Rebetol - instructions for use, dose, side effects, contraindications

Composition of ink for inscribing the capsule shell: shellac, ethanol, isopropanol, butanol, propylene glycol, ammonium hydroxide, blue aluminum varnish based on indigo carmine.

* - depending on the supplier of capsules (Capsugel or Shionogi)

Description:

Hard gelatin capsule size №1, consisting of a body and a lid matte-white. On the body blue ink is applied "200 mg" and a blue strip, and on the cap - letters "SP" and a blue strip. Capsules contain white powder.

Pharmacotherapeutic group:An antiviral agent.

ATX: & nbsp

J.05.A.B Nucleosides and nucleotides

J.05.A.B.04 Ribavirin

Pharmacodynamics:

Ribavirin is a synthetic analogue of nucleosides, active in vitro for some RNA and DNA viruses. Signs of inhibition of enzymes specific for the hepatitis virus C (BHS), or suppression of HCV replication with ribavirin, or intracellular metabolites of ribavirin in physiological concentrations was not detected. Monotherapy with ribavirin does not lead to elimination

HCV (hepatitis C virus RNA) or improvement in liver histology after 6-12 months of use and during 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 more effective than monotherapy with interferon alfa-2b or peginterferoic alfa-2b.

The mechanism by which ribavirin in combination with interferon alpha-2b or peginterferoic 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_max=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 h respectively. Ribavirin absorbed almost completely: only about 10% labeled dose is released through the intestine.However, 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 up to 1200 mg. The volume of distribution is approximately 5000 l. 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 basically transport occurs with the participation of an equilibrium nucleotide transporter of the type e_s (nitrobenzyl-guanosine-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 ribavirin concentrations in whole blood and plasma is approximately 60:1. A high concentration of ribavirin in whole blood is due to the accumulation of ribavirin in erythrocytes.

Metabolism

The metabolism of ribavirin is carried out in two ways: 1) reversible phosphorylation and 2) hydrolytic reactions, including deribosylation and amide hydrolysis to form a triazole carboxyl metabolite. Ribavirin and its metabolites (triazolkarboksamid and triazolecarboxylic acid) excreted by the kidneys.

Excretion

With multiple reception ribavirin accumulates in large amounts in blood plasma: the ratio AUC_12h, at repeated and single reception is equal to 6: 1. Ingestion (600 mg 2 once a day), the equilibrium concentration of ribavirin in the plasma was reached by the end 4 weeks and was approximately 2200 ng / ml. After discontinuation, the half-life of ribavirin was about 298 that, apparently, reflects its delayed excretion from the 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 in comparison with blood 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.

The bioavailability of ribavirin when receiving a single oral dose is increased while eating a high-fat diet (AUC_tf and C_max increase 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 compared with the control group (creatinine clearance> 90 ml / min) is changing, namely, an increase AUC and the maximum concentration of ribavirin in the blood (C_max). 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 when receiving a single dose in patients with mild, moderate or severe hepatic insufficiency (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 (older 65 years) was not conducted. 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 according to 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. The clearance increased with the body weight and decreased at the age of 40 years. The effect of these covariates on ribavirin clearance is of limited clinical relevance due to significant residual variability not accounted for by this model. Pharmacokinetic parameters of ribavirin in children from 3 before 18 years are similar to those in adults.

Indications:

Triple therapy:

Treatment of chronic viral hepatitis C (genotype 1 hepatitis C virus) in combination with bocetrevir and peginterferon alfa-2b in adult patients (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 before 18 years only in combination with interferon alpha-2b or peginterferon alfa-2b. Preparation Rebetol® as monotherapy is not applied.

- double therapy - treatment of chronic viral hepatitis C in combination with peginterferon alfa-2b in adults with compensated cirrhosis and / or with clinically stable HIV infection.

Children from 3 before 18 years

- double therapy - treatment of chronic viral hepatitis C in combination with interferon alpha-2b (with Intron® A) or peginterferon alfa-2b in patients of childhood (from 3 years), seropositive to RNA of hepatitis C virus, which have no signs of decompensation of liver disease, which had previously been treated.

