Ribavirin-SZ - instructions for use, doses, side effects, contraindications

Ribavirin is a synthetic analogue of nucleosides, active in vitro for some RNA and DNA viruses. Signs of inhibition of enzymes specific for hepatitis C virus (HCV), or inhibition of HCV replication by either ribavirin or intracellular metabolites of ribavirin in physiological concentrations were not detected.

Monotherapy with ribavirin does not lead to the elimination of HCV (hepatitis C virus RNA) or to an improvement in the histological characteristics of the liver after 6-12 months of administration of the drug and within 6 months of follow-up.The use of ribavirin as the only therapeutic agent for hepatitis C, including chronic forms, is ineffective.

Combined treatment with ribavirin and interferon alfa-2b or peginterferon alfa-2b patients with hepatitis C are more effective than monotherapy with interferon alpha-2b or peginterferon alfa-2b. The mechanism by which ribavirin in combination with interferon alpha-2b or peginterferon alfa-2b exhibits an antiviral effect, in particular against HCV, is unknown.

Pharmacokinetics:

Suction

Ribavirin is rapidly absorbed after ingestion of a single dose of the drug (T_mOh= 1.5 h), after which it is quickly distributed in the body. Removing ribavirin from the body is slow. The values of the half-periods of absorption, distribution and excretion of a single dose are 0.05, 3.73 and 79 hours, respectively. Ribavirin absorbed almost completely: only about 10% labeled dose is released through the intestine. Nevertheless, the absolute bioavailability is approximately 45-65%. which, apparently, is associated with the effect of "primary transmission" through the liver. There is a linear relationship between dose and area under the concentration-time curve (AUC_tf) when taking ribavirin in single doses from 200 to 1200 mg.The distribution volume is approximately 5000 liters. Ribavirin does not bind to plasma proteins.

Distribution

The transfer of ribavirin outside the plasma has been studied in particular for erythrocytes. It was shown that mainly transport occurs with the participation of an equilibrium nucleoside carrier type e_s (nitrobenzylthioinosin-sensitive). The transporter of this type is present in virtually all cell types and may be the main factor affecting the distribution of ribavirin. The ratio of concentrations of ribavirin in whole blood and plasma is approximately 60: 1. The high concentration of ribavirin in whole blood is due to the accumulation of ribavirin in the erythrocytes.

Metabolism

The metabolism of ribavirin is carried out in two ways: 1) reversible phosphorylation and 2) hydrolytic reactions involving deibosylation and amide hydrolysis to form a triazole carboxyl metabolite. Ribavirin and its metabolites (triazolcarboxamide and triazolecarboxylic acid) are excreted from the body by the kidneys.

Excretion

With multiple reception ribavirin accumulates in large quantities and blood plasma: the ratio AUC_12h at repeated and single reception is equal to 6:1. When ingestion (600 mg twice a day), the equilibrium concentration of ribavirin in the plasma was reached by the end of 4 weeks and was approximately 2200 ng / ml. After discontinuation, the half-life of ribavirin was approximately 298 hours, which, apparently, reflects its delayed excretion from body fluids and tissues, excluding blood plasma.

The content of ribavirin in seminal fluid was studied. The concentration of ribavirin in the seminal fluid is approximately 2 times higher than in serum. Despite this, the systemic exposure of ribavirin in a female partner after intercourse with a patient taking ribavirin, was very low in comparison with the therapeutic concentration of ribavirin in the blood plasma.

Bioavailability of ribavirin when taking a single dose inside increases with simultaneous intake of food with a high fat content (AUC_tf and C_mOhincrease by 70%). Perhaps the increased bioavailability in this study was due to delayed intestinal transit of ribavirin or an altered pH.

The clinical significance of the results of a single dose study is unknown.In a clinical study evaluating the efficacy to achieve the maximum concentration of ribavirin in the blood plasma, patients were recommended to take ribavirin at the same time as food.

The pharmacokinetics of ribavirin after single dose administration in patients with renal insufficiency in comparison with the control group (creatinine clearance> 90 ml / min) changes, namely an increase AUC and the maximum concentration of ribavirin in the blood (C_mOh). This change is most likely due to a decrease in the true clearance in these patients. The concentration of ribavirin in plasma during hemodialysis does not change significantly.

The pharmacokinetics of ribavirin in single dose patients with mild, moderate or severe hepatic impairment (classes A, B or C according to the Child-Pugh classification) is similar to the pharmacokinetics of ribavirin in healthy volunteers.

A separate assessment of pharmacokinetic parameters in elderly patients (over 65 years) not carried out. However, in pharmacokinetic studies of the population, age was not a key factor affecting the pharmacokinetics of ribavirin.The main factor affecting the pharmacokinetics of ribavirin is the function of the kidneys.

Pharmacokinetic analysis of the population was carried out using randomly selected values of ribavirin concentration in serum but given in four clinical studies.

The developed model of clearance showed that the main covariants were body weight, sex, age and creatinine concentration in the blood serum.

In men The clearance was 20% higher than that of women. Clearance increased from body weight and declined at the age of over 40. The effect of these covariants on ribavirin clearance is of limited clinical relevance due to significant residual variability not accounted for by the dianum model.

Pharmacokinetic parameters of ribavirin in children from 3 to 18 years similar to those of adults.

Indications:

Triple therapy:

Treatment of chronic viral hepatitis C (genotype 1 of the hepatitis C virus) in combination with bocetrevir and peginterferon alfa-2b in adults (18 years and older) with compensated liver disease who had not previously received antiviral therapy, or in patients in whom previous antiviral treatment was ineffective.

Double therapy:

Treatment of chronic viral hepatitis C in adult patients and children from 3 to 18 years only in combination with interferon alpha-2b or peginterferon alfa-2b. The drug Ribavirin-SZ as a monotherapy is not applied.

Patients who had not previously received therapy

Adults

triple therapy - treatment of chronic viral hepatitis C (genotype 1 of the hepatitis C virus) in combination with peginterferon alfa-2b and bocetrevir in adults with compensated liver disease;
double therapy - treatment of chronic viral hepatitis C in combination with interferon alpha-2b or peginterferon alfa-2b in adult patients seropositive to hepatitis C virus RNA, showing no signs of decompensation of liver disease, with increased activity of ALT that had not previously received therapy;
double therapy - treatment of chronic viral hepatitis C in combination with peginterferon alfa-2b in adult patients with compensated cirrhosis and / or clinically stable HIV infection.

Children from 3 to 18 years old

double therapy - treatment of chronic viral hepatitis C in combination with interferon alpha-2b (preparation Intron® A) or peginterferon alfa-2b in children (from 3 years old), seropositive to RNA of hepatitis C virus,no signs of decompensation of liver disease, which had not previously been treated.

When deciding whether to treat pediatric patients, it is important to consider that combination therapy may cause growth retardation in some patients in childhood. The decision on the appointment of treatment should be made on a case-by-case basis (see section "Special instructions").

Patients who received previous therapy

Adults

triple therapy - treatment of chronic viral hepatitis C (genotype 1 of the hepatitis C virus) in combination with peginterferon alfa-2b and bocetrevir in adults with compensated liver disease in whom previous antiviral treatment was ineffective;
dual therapy - treatment of chronic viral hepatitis C in combination with peginterferon alfa-2b in adult patients in whom prior interferon-alpha (pegylated or non-pegylated) therapy with ribavirin or interferon monotherapy proved ineffective;
double therapy - treatment of chronic viral hepatitis C in adult patients in combination with interferon alpha-2b,previously received interferon alfa monotherapy (with the normalization of ALT activity at the end of the treatment course), who subsequently developed a relapse of the disease.

When prescribing combination therapy, it is also necessary to follow the instructions for the medical use of interferon alfa-2b, peginterferon alfa-2b and boceprevir.

