasma concentrations of ribavirin.

Effect of food. The bioavailability of a single oral dose of ribavirin increases when administered with a high-fat meal (both AUCtf and Cmax increase by 70%). This increased bioavailability may be due to slower transit or altered pH.

Renal function. In patients with renal impairment, the pharmacokinetics of ribavirin after single administration are altered (AUCtf and Cmax values increase) compared to controls (creatinine clearance > 90 mL/min). This change is primarily due to reduced actual clearance in these patients. Ribavirin concentrations do not undergo significant changes during hemodialysis.

Hepatic function. The pharmacokinetics of ribavirin after single-dose administration in patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, or C) are similar to those in healthy volunteers in the control group.

Elderly patients (≥ 65 years). No specific pharmacokinetic studies were conducted in elderly patients. However, in conducted studies, age was not a major factor influencing ribavirin kinetics; the primary influencing factor is renal function.

Children.

The pharmacokinetics of ribavirin in combination with peginterferon α-2b or interferon α-2b (dose-normalized) were not different between adults and children aged 5 to 16 years.

Clinical characteristics.

Indications.

Triple therapy.

Virorib® in combination with boceprevir and peginterferon α-2b is indicated for the treatment of chronic hepatitis C (genotype 1) in adult patients (aged 18 years and older) with compensated liver disease who have not previously been treated, or in whom prior treatment was ineffective.

Instructions for use of peginterferon α-2b and boceprevir should be consulted when Virorib® is used in combination with these agents.

Dual therapy.

Virorib® is indicated for the treatment of chronic hepatitis C in adults, adolescents, and children aged 3 years and older; the drug should be used only in combination with peginterferon α-2b or interferon α-2b. Virorib® must not be used as monotherapy.

Instructions for use of peginterferon α-2b or interferon α-2b should be consulted when Virorib® is used in combination with these agents.

There is no information on the safety or efficacy of using Virorib® with other forms of interferon (i.e., other than α-2b).

Patients who have not previously been treated.

Adults (aged 18 years and older).

Virorib® is indicated:

• in triple therapy regimen: in combination with peginterferon α-2b and boceprevir for the treatment of chronic hepatitis C (genotype 1) in adult patients with compensated liver disease;
• in dual therapy regimen: in combination with interferon α-2b or peginterferon α-2b for the treatment of chronic hepatitis C in treatment-naïve adult patients (in the absence of liver decompensation, with elevated ALT levels, and positive hepatitis C virus RNA test (HCV RNA));
• in dual therapy regimen: in combination with peginterferon α-2b for the treatment of chronic hepatitis C in patients with compensated cirrhosis and/or clinically stable concomitant HIV infection.

Dual therapy.

Children aged 3 years and older, adolescents.

Virorib® is indicated in combination with peginterferon α-2b or interferon α-2b for the treatment of chronic hepatitis C in children aged 3 years and older and in adolescents who have not previously been treated, in the absence of liver decompensation and in the presence of hepatitis C virus RNA.

If deferring treatment until adulthood is being considered, it should be remembered that combination therapy may induce growth retardation, which may be irreversible in some patients. The decision on treatment should be made individually for each patient.

Patients who have previously been treated.

Adults.

Virorib® is indicated:

• in triple therapy regimen: in combination with peginterferon α-2b and boceprevir for the treatment of chronic hepatitis C (genotype 1) in adult patients with compensated liver disease;
• in dual therapy regimen: in combination with peginterferon α-2b for the treatment of chronic hepatitis C in cases where prior treatment with α-interferon alone (pegylated or non-pegylated) or its combination with ribavirin was ineffective;
• in dual therapy regimen: in combination with interferon α-2b for the treatment of chronic hepatitis C in cases where prior monotherapy with α-interferon was initially effective (normalization of ALT by the end of treatment) but was followed by relapse.

Contraindications.

Hypersensitivity to ribavirin or to any other component of the medicinal product.

Pregnancy. Treatment must not be initiated unless a negative pregnancy test result has been obtained immediately prior to starting therapy.

Men whose female partners are pregnant.

Breastfeeding period.

Severe cardiac diseases, including unstable or uncontrolled forms observed within 6 months prior to the start of treatment.

Severe debilitating diseases.

Chronic renal failure or creatinine clearance < 50 mL/min and/or conditions requiring hemodialysis.

Severe hepatic impairment (Child-Pugh class B or C) or decompensated cirrhosis.

Hemoglobinopathies (e.g., thalassemia, sickle cell anemia).

Peginterferon α-2b is contraindicated in patients co-infected with hepatitis C virus/HIV with liver cirrhosis and hepatic function impairment ≥ 6 points on the Child-Pugh classification.

History or clinical evidence of severe psychiatric disorders, including severe depression, suicidal ideation, or suicide attempt in children and adolescents.

History of autoimmune hepatitis or other autoimmune diseases (due to combination with peginterferon α-2b or interferon α-2b).

Interaction with other medicinal products and other forms of interaction.

Interaction studies were conducted only in adult patients.

In vitro studies using human liver microsomal preparations indicate that cytochrome P450 enzymes are not involved in the metabolic transformations of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. Toxicological testing provides no basis to assume that ribavirin stimulates hepatic enzyme activity. Therefore, the likelihood of interaction with cytochrome P450 is minimal.