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

Patients, previously treated

Adults

- triple therapy - treatment of chronic viral hepatitis C (genotype 1 hepatitis C virus) in combination with peginterferon alfa-2b and bocetrevir in adult patients c compensated liver disease, in which previous antiviral treatment was ineffective;

- double therapy - treatment of chronic viral hepatitis C in combination with peginterferon alfa-2b in adult patients in whom prior therapy with interferon alfa (pegylated or non-pegylated) and ribavirin or interferon monotherapy has proved ineffective;

- double therapy - treatment of chronic viral hepatitis C in adult patients in combination with interferon alpha-2b, previously received monotherapy with interferon alfa (with normalization of activity ALT by the end of the treatment course), who subsequently had a relapse of the disease.

When appointing a combination therapy should also be guided by instructions for the medical use of interferon alfa, 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's age until 3 years and body weight less than 25 kg;

- severe heart disease, 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 according to anamnesis (only for children from 3 before 18 lay down);

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

- severe hepatic impairment (classes B or C Child-Pugh classification) or decompensated liver cirrhosis;

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

- cirrhosis of the liver with hepatic insufficiency in patients with co-infection with HCV / HIV (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 BAAPT (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 drug Rebetol® it 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 being one-twentieth of the recommended human dose.

- Genotoxicity: ribavirin induces genotoxicity.

Women of childbearing age / contraception of women and men

Female Patients: Rebetol® 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 Rebetol® should not be started before receiving a negative pregnancy test. Women of childbearing age should use effective contraception during treatment and during 4 months after completion of therapy; pregnancy tests should be conducted monthly. If during treatment or during 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: It is necessary to take special measures to avoid pregnancy in partners of male patients taking Rebetol®. 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 approximately 300 pregnancy, 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 Rebetol® and during 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. Dose of Rebetol® is calculated based on the patient's body weight. Capsules of the drug Rebetol® must be taken orally daily (morning and evening) during meals. 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.

Preparation Rebetol® should be used in combination with peginterferon alfa-2b or interferon alpha-2b (double therapy) or in adult patients with chronic hepatitis C genotype I in combination c boceprevir and peginterferoic alfa-2b (triple therapy).

Information on the use of bocetrevir, pegggerferon alfa-2b or interferon alfa-2b is presented in the instructions for the use of these medicines.

Recommended doses

Adult patients

Dose of Rebetol® is calculated based on the patient's body weight (Table 1). Preparation Rebetol® should be used in combination with peginterferon alfa-2b (1,5 mkg / kg / week) or interferon alfa-2b (3 million ME З 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 Rebetol® based on 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 Rebetol®	Number of capsules by 200 mg	Mode dosing
<65	800 mg	4	2 capsules in the morning, 2 capsules in the evening
65-80	1000 mg	5	2 capsules in the morning, 3 capsules in the evening
81-105	1200 mg	6	3 capsules in the morning, 3 capsules in the evening
>105	1400 mg	7	3 capsules in the morning. 4 capsules in the evening

Preparation Rebetol® in capsules in combination with bocetrevir and peginterferon alfa-2b or only c 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 to 4 or 12 week, a sustained virologic response is achieved. These patients should be considered the probability of withdrawal of treatment.

- Genotype 1:

- In patients in whom HCV RNA is not determined by 12 week of treatment, treatment should continue 9 months (i.e., total 48 weeks).

- In patients with a detectable, but >2 log₁₀ decrease in PHK HCV compared with baseline 12 week of treatment, an evaluation of treatment should be 24 week and, if PHK HCV is not defined, the full course of therapy should be continued (ie, total 48 weeks).

If PHK HCV on 24 week of treatment is still determined, it is necessary to cancel therapy.

- In patients with HCV genotype 1 and low viral load (<600000 IU / ml), for which 4 and 24 weeks of treatment PHK HCV is not defined, treatment should either be discontinued after a 24-week course, or continued for additional 24 weeks (ie, the total duration of the course will be 48 weeks). However, the course duration 24 weeks may be associated with a higher risk of recurrence than course duration 48 weeks.

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

- Genotype 4. In general, it is believed that patients who have a HCV genotype 4, are more difficult to treat. Limited research data (n= 66) indicate that such patients can undergo a course of therapy that is equivalent to the course for patients with HCV genotype 1.

