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

Composition:1 tablet contains
active substance: ribavirin - 200 mg;
Excipients: lactose monohydrate, potato starch, microcrystalline cellulose, croscarmellose sodium (impellose), silicon dioxide colloid (aerosil), magnesium stearate.

Description:Tablets are white or white with a yellowish hue of a color of flat-cylindrical shape, with a facet and a risk.

Pharmacotherapeutic group:An antiviral agent.

ATX: & nbsp

J.05.A.B Nucleosides and nucleotides

J.05.A.B.04 Ribavirin

Pharmacodynamics:Ribavirin - an antiviral agent of direct action, a synthetic analogue of nucleosides.
Ribavirin rapidly penetrates into virus-infected cells and is easily phosphorylated by intracellular adenosine kinase to metabolites - mono-, di- and triphosphates. Ribavirin triphosphate is a potent competitive inhibitor of inosine monophosphate dehydrogenase, viral RNA polymerase and viral mRNA-guanylyltransferase. Inhibition of the latter stops capping mRNA, which leads to a significant depletion of intracellular reserves of guanosine triphosphate, suppression of the synthesis of the virus-specific protein and viral RNA. Ribavirin is also built into the viral genome, causing fatal mutations. Ribavirin inhibits the replication of new virions, which leads to a decrease in viral load; the drug selectively inhibits the synthesis of viral RNA, without suppressing the synthesis of RNA in healthy cells. The mechanism by which ribavirin in combination with interferon alpha-2b or peginterferon alfa-2b realizes its antiviral effect against the hepatitis C virus (HCV), has not been fully clarified. It is believed that the synergism of ribavirin and interferon alfa-2b or peginterferon alfa-2b against HCV is due to the acceleration of ribovirin phosphorylation in the presence of interferon. Monotherapy for hepatitis C with ribavirin is ineffective. Ribavirin, like its metabolites, do not show signs of suppressing replication and / or inhibition of enzymes specific for hepatitis C virus (HCV).
The most sensitive to ribavirin DNA viruses are herpes simplex virus, adenoviruses, smallpox viruses, Marek's diseases; RNA viruses - influenza A, B viruses, paramyxoviruses (parainfluenza, mumps, Newcastle disease), reoviruses, arenaviruses (Lassa fever virus, Bolivian hemorrhagic fever),Bunyaviruses (Rift Valley fever virus, Congo-Crimean fever virus), hantaviruses (hemorrhagic fever virus with renal or pulmonary syndrome), paramyxoviruses; oncogenic RNA viruses, including cytomegalovirus and human papillomavirus.
Ribavirin-insensitive DNA viruses - Varicella zoster, pseudorabies virus, cowpox; RNA viruses - enteroviruses, rhinoviruses, encephalitis virus of the forest Semliki.

Pharmacokinetics:

Absorption by oral administration is rapid. Bioavailability at reception on an empty stomach makes 45%, with simultaneous intake with food - 65% - 70%. There is an effect of "first passage" through the liver. Time to reach the maximum concentration - 1-1,5h. Average maximum concentration (C_max) in plasma: about 5 μmol / l at the end 1 Weeks of admission in a dose 200 mg every 8 hours and about 11 μmol / l at the end 1 Weeks of admission in a dose 400 mg every 8 hours. Dependence of the area under the pharmacokinetic curve (AUC) from the dose linear; from C_max - nonlinear.

C plasma proteins ribavirin binds slightly. When administered orally 600 mg 2 an equilibrium concentration (C_ss) is reached by the end 4 weeks and is 2200 ng / ml.

The drug is intensively distributed to organs and tissues; penetrates the blood-brain barrier, is found in the brain, in the cerebrospinal fluid, in the secretion of the airways and red blood cells. The half-distribution period is 3,7 h. The amount of distribution (V_d) from 647 before 5000 l. A large amount of ribavirin triphosphate accumulates in erythrocytes. Next, almost no output from them; therefore, considering the negative impact on the reproductive system, until the pool of red blood cells is fully updated (no less than 6 months), patients of reproductive age should carefully observe contraception. Significant concentration of the drug (67% from that in plasma) is found in the cerebrospinal fluid. The ratio of bioavailability indicators for course and single admission is equal to 6:1.

The metabolism of ribavirin occurs in two ways: reversible phosphorylation and cleavage (deibosylation and amide hydrolysis with the formation of a triazole carboxyl metabolite).

Ribavirin is excreted slowly from the body. The half-life (T1/2) after a single dose 200 mg is from 1 before 2 hours from plasma to 40 days from erythrocytes. After discontinuing admission T1/2 is about 300 h. Ribavirin and its metabolites are excreted primarily through the kidneys. For the first 24 h in unchanged form is displayed near 7% preparation for 48 h - about 10%. Through the intestine, only 10% unchanged ribavirin.

When taking the drug, patients with renal insufficiency AUC and C_max Ribavirin increase, which is due to a decrease in true clearance. In liver failure (A, B and C Child-Pugh classes), the pharmacokinetics of ribavirin does not change.

On the cytochrome P450 system ribavirin does not affect.