By inhibiting inosine monophosphate dehydrogenase, ribavirin may affect the metabolism of azathioprine, leading to accumulation of 6-methylthioinosine monophosphate, which is associated with myelotoxicity in patients receiving azathioprine. Concomitant use of pegylated α-interferon and ribavirin with azathioprine should be avoided. In individual cases where the benefit of using ribavirin concomitantly with azathioprine outweighs the potential risk, frequent hematological monitoring is recommended during concomitant administration to detect signs of myelotoxicity, and if such signs occur, the use of these agents should be discontinued.

No studies on interactions between ribavirin and other medicinal products have been conducted, except with peginterferon α-2b, interferon α-2b, and antacids.

Interferon α-2b. Pharmacokinetic studies using multiple doses showed no pharmacokinetic interactions between ribavirin and peginterferon α-2b or interferon α-2b.

Antacids. The bioavailability of ribavirin 600 mg was reduced when co-administered with an antacid containing magnesium and aluminum compounds or simethicone; the AUCtf decreased by 14%. The reduction in bioavailability in this study may have been due to delayed transport of ribavirin or changes in pH. This interaction is considered not to be clinically significant.

Nucleoside analogs. The use of nucleoside analogs alone or in combination with other nucleosides may lead to lactic acidosis. Ribavirin in vitro increases the levels of phosphorylated metabolites of purine nucleosides. This effect may potentiate the risk of lactic acidosis caused 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), some of which were fatal, have been reported.

Exacerbation of ribavirin-induced anemia has been reported when zidovudine was used as part of an HIV treatment regimen, although the exact mechanism has not yet been elucidated. Due to the increased risk of anemia, ribavirin is not recommended for concomitant use with zidovudine. The concomitant regimen of zidovudine and ribavirin should be reviewed in the context of highly active antiretroviral therapy (HAART) if anemia occurs. This is particularly important for patients who have previously experienced anemia during zidovudine use.

The potential for interaction with ribavirin persists for 2 months (5 half-lives of ribavirin) after discontinuation of the drug due to its long elimination half-life.

No interaction between ribavirin and non-nucleoside reverse transcriptase inhibitors or protease inhibitors has been observed.

Published data on the concomitant use of abacavir and ribavirin are conflicting. Some data suggest a risk of reduced response to pegylated interferon/ribavirin treatment in patients co-infected with hepatitis C virus and HIV who are receiving abacavir as part of antiretroviral therapy. Precautions should be taken when using these drugs concomitantly.

Special precautions for use.

Psychiatric disorders and central nervous system (CNS) disorders. In some patients, severe CNS disorders including depression, suicidal ideation, and suicide attempts have been reported during combination therapy with ribavirin and peginterferon α-2b or interferon α-2b, as well as during the 6-month observation period after discontinuation of such treatment. Suicidal ideation or suicide attempts during treatment and the 6-month post-treatment observation period occurred more frequently in children and adolescents treated with ribavirin in combination with interferon α-2b than in adult patients (2.4% compared to 1%). In children and adolescents, as in adults, other psychiatric disorders (e.g., depression, emotional lability, and somnolence) occurred. Other CNS disorders observed with α-interferons include aggressive behavior (sometimes directed toward others, e.g., homicidal ideation), bipolar disorder, mania, confusion, and mental status changes.

Patients must be carefully monitored for any signs or symptoms of psychiatric disorders. If such symptoms occur, the prescribing physician should assess the potential severity of these adverse effects and the need for appropriate treatment. If psychiatric symptoms do not resolve or worsen, or if suicidal or homicidal ideation occurs, discontinuation of treatment with ViroRib® in combination with peginterferon α-2b or interferon α-2b is recommended, and appropriate psychiatric assistance should be provided if necessary.

Patients with a history of or clinical manifestations of severe psychiatric disorders. If combination therapy with ViroRib® and peginterferon α-2b or interferon α-2b is deemed necessary for adult patients with clinical or historical evidence of severe psychiatric disorders, treatment should be initiated only after appropriate individual assessment and concomitant psychiatric management.

The use of ViroRib® and peginterferon α-2b or interferon α-2b for the treatment of children and adolescents with clinical or historical evidence of severe psychiatric disorders is contraindicated.

Patients who use/abuse psychoactive substances. Patients with hepatitis C virus infection who concurrently use psychoactive substances (including alcohol, marijuana) have a high risk of developing psychiatric disorders or exacerbation of existing psychiatric conditions during α-interferon therapy. If α-interferon therapy is necessary for such patients, the presence of psychiatric comorbidities and the potential for substance use should be carefully evaluated, and appropriate measures taken before initiating therapy. A multidisciplinary approach, including a psychologist or addiction specialist, should be considered if necessary (for assessment, treatment, and ongoing monitoring). Patients should be closely monitored during and after therapy. Early intervention for recurrence or development of psychiatric disorders and psychoactive substance use is recommended.

Hemolysis. Clinical data show decreased hemoglobin levels (< 10 g/dL) in adult patients and in children and adolescents treated with ribavirin in combination with peginterferon α-2b or interferon α-2b. Although ribavirin has no direct effect on the cardiovascular system, anemia associated with ribavirin use may affect cardiac function and/or exacerbate symptoms of coronary artery disease. Therefore, ViroRib® should be used with caution in patients with cardiac disease. Cardiovascular status should be evaluated before initiating treatment and during therapy. Therapy should be discontinued if any signs of worsening cardiovascular status occur.

