Ribavirin-pharmex
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIBAVIRIN-PHARMEX (RIBAVIRIN-PHARMEX)
Composition:
Active substance: ribavirin;
1 capsule contains ribavirin 200 mg;
Excipients: lactose monohydrate, magnesium stearate, sodium croscarmellose, microcrystalline cellulose;
Capsule shell: gelatin, titanium dioxide (E 171), azorubine (E 122).
Pharmaceutical form. Hard capsules.
Main physicochemical properties: hard gelatin capsules size 1. Body and cap are red-colored. The capsule contents are white or almost white powder.
Pharmacotherapeutic group. Direct-acting antiviral agents. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. ATC code J05A B04.
Pharmacological Properties
Pharmacodynamics
RIBAVIRIN-PHARMEKS (ribavirin) is a synthetic nucleoside analogue with activity in vitro against certain RNA and DNA viruses. The mechanism by which ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b exerts its effect on hepatitis C virus is unknown. Monotherapy with ribavirin for chronic hepatitis C does not lead to viral elimination (HCV RNA) or improvement in liver histology after 6–12 months of therapy and during the subsequent 6-month follow-up period. However, in clinical trials, combination therapy with ribavirin and peginterferon alfa-2b or interferon alfa-2b resulted in higher treatment response rates compared to monotherapy with peginterferon alfa-2b or interferon alfa-2b.
Pharmacokinetics
Ribavirin is readily absorbed after oral administration of a single dose (Tmax = 1.5 hours) and rapidly distributed throughout the body. The elimination phase is prolonged. The half-lives of absorption, distribution, and elimination after a single dose are approximately 0.05, 3.73, and 79 hours, respectively. Ribavirin is extensively absorbed, with only about 10% of a radiolabeled dose excreted in feces. However, absolute bioavailability is approximately 45–65%, possibly due to first-pass metabolism. A linear relationship exists between dose and bioavailability parameters (AUCtf) following single oral doses of ribavirin ranging from 200 to 1200 mg. The volume of distribution is approximately 5000 L. Ribavirin does not bind to plasma proteins.
Following single oral administration of ribavirin, high pharmacokinetic variability has been demonstrated both within individual patients and among different patients (intra-patient variability in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) is approximately 30%), which may be explained by extensive first-pass metabolism and significant transport into and out of the bloodstream.
Non-plasma transport of ribavirin has been particularly well studied in erythrocytes. It has been shown that overall transport occurs via an equilibrative nucleoside transporter of the es type. This transporter is present in nearly all cell types and may contribute to the large volume of distribution of ribavirin. The whole blood-to-plasma concentration ratio of ribavirin is approximately 60:1; the excess ribavirin in whole blood exists as ribavirin nucleotides sequestered within erythrocytes.
Ribavirin is metabolized via two pathways: reversible phosphorylation and degradative transformations, including deribosylation and amide hydrolysis, leading to the formation of a triazole carboxylic acid metabolite. Both ribavirin itself and its metabolites—triazole carboxamide and triazole carboxylic acid—are excreted in urine.
With repeated administration, ribavirin extensively accumulates in plasma; the ratio of bioavailability parameters (AUC12h) after multiple versus single dosing is 6. Following oral administration (600 mg twice daily), steady-state plasma concentrations of ribavirin were achieved by the end of week 4, averaging approximately 2200 ng/mL. After discontinuation, the elimination half-life was approximately 298 hours, suggesting slow release from extravascular compartments.
Ability to penetrate seminal fluid. The ability of ribavirin to penetrate seminal fluid has been studied. Ribavirin concentrations in seminal fluid are approximately twice those in serum. However, systemic exposure in women following sexual contact with men receiving ribavirin therapy remains very 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 increase in bioavailability may be due to delayed transit or altered pH. The clinical significance of these findings is unknown. In the main clinical efficacy study aimed at achieving optimal Cmax of ribavirin, patients were instructed to take ribavirin with food.
Renal function. In patients with renal impairment, the pharmacokinetics of ribavirin after single-dose administration are altered (increased AUCtf and Cmax) compared to patients with creatinine clearance > 90 mL/min. This change is primarily due to reduced clearance in these patients. Ribavirin concentrations do not significantly change during hemodialysis.
Hepatic function. The pharmacokinetics of ribavirin after administration of a single dose in patients with mild, moderate, or severe hepatic impairment (Child–Pugh classes A, B, or C) are similar to those observed in healthy control volunteers.
Elderly patients (≥ 65 years). No specific pharmacokinetic studies were conducted in elderly patients. However, in a population pharmacokinetic analysis, age was not a major factor influencing ribavirin kinetics; renal function was the primary determinant.
Population pharmacokinetic analysis was performed based on serum concentration data collected periodically in four controlled clinical trials. The developed clearance model identified body weight, sex, age, and serum creatinine level as the main covariates. Clearance in males was approximately 20% higher than in females. Clearance increased with body weight and decreased in individuals over 40 years of age. Due to the substantial unexplained variability in the data, the clinical significance of these covariates on ribavirin clearance is considered minor.
Children and adolescents
Ribavirin in combination with peginterferon alfa-2b
The pharmacokinetic properties of ribavirin and peginterferon alfa-2b following multiple dosing were evaluated in a clinical study in children and adolescents with chronic hepatitis C. It was estimated that in children and adolescents receiving peginterferon alfa-2b at a dose of 60 mcg/m² weekly, the logarithmically transformed ratio of systemic exposure over the dosing interval was 58% higher (90% confidence interval: 141–177%) than that observed in adult volunteers receiving 1.5 mcg/kg weekly. In this study, the dose-normalized pharmacokinetics of ribavirin did not differ from data previously obtained in studies of ribavirin in combination with interferon alfa-2b in both pediatric and adult patients.
Ribavirin in combination with interferon alfa-2b
The dose-normalized pharmacokinetics of ribavirin and interferon alfa-2b were similar in adults and children aged 5 to 16 years.