Contraindications:

- Hypersensitivity to ribavirin or any other component of the drug;

- pregnancy and the period of breastfeeding (see the section on "Application during pregnancy and during breastfeeding");

- children under 3 years of age and body weight less than 25 kg;

- severe heart diseases, including unstable and uncontrolled forms that existed for at least 6 months prior to treatment (see section "Special instructions");

- severe depression, suicidal thoughts or attempts, including anamnesis (only for children 3 to 18 years old);

- chronic renal failure, creatinine clearance below 50 ml / min, the need for hemodialysis;

- severe violations of liver function (classes B or C according to the Child-Pugh classification) or decompensated cirrhosis of the liver;

- hemoglobinopathies (for example, thalassemia, sickle cell anemia);

- cirrhosis of the liver with hepatic insufficiency in patients with HCV / HIV co-infection (Child-Pugh index> 6);

- diseases of the thyroid gland, if they are not amenable to drug correction;

- autoimmune hepatitis or other autoimmune diseases;

- rare hereditary diseases, such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption;

- patients with severe debilitating diseases.

Carefully:

- Diseases of the cardiovascular system (not related to the categories indicated in the contraindications);

- severe lung diseases (eg, chronic obstructive pulmonary disease);

- diabetes mellitus with ketoacidotic coma;

- disorders associated with the coagulating system of blood (for example, with thrombophlebitis, pulmonary embolism) or significant oppression of the hematopoietic function of the bone marrow;

- combined treatment with HAART (highly active antiretroviral therapy) with concomitant HIV infection (due to toxic effects on the mitochondrial apparatus and an increased risk of lactic acidosis);

- severe depression, suicidal thoughts or attempts, including on anamnesis (adults only).

Pregnancy and lactation:

Pregnancy

During pregnancy, the use of the drug Ribavirin-SZ is contraindicated.

Fertility

Preclinical data:

- Fertility: in animal studies ribavirin had a reversible effect on spermatogenesis.

- Teratogenicity: in the studies, a significant teratogenic and / or embryocidal potential of ribavirin was demonstrated in all animal species, with a minimum dose of ribavirin one-twentieth of the recommended human dose.

- Geneticity: ribavirin induces genotoxicity.

Women of childbearing age / contraception of women and men

Female Patients: drug Ribavirin-SZ is contraindicated for use in pregnant women (see section "Contraindications"). It is necessary to take special measures to avoid the onset of pregnancy in patients. Treatment with Ribavirin-SZ should not be started before receiving a negative pregnancy test. Women of childbearing age should use effective contraception during treatment and within 4 months after completion of therapy; pregnancy tests should be conducted monthly.If during pregnancy or within 4 months after it comes pregnancy, the patient should be warned about the risk of significant teratogenic effects of ribavirin on the fetus.

Male patients and their female partners: is necessary take special measures to avoid pregnancy in partners of male patients taking Ribavirin-SZ. The accumulation of ribavirin occurs intracellularly, while it is very slowly excreted from the body. It is not known whether ribavirin, falling into the semen, teratogenic or genotoxic effects on the human embryo / fetus. According to some 300 pregnancies, in which the child's father took ribavirin, there was no increased risk of developing fetal pathologies or any special type of intrauterine development disorder compared to the general population. Nevertheless, male patients or their female partners should use effective contraception during treatment with Ribavirin-SZ and within 7 months after treatment. Male patients, whose female partners are pregnant, need to use a condom to minimize the transfer of ribavirin to the partner.

Breastfeeding period

It is not known whether ribavirin with breast milk. Because of possible adverse reactions in infants with breastfeeding before starting therapy, breastfeeding should be discontinued.

Dosing and Administration:

Inside. The dose of Ribavirin-C3 is calculated based on the patient's body weight. Capsules of the drug Ribavirin-SZ should be taken orally every day (morning and evening) while taking the food. Special precautions for the destruction of unused medicinal product is not required.

Treatment should begin and then constantly monitor the therapist with experience in the treatment of chronic hepatitis C.

The drug Ribavirin-SZ should be used in combination with peginterferon alfa-2b or interferon alpha-2b (dual therapy) or in adult patients with chronic hepatitis C of genotype 1 in combination with boceprevirov and peginterferon alfa-2b (triple therapy). Information on the use of boceprevir, peginterferon alfa-2b or interferon alfa-2b is presented in the instructions for the use of these medicines.

Recommended doses

Adult patients

The dose of Ribavirin-SZ is calculated based on the patient's body weight (Table 1). The drug Ribavirin-SZ should be used in combination with peginterferon alfa-2b (1.5 mcg / kg / week) or interferon alfa-2b (3M ME 3 times a week). The choice of the combined scheme is based on the features of the patient's illness. The drugs used should be selected based on the perceived efficacy and safety of the combination therapy individually for each patient. Information on the use of boceprevir in triple therapy is provided in the instruction manual for the use of bocetrevira.

Table 1. Dose of Ribavirin-C3 on the basis of body weight for patients with HCV only or co-infection with HCV / HIV of any genotype

Body weight of the patient (kg)	The daily dose of Ribavirin-SZ	Mode dosing
<65	800 mg	400 mg in the morning 400 mg in the evening
65-80	1000 mg	400 mg in the morning 600 mg in the evening
81 - 105	1200 mg	600 mg in the morning 600 mg in the evening
> 105	1400 mg	600 mg in the morning 800 mg in the evening

Ribavirin-C3 in capsules in combination with bocetrevir and peginterferon alfa-2b or only with peginterferon alfa-2b:

Duration of treatment. Patients who had not previously received therapy

Triple therapy:

Information is provided in the instructions for the use of preparations of bocepreviir and peginterferon alfa-2b.

Double therapy with peginterferon alfa-2b:

The ability to predict a sustainable virologic response: It is unlikely that patients infected with the genotype 1 virus who can not reach undetectable HCV RNA in the blood or demonstrate an adequate virologic response at 4 or 12 weeks have achieved a sustained virologic response. These patients should be considered the probability of withdrawal of treatment.

- Genotype 1:

In patients in whom HCV RNA is not determined at week 12, treatment should continue for another 9 months (ie, only 48 weeks).
In patients with a detectable, but ≥ 2 log₁₀ a decrease in HCV RNA compared to baseline at week 12 of treatment should be assessed at week 24 and, if no HCV RNA is detected, the full course of therapy should be continued (ie, only 48 weeks). If HCV RNA at 24 weeks of treatment is still being determined, it is necessary to cancel therapy.
In patients with HCV genotype 1 and low viral load (<600,000 IU / mL) who are not defined for 4 and 24 weeks of HCV RNA treatment, treatment should either be discontinued after a 24-week course,or continued for an additional 24 weeks (ie, the total course duration is 48 weeks). However, a course of 24 weeks may be associated with a higher risk of recurrence than a course lasting 48 weeks.

- Genotype 2 or 3. For all patients, dual therapy is recommended for 24 weeks, except for patients with HCV / HIV co-infection, for whom the course of treatment should be 48 weeks.

- Genotype 4. In general, it is believed that patients who have a genotype 4 HCV are more difficult to treat. The limited data from the study (n = 66) indicate that such patients can undergo a course of therapy that is equivalent to the course for patients with HCV genotype I.

Duration of treatment. Patients with HCV / HIV co-infection who had not previously received therapy

Double therapy:

The recommended duration of treatment with Ribavirin-SZ in a dose calculated on the basis of body weight (see Table 1) in patients with co-infection with HCV / HIV is 48 weeks of dual therapy, regardless of the HCV genotype.

The possibility of predicting the response and its absence in patients with HCV / HIV co-infection who had not previously received treatment

Early virologic response at week 12, defined as 2 log₁₀a reduction in viral load or undetectable HCV RNA values, is an indicator of a sustained response. Negative predictive response in patients with HCV / HIV co-infection who received ribavirin in combination with peginterferon alfa-2b, was 99% (67/68). A positive value from a predictable response of 50% was observed in patients with co-infection with HCV / HIV who received double therapy (52/104).