Cardiovascular system. Adult patients with a history of congestive heart failure, myocardial infarction, and/or arrhythmia should be under continuous medical supervision. Electrocardiography is recommended before and during treatment for patients with cardiac disease. Arrhythmias (mainly supraventricular) are usually manageable with standard therapy but may require discontinuation of treatment. There are no data on the use of combination therapy in children and adolescents with a history of cardiovascular disease.

Immediate-type hypersensitivity. If an acute hypersensitivity reaction occurs (e.g., urticaria, angioedema, bronchospasm, anaphylaxis), ViroRib® should be discontinued immediately and appropriate treatment initiated. Transient rashes are not a reason to discontinue therapy.

Ophthalmological changes. Ribavirin is used in combination with α-interferons. Rare cases of retinopathy, including retinal hemorrhage, retinal exudates, papilledema, optic neuritis, and retinal artery or vein occlusion, which may lead to visual impairment, have been reported during combination therapy with α-interferons. All patients should undergo ophthalmological examination before starting treatment. Any patient who develops signs of eye disease or visual disturbances should undergo immediate and complete ophthalmological evaluation. Patients with pre-existing ophthalmological disorders (e.g., diabetic or hypertensive retinopathy) should undergo periodic ophthalmological examinations during combination therapy with α-interferons. Combination therapy with α-interferons should be discontinued in patients who develop new or worsening ophthalmological disorders.

Liver function. All patients who show signs of significant worsening of liver function during treatment should be closely monitored. Therapy should be discontinued in patients who develop prolonged coagulation times, which may indicate hepatic decompensation.

Potential for enhanced immunosuppression. Cases of pancytopenia and bone marrow suppression have been reported 3–7 weeks after concomitant use of peginterferon and ribavirin with azathioprine. This myelotoxicity resolved within 4–6 weeks after discontinuation of both hepatitis C antiviral therapy and azathioprine, and did not recur upon subsequent individual re-administration of either drug.

HIV and hepatitis C virus co-infection.

Mitochondrial toxicity and lactic acidosis. Caution is required in HIV-infected patients with concomitant hepatitis C virus infection who are receiving nucleoside reverse transcriptase inhibitors (particularly didanosine and stavudine) in combination with ribavirin and interferon α-2b. Physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitors during ribavirin therapy. Ribavirin is not recommended for use with didanosine and stavudine due to the risk of mitochondrial toxicity and to avoid potential additive mitochondrial toxicity.

Hepatic decompensation in patients with HIV and hepatitis C virus co-infection and progressive cirrhosis. In patients with concomitant HIV infection and progressive cirrhosis receiving antiretroviral therapy (ART), the risk of hepatic decompensation and fatal outcome may increase. Additional use of α-interferons alone or in combination with ribavirin further increases this risk in such patients. Other baseline factors in co-infected patients that may increase the risk of hepatic decompensation include treatment with didanosine and elevated serum bilirubin levels. Close monitoring and assessment of liver function using the Child-Pugh classification are required in co-infected patients receiving both antiretroviral and anti-hepatitis therapy. Hepatitis treatment should be discontinued immediately if hepatic decompensation occurs, and the antiretroviral regimen should be re-evaluated.

Hematological disorders in patients with HIV and hepatitis C virus co-infection. In co-infected patients receiving ART and ribavirin in combination with peginterferon α-2b, the risk of hematological disorders (e.g., neutropenia, thrombocytopenia, and anemia) may be increased compared to patients with hepatitis C virus infection alone. Most such disorders resolve with dose reduction, but careful monitoring of hematological parameters is required. The risk of anemia is increased in patients treated with ribavirin and zidovudine; therefore, ribavirin is not recommended for use with zidovudine.

Patients with reduced CD4 cell counts. Data on the efficacy and safety of treatment in patients co-infected with HIV and hepatitis C virus with CD4 cell counts < 200/μL are limited. Treatment of patients with low CD4 cell counts should be conducted with caution.

The prescribing information for the respective antiretroviral drugs used concomitantly with hepatitis C virus treatment agents should be followed (for information on the toxicity of each drug and potential increased toxicity when ribavirin and peginterferon α-2b are used together).

Dental and periodontal disorders. Dental and periodontal disorders (which may lead to tooth loss) have been reported in patients receiving combination therapy with ribavirin and peginterferon α-2b or interferon α-2b. In addition, dry mouth may adversely affect teeth and oral mucosa during long-term combination therapy with ribavirin and peginterferon α-2b or interferon α-2b. Patients should be advised to brush their teeth thoroughly twice daily and undergo regular dental examinations. Furthermore, vomiting may occur in some patients, after which they should thoroughly rinse their mouth.

Laboratory tests. All patients should undergo a complete blood count (CBC with differential) and biochemical blood tests (electrolytes, serum creatinine, liver function tests, uric acid) before starting therapy. The following baseline blood values are acceptable before initiating combination therapy:

• Hemoglobin: ≥ 120 g/L (women) and ≥ 130 g/L (men);
  Children and adolescents: ≥ 110 g/L (girls) and ≥ 120 g/L (boys);
• Platelets: ≥ 100 × 10⁹/L;
• Neutrophils: ≥ 1.5 × 10⁹/L.