Clinical characteristics.
Indications.
Triple therapy
RIBAVIRIN-PHARMEKS in combination with boceprevir and peginterferon alfa-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 has failed.
The prescribing information for peginterferon alfa-2b and boceprevir should be consulted when RIBAVIRIN-PHARMEKS is used in combination with these agents.
Dual therapy
The medicinal product RIBAVIRIN-PHARMEKS is indicated for the treatment of chronic hepatitis C in adults and children aged 3 years and older; the drug should only be used in combination with peginterferon alfa-2b or interferon alfa-2b. RIBAVIRIN-PHARMEKS must not be used as monotherapy.
The prescribing information for peginterferon alfa-2b or interferon alfa-2b should be consulted when RIBAVIRIN-PHARMEKS is used in combination with these agents.
There is no information available on the safety or efficacy of using RIBAVIRIN-PHARMEKS with other forms of interferon (i.e., other than alfa-2b).
Patients who have not previously been treated
Adults (aged 18 years and older)
The medicinal product RIBAVIRIN-PHARMEKS is indicated:
- in triple therapy regimen: in combination with peginterferon alfa-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 alfa-2b or peginterferon alfa-2b for the treatment of chronic hepatitis C in adult patients who have not previously been treated (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 alfa-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 adolescents
The medicinal product RIBAVIRIN-PHARMEKS is indicated in combination with peginterferon alfa-2b or interferon alfa-2b for the treatment of chronic hepatitis C in children aged 3 years and adolescents who have not previously been treated, in the absence of liver decompensation and with detectable 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
The medicinal product RIBAVIRIN-PHARMEKS is indicated:
- in triple therapy regimen: in combination with peginterferon alfa-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 alfa-2b for the treatment of chronic hepatitis C in cases where prior treatment with interferon alfa alone (pegylated or non-pegylated) or its combination with ribavirin was ineffective;
- in dual therapy regimen: in combination with interferon alfa-2b for the treatment of chronic hepatitis C in cases where prior monotherapy with interferon alfa was initially effective (normalization of ALT by the end of treatment course), but relapse subsequently occurred.
Contraindications.
Hypersensitivity to ribavirin or to any component of the medicinal product.
Pregnancy. Therapy should not be initiated until a negative pregnancy test result is obtained.
Men whose female partners are pregnant.
Breastfeeding.
Severe cardiac diseases, including unstable and uncontrolled forms observed within 6 months prior to the start of treatment.
Severe debilitating diseases.
Chronic renal failure or creatinine clearance < 50 mL/min. Also contraindicated in patients undergoing hemodialysis.
Severe hepatic impairment (Child-Pugh class B or C) or decompensated cirrhosis of the liver.
Hemoglobinopathies (e.g., thalassemia, sickle cell anemia).
Peginterferon α-2b is contraindicated in patients coinfected with hepatitis C virus/HIV with liver cirrhosis and hepatic dysfunction ≥ 6 points on the Child-Pugh classification.
Contraindicated in children and adolescents with a history or clinical evidence of severe psychiatric disorders, particularly depression, suicidal ideation, or suicide attempt.
Autoimmune hepatitis or other autoimmune diseases in medical history (due to combination with peginterferon alfa-2b or interferon alfa-2b).
Interaction with other medicinal products and other forms of interaction.
Based on in vitro studies using human liver microsomal preparations, cytochrome P450 enzymes are not involved in the metabolic transformations of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. Toxicological studies provide no evidence 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 treatment. Concomitant use of pegylated alpha-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 monitoring of hematological parameters is recommended during concomitant use to detect signs of myelotoxicity, and treatment with these agents should be discontinued if such signs occur.
No studies have been conducted on the interaction of ribavirin with other medicinal products except peginterferon alfa-2b, interferon alfa-2b, and antacids.
Interferon alfa-2b
Pharmacokinetic studies showed no evidence of interaction between ribavirin and peginterferon alfa-2b or interferon alfa-2b when used concomitantly.
Antacids
The bioavailability of a 600 mg dose of ribavirin was reduced when administered concomitantly 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 analogues
The use of nucleoside analogues alone or in combination with other nucleosides may lead to the development of lactic acidosis. Ribavirin in vitro increases the levels of phosphorylated metabolites of purine nucleosides. This effect increases the risk of lactic acidosis induced by purine nucleoside analogues (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.
When zidovudine is used in HIV treatment regimens, cases of exacerbated anemia due to ribavirin treatment have been observed, although the exact mechanism of this interaction remains unknown. Due to the increased risk of anemia, ribavirin is not recommended for concomitant use with zidovudine. The regimen of concomitant use of zidovudine and the medicinal product RIBAVIRIN-PHARMEKS 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 with zidovudine use.
The potential for interaction with RIBAVIRIN-PHARMEKS persists for 2 months (5 half-lives of ribavirin) after discontinuation of treatment due to the long elimination half-life.
There is no evidence of interaction between the medicinal product RIBAVIRIN-PHARMEKS and non-nucleoside reverse transcriptase inhibitors or protease inhibitors.
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 with hepatitis C virus/HIV coinfection who are receiving abacavir as part of antiretroviral therapy. Precautions should be taken when using these drugs concomitantly.
Special precautions.
Based on clinical trial data, ribavirin monotherapy is not effective; therefore, the medicinal product RIBAVIRIN-PHARMEKS should not be used as the sole therapeutic agent for the treatment of hepatitis C. The efficacy and safety of combination therapy have been established only for ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b, injection solution.
Decisions regarding the necessity of liver biopsy prior to initiating therapy should be guided by current treatment guidelines.