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

Double therapy:

The recommended duration of treatment with Rebetol® in a dose based on body weight (see Table 1), in patients with co-infection with HCV / HIV is 48 weeks of double therapy, regardless of the genotype of HCV.

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

Early virological response to 12 week, defined as 2 Iog₁₀ a reduction in viral load or undetectable HCV RNA values, is an indicator of a sustained response. A negative predictive response parameter in patients with co-infection with HCV / HIV who received Rebetol ® in combination with peginterferon alfa-2b, amounted to 99% (67/68). A positive value from a predictable response in 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 peghinterferon alfa-2b:

The ability to predict a sustainable virologic response: all patients, regardless of the genotype of HCV, in whom the pH valueK HCV in the serum was below the detection limit at 12 week, should receive a course of treatment for 48 weeks.

It is unlikely that patients who had previously received treatment who did not receive a virologic response (ie, PHK HCV below detection limits) at 12 week, a virologic response to 48 week of therapy.

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

Preparation Rebetol® 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 that continued 1 year, for patients who did not receive a virologic response through 6 months (ie HCV RNA values below detection limits), the likelihood of further virologic response was extremely low (i.e., the value of HCV RNA is lower than detection limits through 6 months after the withdrawal of treatment).

- Genotype 1. Double therapy should continue 6 months (i.e., total 1 year) in patients with lack of PHK HCV through 6 months after treatment.

- Genotypes other than 1. The decision to extend 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, bridged liver fibrosis).

Children from 3 before 18 years (double therapy)

Dose of the drug Rebegol® for children from 3 before 18 years should be calculated on the basis of body weight, the dose of peginterferon alfa-2b and interferon alfa-2b (Intron preparation® A) on the basis of the surface area of the body.

Dose for combination therapy with peginterferon alfa-2b in children from 3 before 18 years:

The recommended dose of peginterferon alfa-2b is 60 μg / m²/ week subcutaneously in combination with Rebetol® 15 mg / kg / day (Table 2).

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

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

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

Body weight of the patient (kg)	Daily dose preparation Rebetol®	Number of capsules 200 mg	Dosing regimen
25-36	400 mg	2 capsules	1 capsule in the morning, 1 capsule in the evening
37-49	600 mg	3 capsules	1 capsule in the morning, 2 capsules in the evening
50-65	800 mg	4 capsules^b	2 capsules in the morning, 2 capsules in the evening
>65	See table for calculating doses for adult patients (Table 1)

The duration of treatment in children from 3 before 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 before 18 years (negative predictive value for interferon alfa-2b/ Rebetol® preparation is 96%) It was found that, if 12 week virologic response is not achieved, there will not be a later response. Therefore, it is recommended that children 3 before 18 years, receiving combined therapy in the form of interferon alfa-2b (pegylated or non-pegylated) and Rebetol®, this treatment was withdrawn if 12 week value PHK HCV decreased by <2 Iog₁₀ compared with the pre-treatment value, or if 24 week of treatment they are determined by HCV RNA.

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

- Genotype 4: in a clinical study of the use of peginterferon alfa-2b/ Rebetol® took part only 5 children from 3 before 18 years with HCV genotype 4. The recommended duration of dual therapy is 1 year. Treatment with peginterferon alfa-2b/ Rebetol ® in children from 3 before 18 years should be discontinued if the value of HCV RNA is 12 the week declined <2 Iog₁₀compared with the pre-treatment value, or if 24 week of treatment they are determined by HCV RNA.

Correction of the dosing regimen for all patients

Combination therapy:

If the use of combination therapy with Rebetol® and peginterferon alfa-2b or interferon alpha-2b, or the drug Rebetol® and peginterferon alfa-2b and boceprevir there are serious adverse reactions or deviations of these laboratory tests, it is necessary to change the dose according to the Table 3, if possible, until 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	The dose reduction of Rebetol® alone (see Note 1), if:	Dose reduction only interferon alpha-2b or peginterferon alpha-2b (cm. Note 2), if:	*Termination of therapy, if :**
Concentration hemoglobin	< 100 g / l	-	<85 g / l
adults: hemoglobin concentration in patients with heart disease in stable form children from 3 before 18 years hemoglobin concentration	The concentration of hemoglobin decreased by >20 g / l for any 4 weeks during treatment (continuous use of a reduced dose)		< 120 g / l through 4 weeks after dose reduction
	Mr.e 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 x 10⁹/ l
platelet count	-	adults: <50 x 10⁹/ l children from 3 before 18 years: <70 x 10⁹/ l	adults: <25 x 10⁹/ l children from 3 before 18 years: <50 x 10⁹/l
concentration of bound bilirubin	-	-	2,5 x w^**
concentration free bilirubin	> 0,05 g / l	-	during >4 weeks adults: >0,04 g / l children from 3 before 18 years: when treating interferon alfa-2b > 0,05 g / l in the treatment peginterferon alpha-2b > 0.04 g / l
concentration creatinine	-	-	> 0,02 g / l
creatinine clearance	-	-	abolish the drug rebetol®, if <50 ml / min
alanine- aminotransferase or aspartate- aminotransferase	-	-	2 x (base value) and >10 x w^{^[1]} or 2 x (basic value) and> 10 x

* see the criteria for changing the doses and discontinuing medicines of peginterferon alfa-2b and interferon alfa-2b in the instructions for the use of these medicines.

** brn is the upper limit of the norm.

note 1: in adults, the first reduction in the dose of rebetol® is 200 mg / day (in patients taking 1400 mg per day, the dose reduction should be 400 mg / day). If necessary, a second dose reduction of the drug Rebetol® is additional 200 mg / day. patients whose daily dose of rebetol® is reduced to 600 mg, take one capsule 200 mg / day in the morning and two capsules 200 mg in the evening.

in children from 3 before 18 years, taking the drug rebetol® and peginterferon alfa-2b/ The first reduction in the dose of rsbetol® is up to 12 mg / kg / day, the second dose reduction of the drug rsbetol® is up to 8 mg / kg / day.in children from 3 before 18 years, taking the drug rebetol® and interferon alfa-2b, the dose of the drug rebetol is reduced to 7,5 mg / kg / day.

note 2: in adult patients taking the drug rebetol® and peginterferon alfa-2b, the first reduction in the dose of peginterferon alfa-2b is up to 1 mkg / kg / week. if necessary, a second dose reduction of peginterferon alfa-2b - before 0,5 mkg / kg / week.

in children from 3 before 18 years, taking the drug rebetol® and peginterferon alfa-2b, the first reduction in the dose of peginterferon alfa-2b is up to 40 μg / m²/ weektla, the second reduction in the dose of peginterferon alfa-2b is up to 20 mcg / m / week.

in adults and children from 3 before 18 years, taking the drug rebetol® and interferon alfa-2b, should reduce the dose of interferon alfa-2b at 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, prior to the initiation of Rebetol® therapy, it is recommended that renal function be assessed in all patients. patients with creatinine clearance <50 ml / min can not take the drug rebetol® (see the "contraindications" section). 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 the drug rebetol® and peginterferon alfa-2b/ interferon alpha-2b necessary cancel.

application in case of liver dysfunction

between the reception of ribavirin and the functions of the liver, there is no pharmacokinetic relationship. thus, there is no need to adjust the dose of the drug rebetol® in patients with impaired liver function. the use of ribavirin is contraindicated in patients with severe hepatic impairment or decompensated liver cirrhosis (see the "contraindications" section).

use in the elderly (older 65 years)

Mr.e There is a significant dependence of the pharmacokinetics of ribavirin on the patient's age. however, as in younger patients, the function of the kidneys must be evaluated before starting the use of the drug rebetol®.

use in patients younger 18 years

The drug rebetol® can be used in combination with peginterferon alfa-2b or interferon alpha-2b in children from 3 before 18 years. safety and efficacy of the drug rebetol® 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 vsc / vich

in patients taking nucleoside reverse transcriptase inhibitors (nit) 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 the use of the drug Rebetol® 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 Rebetol ® in combination with interferon alfa-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 in comparison c described below.

The adverse reactions listed below are based on clinical trials in adult patients who did not previously take interferon, whose treatment was performed during 1 year, and on the basis of data on the use of the drug in the post-marketing period. A certain number of unwanted reactions, usually attributed to interferon therapy, but also registered with hepatitis therapy C (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 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: Often - viral infections, pharyngitis; often - bacterial infections (including sepsis), fungal infection, influenza, respiratory infections, bronchitis, infection caused by the herpes simplex virus, sinusitis, otitis media, rhinitis, urinary tract infection; infrequently - infection 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.