Laboratory tests should be performed at weeks 2 and 4 of treatment and thereafter as clinically indicated. HCV RNA levels should be monitored periodically during therapy.

Women of childbearing potential. Women undergoing treatment and female sexual partners of men undergoing treatment must perform monthly pregnancy tests throughout the treatment period and for 4 months and 7 months, respectively, after completion of treatment, as ribavirin is contraindicated in pregnancy.

Ribavirin may increase serum uric acid concentration due to hemolysis of erythrocytes; therefore, patients predisposed to this condition should be closely monitored for signs of gout.

Excipients.

The product contains lactose. Patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

The product contains Ponceau 4R (E 124), Sunset Yellow FCF (E 110), and Carmoisine (E 122), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy. The use of ViroRib® is contraindicated during pregnancy.

Breastfeeding. It is unknown whether ribavirin is excreted in human breast milk. Due to the potential for adverse reactions in the infant, breastfeeding must be discontinued before starting treatment.

Women of childbearing potential/contraception in men and women.

Women (patients). ViroRib® must not be used during pregnancy. To prevent pregnancy, patients must use effective contraception. Therapy should not be initiated until a negative pregnancy test result is obtained. Women of childbearing potential and their sexual partners must use effective contraceptive methods during treatment and for 9 months after completion of treatment; monthly standard pregnancy tests should be performed during this period. If a woman becomes pregnant during treatment or within 9 months after completion of treatment, she should be informed of the significant teratogenic risk of ribavirin to the fetus.

Men (patients) and their partners. Effective contraception must be used to prevent pregnancy in female partners of men treated with ViroRib®. Ribavirin accumulates in cells and is eliminated very slowly from the body. The potential teratogenic or genotoxic effect of ribavirin present in semen on the embryo/fetus remains unknown. Although prospective monitoring of approximately 300 pregnancies with paternal exposure to ribavirin did not reveal an increased risk of congenital malformations compared to the general population or any specific pattern, men (patients) and their sexual partners of reproductive age should use an effective method of contraception during ribavirin treatment and for 6 months after its completion. Monthly standard pregnancy tests should be performed during this period. Men whose partners are pregnant should be informed of the need to use condoms to minimize the transfer of ribavirin into the woman's body.

Ability to affect reaction rate when driving or operating machinery.

Ribavirin has no effect or only a negligible effect on the ability to drive or operate machinery; however, this ability may be altered when ribavirin is used in combination with peginterferon α-2b or interferon α-2b. Therefore, patients who experience fatigue, somnolence, or confusion during treatment are advised to avoid driving or operating machinery.

Method of administration and dosage.

Treatment should be administered by a physician experienced in managing patients with hepatitis C.

VIRORIB® must be used in combination either with peginterferon α-2b or with interferon α-2b (dual-drug regimen), or in adult patients with chronic hepatitis C (genotype 1) — in combination with boceprevir and peginterferon α-2b (triple-drug regimen).

When prescribing combination therapy, the respective package leaflets for boceprevir, peginterferon α-2b, and interferon α-2b should also be consulted.

Dosage.

The dose of VIRORIB® depends on the patient's body weight. VIRORIB®, capsules, should be taken orally with food, daily, in two divided doses (morning and evening).

Adult patients.

The dose of VIRORIB® depends on the patient's body weight (see Table 1).

VIRORIB® must be used in combination with either peginterferon α-2b (1.5 mcg/kg/week) or interferon α-2b (3 million IU three times weekly). The combination regimen should be determined individually by the physician, taking into account the expected efficacy and safety of the chosen combination.

Table 1. Dose of VIRORIB® (according to body weight) for patients with hepatitis C monoinfection or hepatitis C/HIV co-infection, regardless of genotype.

Duration of therapy in patients who have not previously received treatment.

Three-drug treatment regimen.

Refer to the prescribing information for boceprevir and peginterferon α-2b.

Two-drug treatment regimen (with peginterferon α-2b).

Prediction of sustained virological response. In patients infected with hepatitis C virus (HCV) genotype 1 in whom HCV RNA levels have not decreased below the lower limit of detection, or in whom an adequate virological response has not been achieved after 4 or 12 weeks of treatment, the likelihood of achieving a sustained virological response is very low; therefore, such patients should discontinue this therapy.

Genotype 1.

In patients in whom HCV RNA becomes undetectable after 12 weeks of treatment, therapy should be continued for an additional 9 months (total of 48 weeks).

For patients in whom HCV RNA levels decrease by ≥ 2 log compared to baseline after 12 weeks of treatment, a repeat assessment should be performed at week 24 of treatment. If HCV RNA remains below the lower limit of detection at week 24, a full course of treatment should be completed (i.e., total of 48 weeks). However, if HCV RNA remains above the lower limit of detection at week 24, treatment should be discontinued.

For a subgroup of patients infected with genotype 1 and low viral load (< 600,000 IU/mL), in whom HCV RNA is undetectable after 4 weeks of treatment and remains undetectable at week 24, treatment may either be discontinued after these 24 weeks or continued for an additional 24 weeks (i.e., total treatment duration of 48 weeks). However, with a total treatment duration of 24 weeks, the risk of relapse may be increased compared to a 48-week treatment duration.