Indications:Chronic hepatitis C (patients not previously treated with interferon alfa-2b and peginterferon alfa-2b; during exacerbation after course monotherapy interferon alfa-2b and peginterferon alfa-2b; patients refractory to monotherapy with interferon alfa-2b and peginterferon alfa-2b ).

Contraindications:Hypersensitivity to ribavirin and / or to any of the excipients; pregnancy and lactation; chronic heart failure IIb-III st, myocardial infarction; severe heart disease (including unstable and resistant to therapy forms); Thyroid disease, resistant to therapy; hemoglobinopathy (including thalassemia, sickle cell anemia); severe kidney disease (incl.chronic renal failure / CC less than 50 ml / min / need for hemodialysis); severe liver dysfunction or decompensated hepatic cirrhosis; severe depression, suicidal intentions or suicide attempts (including in history); autoimmune diseases (including autoimmune hepatitis); age to 18 years; lactose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome.

Carefully:Elderly age, chronic heart failure, severe lung diseases (including chronic obstructive pulmonary disease), decompensated diabetes mellitus with a tendency to ketoacidosis, thyroid disease (including hyperthyroidism), blood clotting disorders (thrombophlebitis, pulmonary embolism arteries), significant oppression of the hematopoietic function of the bone marrow, myelodepression, hemoglobinopathy (including thalassemia, sickle cell anemia); combination with highly active antiretroviral therapy (BAAPT) with concomitant HIV infection (increased risk of lactic acidosis).

Dosing and Administration:Inside.
Ribavirin is prescribed 400-600 mg, 2 times a day, with an interval of 12 hours. Take ribavirin follows with eating, without chewing, squeezed with enough water. Simultaneously, interferon alfa-2b, subcutaneously, 3 times a week for 3 million ME or peginterferon alfa-2b, subcutaneously, at a dose of 1.5 μg / kg body weight once a week.
Recommended doses of ribavirin, depending on body weight (combination with interferon alfa-2b)

Body mass	The daily dose of ribavirin	Number of tablets
<75 kg	1000 mg	5 (2 morning + 3 in the evening)
>75 kg	1200 mg	6 (3 morning + 3 in the evening)

Recommended doses of ribavirin, depending on body weight (combination with peginterferon alfa-2b)

Body mass	The daily dose of ribavirin	Number of tablets
<65 kg	800 mg	4 (2 morning + 2 in the evening)
65-85 kg	1000 mg	5 (2 morning + 3 in the evening)
>85 kg	1200 mg	6 (3 morning + 3 in the evening)

The duration of the combination therapy with ribavirin with interferon alpha is 24 to 48 weeks. At the same time for previously untreated patients, the duration of the course is at least 24 weeks, and in patients with the virus of genotype 1, the course duration is 48 weeks. In patients who are not susceptible to monotherapy with interferon alfa, as well as when the disease recurs, the course duration is at least 6 months. The minimum course of treatment is 16 weeks, the maximum - 52 weeks (1 year).
In the event of serious adverse events or abnormalities in laboratory indicators during administration, the dose should be adjusted in accordance with the following recommendations or suspend the drug until the undesirable events disappear.

Modification of the dosing regimen
Laboratory indicators	Dose reduction only *ribavirin to 600 mg / day , if:**	Dose reduction only interferon alpha-2b or peginterferon alfa-2b on 50%, if:	Discontinuation of ribavirin and interferon alfa-2b or peginterferon alfa-2b, if:
Hemoglobin	<10 g / dL	-	<8.5 g / dL
Hemoglobin (patients with compensated heart disease)	The hemoglobin content decreased by >2 g / dL for any 4 weeks during treatment (continued use of a reduced dose)		<12 g / dL through 4 weeks after a dose reduction
Leukocytes	-	<1500 / μL	<1000 / μL
Neutrophils	-	<750 / μL	<500 / μL
Platelets	-	<50000 / μL	<25000 / μL
Total bilirubin		-	2.5 x VGN **
Free bilirubin	>5 mg / dL	-	>4 mg / dL (for more 4 weeks)
Creatinine	-	-	>2 mg / dL
ALT / AST			2 x (base value) and >10 x VGN **
* Patients who had reduced the dose of ribavirin before 600 mg / day should be taken 1 tablet 200 mg in the morning and 2 tablets by 200 mg in the evening
** the upper limit of the norm
If, after dose adjustment, the tolerability of ribavirin does not improve, the use of this drug, as well as interferon alfa-2b or peginterferon alfa-2b should stop