Psychiatric disorders and central nervous system (CNS) disorders. Significant CNS disorders, including depression, suicidal thoughts, and suicide attempts, have been observed in some patients during combination therapy with ribavirin and peginterferon alfa-2b or interferon alfa-2b, even during the 6-month observation period after discontinuation of such treatment. Suicidal thoughts or suicide attempts during treatment and the 6-month post-treatment observation period occurred more frequently in children and adolescents receiving ribavirin in combination with interferon alfa-2b than in adult patients. In children and adolescents, as in adults, other psychiatric disorders (e.g., depression, emotional lability, and somnolence) also occurred. Other CNS disorders observed with the use of alfa-interferons include aggressive behavior (sometimes directed toward others, e.g., homicidal ideation), bipolar disorder, mania, confusion, and mental status changes.
Patients require careful monitoring for signs of psychiatric disorders. If such symptoms occur, the prescribing physician should assess the potential severity of these adverse reactions and the need for appropriate treatment. If psychiatric symptoms do not resolve or worsen, or if suicidal or homicidal ideation develops, discontinuation of treatment with RIBAVIRIN-PHARMEKS in combination with peginterferon alfa-2b or interferon alfa-2b is recommended, and psychiatric support should be provided as needed.
Patients with a history of or clinical manifestations of severe psychiatric disorders. If combination therapy with RIBAVIRIN-PHARMEKS and peginterferon alfa-2b or interferon alfa-2b is deemed necessary for adult patients with clinical or historical evidence of severe psychiatric or borderline disorders, therapy should be initiated only after appropriate individualized assessment and concurrent psychiatric management.
The use of RIBAVIRIN-PHARMEKS and peginterferon alfa-2b or interferon alfa-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 (alcohol, marijuana, etc.) are at high risk of developing psychiatric disorders or exacerbation of existing psychiatric conditions during interferon alfa treatment. If interferon alfa treatment is necessary for such patients, the presence of psychiatric comorbidities and 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 as needed (for assessment, treatment, and ongoing monitoring). The patient's condition should be closely monitored during and after treatment. Early intervention for recurrence or development of psychiatric disorders and psychoactive substance use is recommended.
Hemoglobin levels below 10 g/dL have been observed in adult patients, as well as in children and adolescents, treated with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b. Although ribavirin has no direct effect on the cardiovascular system, anemia associated with RIBAVIRIN-PHARMEKS may exacerbate heart failure and/or worsen symptoms of coronary artery disease. Therefore, RIBAVIRIN-PHARMEKS should be prescribed with caution in patients with heart disease. Cardiovascular status should be assessed before initiating treatment and monitored throughout therapy. If any signs of worsening cardiovascular status occur, treatment should be discontinued.
Cardiovascular system. Adult patients with current or previous congestive heart failure, myocardial infarction, and/or arrhythmia should be under continuous medical supervision. Electrocardiography is recommended for patients with heart disease before and during treatment. Arrhythmias (mainly supraventricular) are usually manageable with standard therapy but may require treatment discontinuation. 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 (e.g., urticaria, angioedema, bronchospasm, anaphylaxis) occurs, RIBAVIRIN-PHARMEKS should be discontinued immediately and appropriate treatment initiated. Transient skin rashes are not a reason to discontinue treatment.
Ophthalmological changes. Ribavirin is used in combination with alfa-interferons. Rare cases of retinopathy, including retinal hemorrhage and exudates, optic disc edema, optic nerve neuropathy, and retinal artery or vein occlusion, potentially leading to visual impairment, have been reported with alfa-interferon combination therapy. All patients should undergo ophthalmological examination before starting treatment. If ocular symptoms develop or vision deteriorates, a complete ophthalmological examination should be performed immediately. Patients with pre-existing ophthalmological conditions (e.g., diabetic or hypertensive retinopathy) should undergo periodic ophthalmological examinations during alfa-interferon combination therapy. If new or worsening ophthalmological disorders occur, combination therapy with alfa-interferons should be discontinued.
Liver function. All patients who show signs of significant worsening of liver function during treatment should be closely monitored. Treatment should be discontinued in patients with evidence of coagulation abnormalities, 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 hepatitis C antiviral therapy and azathioprine, and did not recur upon subsequent individual use of either drug.
HIV and hepatitis C virus co-infection.
Mitochondrial toxicity and lactic acidosis. Treatment should be administered with caution in patients with HIV infection and concurrent hepatitis C virus infection who are receiving nucleoside reverse transcriptase inhibitors (particularly didanosine and stavudine) in combination with ribavirin and interferon alfa-2b. Physicians should closely monitor markers of mitochondrial toxicity and lactic acidosis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitors during ribavirin treatment. Specifically, RIBAVIRIN-PHARMEKS is not recommended to be taken concomitantly with didanosine and stavudine due to the risk of mitochondrial toxicity and to avoid compounding mitochondrial toxicity.
Hepatic decompensation in patients with HIV and hepatitis C virus co-infection and progressive cirrhosis. Patients with concurrent HIV infection and progressive cirrhosis receiving antiretroviral therapy (ART) have an increased risk of hepatic decompensation and fatal outcomes. Additional use of alfa-interferons alone or in combination with ribavirin increases this risk in this patient population. Other factors increasing the risk of hepatic decompensation in co-infected patients include treatment with didanosine and elevated serum bilirubin levels. Co-infected patients receiving both antiretroviral therapy and hepatitis C treatment require close monitoring and assessment of liver dysfunction severity according to the Child–Pugh classification. If hepatic decompensation occurs, hepatitis C treatment should be discontinued immediately, and the antiretroviral therapy regimen should be re-evaluated.
Hematological disorders in patients with HIV and hepatitis C virus co-infection. Patients with concurrent HIV infection receiving ART and ribavirin in combination with peginterferon alfa-2b have an increased risk of hematological disorders (e.g., neutropenia, thrombocytopenia, and anemia) compared to patients with hepatitis C virus infection alone. Most of these disorders resolve with dose reduction, but such patients require close monitoring of hematological parameters. The risk of anemia is increased in patients receiving ribavirin and zidovudine; therefore, ribavirin is not recommended for concomitant use with zidovudine.
Patients with reduced CD4 cell count. 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 consulted for information on individual drug toxicities and potential for increased toxicity with concomitant use of ribavirin and peginterferon alfa-2b.