Genotype 2 or 3. The recommended duration of treatment is 24 weeks for all patients, except for patients with concomitant HIV infection, who should be treated for 48 weeks.

Genotype 4. Patients infected with genotype 4 are considered more difficult to treat; however, limited clinical data (n = 66) have shown similarities in treatment outcomes between these patients and those infected with genotype 1.

Duration of therapy in patients co-infected with hepatitis C virus and HIV who have not previously received treatment.

Two-drug treatment regimen. For patients with concomitant HIV infection, the recommended duration of treatment with Virorib® at a body weight-dependent dose (see Table 1) is 48 weeks regardless of genotype.

Prediction of response or non-response in treatment-naïve patients co-infected with hepatitis C virus and HIV.

An early virological response at week 12 of treatment (a decrease in viral load by 2 log or HCV RNA below the lower limit of detection) is a predictive factor for achieving a sustained virological response. In the negative predictive group (patients who did not demonstrate an early virological response), 99% of patients (67 out of 68) did not achieve a sustained virological response when treated with combination therapy of ribavirin and peginterferon α-2b. In the positive predictive group (patients who demonstrated an early virological response), 50% of patients (52 out of 104) achieved a sustained virological response with combination therapy.

Duration of treatment in retreatment.

Three-drug treatment regimen. Refer to the prescribing information for boceprevir and peginterferon α-2b.

Two-drug treatment regimen (with peginterferon α-2b).

Prediction of sustained virological response. All patients, regardless of genotype, in whom HCV RNA becomes undetectable after 12 weeks of treatment, should complete a 48-week course of therapy. In retreatment, for patients in whom there is no virological response after 12 weeks of treatment (i.e., HCV RNA has not decreased below the lower limit of detection), the likelihood of achieving a sustained virological response after 48 weeks of treatment is very low.

For patients infected with genotype 1 who did not respond to prior treatment, the benefit of retreatment for longer than 48 weeks has not been studied with combination therapy using pegylated interferon α-2b and ribavirin.

Use of Virorib®, capsules, in combination with interferon α-2b (only in the two-drug treatment regimen).

Duration of therapy with interferon α-2b.

Based on clinical trial results, the recommended duration of treatment is at least 6 months. In clinical trials where treatment lasted for 1 year, patients who did not achieve a virological response after 6 months of treatment (HCV RNA below the limit of detection) had a very low probability of achieving a sustained virological response (HCV RNA below the limit of detection for 6 months after the end of therapy).

Genotype 1. For patients in whom HCV RNA is undetectable after 6 months of treatment, therapy should be continued for an additional 6 months (i.e., total of 1 year).

Any other genotype. For patients in whom HCV RNA is undetectable after 6 months of treatment, the decision to continue therapy up to 1 year should be based on other prognostic factors (e.g., patient age > 40 years, male sex, bridging liver fibrosis).

Children (two-drug treatment regimen).

Virorib® may be used in children with a body weight of at least 47 kg who are able to swallow capsules.

The dose of Virorib® for children and adolescents should be based on body weight, while the dose of peginterferon α-2b and interferon α-2b should be based on body surface area.

Dosage for children in combination therapy with peginterferon α-2b.

Virorib® at a dose of 15 mg/kg/day is recommended in combination with peginterferon α-2b for subcutaneous administration at a dose of 60 μg/m² weekly (Table 2).

Dosage for children in combination therapy with interferon α-2b.

In clinical trials conducted in this patient group, ribavirin and interferon α-2b were administered at doses of 15 mg/kg/day and 3 million IU/m² three times per week, respectively (Table 2).

Table 2. Dose of Virorib® for children and adolescents according to body weight when used in combination with interferon α-2b or peginterferon α-2b

Duration of treatment in children and adolescents.

Genotype 1. The recommended duration of treatment is 1 year. Children and adolescents receiving treatment with interferon α-2b (pegylated or non-pegylated) in combination with Virorib® should discontinue such treatment if HCV RNA levels have decreased by < 2 log₁₀ compared to baseline after 12 weeks of treatment, or if HCV RNA is still detectable after 24 weeks of treatment.

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 receiving treatment with peginterferon α-2b in combination with Virorib® should discontinue such treatment if HCV RNA levels have decreased by < 2 log₁₀ compared to baseline after 12 weeks of treatment, or if HCV RNA is still detectable after 24 weeks of treatment.

Dose modification for all patients.

Combination therapy.

In the event of severe adverse reactions or significant laboratory abnormalities during combination therapy with Virorib® and peginterferon α-2b or interferon α-2b, or with Virorib®, peginterferon α-2b, and boceprevir, dose modifications (as indicated in Table 3) should be implemented until adverse reactions resolve. Dose reduction of boceprevir is not recommended. Since adherence to the treatment regimen may be important for treatment outcome, the dose should be maintained as close as possible to the recommended standard dose. A potential negative impact of ribavirin dose reduction on efficacy outcomes cannot be excluded.

Table 3. Recommendations for dose adjustment based on laboratory parameters

* ULN – upper limit of normal.

** Dose modification and discontinuation recommendations for interferon α-2b and pegylated interferon α-2b should follow the instructions for medical use of peginterferon α-2b or interferon α-2b.