Duration of treatment. Patients receiving re-treatment

Triple therapy:

See instructions for use of the medicinal products of boceprevir and peginterferon alfa-2b.

Double therapy with peginterferon alfa-2b:

The ability to predict a sustainable virologic response: all patients, regardless of the HCV genotype, whose serum HCV RNA value was below detection limits at 12 weeks, should receive treatment within 48 weeks.

It is unlikely that a virologic response will be reached at week 48 of the therapy in patients previously treated who did not achieve a virologic response (ie HCV RNA value below the detection limit) at week 12.

Repeated treatment lasting more than 48 weeks in patients with HCV genotype 1 without responding to previous therapy using combination therapy with pegylated interferon alfa-2b and ribavirin has not been studied.

Ribavirin-C3 in capsules in combination with interferon alpha-2b (only double therapy):

The duration of treatment with interferon alpha-2b:

Based on the results of clinical studies, patients are advised to receive double therapy for at least 6 months. During clinical trials lasting 1 year, for patients who did not achieve a virologic response at 6 months of treatment (ie, HCV RNA values below detection limits), the likelihood of further virologic response was extremely low (i.e., value HCV RNA is below detection limits 6 months after discontinuation of treatment).

- Genotype 1. Dual therapy should continue for another 6 months (ie, only 1 year) in patients with no HCV RNA 6 months after treatment.

- Genotypes other than 1. The decision to prolong the dual therapy to 1 year in patients with no HCV RNA after 6 months of treatment should be due to other prognostic factors (for example, age> 40 years, male sex, bridging liver fibrosis).

Children from 3 to 18 years (double therapy)

The dose of Ribavirin-SZ for children 3 to 18 years of age should be calculated on the basis of body weight, the dose of peginterferon alfa-2b and interferon alfa-2b (preparation Intron ® A) - based on body surface area.

Dose for combination therapy with peginterferon alfa-2b in children from 3 to 18 years: The recommended dose of peginterferon alfa-2b is 60 μg / m²/ week subcutaneously in combination with the drug Ribavirin-SZ 15 mg / kg / day (Table 2).

Dose for combination therapy with interferon alpha-2b (with Intron® A) in children from 3 to 18 years:

In clinical studies conducted in this patient population, ribavirin and interferon alfa-2b were used at a dose of 15 mg / kg / day and 3 million IU / m² 3 times a week, respectively (Table 2).

Table 2. The dose of Ribavirin-SZ on the basis of body weight when used as a combination therapy with interferon alfa-2b (by Intron ® A) or peginterferon alfa-2b in children from 3 to 18 years

Body weight of the patient (kg)	The daily dose of Ribavirin-SZ	Dosing regimen
25-36	400 mg	200 mg in the morning, 200 mg in the evening
37-49	600 mg	200 mg in the morning, 400 mg in the evening
50-65	800 mg	400 mg in the morning, 400 mg in the evening
>65	See table for calculating doses for adult patients (Table 1)

Duration of treatment in children from 3 to 18 years

- Genotype 1: the recommended duration of dual therapy is 1 year. In clinical trials of combination therapy with standard interferon in children 3 to 18 years of age (negative predictive value for interferon alpha-2b / Ribavirin-C3 is 96%), it was found that if patients do not receive a virologic response at week 12, later the answer will not be achieved. Therefore, it is recommended that in children aged 3 to 18 years who receive combination therapy in the form of interferon alpha-2b (pegylated or non-pegylated) and Ribavirin-C3, this treatment was reversed if at 12 weeks the HCV RNA value decreased by <2 log₁₀ compared with the value before treatment, or if at the 24th week of treatment they are determined by HCV RNA.

- Genotype 2 or 3: the recommended duration of dual therapy is 24 weeks.

- Genotype 4: in the clinical study of the use of peginterferon alfa-2b / Ribavirin-SZ only 5 children from 3 to 18 years of age with HCV genotype 4 participated. The recommended duration of double therapy is 1 year.Treatment with peginterferon alfa-2b / Ribavirin-SZ in children 3 to 18 years of age should be discontinued if the HCV RNA value at 12 weeks decreased <2 log₁₀ compared with the value before treatment, or if at the 24th week of treatment they are determined by HCV RNA.

Dosage adjustment for all patients

Combination therapy:

If the use of combination therapy with Ribavirin-SZ and peginterferon alfa-2b or interferon alpha-2b, or Ribavirin-C3 and peginterferon alfa-2b and boceprevir, serious adverse reactions or deviations in these laboratory tests are observed, it is necessary to change the doses according to Table 3, if possible, until the reactions disappear completely. Decreasing the dosage of boceprevir is not recommended. In clinical studies for dose modification guidelines have been developed (Table 3). Since strict adherence to the regimen is very important for its outcome, the dose should be as close as possible to the recommended standard dose. It should be taken into account the possible negative effect of reducing the dose of ribavirin on the effectiveness of treatment.

Table 3.Methodical instructions for changing the doses of combination therapy on the basis of laboratory data

Laboratory indicators	Reduction of the dose of only the drug Ribavirin-SZ (see Fig. Note 1) if:	Dose reduction only interferon alpha-2b or peginterferon alfa-2b (see Note 2), if:	*Termination of therapy, if :**
Concentration hemoglobin	< 100 g / l	-	< 85 g / l
Adults: Concentration of hemoglobin in patients with heart disease in stable form	The concentration of hemoglobin decreased by > 20 g / L for any 4 weeks during treatment (continuous use of a reduced dose)		< 120 g / L 4 weeks after dose reduction
Children from 3 to 18 years old Concentration of hemoglobin	Not applicable (see section "Special instructions")
Number of leukocytes	-	< 1.5 x 10⁹ l	<1.0 x 10⁹ l
Number of neutrophils	-	<0.75 x 10⁹ l	< 0,5 < 10⁹ l
Platelet count	-	Adults: < 50 x 10⁹ l Children from 3 to 18 years old: < 70 x 10⁹l	Adults: <25 x 10⁹ l Children from 3 to 18 years: <50 x 10⁹ l
Concentration of bound bilirubin	-	-	2.5 x VGN **
Concentration free bilirubin	> 0.05 g / l	-	for> 4 weeks Adults: 0.04 g / l Children from 3 to 18 years old: when treating interferon alpha-2b 0.05 g / l when treated with peginterferon alfa-2b 0.04 g / l
Concentration creatinine	-	-	> 0.02 g / l
Creatinine clearance	-	-	Discontinue Ribavirin-C3 if <50 ml / min
Alaninaminotransferase or Aspartate aminotransferase	-	-	2 x (basic value) and> 10 x VGN or 2 x (basic value) and > 10 x VGN

*Cm. criteria for dose changes and withdrawal of peginterferon alfa-2 medicinesb and interferon alfa-2b in the instructions for the use of these medicines.

** VGN - the upper limit of the norm.

Note 1: in adult patients, the first dose reduction of Ribavirin-C3 is 200 mg / day (in patients taking 1,400 mg per day, the dose reduction should be 400 mg / day). If necessary, a second reduction in the dose of Ribavirin-C3 is an additional 200 mg / day. Patients in whom the daily dose of Ribavirin-C3 is reduced to 600 mg, take 200 mg / day in the morning and 400 mg in the evening.

In children from 3 to 18 years old, taking the drug Ribavirin-SZ and peginterferon alfa-2b, the first reduction in the dose of Ribavirin-SZ is up to 12 mg / kg / day. The second reduction in the dose of Ribavirin-SZ is up to 8 mg / day / day. In children from 3 to 18 years old, taking the drug Ribavirin-SZ and interferon alfa-2b, the dose of Ribavirin-C3 is reduced to 7.5 mg / kg / day.

Note 2: in adult patients taking Ribavirin-SZ and peginterferon alfa-2b, the first reduction in the dose of peginterferon alfa-26 is up to 1 μg / kg / week. If necessary, a second dose reduction of peginterferon alfa-2b - up to 0.5 mcg / kg / week.