Dental and periodontal disorders. Dental and periodontal disorders, potentially leading to tooth loss, have been reported in patients receiving combination therapy with ribavirin and peginterferon alfa-2b or interferon alfa-2b. Additionally, dry mouth may adversely affect teeth and oral mucosa during prolonged combination therapy with ribavirin and peginterferon alfa-2b or interferon alfa-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 parameters are considered acceptable before initiating combination therapy:
- Hemoglobin: ≥ 120 g/L (women) and ≥ 130 g/L (men) for adults;
≥ 110 g/L (girls) and ≥ 120 g/L (boys) for children and adolescents; - 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 periodically monitored during treatment.
Women of reproductive age. Women undergoing treatment and female sexual partners of men undergoing treatment should undergo monthly pregnancy tests throughout the entire treatment period and for 4 and 7 months, respectively, after completion of treatment, as ribavirin cannot be used during pregnancy.
Increased uric acid concentration may occur with RIBAVIRIN-PHARMEKS due to hemolysis; therefore, patients predisposed to such conditions should be closely monitored for signs of gout.
Excipients. One capsule of RIBAVIRIN-PHARMEKS contains 40 mg of lactose. Patients with known sugar intolerances should consult their physician before taking this medicinal product. The product should not be used in patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
The presence of the azo dye azorubine (E 122) in the capsule shell may cause allergic reactions.
Use during pregnancy or breastfeeding.
Ribavirin use is contraindicated during pregnancy.
Women of reproductive age/contraception in men and women.
Women (patients). Ribavirin must not be used in pregnant women. To prevent pregnancy, female patients must use effective contraception. Ribavirin treatment should not be initiated unless a negative pregnancy test result is obtained immediately before starting treatment. Women of reproductive age and their sexual partners must use effective contraceptive methods during treatment and for 9 months after completion of treatment; a standard pregnancy test should be performed monthly during this period. Women must be informed of the significant teratogenic risk of ribavirin to the fetus if pregnancy occurs during treatment or within 4 months after completion of treatment.
Male patients and their sexual partners. Effective contraception must be used to prevent pregnancy in sexual partners of men treated with ribavirin. Ribavirin accumulates in cells and is very slowly eliminated from the body. The potential teratogenic or genotoxic effects of ribavirin present in semen on the human embryo/fetus are unknown. Male patients and their female partners of reproductive age must use effective contraceptive methods during ribavirin treatment and for 7 months after completion of treatment. Male patients should use condoms to prevent semen exposure if their partner is pregnant.
Breastfeeding period. It is unclear whether ribavirin is excreted in breast milk. Due to the potential for adverse reactions in the infant, breastfeeding must be discontinued before starting treatment.
Fertility (preclinical data)
Fertility: animal studies have shown that ribavirin reversibly affects spermatogenesis.
Teratogenicity: ribavirin demonstrated marked teratogenic and/or embryocidal potential in all animal species tested at doses equivalent to 1/20 of the recommended human dose.
Genotoxicity: ribavirin induces genotoxicity.
Ability to affect reaction speed when driving or operating machinery.
Ribavirin has no effect or only a minor effect on the ability to drive or operate machinery; however, when combined with peginterferon alfa-2b or interferon alfa-2b, this effect may change. Therefore, patients experiencing fatigue, somnolence, dizziness, or confusion during treatment are advised to avoid driving or operating machinery.
Dosage and Administration
Treatment should be prescribed by a physician experienced in managing patients with hepatitis C.
The medicinal product RIBAVIRIN-PHARMEKS must be used in combination either with peginterferon alfa-2b or with interferon alfa-2b (dual-drug regimen), or in adult patients with chronic hepatitis C (genotype 1) in combination with boceprevir and peginterferon alfa-2b (triple-drug regimen).
When prescribing combination therapy, the prescribing information for boceprevir, peginterferon alfa-2b, or interferon alfa-2b should also be followed.
Dosage
The dose of RIBAVIRIN-PHARMEKS depends on the patient's body weight. RIBAVIRIN-PHARMEKS, capsules, should be taken orally with food, daily, in two divided doses (morning and evening).
Adults
The dose of RIBAVIRIN-PHARMEKS depends on the patient's body weight (see Table 1).
RIBAVIRIN-PHARMEKS must be used in combination either with peginterferon alfa-2b (1.5 mcg/kg/week) or with interferon alfa-2b (3 million IU three times weekly). The choice of combination therapy regimen should be individualized, taking into account the expected efficacy and safety of the selected combination.
Table 1
RIBAVIRIN-PHARMEKS dosage (depending on body weight) for patients with hepatitis C virus monoinfection or hepatitis C virus/HIV co-infection, regardless of genotype
| Body weight of the patient (kg) |
Daily dose, mg |
Number of 200 mg capsules |
| < 65 |
800 |
4 (2 in the morning, 2 in the evening) |
| 65-80 |
1000 |
5 (2 in the morning, 3 in the evening) |
| 81-105 |
1200 |
6 (3 in the morning, 3 in the evening) |
| > 105 |
1400 |
7 (3 in the morning, 4 in the evening) |
Duration of therapy in treatment-naïve patients
Triple therapy regimen
Refer to the medical instructions for boceprevir and peginterferon alfa-2b.
Dual therapy regimen (with peginterferon alfa-2b)
Prediction of sustained virological response. In patients infected with hepatitis C virus genotype 1 in whom HCV-RNA has not decreased below the lower limit of quantification or who have not achieved an adequate virological response after 4 or 12 weeks of treatment, the probability of achieving a sustained virological response is very low; therefore, such patients should discontinue this treatment.
Genotype 1: For patients who have demonstrated a virological response at week 12 of treatment, therapy should be continued for the next 9 months (total of 48 weeks).
For patients who have achieved at least a ≥ 2 log reduction in HCV-RNA levels by week 12 compared to baseline, a reassessment should be performed at week 24 of treatment. If HCV-RNA is below the lower limit of detection at that time, a full course of treatment (i.e., total of 48 weeks) should be completed. However, if HCV-RNA remains above the lower limit of detection at week 24, treatment should be discontinued.