Note 1. For adult patients, the dose of Virorib® should initially be reduced by 200 mg daily (except for patients receiving a dose of 1400 mg, for whom the dose should be reduced by 400 mg daily). If necessary, the dose should be further reduced by 200 mg daily. Patients whose dose of Virorib® has been reduced to 600 mg daily should take 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening.

For children and adolescents receiving Virorib® in combination with peginterferon α-2b, the dose of Virorib® should initially be reduced to 12 mg/kg daily, and then to 8 mg/kg daily. For children and adolescents receiving Virorib® in combination with interferon α-2b, the dose of Virorib® should be reduced to 7.5 mg/kg daily.

Note 2. For adult patients receiving Virorib® in combination with peginterferon α-2b, the dose of peginterferon α-2b should initially be reduced to 1 μg/kg weekly. If necessary, the dose of peginterferon α-2b should be further reduced to 0.5 μg/kg weekly.

For children and adolescents receiving Virorib® in combination with peginterferon α-2b, the dose of peginterferon α-2b should initially be reduced to 40 μg/m² weekly, and then to 20 μg/m² weekly.

For adult patients, as well as for children and adolescents receiving Virorib® in combination with interferon α-2b, the dose of interferon α-2b should be halved.

Specific patient groups.

Use in renal impairment. Due to reduced creatinine clearance in patients with impaired renal function, the pharmacokinetics of ribavirin is altered in such patients. Therefore, renal function should be assessed in all patients prior to initiating therapy with Virorib®. Virorib® is not recommended for patients with creatinine clearance below 50 mL/min. Patients with renal impairment should be closely monitored for the development of anemia. If serum creatinine concentration increases to > 2.0 mg/dL (Table 3), treatment with Virorib® and peginterferon α-2b or interferon α-2b should be discontinued.

Use in hepatic impairment. No pharmacokinetic effect of ribavirin on liver function has been observed. Therefore, dose adjustment of Virorib® is not required in patients with impaired liver function. Ribavirin is contraindicated in patients with severe hepatic dysfunction or decompensated cirrhosis.

Use in elderly patients (≥ 65 years of age). There is no clear age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function should be evaluated prior to initiating therapy with Virorib®.

Use in patients under 18 years of age. Virorib® in combination with peginterferon α-2b or interferon α-2b is indicated for children aged 3 years and older and adolescents. The choice of treatment regimen depends on individual patient characteristics. The safety and efficacy of Virorib® in combination with other forms of interferon (i.e., other than α-2b) have not been evaluated in this patient population.

Use in patients with concomitant HIV infection. In patients receiving nucleoside reverse transcriptase inhibitors in combination with ribavirin plus peginterferon α-2b or interferon α-2b, there may be an increased risk of mitochondrial toxicity, lactic acidosis, and hepatic failure. When prescribing such therapy, the instructions for medical use of the respective antiretroviral agents should also be followed.

Children.

Growth and development (children and adolescents).

During 48-week combination therapy with interferon (standard and pegylated)/ribavirin in patients aged 3 to 17 years, weight loss and growth retardation were frequently observed. Long-term data on treatment of children with pegylated interferon/ribavirin combination indicate significant growth retardation, even after more than 5 years since treatment discontinuation.

Individual benefit-risk assessment in children.

The expected benefit of treatment should be carefully weighed against safety data obtained from clinical trials in children and adolescents.

• It is important to consider that combination therapy may induce growth delay, resulting in reduced growth velocity in some patients.
• The risk should be weighed against disease characteristics such as signs of disease progression (especially fibrosis), concomitant conditions that may negatively affect disease progression (e.g., concomitant HIV infection), and prognostic factors related to virological response (HCV genotype and viral load).

If possible, treatment in children should be initiated after the pubertal growth spurt to minimize the risk of growth delay. Although data are limited, no signs of long-term consequences on sexual maturation were observed during 5 years of follow-up.

Additional monitoring of thyroid function in children and adolescents.

Data indicate that in some children treated with ribavirin and interferon α-2b (pegylated and non-pegylated), elevated TSH levels and transient decrease in hormone levels (below the lower limit of normal) have been observed. TSH levels should be determined before initiating interferon α-2b therapy. If any thyroid pathology is detected, standard treatment is recommended. If TSH levels can be maintained within the normal range with medication, treatment with interferon α-2b (pegylated and non-pegylated) may be initiated. Thyroid dysfunction has been observed during treatment with ribavirin and interferon α-2b, as well as with ribavirin and peginterferon α-2b. If thyroid pathology is detected, thyroid status should be evaluated and appropriate treatment initiated. In children and adolescents, thyroid function (including TSH levels) should be monitored every 3 months.

Overdose.

Treatment regimen with three drugs. (See package insert for boceprevir.)

Treatment regimen with two drugs. The highest known overdose of ribavirin was 10 g (50 capsules of 200 mg) taken together with 39 million IU of interferon α-2b as an injectable solution (13 subcutaneous injections of 3 million IU). This amount was ingested by a patient in a suicide attempt over the course of one day. The patient was observed for 2 days in an intensive care unit; no adverse reactions related to overdose were observed during this period.

Treatment: Discontinue the drug and provide symptomatic therapy.