Disturbances from the blood system and lymphatic system: Often - Anemia, neutropenia; often Hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia; 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;

Metabolism and nutrition: Oftenanorexia; often - Hyperglycemia, hyperuricemia, hypocalcemia, dehydration, increased appetite; infrequently diabetes mellitus, hypertriglyceridemia.

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

From the nervous system: Often - headache, dizziness, dry mouth, impaired concentration; 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) *, rarely - hemorrhage in the brain *, cerebrovascular ischemia *, encephalopathy *, polyneuropathy *; unknown - paralysis of the facial nerve, mononeuropathy.

Co hand organ of vision: often- visual impairment, blurred vision, conjunctivitis, eye irritation, eye pain, distortion of visual perception, lacrimal gland pathology, dry eyes; rarelyhemorrhages in the retina *, retinopathy (including macular edema) *, retinal arterial thrombosis *, retinal vein thrombosis *, optic neuritis *, optic disc swelling *, visual acuity reduction or loss of visual fields *, exudate in the chum net.

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- palpitation, tachycardia; infrequently- myocardial infarction; rarely- Cardiomyopathy, arrhythmia *; 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; rarely ischemia of peripheral tissues.

From the respiratory system, chest and mediastinum: Often - shortness of breath, cough; often- nasal bleeding, 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; rarely - pulmonary infiltrates *, pneumonitis *, interstitial pneumonitis *.

From the gastrointestinal tract: 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; rarely- ulcerative colitis*; unknown - violations from the periodontal, dental disorders, pigmentation of the tongue.

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

From the skin and subcutaneous fat: 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, disorders from the nails *; rarely - sarcoidosis of the skin; rarely- Stevens-Johnson syndrome *, toxic epidermal necrolysis *, multiforme exudative erythema *.

From the osteomuscular system and connective tissue: 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 side of the kidneys and the urinary system: often - frequent urination, polyuria, urinary incontinence; rarely- impaired renal function, renal failure *; 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, violations of the vagina; 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 injection site: Often - inflammation at the injection site, reactions at the injection site, fatigue, chills, fever, flu-like symptoms, asthenia, irritability; often - pain in the chest, 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: 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 un-pentylated).

Have 30% patients taking the drug Rebetol® and peginterferopal-2b, and y 37% patients taking the drug Rebetol® and interferon alfa-2b, a decrease in hemoglobin concentrations was observed for more than 4 g / dL.

Have 14% adults and 7% children from 3 before 18 years who took the drug Rebetol®

in combination with peginterferon alfa-2b or interferon alpha-2b, hemoglobin concentrations decreased to 10 g / dL and below.

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

An increase in the concentrations of uric acid and indirect bilirubin associated with hemolysis was observed in some patients taking Rebetol ® in combination with peginterferon alfa-2b or interferon alpha-2b in clinical studies, but through 4 After a week of treatment, the concentrations returned to their original 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 Rebetol ® in combination with peginterferon alfa-2b, other adverse reactions (not observed in patients with hepatitis C alone), whose frequency was >5%, Candidiasis of the oral cavity (14%), acquired lipodystrophy (13%), decrease in lymphocyte concentration Cd4 (8%), loss of appetite (8%), an increase in the activity of gamma-glutamyltransferase (9%), backache (5%). increase in the activity of amylase in the blood (6%), increase in the concentration of lactic acid in the blood (5%). cytolytic hepatitis (6%), increased lipase activity (6%) and pain in the limbs (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 values the patients from co-infectious HCV / HIV

Although hematologic abnormalities in the form of neutropenia, thrombocytonism and anemia were more common in patients with co-infection with HCV / HIV. most of these reactions were amenable to correction by dose modification and rarely required the withdrawal of therapy (see section "Special instructions"). Hematologic disorders were more often recorded in patients taking Rebetol ® in combination with peginterferon alfa-2b, than in patients taking Rebetol ® in combination with interferon alpha-2b. Po the decrease in the absolute number of neutrophils below 500 cells / mm³, as well as a decrease in the number of platelets below 50000 / mm³ was observed in 4% (8/194) patients taking Rebetol ® in combination with peginterferon alfa-2b. Anemia (hemoglobin <9,4 g / dl) was registered in 12% (23/194) patients who received Rebetol ® in combination with peginterferon alfa-2b.