For the subgroup of patients infected with genotype 1 and low viral load (< 600,000 IU/mL), in whom HCV-RNA is undetectable at week 4 and remains negative 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, a 24-week total treatment duration is associated with an increased risk of relapse compared to a 48-week treatment duration.
Genotype 2 or 3: The recommended duration of treatment is 24 weeks for all patients, except for those with concomitant HIV infection, who should be treated for 48 weeks.
Genotype 4: Patients infected with genotype 4 are considered more difficult to treat; data suggest similarities in treatment response to patients with genotype 1.
Duration of therapy in treatment-naïve patients coinfected with hepatitis C virus and HIV
Dual therapy regimen. For patients with concomitant HIV infection, the recommended duration of treatment with ribavirin at a weight-based dose (see Table 1) is 48 weeks, regardless of genotype.
Prediction of response or non-response in treatment-naïve patients coinfected with hepatitis C virus and HIV
An early virological response at week 12 of treatment (a 2 log reduction in viral load or HCV-RNA below the lower limit of detection) is a predictive factor for achieving a sustained virological response.
Duration of retreatment
Triple therapy regimen. Refer to the medical instructions for boceprevir and peginterferon alfa-2b.
Dual therapy regimen (with peginterferon alfa-2b)
Prediction of sustained virological response. For all patients, regardless of viral genotype, in whom HCV-RNA decreases below the lower limit of detection by week 12 of treatment, a 48-week treatment course is recommended. In retreatment, for patients who do not achieve a virological response by week 12 (i.e., HCV-RNA has not decreased below the lower limit of detection), the probability of achieving a sustained virological response after 48 weeks of treatment is very low.
The benefit of retreatment exceeding 48 weeks has not been studied in patients with genotype 1 who did not respond to prior treatment, when using combination therapy with pegylated interferon alfa-2b and ribavirin.
Use of RIBAVIRIN-PHARMEKS (capsules) in combination with interferon alfa-2b (only in dual therapy regimen)
Duration of therapy with interferon alfa-2b. Based on clinical trial results, the recommended duration of treatment is at least 6 months. In these clinical trials, where treatment lasted for 1 year, the probability of achieving a sustained virological response (HCV-RNA below the lower limit of detection 6 months after the end of treatment) was very low in patients who did not achieve a virological response after 6 months of treatment (HCV-RNA above the lower limit of detection).
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 treatment up to 1 year should be based on other prognostic factors (e.g., patient age > 40 years, male sex, bridging liver fibrosis).
Children (dual therapy regimen)
Note: Patients with body weight less than 47 kg or who cannot swallow capsules should be prescribed ribavirin 40 mg/mL oral solution.
Ribavirin dosage for children and adolescents is based on body weight, while peginterferon alfa-2b and interferon alfa-2b dosages are based on body surface area.
Dosing for children in combination with peginterferon alfa-2b
Ribavirin at a dose of 15 mg/kg per day is recommended in combination with peginterferon alfa-2b for subcutaneous administration at a dose of 60 µg/m² weekly (see Table 2).
Dosing for children in combination with interferon alfa-2b
In studies conducted in this patient group, ribavirin and interferon alfa-2b were administered at doses of 15 mg/kg per day and 3 million IU/m² three times weekly, respectively (see Table 2).
Table 2
Ribavirin dosage for children and adolescents according to body weight when used in combination with interferon alfa-2b or peginterferon alfa-2b
| Body weight of the patient, kg |
Daily dose, mg |
Number of 200 mg capsules |
| 47-49 |
600 |
3 (1 in the morning, 2 in the evening) |
| 50-65 |
800 |
4 (2 in the morning, 2 in the evening) |
| > 65 |
Corresponds to the adult dosing (see Table 1) |
|
Duration of treatment in children and adolescents
Genotype 1: The recommended duration of treatment is 1 year. Children and adolescents receiving treatment with interferon alfa-2b (pegylated or non-pegylated) in combination with ribavirin should discontinue such treatment if, after 12 weeks of therapy, HCV-RNA levels have decreased by less than 2 log10 compared to baseline, 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 alfa-2b in combination with ribavirin should discontinue such treatment if, after 12 weeks of therapy, HCV-RNA levels have decreased by less than 2 log10 compared to baseline, or if HCV-RNA is still detectable after 24 weeks of treatment.
Dose modification for all patients
Combination therapy
In the event of serious adverse reactions or laboratory abnormalities during therapy with ribavirin and peginterferon alfa-2b or interferon alfa-2b, the dose of each drug should be adjusted until adverse reactions resolve. Based on clinical trial experience, a dose modification scheme for combination therapy has been established (see Table 3). To achieve optimal treatment outcome, it is important to adhere to the prescribed treatment regimen; therefore, doses should be maintained as close as possible to the recommended standard doses. A negative impact of ribavirin dose reduction on treatment efficacy cannot be excluded.
Table 3
Recommended dose adjustments based on laboratory parameters
| Laboratory parameters |
Reduce daily dose of RIBAVIRIN-PHARMEKS only (see note 1) if: |
Reduce dose of peginterferon alfa-2b or interferon alfa-2b only (see note 2) if: |
Discontinue combination therapy if: |
| Hemoglobin |
< 10 g/dL |
- |
< 8.5 g/dL |
| Adults: hemoglobin levels in patients with history of heart disease, stable course |
Hemoglobin level decreased by ≥ 2 g/dL within any 4 weeks of treatment |
< 12 g/dL at 4 weeks of treatment after dose reduction |
|
| Leukocyte count |
- |
< 1.5×10⁹/L |
< 1.0×10⁹/L |
| Neutrophil count |
- |
< 0.75×10⁹/L |
< 0.5×10⁹/L |
| Platelet count |
- |
< 50×10⁹/L (adults) |
< 25×10⁹/L (adults) |
| Direct bilirubin level |
- |
- |
2.5×ULN* |
| Indirect bilirubin level |
> 5 mg/dL |
- |
> 4 mg/dL (adults) |
| Serum creatinine level |
- |
- |
> 2.0 mg/dL |
| Creatinine clearance |
- |
- |
Discontinue RIBAVIRIN-PHARMEKS if creatinine clearance < 50 mL/min |
| ALT/AST |
- |
- |
2 × baseline level and > 10×ULN** |
* ULN – upper limit of normal.