Adverse reactions.

Use of ribavirin in combination with direct-acting antiviral medicinal products.

Based on the analysis of safety data obtained during clinical trials involving adult patients receiving direct-acting antiviral medicinal products in combination with ribavirin, the most commonly reported adverse reactions associated with ribavirin were anaemia, nausea, vomiting, asthenia, fatigue, insomnia, cough, dyspnoea, pruritus, and skin rashes. Most of these adverse reactions, except for anaemia, were not serious and resolved without discontinuation of therapy.

Adults.

Infections and infestations: viral 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 infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps): unspecified neoplasm.

Blood and lymphatic system disorders: anaemia, haemolytic anaemia, aplastic anaemia, leucopenia, lymphopenia, neutropenia, thrombocytopenia, pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, lymphadenopathy.

Immune system disorders: drug hypersensitivity, acute hypersensitivity reactions including urticaria, angioedema, bronchospasm, anaphylaxis, sarcoidosis, rheumatoid arthritis (new onset or exacerbation), Vogt–Koyanagi–Harada syndrome, systemic lupus erythematosus, vasculitis.

Endocrine disorders: hypothyroidism, hyperthyroidism.

Metalbolic and nutritional disorders: anorexia, increased appetite, hyperglycaemia, diabetes mellitus, hyperuricaemia, hypocalcaemia, dehydration, hypertriglyceridaemia.

Psychiatric disorders: depression, apathy, tearfulness, restlessness, emotional lability, aggressive behaviour, agitation, irritability, mood alteration, unusual behaviour, nervousness, panic attack, confusion, insomnia, sleep disorder, abnormal dreams, suicidal ideation, suicide, homicidal ideation, suicide attempt, psychosis, hallucinations, mania, bipolar disorder, decreased libido, mental status change.

Nervous system disorders: headache, migraine, dizziness, dry mouth, taste disturbance, dysgeusia, dysphonia, decreased concentration, amnesia, memory impairment, ataxia, paraesthesia, hypoaesthesia, hyperaesthesia, somnolence, attention impairment, tremor, neuropathy, peripheral neuropathy, convulsions, cerebral haemorrhage, cerebral ischaemia, encephalopathy, polyneuropathy, facial paralysis, mononeuropathy.

Eye disorders: visual impairment, blurred vision, visual acuity disturbance, decreased visual acuity or visual field constriction, conjunctivitis, eye irritation, eye pain, lacrimal gland disorders, dry eyes, retinal haemorrhage, retinopathy (including macular oedema), retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema, retinal exudates, serous retinal detachment.

Ear and labyrinth disorders: vertigo, hearing impairment/hearing loss, tinnitus, ear pain.

Cardiac disorders: palpitations, tachycardia, arrhythmia, myocardial infarction, cardiomyopathy, ischaemic heart disease, pericardial effusion, pericarditis, arterial hypotension, arterial hypertension, flushing, vasculitis, peripheral ischaemia.

Respiratory, thoracic and mediastinal disorders: dyspnoea, nasal congestion, rhinorrhoea, epistaxis, respiratory distress, cough, congestion in airways, sinus congestion, increased upper respiratory tract secretion, throat and pharyngeal pain, pulmonary infiltrate, pneumonitis, interstitial pneumonitis.

Gastrointestinal disorders: stomatitis, ulcerative stomatitis, oral ulcers, mouth pain, glossitis, cheilitis, gingivitis, gum haemorrhage, tongue pigmentation, dental disorders, periodontal disorders, dental complications, nausea, vomiting, dyspepsia, abdominal pain, right upper abdominal quadrant pain, gastroesophageal reflux, abdominal distension, flatulence, colitis, diarrhoea, frequent loose stools, constipation, ischaemic colitis, ulcerative colitis, pancreatitis.

Hepatobiliary disorders: hepatomegaly, jaundice, hyperbilirubinaemia, hepatotoxicity (including fatal cases).

Skin and subcutaneous tissue disorders: alopecia, hair structure abnormalities, nail disorders, pruritus, dry skin, rash, maculopapular rash, erythematous rash, psoriasis, psoriasis exacerbation, eczema, photosensitivity reaction, night sweats, increased sweating (hyperhidrosis), dermatitis, acne, furunculosis, erythema, urticaria, skin disorders, bruising, cutaneous sarcoidosis, Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders: arthralgia, arthritis, back pain, limb pain, bone pain, musculoskeletal pain, myalgia, muscle weakness, rhabdomyolysis, myositis, muscle spasms.

Renal and urinary disorders: urinary frequency, polyuria, abnormal urine colour, renal failure, renal function impairment, nephrotic syndrome.

Reproductive system and breast disorders: women: amenorrhoea, menorrhagia, menstrual cycle disturbance, dysmenorrhoea, breast pain, ovarian disorders, vaginal disorders; men: impotence, prostatitis, erectile dysfunction, sexual dysfunction (unspecified).

General disorders and administration site conditions: fatigue, chills, pyrexia, influenza-like symptoms, asthenia, irritability, chest pain, chest discomfort, peripheral oedema, malaise, unusual feeling, thirst, facial swelling.

Investigations: weight decrease, cardiac murmur.

Patients with concomitant HIV infection.