Decrease in the number of lymphocytes Cd4

Treatment with Rebetol ® in combination with peginterferon alfa-2b was associated with a decrease in the absolute number of cells Cd4+ during 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. Application Rebetol ® 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 administration 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 Rebetol® and peginterferon alfa-2b should read the instructions for the medical use of each of the drugs used.

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

In combination with peginterferon alfa-2b

In a clinical trial, 107 children (from 3 before 18 years) who received combination therapy with peginterferon alfa-2b and Rebetol®, dose changes were required in 25% 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 Rebetol® preparation up to 48 weeks, there was a decrease in the rate of growth, which led to the fact that the growth of some patients was below the norm (see section "Special instructions"). Reduced body weight and growth inhibition were very common phenomena during treatment (at the end of treatment, the mean decrease from baseline in body weight and growth was 15 and 8 androcentiles, respectively); The growth rate (<3rd percentile y 70% patients).

At the end 24 weeks after the end of treatment, the mean decrease from baseline body weight and growth was 3 and 7 percentiles, respectively, and 20% children showed a decrease in the rate of growth (<3rd percentile). 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 receiving treatment for 48 weeks. From the moment before the start of treatment, until the end of the observation, the percentile of growth in children treated for 24 and 48 pedel, declined by 1,3 and 9,0 percentiles, respectively. Decreased growth in 24% children (11/46) who received treatment for 24 weeks, and 40% children (19/48) who received treatment for 48 weeks, reached more 15 percentiles from the moment preceding treatment, up to the end year study with subsequent follow-up as compared with the baseline value. Have 11% children (5/46) who received therapy for 24 weeks and 13% children (6 of 48), received therapy for 48 weeks, there was a decrease in growth relative to the baseline by more than 30 percentile of the ratio of height to age from the time before treatment to the end of a five-year study followed by follow-up. C the moment preceding treatment, until the end of the five-year study followed by observation, weight loss was 1,3 percentile in children who received treatment for 24 weeks, and 5,5 percentile in children who received treatment for 48 weeks. The body mass index decreased by 1,8 and 7,5 percentiles, 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 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) cases and included pain at the injection site (1%), pain in the limbs (1%), headache (1%), neutropenia (1%) and fever (4%). Essential adverse reactions in this patient population were nervousness (8%), aggression (3%), anger (2%), depression / depressed mood (4%) and hypothyroidism of the thyroid gland (3%). Five patients took levothyroxine for hypothyroidism / increased thyroid stimulating hormone (TSH).

In combination with interferon alpha-2b

In clinical trials 118 children from 3 before 16 years, who received combined therapy with interferon alpha-2b and Rebetol®, 6% treatment was discontinued because of unwanted reactions. In general, the profile of adverse reactions in a limited population of children from 3 before 18 years was similar to the profile observed in adults, but in fears of growth retardation arose due to a decrease in the growth rate during the treatment (mean decrease in growth 9 percentile) and body weight (mean weight loss 13 percentiles). During 5 years of follow-up, the average growth in 44 percentile, which was below the average for a normal population and less than their average primary growth (48 percentiles). Twenty (21%) of 97 children had >15 percentiles of declining growth, of which 10 of 20 children had >30 Percentage 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 height in adulthood is known (10-12 years after the end of therapy), which showed that 12 There was a deficit in growth (more 15 percentiles). During combined therapy with interferon alpha-2b and Rebetol® preparation up to 48 weeks, there was a decrease in the rate of growth, which led to the fact that 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% compared with 1%) during treatment and during 6 months of follow-up. As in adult patients, children 3 before 18 years, other disorders of the mental sphere also developed (for example, depression, emotional lability and drowsiness) (see section "Special instructions"). In addition, lesions at the injection site, fever, anorexia, vomiting and emotional lability were more common in children from 3 before 18 years compared with older patients. Dose changes were required in 30% cases, mainly due to anemia and neutropenia. The adverse reactions listed below are based on two multicenter clinical studies of the use of Rebetol® in combination with interferon alpha-2b or peginterferon alfa-2b in children from 3 before 18 years.Undesirable reactions are represented by 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: Often - 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 benign, malignant and unspecified (including cysts and polyps): often - unspecified neoplasms.