In children aged 3 to 18 years taking Ribavirin-C3 and peginterferon alfa-2b, the first reduction in the dose of peginterferon alfa-2b is up to 40 μg / m²/ week, the second reduction in the dose of peginterferon alfa-2b is up to 20 μg / m²/a week.

In adults and children from 3 to 18 years of age, taking the drug Ribavirin-SZ and interferon alfa-2b, should reduce the dose of interferon alfa-2b in 2 times.

Special patient groups

Application for renal dysfunction

The pharmacokinetics of ribavirin is altered in patients with impaired renal function due to a decrease in the apparent clearance of creatinine in these patients. Thus, before starting therapy with the drug Ribavirin-SZ, it is recommended to evaluate the kidney function in all patients. Patients with creatinine clearance <50 ml / min can not take Ribavirin-SZ (see "Contraindications"), Patients with impaired renal function should be under more careful control for the development of anemia. If the serum creatinine concentration increases to> 0.02 g / l (Table 3), then treatment with Ribavirin-SZ and peginterferon alfa-2b/ interferon alpha-2b necessary cancel.

Application for violations of liver function

There is no pharmacokinetic relationship between ribavirin intake and liver function. Thus, there is no need to adjust the dose of Ribavirin-C3 in patients with impaired liver function. The use of ribavirin is contraindicated in patients with severe hepatic impairment or decompensated liver cirrhosis (see section "Contraindications").

Application in the elderly (over 65 years)

There is no significant dependence of the pharmacokinetics of ribavirin on the patient's age. However, as in younger patients, before starting to use Ribavirin-C3 it is necessary to evaluate the kidney function.

Use in patients younger than 18 years of age

The drug Ribavirin-SZ can be used in combination with peginterferon alfa-2b or interferon alpha-2b in children from 3 to 18 years. Safety and effectiveness of Ribavirin-SZ in combination with other forms of interferon (ie, not alpha-2b) in this category of patients have not been studied.

Patients with co-infection with HCV / HIV

In patients taking nucleoside reverse transcriptase inhibitors (NRTIs) in combination with ribavirin and interferon alpha-2b or peginterferon alfa-2b, there may be an increased risk of developing mitochondrial toxicity, lactate acidosis and decompensation of liver diseases (see section "Special instructions"). It is necessary to read the instructions for the medical use of these medicines.

Side effects:

Adult patients

Triple therapy

See the instructions for the medical use of bocetrevira.

Double Therapy

The safety of ribavirin was evaluated according to four clinical studies in patients who had not previously taken interferon alfa-2b (patients who had not previously received interferon therapy): two studies examined the use of ribavirin in combination with interferon alpha-2b, in two - in combination with peginterferon alfa-2b.

In patients who previously received interferon alfa-2b and ribavirin or whose treatment lasted less than the standard time, an improved safety profile could be observed compared to the one described below. The adverse reactions listed below are based on clinical trials in adult patients who did not take interferon for at least 1 year and on the basis of the application data in the post-marketing period.

A number of unwanted reactions commonly attributed to interferon therapy, but also registered with hepatitis C therapy (in combination with ribavirin) are also presented below. Data on adverse reactions presented in the instructions for the medical use of peginterferon alfa-2b and interferon alfa-2b, may also be applicable to monotherapy with interferons.

Undesirable reactions are represented by the classes of organs and systems in order of decreasing frequency in accordance with the following categories: very often (≥1 / 10); often (≥1 / 100 to <1/10); infrequently (≥1 / 1000 to <1/100); rarely (≥1 / 10000 to <1/1000); very rarely (<1/10000); is unknown. In each group of frequencies, undesirable reactions are presented in order of decreasing severity.

Infectious diseases: very often - viral infections, pharyngitis; often bacterial infections (including sepsis), fungal infection, influenza, respiratory tract infections, bronchitis, infection caused by herpes simplex virus, sinusitis, otitis media, rhinitis, urinary tract infection; infrequently - infections at the injection site, infection of the lower respiratory tract; rarely - pneumonia *.

Neoplasms are benign, malignant and unspecified (including cysts and polyps): often - unspecified neoplasms.

Disorders from the blood and lymphatic system: very often - anemia, neutropenia; often - hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia; very rarely aplastic anemia *; unknown - true erythrocyte aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

From the immune system: infrequently - hypersensitivity; rarely - sarcoidosis *; Rheumatoid arthritis (first arising or worsening of the condition); unknown - Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions, including hives, angioedema, bronchospasm, anaphylaxis.

From the endocrine system: often - hypothyroidism, hyperthyroidism.

From the side of metabolism and nutrition: very often - anorexia; often - hyperglycemia, hyperuricemia, hypocalcemia, dehydration, increased appetite; infrequently - diabetes, hypertriglyceridemia *.

From the side of the psyche: very often - depression, insomnia, emotional lability, anxiety; often - suicidal thoughts, psychosis, aggressive behavior, confusion, agitation, anger,mood changes, pathological behavior, nervousness, sleep disorders, decreased libido, apathy, anxious dreams, tearfulness; infrequently suicidal attempts, panic attack, hallucinations; rarely - bipolar disorder *; very rarely - suicide *; unknown - homicidal thoughts *, mania *, change in mental status.

From the nervous system: very often - headache, dizziness, dry mouth, violation of concentration of attention; often - amnesia, memory impairment, syncope, migraine, ataxia, paresthesia, dysphonia, loss of taste, hypoesthesia, hyperesthesia, hypertonia, drowsiness, attention disturbance, tremor, taste perversion; infrequently - neuropathy, peripheral neuropathy; rarely convulsive seizures (convulsions) *; very rarely - cerebral hemorrhage *, cerebrovascular ischemia *, encephalopathy *, polyneuropathy *; unknown - paralysis of the facial nerve, mononeuropathy.

From the side of the organ of vision: often - impaired vision, blurred vision, conjunctivitis, eye irritation, eye pain, distortion of visual perception, lacrimal gland pathology, dry eyes; rarely - haemorrhage in the retina *, retinopathy (including macular edema) *,thrombosis of retinal arteries *, retinal vein thrombosis *, optic neuritis *, optic disc swelling *, visual acuity reduction or loss of visual fields *, exudate in the retina.

From the organs of hearing and balance: often - vertigo, disorder or loss of hearing, ringing in the ears, pain in the ears.

From the heart: often - a feeling of palpitations, tachycardia; infrequently, myocardial infarction; rarely - cardiomyopathy, arrhythmia *: very rarely - ischemia of the heart *; unknown - pericardial effusion *, pericarditis *.

From the side of the vessels: often - lowering blood pressure, increasing blood pressure, "hot flashes"; rarely - vasculitis; very rarely - ischemia of peripheral tissues *.

On the part of the respiratory system, the organs of the thorax and the mediastinum: very often - shortness of breath, cough; often - nosebleeds, respiratory disorders, airway obstruction, sinusitis, edema of the nasal mucosa, rhinorrhea, increased secretion of the mucous membrane of the upper respiratory tract, sore throat, unproductive cough; very rarely - pulmonary infiltrates *, pneumonitis *, interstitial pneumonitis *.

From the gastrointestinal tract: very often - diarrhea, vomiting, nausea, abdominal pain; often ulcerative stomatitis, stomatitis, ulcers in the oral cavity, colitis, pain in the right upper quadrant of the abdomen, dyspepsia, gastrointestinal reflux *, glossitis, cheilitis, bloating, bleeding gums, gingivitis, frequent loose stools, dental lesions, constipation, flatulence; infrequently - pancreatitis, pain in the oral cavity; rarely - ischemic colitis; very rarely - ulcerative colitis *; it is not known - violations from the periodontal, dental disorders, pigmentation of the tongue.

From the hepatobiliary system: often - hepatomegaly, jaundice, hyperbilirubinemia *; very rarely - hepatotoxicity (including fatal) *.