** Dose modification and discontinuation of interferon alfa-2b and pegylated interferon alfa-2b should be guided by the prescribing information for peginterferon alfa-2b or interferon alfa-2b.
Note 1. For adult patients, the ribavirin dose should initially be reduced by 200 mg per day (except for patients receiving a 1400 mg dose, for whom the dose should be reduced by 400 mg per day). If necessary, the dose should be further reduced by 200 mg per day. Patients whose ribavirin dose has been reduced 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 receiving ribavirin in combination with peginterferon alfa-2b, the ribavirin dose should initially be reduced to 12 mg/kg per day, and upon further reduction, to 8 mg/kg per day. For children and adolescents receiving ribavirin in combination with interferon alfa-2b, the ribavirin dose should be reduced to 7.5 mg/kg per day.
Note 2. For adult patients receiving ribavirin in combination with peginterferon alfa-2b, the peginterferon alfa-2b dose should initially be reduced to 1 mcg/kg weekly. If necessary, the peginterferon alfa-2b dose should be reduced to 0.5 mcg/kg weekly.
For children and adolescents receiving ribavirin in combination with peginterferon alfa-2b, the peginterferon alfa-2b dose should initially be reduced to 40 mcg/m² weekly, and upon further reduction, to 20 mcg/m² weekly.
For adult patients, as well as for children and adolescents receiving ribavirin in combination with interferon alfa-2b, the interferon alfa-2b dose should be halved.
Special patient groups
Use in renal impairment. Due to significantly reduced creatinine clearance in patients with renal dysfunction, the pharmacokinetics of ribavirin are altered. Therefore, renal function should be assessed in all patients prior to initiating ribavirin therapy. Ribavirin is not recommended for patients with creatinine clearance below 50 mL/min. Patients with impaired renal function should be closely monitored for the development of anemia. If serum creatinine concentration exceeds 2.0 mg/dL (see Table 3), ribavirin and peginterferon alfa-2b or interferon alfa-2b should be discontinued.
Use in hepatic impairment. No pharmacokinetic effect of ribavirin on liver function has been observed. Therefore, dose adjustment of ribavirin is not required in patients with hepatic insufficiency. Ribavirin is contraindicated in cases of severe hepatic dysfunction or decompensated liver cirrhosis.
Use in elderly patients (≥ 65 years of age). There is no clear age-related effect on the pharmacokinetics of ribavirin. However, as with younger patients, renal function should be assessed prior to initiating ribavirin therapy.
Use in patients under 18 years of age. Ribavirin in combination with peginterferon alfa-2b or interferon alfa-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 ribavirin in combination with other interferon formulations (i.e., other than alfa-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 and peginterferon alfa-2b or interferon alfa-2b, the risk of mitochondrial toxicity, lactic acidosis, and hepatic failure increases. When prescribing such therapy, the prescribing information for the respective antiretroviral agents should also be followed.
Children.
Growth and development (children and adolescents). In children aged 3 to 17 years, weight loss and growth retardation have frequently been observed during treatment with interferon (standard or pegylated) in combination with ribavirin for up to 48 weeks. Long-term data on treatment with pegylated interferon/ribavirin combination also indicate significant growth suppression. In 32% of patients, a decline in height percentile of >15 percentile points from baseline was observed 5 years after completion of therapy. Long-term data on treatment with standard interferon/ribavirin combination also show significant growth suppression (decline in height percentile of >15 points from baseline) in 21% of children, even when treatment ended more than 5 years earlier. Final adult height data are available for 14 of these children; according to the data, 12 patients still had a height deficit of >15 percentile points 10–12 years after completion of treatment.
Individual benefit-risk assessment in children. The expected benefit of treatment should be carefully evaluated.
It is important to consider that combination therapy may cause growth retardation, the reversibility of which is uncertain.
The risk should be assessed considering the disease course in the child, such as signs of disease progression (e.g., presence of fibrosis), concomitant conditions that may accelerate disease progression (e.g., concomitant HIV infection), and prognostic factors for treatment response (e.g., HCV genotype and viral load).
To minimize the risk of growth retardation, treatment should, whenever possible, be initiated after completion of sexual maturation. Data on the long-term impact on sexual maturation are lacking.
Monitoring thyroid function in children and adolescents. Prior to initiating therapy with interferon alfa-2b, serum thyroid-stimulating hormone (TSH) levels should be measured. Any identified thyroid dysfunction should be corrected with standard therapy. If TSH levels can be maintained within the normal range with medication, treatment with interferon alfa-2b (pegylated or non-pegylated) may be initiated. If symptoms of thyroid dysfunction develop during alpha-interferon therapy, thyroid status should be evaluated and appropriate treatment initiated. In children and adolescents, thyroid function should be monitored every 3 months (e.g., by measuring TSH levels).
Overdose.
Treatment with three drugs (see boceprevir prescribing information).
Treatment with two drugs. The highest known overdose of ribavirin involved 10 g (50 capsules of 200 mg) taken together with 39 million IU of interferon alfa-2b as an injectable solution (13 subcutaneous injections of 3 million IU each). 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.
Adverse Reactions
Adults
Triple therapy regimen
Refer to the boceprevir medical instructions for use.
Patients who were treated with ribavirin in combination with alpha-2b interferon due to relapse after prior interferon therapy, or who were treated over a shorter period, may experience a better safety profile than that described below.