Disturbances from the blood system and lymphatic system: Often - Anemia, neutropenia; often - Thrombocytopenia, lymphadenopathy.

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

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

From the side of the psyche: 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: Often- headache, dizziness; often - hyperkinesia, 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, impaired vision, impairment 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, palpitation.

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

From the respiratory system, chest and mediastinum: often - shortness of breath, rapid breathing, nosebleed, cough, nasal congestion, nose irritation, rhinorrhea, sneezing, sore throat; infrequently - wheezing, discomfort in the nose.

From the gastrointestinal tract: Often - pain in the abdomen, 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 stool, toothache, dental abnormalities, discomfort in the stomach, pain in the oral cavity ; infrequently - gingivitis.

From the hepatobiliary system: often- impaired liver function; infrequently - hepatomegaly.

From the skin and subcutaneous fat: 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.

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

From the side of the kidneys and the 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 disorders, vaginal disorders, men: testicular pain; infrequently - Women: dysmenorrhea.

On the part of the body as a whole: 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 the chest, 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: Often - decrease in the growth rate (decrease in growth and / or body weight at a given age); often - Increased concentration of TSH, increased thyroglobulin concentration; infrequently positive antibodies to the thyroid gland.

Injuries and poisonings: often - damage to the skin; infrequently - Contusion.

Most laboratory changes in clinical studies of the use of the drug Rebetol® / 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 in clinical trials with Rebetol® / peginterferon alfa-2b changes in laboratory values were observed, a few weeks after the end of therapy they came to normal values.

Overdose:

Triple therapy

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

Double Therapy

The known maximum accepted dose of Rebetol® was 10 g ribavirin in capsules (50 capsules for 200 mg) and 39 million ME interferon alfa-2b in the form of a solution for injection (13 subcutaneous injections for 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; for that no undesirable phenomena associated with overdose were observed.
Antidote is unknown, hemodialysis and peritoneal dialysis are ineffective, treatment is symptomatic.

Interaction:

The study of interaction with other drugs was conducted only with the participation of adult patients.

According to the research results in vitro, conducted on microsomal preparations of human and rat liver, no metabolism of ribavirin due to cytochrome P450 isoenzymes was established. Ribavirin does not inhibit cytochrome P450 isoenzymes. Data from toxic studies do not indicate that ribavirin induces liver enzymes. Thus, there is only a minimal possibility of interactions associated with cytochrome P450 isoenzymes.

Ribaviri, 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 the drug Rebetol® and other medicines, with the exception of peginterferon alfa-2b, interferon alfa-2b and antacids, was not carried out.

Interferon alfa-2b: in a pharmacokinetic study using multiple doses, 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, bioavailability of ribavirin 600 mg decreased; AUC_tf decreased by 14%. It is possible that a decrease in the bioavailability of ribavirin in this study 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 legal outcome.

When zidovudine was included in the HIV treatment regimen, ribavirin was given, although the exact mechanism of this phenomenon is not known. The simultaneous use of ribavirin and zidovudine is not recommended because of the increased risk of developing 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 appointed. This is especially important for patients with a history of anemia caused by zidovudine.

The possibility of interactions can persist 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 Rebetol® can not be used in the form of monotherapy. Safety and efficiency 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 a liver biopsy before enrollment, but in certain cases (for example, in patients with HCV 2 and 3 genotype) 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 during 6 months after the abolition of treatment, some patients experienced severe disruption from the CNS, in particular depression, suicidal ideation or suicide attempts. In children from 3 before 18 years who took the drug Rebetol ® in combination with interferon alpha-2b, suicidal thoughts or suicide attempts were more frequent than in adults (2,4% compared with 1%) during treatment and during the subsequent 6-month follow-up period. As in adults, in children from 3 before 18 years, there were other undesirable mental reactions (for example, 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 Rebetol® and peginterferon alfa-2b or interferon alpha-2b and prescribe appropriate psychiatric treatment.