From the skin and subcutaneous fat: very often - alopecia, itching, dry skin, rash; often psoriasis, worsening of the already existing psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furunculosis, erythema, urticaria, skin disorders, bruising, sweating, hair structure disorder, violations of the nails *; rarely - sarcoidosis of the skin; very rarely - Stevens-Johnson syndrome *, toxic epidermal necrolysis *, multiforme exudative erythema *.

From the musculoskeletal system and connective tissue: very often - arthralgia, myalgia, pain in muscles and bones; often - arthritis, back pain, muscle spasms, pain in the limbs; infrequently - pain in the bones, muscle weakness; rarely rhabdomyolysis *, myositis *.

From the kidneys and urinary system: often - frequent urination, polyuria, impaired urine output; rarely - renal dysfunction, kidney failure *; very rarely - nephrotic syndrome *.

From the side of the system of reproductive organs and mammary glands: often - women: amenorrhea, menorrhagia, menstrual irregularity, dysmenorrhea, pain in the mammary glands, dysfunction of the ovaries, vaginal dysfunction; men: impotence, prostatitis, erectile dysfunction, sexual dysfunction (without specifying an exact diagnosis) *.

On the part of the body as a whole, as well as reactions at the site of administration: very often - inflammation at the injection site, reactions at the injection site, fatigue, chills, fever, flu-like symptoms, asthenia, irritability; often - chest pain, chest discomfort, peripheral edema, malaise, pain at the injection site, sensory disturbance, thirst; infrequently - swelling of the face; rarely - necrosis of the injection site.

Laboratory and instrumental data: very often - weight loss; often - heart murmur.

*Because the ribavirin is always prescribed in combination with interferon alpha, and listed undesirable reactions are registered in the post-marketing period, the frequency of reactions can not be determined. The frequency indicated above is based on clinical trials of ribavirin in combination with interferon alfa-2b (pegylated or non-pegylated).

In 30% of patients who took ribavirin and peginterferon alfa-2b, and in 37% of patients taking ribavirin and interferon alfa-2b, a decrease in hemoglobin concentrations of more than 4 g / dl was observed.

In 14% of adult patients and in 7% of children from 3 to 18 years of age who took ribavirin in combination with peginterferon alfa-2b or interferon alpha-2b, the concentration of hemoglobin decreased to 10 g / dL and lower.

In most cases, mild degrees of anemia, neutropenia and thrombocytopenia (1 or 2 degrees on the WHO scale) have been reported. Some cases of severe neutropenia in patients taking ribavirin in combination with peginterferon alfa-2b (WHO scale, grade 3: 39 of 186 [21%], and the WHO scale, grade 4: 13 of 186 [7%], grade 3 leukopenia on the WHO scale was reported in 7% of patients in this group.

An increase in the concentrations of uric acid and indirect bilirubin associated with hemolysis was observed in some patients taking ribavirin in combination with peginterferon alfa-2b or interferon alpha-2b in clinical trials, but 4 weeks after the end of treatment, the concentrations returned to baseline values. In a few cases, gout was recorded among patients with elevated uric acid concentrations, but none of them required treatment change, and no one was excluded from clinical studies.

Patients with co-infection with HCV / HIV

In patients with co-infection with HCV / HIV receiving ribavirin in combination with peginterferon alfa-2b, other undesirable reactions (not observed in patients with hepatitis C alone), whose frequency was> 5%, were: oral candidiasis (14%), acquired lipodystrophy (13%), decreased lymphocyte concentration Cd4 (8%), decreased appetite (8%), increased activity of gamma-glutamyltransferase (9%), back pain (5%), increased blood amylase activity (6%), increased lactic acid concentration in the blood (5% ), cytolytic hepatitis (6%), increased lipase activity (6%), and pain in the extremities (6%).

Mitochondrial toxicity

Mitochondrial toxicity and lactate acidosis have been reported in HIV-positive patients taking NRTI and ribavirin for the treatment of hepatitis C (see section "Special instructions").

Laboratory indicators in patients with co-infection with HCV / HIV

Although hematological abnormalities in the form of neutropenia, thrombocytopenia and anemia were more common in patients with HCV / HIV co-infection, most of these reactions were amenable to dose adjustment and rarely required the withdrawal of therapy (see section "Special instructions").

Hematologic disorders were more often recorded in patients who took ribavirin in combination with peginterferon alfa-2bthan in patients taking ribavirin in combination with interferon alpha-2b. According to the study, a decrease in the absolute number of neutrophils below 500 cells / mm³, as well as a decrease in the number of platelets below 50,000 / mm³ was observed in 4% (8/194) of patients taking ribavirin in combination with peginterferon alfa-2b. Anemia (hemoglobin <9.4 g / dl) was recorded in 12% (23/194) of patients taking ribavirin in combination with peginterferon alfa-2b.

Decrease in the number of lymphocytes Cd4

Treatment with ribavirin in combination with peginterferon alfa-2b was associated with a decrease in the absolute number of cells Cd4+ for the first 4 weeks without decreasing the percentage of cells Cd4+. Reduction in the number of cells Cd4+ was reversible after dose reduction or discontinuation of therapy. The use of ribavirin in combination with peginterferon alfa-2b did not have a significant adverse effect on HIV viremia control during or after treatment. Safety data for patients with co-infection with the number of cells Cd4+ <200 / μL are limited (n= 25) (see section "Special instructions").

With the joint intake of antiretroviral drugs and drugs for the treatment of HCV to detect the specific toxicity of each drug and the development of cross-reactivity of the drug Ribavirin-SZ and peginterferon alfa-2b should read the instructions for the medical use of each of the drugs used.

Children from 3 to 18 years (only double therapy):

In combination with peginterferon alfa-2b

In a clinical study in 107 children (3 to 18 years) who received combination therapy with peginterferon alfa-2b and ribavirin, dose changes were required in 25% of cases, mostly due to anemia, neutropenia and weight loss.

In general, the profile of adverse reactions in children corresponded to the profile observed in adults, although there was a possibility of growth retardation.

During combined therapy with pegylated interferon alpha-2b and ribavirin for up to 48 weeks, a decrease in the rate of growth was observed, which led to the growth of some patients was below the norm (see section "Special instructions").

Weight loss and growth retardation were very frequent during treatment (at the end of treatment, the average decrease from the initial body weight and growth was 15 and 8 percentile, respectively); The growth rate (<third percentile in 70% of patients) also decreased.

At the end of 24 weeks of follow-up after treatment, the mean decrease from baseline body weight and height was 3 and 7 percentile, respectively, and a decrease in growth rate (<3rd percentile) was observed in 20% of children.

94 of 107 children participated in a five-year long-term study followed by follow-up.The effect of the drug on growth was lower in children treated for 24 weeks, compared with children treated for 48 weeks. From the moment before the start of treatment to the end of the observation, the percentile of growth in children treated for 24 and 48 weeks decreased by 1.3 and 9.0 percentile, respectively. Decreased growth in 24% of children (11/46) who received treatment within 24 weeks, and 40% of children (19/48) who received treatment for 48 weeks reached more than 15 percentile from the time before treatment until the end of a five-year study followed by follow-up compared to baseline. U 11% of children (5/46) who received therapy for 24 weeks and 13% of children (6 of 48) who received therapy for 48 weeks had a decrease in growth relative to the baseline by more than 30 percent of the growth-to-age ratio from the time before treatment, until the end of a five-year study followed by follow-up. From the time before treatment to the end of the five-year study followed by observation, weight loss was 1.3 percentile in children treated for 24 weeks and 5.5 percentile in children treated for 48 weeks.The body mass index decreased by 1.8 and 7.5 percentile, respectively.

In this study, the most common reactions in all patients were fever (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%) and redness at the injection site (29%).