Infections and infestations: viral infection, pharyngitis, bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infections, injection site infection, lower respiratory tract infection, pneumonia.
Benign, malignant and unspecified neoplasms (including cysts and polyps): unspecified neoplasm.
Blood and lymphatic system disorders: anemia, neutropenia, hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.
Immune system disorders: drug hypersensitivity, sarcoidosis, rheumatoid arthritis (new or exacerbated), Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchospasm, anaphylaxis.
Endocrine disorders: hypothyroidism, hyperthyroidism.
Metabolic and nutritional disorders: anorexia, hyperglycemia, hyperuricemia, hypocalcemia, dehydration, increased appetite, diabetes mellitus, hypertriglyceridemia.
Psychiatric disorders: depression, anxiety, emotional lability, insomnia, suicidal ideation, psychosis, aggressive behavior, confusion, agitation, irritability, mood changes, unusual behavior, nervousness, sleep disorders, decreased libido, apathy, unusual dreams, tearfulness, suicide attempt, panic attack, hallucinations, bipolar disorder, suicide, homicidal ideation, mania, change in mental status.
Nervous system disorders: headache, dizziness, dry mouth, difficulty concentrating, amnesia, memory impairment, dizziness, migraine, ataxia, paresthesia, dysphonia, taste disturbance, hypoaesthesia, hyperaesthesia, hypertension, somnolence, attention disturbance, tremor, dysgeusia, neuropathy, peripheral neuropathy, seizures (convulsions), cerebrovascular hemorrhage, cerebrovascular ischemia, encephalopathy, polyneuropathy, facial paralysis, mononeuropathy.
Eye disorders: vision impairment, blurred vision, conjunctivitis, eye irritation, eye pain, visual acuity disturbance, lacrimal gland disorders, dry eyes, retinal hemorrhage, retinopathy (including macular edema), retinal artery occlusion, retinal vein occlusion, optic neuritis, papilledema, decreased visual acuity or visual field, retinal exudates, serous retinal detachment.
Ear and labyrinth disorders: vertigo, hearing impairment/hearing loss, tinnitus, ear pain.
Cardiac disorders: palpitations, tachycardia, myocardial infarction, cardiomyopathy, arrhythmia, ischemic heart disease, pericardial effusion, pericarditis, arterial hypotension, arterial hypertension, facial flushing, vasculitis, peripheral ischemia.
Respiratory, thoracic and mediastinal disorders: dyspnea, cough, epistaxis, respiratory distress, congestion of respiratory tract, sinus congestion, nasal congestion, rhinorrhea, increased upper respiratory tract secretion, throat and pharynx pain, non-productive cough, pulmonary infiltrate, pneumonitis, interstitial pneumonitis.
Gastrointestinal disorders: diarrhea, vomiting, nausea, abdominal pain, ulcerative stomatitis, stomatitis, mouth ulcers, colitis, right upper quadrant abdominal pain, dyspepsia, gastroesophageal reflux, glossitis, cheilitis, bloating, gingival bleeding, gingivitis, frequent loose stools, toothache, constipation, flatulence, pancreatitis, mouth pain, ischemic colitis, ulcerative colitis, periodontal disorders, dental disorders, tongue pigmentation.
Hepatobiliary disorders: hepatomegaly, jaundice, hyperbilirubinemia, hepatotoxicity (including fatal cases).
Skin and subcutaneous tissue disorders: alopecia, pruritus, dry skin, rash, psoriasis, worsening of psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furunculosis, erythema, urticaria, skin disorders, bruising, increased sweating, pathological hair structure changes, nail disorders, cutaneous sarcoidosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, musculoskeletal pain, arthritis, back pain, muscle cramps, limb pain, bone pain, muscle weakness, rhabdomyolysis, myositis.
Renal and urinary disorders: frequent urination, polyuria, abnormal urine color, renal function impairment, renal failure, nephrotic syndrome.
Reproductive system and breast disorders:
Females – amenorrhea, menorrhagia, menstrual cycle disturbance, dysmenorrhea, breast pain, ovarian disorders, vaginal disorders;
Males – impotence, prostatitis, erectile dysfunction, sexual dysfunction (unspecified).
General disorders and administration site conditions: injection site inflammation, injection site reaction, fatigue, chills, pyrexia, influenza-like symptoms, asthenia, irritability, chest pain, chest discomfort, peripheral edema, malaise, injection site pain, unusual feeling, thirst, facial swelling, injection site necrosis.
Investigations: weight loss, heart murmur.
Most cases of anemia, neutropenia, and thrombocytopenia were mild (Grade I–II according to WHO classification). A few cases of more pronounced neutropenia were observed in patients treated with ribavirin and peginterferon alfa-2b. Among patients with elevated uric acid levels, a small number developed clinical signs of gout during combination therapy, but dose adjustment was not required in any case.
Patients with concomitant HIV infection
In patients with concomitant HIV infection receiving ribavirin in combination with peginterferon alfa-2b, adverse reactions not observed in patients with hepatitis C monoinfection included: oral candidiasis, acquired lipodystrophy, decreased CD4 lymphocyte count, decreased appetite, increased gamma-glutamyltransferase levels, back pain, increased blood amylase levels, increased blood lactate levels, cytolytic hepatitis, increased lipase levels, and limb pain.
Mitochondrial toxicity
In HIV-infected patients receiving antiretroviral therapy (ART) and combination therapy with ribavirin for concomitant hepatitis C virus infection, cases of mitochondrial toxicity and lactic acidosis have been reported.
Laboratory findings in patients with concomitant HIV infection
In patients with concomitant HIV infection, hematological toxicity signs such as neutropenia, thrombocytopenia, and anemia occurred more frequently, but in most cases these abnormalities resolved with dose modification and did not require premature discontinuation of treatment. Hematological disorders occurred more frequently in patients receiving ribavirin in combination with peginterferon alfa-2b compared to those receiving ribavirin with interferon alfa-2b.