In patients with concomitant HIV infection receiving ribavirin in combination with peginterferon α-2b, additional adverse reactions not observed in patients with hepatitis C monoinfection included: oral candidiasis, acquired lipodystrophy, decreased CD4 lymphocyte count, decreased appetite, increased gamma-glutamyl transferase levels, back pain, increased blood amylase levels, increased blood lactate levels, cytolytic hepatitis, increased lipase levels, and limb pain.

Mitochondrial toxicity.

Cases of mitochondrial toxicity and lactic acidosis have been reported in HIV-infected patients receiving highly active antiretroviral therapy (HAART) and combination treatment with ribavirin for concomitant hepatitis C virus infection.

Laboratory findings in patients with concomitant HIV infection.

Haematological toxicity signs such as neutropenia, thrombocytopenia, and anaemia occurred more frequently in patients with concomitant HIV infection, but in most cases these abnormalities resolved with dose adjustment and did not require premature discontinuation of treatment. Haematological disorders occurred more frequently in patients receiving ribavirin in combination with peginterferon α-2b compared to those receiving ribavirin with interferon α-2b.

Decrease in CD4 lymphocyte count.

Treatment with ribavirin in combination with peginterferon α-2b during the first 4 weeks was associated with a decrease in absolute CD4+ cell count, although the percentage of CD4+ cells did not decline. This reduction in absolute CD4+ cell count was reversible upon dose reduction or discontinuation of treatment. Use of ribavirin in combination with peginterferon α-2b was not associated with a significant negative impact on HIV viraemia control during treatment or follow-up. Safety data in patients with concomitant HIV infection and CD4 count < 200 cells/μL are limited.

Children.

The adverse reaction profile in children is generally similar to that in adults, but certain adverse reactions are age-specific and relate to weight loss and growth retardation, the reversibility of which is unknown. The degree of growth retardation was greatest in prepubertal children.

Infections and infestations: viral infection, influenza, oral herpes, herpes simplex, herpes zoster, bacterial infection, fungal infection, pulmonary infection, nasopharyngitis, pharyngitis, streptococcal pharyngitis, otitis media, pneumonia, sinusitis, dental abscess, urinary tract infection, vaginitis, cellulitis, ascariasis, enterobiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): unspecified neoplasm.

Blood and lymphatic system disorders: anaemia, neutropenia, thrombocytopenia, lymphadenopathy.

Endocrine disorders: hypothyroidism, hyperthyroidism, virilisation.

Metabolic and nutritional disorders: anorexia, increased appetite, decreased appetite, hypertriglyceridaemia, hyperuricaemia.

Psychiatric disorders: depression, insomnia, emotional lability, suicidal ideation, suicidal thoughts, suicide attempts, aggression, confusion, affective lability, behavioural changes, agitation, sleepwalking, anxiety, mood changes, restlessness, nervousness, sleep disturbances, abnormal dreams, apathy, unusual behaviour, depressed mood, emotional disorders, fear, nightmares, irritability.

Nervous system disorders: headache, dizziness, hyperkinesia, tremor, dysphonia, paraesthesia, hypoaesthesia, hyperaesthesia, decreased concentration, somnolence, attention impairment, poor sleep quality, neuralgia, lethargy, psychomotor hyperactivity.

Eye disorders: conjunctivitis, eye pain, visual acuity abnormalities, lacrimal gland disorders, conjunctival haemorrhage, eye pruritus, keratitis, blurred vision, photophobia, serous retinal detachment.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: tachycardia, palpitations, pallor, flushing, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: dyspnoea, tachypnoea, epistaxis, cough, nasal congestion, nasal irritation, rhinorrhoea, sneezing, throat and pharyngeal pain, laboured breathing, nasal discomfort.

Gastrointestinal disorders: abdominal pain, upper abdominal pain, vomiting, diarrhoea, nausea, oral ulcers, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorder, gastrointestinal disorder, constipation, frequent loose stools, toothache, dental disorders, stomach discomfort, mouth pain, gingivitis, gastroenteritis.

Hepatobiliary disorders: liver function abnormalities, hepatomegaly.

Skin and subcutaneous tissue disorders: alopecia, rash, pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorders, nail disorders, skin colour changes, dry skin, erythema, bruising, pigmentation, atopic dermatitis, skin exfoliation.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, musculoskeletal pain, limb pain, back pain, muscle contracture.

Renal and urinary disorders: enuresis, micturition disorder, urinary incontinence, proteinuria.

Reproductive system and breast disorders: girls: amenorrhoea, menorrhagia, menstrual cycle disturbance, vaginal disorders, dysmenorrhoea; boys: testicular pain.

General disorders and administration site conditions: fatigue, increased fatigue, chills, pyrexia, influenza-like symptoms, asthenia, malaise, irritability, chest pain, oedema, feeling of cold, discomfort in chest, facial pain.

Investigations: decreased growth velocity (reduced height and/or body weight for age), increased blood TSH (thyroid-stimulating hormone) levels, increased thyroglobulin levels, presence of antithyroid antibodies.

Injury, poisoning and procedural complications: contusion, skin abrasions.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 capsules in a blister or strip; 10 blisters or strips in a cardboard pack № 100 (10 × 10).

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its business activity.

40020, Ukraine, Sumy region, Sumy, Skryabina St., 54.