Only in 1 patient treatment was discontinued as a result of the development of an undesirable reaction (thrombocytopenia). Most of the adverse reactions reported in this study were mild or moderate. Severe adverse reactions were reported in 7% (8/107) of cases and included pain at the injection site (1%), pain in the extremities (1%), headache (1%), neutropenia (1%) and fever (4% ). Significant adverse reactions in this patient population were nervousness (8%), aggression (3%), anger (2%), depression / depressed mood (4%) and hypothyroidism (3%). Five patients took levothyroxine for hypothyroidism / increased thyroid stimulating hormone (TSH).

In combination with interferon alpha-2b

In clinical studies, 118 children aged 3 to 16 years who received combination therapy with interferon alfa-2b and ribavirin, in 6% of the treatment was discontinued due to adverse reactions.In general, the profile of adverse reactions in a limited population of children between 3 and 18 years old was similar to the profile observed in adults, but there were concerns about the growth retardation in the children's population, as the growth rate (average 9-percentile reduction) body weight (mean weight loss of 13 percentile). During 5 years of follow-up, the average increase in children was 44 percentile, which was below the average for a normal population and less than their average initial growth (48 percentile). Twenty (21%) of 97 children had> 15 percentile growth decline, of which 10 out of 20 children had> 30 percentile reduction in growth from the start of treatment to the end of long-term follow-up (up to 5 years). For 14 of these patients, the total growth in adulthood (10-12 years after the end of therapy) is known, which showed that 12 patients had a growth deficit (more than 15 percentile). During combined therapy with interferon alpha-2b and ribavirin for up to 48 weeks, there was a decrease in growth rate, which led to the growth of some patients to adulthood was below normal.Decrease in the average growth percentile in comparison with the initial value at the end of the long-term follow-up period prevailed in pre-pubertal children (see section "Special instructions").

Moreover, in this group of patients suicidal ideation and suicide attempts were observed more often than in adults (2.4% versus 1%) during treatment and for 6 months of follow-up. As in adult patients, children from 3 to 18 years also developed other mental disorders (eg, depression, emotional lability, and drowsiness) (see section "Special instructions"). In addition, injection site lesions, fever, anorexia, vomiting, and emotional lability were more common in children 3 to 18 years of age compared with older patients. Dose changes were required in 30% of cases, mainly due to anemia and neutropenia.

The adverse reactions listed below are based on two multicenter clinical trials of ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b in children from 3 to 18 years.

Undesirable reactions are represented by the classes of organs and systems in order of decreasing frequency,in accordance with the following categories: very often (> 1/10); often (> 1/100 to <1/10); infrequently (> 1/1000 to <1/100). In each group of frequencies, undesirable reactions are presented in order of decreasing severity.

Infectious diseases: very often - a viral infection, pharyngitis; often fungal infection, bacterial infection, lung infections, nasopharyngitis, streptococcal pharyngitis, otitis media, sinusitis, tooth abscess, influenza, herpes simplex, infections caused by the herpes simplex virus, urinary tract infections, vaginitis, gastroenteritis; infrequently - pneumonia, ascariasis, enterobiasis, shingles, cellulite.

Neoplasms are benign, malignant and unspecified (including cysts and polyps): often - unspecified neoplasms.

Disorders from the blood and lymphatic system: very often - anemia, neutropenia; often - thrombocytopenia, lymphadenopathy.

From the endocrine system: very often - hypothyroidism; often - hyperthyroidism, virilism.

From the side of metabolism and nutrition: very often - anorexia, decreased appetite, increased appetite; often hypertriglyceridemia, hyperuricemia.

From the side of the psyche: very often - depression, insomnia, emotional lability; often - suicidal thoughts, aggressive behavior, confusion, emotional lability, behavioral disorder, agitation, somnambulism, anxiety, mood changes, anxiety, nervousness, sleep disturbance, pathological dreams, apathy; infrequently - behavioral disorders, depressed mood, emotional disorders, fear, anxious dreams.

From the nervous system: very often - headache, dizziness; often - hyperkinesis, tremor, dysphonia, paresthesia, hypesthesia, hyperesthesia, attention deficit disorder, drowsiness, poor sleep quality; infrequently - neuralgia, lethargy, psychomotor agitation.

From the side of the organ of vision: often - conjunctivitis, pain in the eyes, visual impairment, violations of the lacrimal glands; infrequently - hemorrhage in the conjunctiva, itching in the eyes, keratitis, blurred vision, photophobia.

From the organs of hearing and balance: often - vertigo.

From the heart: often - tachycardia, a feeling of palpitations.

From the side of the vessels: often - pallor of the skin, "hot flashes"; infrequent - lowering of blood pressure.

On the part of the respiratory system, the organs of the thorax and the mediastinum: often shortness of breath, rapid breathing, epistaxis, cough, nasal congestion, nose irritation, rhinorrhea, sneezing, sore throat; infrequently - wheezing, discomfort in the nose.

From the gastrointestinal tract: very often - abdominal pain, pain in the upper abdomen, vomiting, diarrhea, nausea; often ulcers in the oral cavity, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, disorders of the rectum, constipation, loose stools, toothache, dental abnormalities, discomfort and stomach, pain and oral cavities; infrequently - gingivitis.

From the hepatobiliary system: often - a violation of liver function; infrequently - hepatomegaly.

From the skin and subcutaneous fat: very often - alopecia, rash; often - itching, photosensitivity reaction, maculopapular rash, eczema, sweating, acne, skin diseases, nail structure disorders, skin discoloration, skin dryness, erythema, hematoma; infrequently - pathological pigmentation, atopic dermatitis, skin peeling.

From the musculoskeletal system and connective tissue: very often - arthralgia, myalgia, muscle pain; often - pain in the limbs, back pain, muscle contractures.

From the kidneys and urinary system: often - enuresis, urination disorders, urinary incontinence, proteinuria.

From the side of the system of reproductive organs and mammary glands: often - women: amenorrhea, menorrhagia, menstrual irregularities, vaginal disorders, men: pain in the testicle; infrequently - women: dysmenorrhea.

From the body as a whole: very often - inflammation at the injection site, reactions at the injection site, erythema at the injection site, pain at the injection site, fatigue, fatigue, fever, chills, flu-like symptoms, asthenia, malaise, irritability; often - pain in a difficult cage, swelling, itching at the injection site, a rash at the injection site, dryness of the injection site, a feeling of cold; infrequently - discomfort in the chest, pain in the face, sealing the injection site.

Laboratory and instrumental data: very often - a decrease in the rate of growth (a decrease in growth and / or body weight at a given age); often - increased concentration of TSH, increased concentration of thyroglobulin; infrequently - positive antibodies to the thyroid gland.

Injuries and poisonings: often - skin lesions; infrequently - concussion.Most laboratory changes in clinical trials of ribavirin / peginterferon alfa-2b were mild or moderate. Reducing the concentration of hemoglobin, leukocytes, platelets, neutrophils and an increase in bilirubin may require a reduction in dose or cancellation of therapy (see section "Method of administration and dose"). Although clinical changes in the treatment of ribavirin / peginterferon alfa-2b showed a change in laboratory values, a few weeks after the end of therapy they came to normal levels.

Overdose:

Triple therapy

Information is provided in the instructions for use of the medicinal product boceprevir.

Double Therapy

The known maximum accepted dose of ribavirin was 10 grams of ribavirin in capsules (25 capsules of 400 mg) and 39 million ME interferon alfa-2b in the form of a solution for injection (13 subcutaneous injections of 3 million ME). These quantities were administered by one patient within one day with the goal of suicide. The patient stayed for 2 days in the emergency room; During this time, no undesirable phenomena associated with overdose were observed.

Antidote is unknown, hemodialysis and peritoneal dialysis are ineffective, treatment is symptomatic.

Interaction:

Study of interaction with other medicinal means was conducted only with the participation of adult patients.

Ribavirin does not inhibit cytochrome P isoenzymes₄₅₀. According to toxic studies there is only a minimal opportunity interactions associated with cytochrome P isoenzymes₄₅₀.