Decrease in CD4 lymphocyte count
Treatment with ribavirin in combination with peginterferon alfa-2b was associated with a decrease in absolute CD4+ cell count during the first 4 weeks, but the relative CD4+ cell count did not decrease. This reduction in absolute CD4+ cell count was reversible upon dose reduction or discontinuation of treatment. Ribavirin in combination with peginterferon alfa-2b was not associated with a significant negative impact on HIV viremia control during treatment or follow-up. Safety data in patients with concomitant HIV infection and CD4 count < 200 cells/μL are limited.
For information on toxicity of each antiretroviral agent and potential increased toxicity when used concomitantly with ribavirin and peginterferon alfa-2b, refer to the medical instructions for use of the respective antiretroviral agents used in concomitant hepatitis C therapy.
Children and adolescents (two-drug regimen only)
In combination with peginterferon alfa-2b
The adverse reaction profile in children and adolescents is generally similar to that in adult patients, but some adverse reactions are age-specific and relate to growth retardation. Growth retardation was observed, and its reversibility is unknown. During treatment, weight loss and growth retardation were very common, and growth velocity was also impaired.
The degree of growth reduction was greatest in prepubertal children.
The most common adverse reactions in all patients were pyrexia, headache, neutropenia, fatigue, anorexia, and erythema at the injection site. Most reported adverse reactions were mild or moderate in severity. Severe adverse reactions included injection site pain, limb pain, headache, neutropenia, and pyrexia. Notable adverse reactions occurring during treatment included nervousness, aggression, irritability, depression/depressed mood, and hypothyroidism.
In combination with interferon alfa-2b
The adverse reaction profile in children and adolescents was generally similar to that in adults, but some adverse reactions were age-specific and related to growth retardation (reduction in height and weight percentiles was observed). During 48 weeks of combination therapy with interferon alfa-2b and ribavirin, growth retardation was observed, and its reversibility is unknown. The reduction in mean height percentile was greatest in prepubertal children, particularly from the start of treatment to the end of the long-term follow-up period.
Additionally, during treatment and the 6-month post-treatment follow-up period, suicidal thoughts and suicide attempts occurred more frequently in children than in adult patients. In children and adolescents, as in adults, other psychiatric disorders (e.g., depression, emotional lability, somnolence) were observed. Furthermore, injection site reactions, pyrexia, anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents than in adults.
The following adverse reactions were observed in children treated with ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b.
Infections and infestations: viral infection, pharyngitis, fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, streptococcal pharyngitis, otitis media, sinusitis, dental abscess, influenza, oral herpes, herpes simplex, urinary tract infections, vaginitis, gastroenteritis, pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): unspecified neoplasm.
Blood and lymphatic system disorders: anemia, neutropenia, thrombocytopenia, lymphadenopathy.
Endocrine disorders: hypothyroidism, hyperthyroidism, virilization.
Metabolic and nutritional disorders: anorexia, increased appetite, decreased appetite, hypertriglyceridemia, hyperuricemia.
Psychiatric disorders: depression, insomnia, emotional lability, suicidal ideation, aggression, confusion, affective lability, behavioral changes, agitation, somnambulism, anxiety, mood changes, restlessness, nervousness, sleep disorders, unusual dreams, apathy, unusual behavior, depressed mood, emotional disorders, fear, night terrors.
Nervous system disorders: headache, dizziness, hyperkinesia, tremor, dysphonia, paresthesia, hypoaesthesia, hyperaesthesia, difficulty concentrating, somnolence, attention disturbance, poor sleep quality, neuralgia, lethargy, psychomotor hyperactivity.
Eye disorders: conjunctivitis, eye pain, visual acuity disturbances, lacrimal gland disorders, conjunctival hemorrhage, eye pruritus, keratitis, blurred vision, photophobia, serous retinal detachment.
Ear and labyrinth disorders: vertigo.
Cardiac disorders: tachycardia, palpitations, pallor, Raynaud's phenomenon, facial flushing, arterial hypotension.
Respiratory, thoracic and mediastinal disorders: dyspnea, tachypnea, epistaxis, cough, nasal congestion, nasal irritation, rhinorrhea, sneezing, throat and pharynx pain, labored breathing, nasal discomfort.
Gastrointestinal disorders: abdominal pain, upper abdominal pain, vomiting, diarrhea, nausea, mouth ulcers, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorders, gastrointestinal disorders, constipation, frequent loose stools, toothache, dental disorders, stomach discomfort, mouth pain, gingivitis.
Hepatobiliary disorders: liver function disturbance, hepatomegaly.
Skin and subcutaneous tissue disorders: alopecia, rash, pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorders, nail disorders, skin color 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 – amenorrhea, menorrhagia, menstrual cycle disturbance, vaginal disorders, dysmenorrhea;
Boys – testicular pain.
General disorders and administration site conditions: injection site inflammation, injection site reaction, erythema at injection site, injection site pain, fatigue, chills, pyrexia, influenza-like symptoms, asthenia, malaise, irritability, chest pain, edema, pain, pruritus at injection site, rash at injection site, dryness at injection site, cold sensation, chest discomfort, facial pain, injection site induration.
Investigations: reduced growth velocity (reduced height and/or weight for age), increased blood thyroid-stimulating hormone levels, increased thyroglobulin levels, presence of antithyroid antibodies.
Injuries, poisoning and procedural complications: skin scratches, injury.
Use of ribavirin in combination with direct-acting antivirals
Based on a review of safety data from clinical trials of direct-acting antivirals in adults used in combination with ribavirin, the most frequently reported adverse reactions were those associated with ribavirin use: anemia, nausea, vomiting, asthenia, fatigue, insomnia, cough, dyspnea, pruritus, and rash. Except for anemia, most of these adverse reactions were non-serious and resolved without discontinuation of treatment.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
10 capsules in a blister; 3 or 6 blisters in a carton.
Prescription status. Prescription only.
Manufacturer.
LLC "FARMEKS GROUP".
Manufacturer's location and address of business activity.
100 Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.