Presence or anamnesis of severe mental illness

If treatment with Rebetol® in combination with peginterferon alfa-2b or interferon alpha-2b is necessary in adult patients with a history of severe mental illness,it should be started only after appropriate diagnosis and treatment of mental illness. Use of Rebetol® and interferon alfa-2b or peginterferon alfa-2b in children from 3 before 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 alpha treatment for these patients is necessary, 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 before 18 years)

During the course of therapy of interferon (non-pegylated and pegylated) and ribavirin up to 48 weeks in patients aged from 3 before 18 years, there was often a decrease in body weight and a decrease in the rate of growth. Analysis of long-term combination therapy with pegylated interferon and ribavirin showed significant growth retardation. Have 32% patients (30/94) observed a decrease in growth with respect to age on >15 percentiles later 5 years after completion of therapy. Long-term follow-up data for children receiving combination therapy with interferon and ribavirin also indicated a significant growth retardation (a decrease in the growth rate of more than pa 15 percentile compared with the original value) y 21% of pediatric patients (n= 20), despite the fact that the treatment was terminated more 5 years ago. For 14 Of these patients, the total height in adulthood is known (through 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 percentiles.

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 from 3 before 18 years (see section "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 progression of the disease (especially fibrosis), the presence of co-morbidities that may affect the progression of the disease (eg, co-infection with HIV), and factors that affect the prognosis of the response on 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% adult patients and 7% children taking Rebetol ® 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. Therefore, the drug Rebetol ® 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 from 3 before 18 years with cardiovascular diseases in the anamnesis.

Hypersensitivity immediate type

If a hypersensitivity reaction of an immediate type develops (eg, urticaria, edema Quincke, bronchoconstriction, anaphylactic shock), the drug Rebetol® 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

AT Rare cases of ribavirin in combination with alpha interferons have been reported for retinopathy, including retinal hemorrhage, retinal retinitis, 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 (for example,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 increasing immunosuppression

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

Control of thyroid function in children from 3 before 18 years

In children (approximately from 12 before 21%), who took the drug Rebetol® and interferon alfa-2b (pegylated and non-pegylated), a decrease in TSH concentration was observed. Have 4% there was a temporary decrease 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 using the drug Rebetol® and interferon alfa-2b and the drug Rebetol® 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. Have children from 3 before 18 years thyroid function (eg, TSH) should be evaluated every 3 month.

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 with 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 undertaken. In particular:

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

- simultaneous use of the drug Rebetol® 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 receiving ΒΑAΡΤ, may be at risk of developing decompensated liver function and death. 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 on the 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 taking ribaviria and zidovudine, are in a 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 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-reactivity with Rebetol® 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 taking Rebetol ® 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 during long-term treatment with Rebetol® 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 Rebetol ® are the following: hemoglobin - >120 g / l (women), >130 g / l (male), >110 g / l (girls), >120 g / l (boys): platelets - >100000/ mm³: neutrophils - >1500 / mm³.

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

Women of childbearing age

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

Women whose partners men are taking Rebetol® should undergo pregnancy tests every month during treatment with Rebetol® and for 7 months after treatment.

The drug Rebetol® can increase the concentration of uric acid due to hemolysis.

Patients with predisposition to gout should be carefully monitored.

Patients from rare hereditary diseases

Each capsule of Rebetol® contains 40 mg of lactose. Patients with rare hereditary disorders of galactose tolerance, deficiency of Lactose lactose or malabsorption of glucose-galactose, this drug is contraindicated.

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

The drug Rebetol® does not adversely affect the ability to drive vehicles and work with machinery. 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 200 mg.

Packaging:By 20 capsules in a blister made of polyvinyl chloride film and aluminum foil.

Storage conditions:

At a temperature not higher 30 ⁰C.

Keep out of the reach of children.

Shelf life:2 years.
Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N011755 / 01

Date of registration:24.12.2009

The owner of the registration certificate:Schering-Plau N. Labo.Schering-Plau N. Labo. Germany

Manufacturer: & nbsp

MSD INTERNATIONAL GmbH (Singapore Branch) Singapore

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp15.08.2015

Illustrated instructions

Instructions

Rebetol® (Rebetol®)