Ribavirin, having an inhibitory effect on inosine monophosphate dehydrogenase, can disrupt the metabolism of azathioprine, leading to the accumulation of 6-methylthioinosine monophosphate, which promotes the appearance of myelotoxicity in patients taking azathioprine. It is necessary to avoid the simultaneous use of pegylated interferons alpha and ribavirin with azathioprine. In some cases, when the benefits of simultaneous use of ribavirin and azathioprine are greater than potential risk, careful monitoring of blood counts is recommended to identify signs of myelotoxicity. If they are present, then treatment with these drugs should be discontinued (see section "Special instructions").

Studies of the interaction of ribavirin and other drugs, with the exception of peginterferon alfa-2b, interferon alfa-2b and antacids, was not carried out.

Interferon alfa-2b: no pharmacokinetic interactions between ribavirin and peginterferon alfa-2b or interferon alpha-2b.

Antacids: with the simultaneous use of an antacid containing magnesium, aluminum or simethicone, the bioavailability of ribavirin 600 mg decreased; AUC_tf decreased by 14%. It is possible that a decrease in the bioavailability of ribavirin was due to a delay in ribavirin transport or a change in pH. This interaction is not recognized clinically significant.

Nucleoside analogues: the use of nucleoside analogs alone or in combination with other nucleosides led to the development of lactate acidosis. Ribavirin increases the number of phosphorylated metabolites of purine nucleosides in vitro. This activity may increase the risk of developing lactic acidosis caused by the analogues of purine nucleosides (for example, didanosine or abacavir).

The simultaneous use of ribavirin and didanosine is not recommended.Mitochondrial toxicity, in particular lactate acidosis and pancreatitis, has been reported, with some having a lethal outcome.

The simultaneous use of ribavirin and zidovudine is not recommended because of the increased risk of anemia (see section "Special instructions"). It is necessary to consider the possibility of substituting zidovudine in combination antiretroviral therapy (Apt), if one has already been assigned. This is especially important for patients with a history of anemia caused by zidovudine.

The possibility of interactions may persist for up to 2 months (5 half-lives of ribavirin) after discontinuing ribavirin therapy due to a long half-life.

There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or protease inhibitors.

The literature presents conflicting data on the simultaneous use of abacavir and ribavirin. Some evidence suggests that patients with HCV / HIV co-infection receiving Apt, containing abacavir, may be at risk of developing a weaker response to pegylated interferon / ribavirin therapy.Care should be taken when using these drugs at the same time.

Special instructions:

Based on the results of clinical studies, it can be argued that the use of ribavirin in the form of monotherapy is not effective and the drug Ribavirin-SZ can not be used in the form of monotherapy. Safety and efficacy were established only for combination therapy with ribavirin and solutions for injection of peginterferon alfa-2b or interferon alfa-2b.

All patients included in the study of chronic hepatitis C had liver biopsy before enrollment, but in certain cases (for example, in patients with HCV 2 and 3 genotypes) treatment can be performed without histological data. The decision on the need for a liver biopsy before treatment should be based on recommendations of current guidelines.

Violations of the psyche and violations of the central nervous system (CNS)

When combined therapy with peginterferon alfa-2b or interferon alpha-2b and even within 6 months after the abolition of treatment in some patients there were severe violations from the CNS,in particular, depression, suicidal thoughts or suicide attempts. In children from 3 to 18 years old who took ribavirin in combination with interferon alpha-2b, suicidal ideation or suicide attempts were more frequent than in adults (2.4% versus 1%) during treatment and during the subsequent 6-month follow-up period. As in adults, children from 3 to 18 years of age experienced other undesirable mental reactions (eg, depression, emotional lability, and drowsiness). Other CNS effects, including aggressive behavior (sometimes directed against others, for example, homicidal thoughts), bipolar disorder, mania, confusion, and altered consciousness have also been observed with the use of alpha interferons. Patients should be carefully monitored for signs or symptoms of mental illness. If such symptoms appear, the attending physician should take into account the potential danger of these undesirable effects and select appropriate drug therapy. If this condition does not pass or becomes more severe and suicidal thoughts or homicidal thoughts are revealed, it is recommended to cancel the treatment with Ribavirin-SZ and peginterferon alfa-2b or interferon alpha-2b and prescribe appropriate psychiatric treatment.

Presence or anamnesis of severe mental illness

If treatment with Ribavirin-SZ in combination with peginterferon alfa-2b or interferon alpha-2b is necessary in adult patients with a history of severe mental illness, it must be initiated only after appropriate diagnosis and treatment of mental illness. Use of Ribavirin-C3 and interferon alfa-2b or peginterferon alfa-2b in children from 3 to 18 years with the presence or anamnesis of severe mental illness is contraindicated.

Patients with a substance use disorder

When treating interferon alfa, patients with hepatitis C who suffer from a substance use disorder (alcohol, marijuana, etc.) are included in the group of patients with an increased risk of developing mental illness or worsening the existing ones. If interferon alfa treatment is necessary for these patients, then the presence of co-morbid mental illness and possible substance misuse should be carefully evaluated before starting therapy.To assess, treat and monitor patients, specialists from other areas, including a psychiatrist or an expert in narcology, may be recruited. During the treatment and after its termination the patient should be under the supervision of a specialist. If you re-occur or develop mental illness or addiction, early intervention is recommended.

Growth and development (children from 3 to 18 years)

During the course of interferon therapy (unPEGylated and pegylated) and ribavirin for up to 48 weeks in patients ages 3 to 18 years is often observed decrease in body weight and a decrease in the growth rate. Analysis of long-term combination therapy with pegylated interferon and ribavirin showed significant growth retardation. In 32% of patients (30/94) there was a decrease in growth with respect to age by> 15 percentile after 5 years after completion of therapy. These long-term monitoring of children who received the combined therapy with interferon and ribavirin, also indicated a significant growth inhibition (decrease of the growth rate of more than 15 percentiles compared to baseline) in 21% pediatric patients (n= 20), despite the fact that the treatment was terminated more than 5 years ago. For 14 of these patients, the total growth in adulthood is known (10-12 years after the end of therapy), which showed that 12 patients had a growth deficit of more than 15 percentile, including two patients whose growth was 3.7 and 4, 6 percentile.

Assessment of the risk / benefit ratio in children:

The relationship between benefit and risk of treatment should be carefully evaluated based on safety data in clinical trials in children aged 3 to 18 (see "Side effect").

- It is important to consider that combined therapy causes growth retardation, which in some patients led to a decrease in growth. The reversibility of this effect is not reliably established.

- This risk should be assessed taking into account the characteristics of the course of the disease in the child, such as signs of disease progression (especially fibrosis), the presence of co-morbidities that may affect the progression of the disease (eg, HIV coinfection), and factors that influence the prognosis of response to therapy (HCV genotype, viral load).

If possible, treatment in children should begin after a growth jump in puberty to reduce the risk of growth retardation. Data on the long-term effect on puberty are absent

Hemolysis

According to clinical studies, a decrease in hemoglobin concentration <10 g / dL was observed in 14% of adult patients and 7% of children taking ribavirin in combination with peginterferon alfa-2b and interferon alpha-2b. Although ribavirin does not directly affect the cardiovascular system, anemia caused by the use of ribavirin, can lead to impaired cardiac function or worsening of cardiovascular diseases. Thus, the drug Ribavirin-SZ should be used with caution in patients with cardiovascular diseases (see the section "Contraindications"). Before the start of therapy, it is necessary to assess the state of the cardiovascular system, and during the therapy it is necessary to monitor its condition. If signs of deterioration appear, treatment should be discontinued (see section "Method of administration and dose").

The cardiovascular system

Adult patients with chronic heart failure, a history of myocardial infarction and / or previous or current cardiac arrhythmias should be monitored.Before the beginning of treatment and during the course of therapy in patients with existing cardiac function disorders, it is necessary to remove electrocardiograms. Cardiac arrhythmias (especially supraventricular arrhythmias) are usually treated as standard, but it may be necessary to cancel therapy.

There are no data on the use of the drug in children aged 3 to 18 years with a history of cardiovascular disease.

Hypersensitivity immediate type

If an immediate type of hypersensitivity reaction develops (for example, urticaria, Quincke's edema, bronchoconstriction, anaphylactic shock), then Ribavirin-S3 should be immediately withdrawn and appropriate therapy should be prescribed. Short-term phenomena of rashes do not require the abolition of treatment.

Changes in vision

In rare cases of ribavirin in combination with alpha interferons, retinopathy has been reported, including retinal haemorrhage, retinal effusion, optic disc swelling, visual neuropathy, and occlusion of the artery or retinal vein, which can lead to loss of vision. All patients at the beginning of treatment should undergo an examination of the ophthalmologist.A patient with complaints of a decrease or loss of vision should immediately get help from an ophthalmologist. Patients with visual impairment (eg diabetic or hypertensive retinopathy) should undergo periodic examinations with an ophthalmologist during combined therapy with interferons alpha. Combination therapy with alpha interferons should be abolished if there is a disability or impaired vision in patients.

Liver function

Any patient with significant impairment of liver function should be under the supervision of a physician. In patients with increased coagulation parameters, indicative of liver decompensation, therapy should be immediately withdrawn.

The possibility of increased immunosuppression

According to the literature, for 3 to 7 weeks of peginterferon and ribavirin use in combination with azathioprine, patients developed pancytopenia and suppressed bone marrow function. Myelotoxicity was reversible within 4-6 weeks after the abolition of antiviral therapy for hepatitis C and azathioprine and did not occur repeatedly when these medications were used separately (see Table 1).section "Interaction with other drugs").

Control of thyroid function in children from 3 to 18 years

In children (approximately 12 to 21%) who took ribavirin and interferon alfa-2b (pegylated and non-pegylated), a decrease in the thyroid-stimulating hormone (TSH) concentration was observed. Another 4% had a temporary decline below the norm limit. Before starting therapy with interferon alpha-2b the concentration of TSH should be evaluated and any dysfunction of the thyroid gland should be treated. Interferon alfa-2 therapyb (pegylated and non-pegylated) can be initiated if the TSH concentration is maintained at the normal level with the help of medications. When ribavirin and interferon alfa-2 are usedb and ribavirin and peginterferon alfa-2b there was a dysfunction of the thyroid gland. If a thyroid dysfunction is detected, the patient should evaluate the presence of thyroid dysfunction and apply appropriate treatment methods. In children from 3 to 18 years, thyroid function (eg, TSH) should be evaluated every 3 months.

HCV / HIV co-infection

Mitochondrial toxicity and lactic acidosis

It is necessary to use with care the therapy with interferon alpha-2b / ribavirin in patients with co-infection of HCV / HIV, taking NRTI (in particular, didanosine and stavudine). In HIV-positive patients taking NRTIs, careful monitoring of the markers of mitochondrial toxicity and lactate acidosis with ribavirin should be carried out. In particular:

- simultaneous use of the drug Ribavirin-SZ and didanosine is not recommended because of the risk of developing mitochondrial toxicity (see section "Interaction with other drugs").

- simultaneous use of the drug Ribavirin-SZ and stavudine should be avoided to reduce the risk of cross mitochondrial toxicity.

Decompensated liver disease in patients with co-infection with HCV / HIV

Patients with progressive cirrhosis who receive HAART may be at risk for developing liver and death decompensation. Interferon alpha therapy alone or in combination with ribavirin may increase this risk in this group of patients.Other factors in such patients, associated with a higher risk of liver decompensation, include the treatment with didanosine and an increase in the serum bilirubin concentration.

Patients receiving both Apt, and therapy for hepatitis, should be under the supervision of a doctor whose task is to assess the liver status on a Child-Pugh scale. In patients with progressive hepatic insufficiency, hepatitis therapy should be discontinued immediately and antiretroviral therapy should be revised.

Hematologic disorders in patients with co-infection with HCV / HIV

Patients with HCV / HIV co-infection receiving peginterferon alfa-2b/ ribavirin and HAART, may be at increased risk of developing hematological disorders (such as neutropenia, thrombocytopenia and anemia) compared with patients with hepatitis C alone. Although most of these events can be corrected by dose reduction, careful monitoring of hematological parameters in the given population (see the sections "Dosing and Administration" and "Side effect"). Patients receiving ribavirin and zidovudine, are in the group at increased risk of developing anemia. Thus, simultaneous use of ribavirin and zidovudine is not recommended (see section "Interaction with other drugs").

Patients with a low value Cd4

Limited data on safety and efficacy (n= 25) in patients with co-infection with HCV / HIV and the value Cd4 less than 200 cells / μl. Thus, in the treatment of patients with a low value Cd4 care must be taken.

Information on the toxic properties of each drug and the likelihood of cross-toxicity of Ribavirin-C3 and peginterferon alfa-2b is presented in the instructions for the medical use of antiretroviral drugs.

Diseases of the teeth and periodontal disease

In patients who took ribavirin and peginterferon alfa-2b or interferon alfa-2b, dental and periodontal diseases that can lead to tooth loss have been reported. In addition, dry mouth can have a negative effect on the teeth and mucous membranes of the mouth with long-term treatment with Ribavirin-SZ and peginterferon alfa-2b or interferon alpha-2b. Patients should brush their teeth twice a day and undergo regular check-ups at the dentist. In addition, some patients may have vomiting. If this reaction occurs, rinse your mouth thoroughly after an attack.

Lab tests

In all patients, standard blood tests (clinical blood count and leukogram, platelet count, electrolyte content, serum creatinine concentration, liver function, uric acid concentration, etc.) should be made in all patients prior to therapy.

The normal values at which you can start therapy with Ribavirin-C3 are the following: hemoglobin ≥ 120 g / l (female), ≥ 130 g / l (male), ≥ 110 g / l (girls), ≥ 120 g / l ( boys); platelets - ≥ 100,000 / mm³; neutrophils - ≥ 1500 / mm³.

Laboratory tests should be performed at 2 and 4 weeks of therapy and then periodically in accordance with the clinical picture. During treatment, the value of HCV RNA should be determined regularly.

Women of childbearing age

Women of childbearing age during treatment and within 4 months after it should conduct pregnancy tests on a monthly basis.

Women,whose partners men take Ribavirin-SZ therapy should conduct pregnancy tests monthly during treatment with Ribavirin-SZ and within 7 months after treatment.

The drug Ribavirin-SZ can increase the concentration of uric acid due to hemolysis.

Patients with predisposition to gout should be carefully monitored.

Patients with rare hereditary diseases

Each capsule of Ribavirin-C3 contains 192 mg of lactose. Patients with rare hereditary disorders of galactose tolerance, deficiency of Lactose lactose or malabsorption of glucose-galactose, the use of this drug is contraindicated.

Effect on the ability to drive transp. cf. and fur:

The drug Ribavirin-SZ does not adversely affect the ability to drive vehicles and work with mechanisms. Despite this, in combination with peginterferon alfa-2b or interferon alpha-2b this effect is possible. Thus, patients who experience fatigue, drowsiness, or confusion during treatment should refrain from driving or working with machinery.

Form release / dosage:

Capsules, 400 mg.

Packaging:

10 capsules per circuit cell packaging

For 30, 60 capsules in a polymer can of BP type from low-density polyethylene with a lid of high-density polyethylene or in a bottle of polymer from low-density polyethylene with a lid of high-density polyethylene.

Each jar, bottle or 3, 6, 9 and 12 contour mesh packages together with the instruction for use is placed in a cardboard box.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003791

Date of registration:17.08.2016

Expiration Date:17.08.2021

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Representation: & nbspNORTH STAR CJSC NORTH STAR CJSC Russia

Information update date: & nbsp09.10.2016

Illustrated instructions

Instructions

Ribavirin-SZ (Ribavirin-SZ)