Side effects:Adverse events with combined therapy may be associated with both ribavirin and interferon alfa-2b or peginterferon alfa-2b, as well as their combination.
On the part of the blood system and hemopoiesis: hemolysis is the main toxic effect of ribavirin. A decrease in hemoglobin (hemolytic anemia) by> 4 g / dl was observed in 37% of patients receiving combination therapy ribavirin+ interferon alpha-2b, and in 30% of patients receiving combination therapy ribavirin+ peginterferon alfa-2b; a decrease in the hemoglobin content below the level of 10 g / dl is observed only in 14% of patients. Possible development of moderate anemia, leukopenia, neutropenia, granulocytopenia and thrombocytopenia. In some cases, development of aplastic anemia is possible.
From the skin and subcutaneous tissues: itching, dry skin, impaired hair structure, rash, erythema, eczema.Rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
From the nervous system: headache, dizziness, tremor, paresthesia, hyperesthesia, depression, irritability, insomnia, drowsiness, restlessness, poor concentration, confusion, emotional lability, nervousness, aggressive behavior, confusion. In some cases - suicidal intentions and attempts.
From the digestive system: dry mouth, nausea, vomiting, diarrhea, abdominal pain, anorexia, constipation, dyspepsia, taste perversion, pancreatitis (when used in combination with interferon alpha-2b), flatulence, stomatitis, glossitis, bleeding gums.
From the endocrine system: dysfunction of the thyroid gland (changing the content of thyroid-stimulating hormone), requiring therapeutic measures; is observed in 3% of patients who did not previously have such disorders.
From the cardiovascular system: chest pain, tachycardia, decreased or increased blood pressure, palpitations, fainting.
From the respiratory system and ENT organs: pharyngitis, cough, dyspnea, bronchitis, sinusitis, rhinitis.
From the genitourinary system: "hot flashes", decreased libido, menstrual disorders, amenorrhea, menorrhagia; prostatitis.
From the musculoskeletal system: myalgia, arthralgia, increased smooth muscle tone.
From the sense organs: lesions of the lacrimal gland, conjunctivitis, visual impairment, hearing impairment / loss, tinnitus.
Laboratory indicators: in some cases - an increase in the concentration of uric acid and indirect bilirubin due to hemolysis; the indicators normalize within 4 weeks after the end of therapy. Very rarely are clinical symptoms of gout; while dose adjustment or cancellation treatment is not required.
Other: otitis media, allergic reactions, weakness, malaise, chills, fever, flu-like syndrome, increased sweating, asthenia, weight loss, thirst, fungal infection, lymphadenopathy, herpetic infection.

Overdose:It was not revealed (one-stage oral administration at a dose of 10 g and a p / c dose of 39 million ME did not reveal the appearance of symptoms associated with overdose).

Interaction:With the combined use of ribavirin and interferon alfa, synergy of their action is noted.
Medicines containing magnesium and aluminum compounds, simethicone reduce the bioavailability of the drug.
Competitive interaction of ribavirin with zidovudine or stavudine can lead to a decrease in antiretroviral activity of both drugs, and an increase in the concentration of RNA-HIV in blood plasma. Therefore, careful monitoring of the concentration of RNA-HIV in the blood of patients treated with ribavirin in combination with one of these two drugs is recommended. In the case of increasing viremia, the regimen should be reconsidered. In addition, when combined with zidovudine increases the risk of hemolytic anemia; and with didanosine, the risk of developing mitochondrial toxicity increases. In combination with purine nucleosides (didanosine, abacavir and others) - the concentration of phosphorylated metabolites increases and the associated risk of lactate acidosis.
Studies on microsomal liver preparations revealed that cytochrome P450 enzymes do not participate in metabolic transformations of ribavirin; as well as ribavirin does not affect the cytochrome P450 system.
The possibility of drug or other interaction with ribavirin may persist for up to 2 months after discontinuation due to delayed excretion.

Special instructions:In connection with the proven teratogenicity of the drug, men and women of reproductive age during treatment and within 6 months after the end of therapy should carefully follow the contraception.
Laboratory tests (clinical analysis of blood counting the leukocyte formula and platelet count, determination of electrolytes, creatinine content, functional liver samples) should be performed before the start of therapy, at 2 and 4 weeks, and then regularly. After 6 months of therapy, a patient should be examined to assess the virologic response. In the absence of a virologic response, treatment with ribavirin in combination with interferon alpha-2b or peginterferon alfa-2b should be discontinued.
In the course of treatment with ribavirin, the maximum decrease in hemoglobin content in most cases occurs 4-8 weeks after the start of treatment. With a decrease in hemoglobin, the dose of ribavirin should be temporarily reduced (see Fig.Table "Modification of the dosing regimen"). Typically, the recommended dose changes provide a recovery level of hemoglobin.
In case of acute manifestation of hypersensitivity (hives, angioedema, bronchospasm, anaphylaxis), the drug should be discontinued immediately. Transient rashes do not serve as a basis for interrupting treatment.
In connection with the possible age-related decrease in the excretory function of the kidneys in elderly patients, it is necessary to determine the parameters of kidney function, in particular, the creatinine clearance, before using the drug.

Effect on the ability to drive transp. cf. and fur:During treatment, persons who are weak, drowsy or disoriented should refrain from driving vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Tablets of 200 mg.

Packaging:For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered. For 30, 50, 60 or 90 tablets in cans of polymeric for medicines, capped with a lid.Each jar or 3, 5, 6, 9 contour mesh packages together with instructions for use in a pack of cardboard.

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.

Terms of leave from pharmacies:On prescription

Registration number:P N002117 / 02

Date of registration:15.07.2009

The owner of the registration certificate:NIZHFARM, JSC NIZHFARM, JSC Russia

Manufacturer: & nbsp

MAKIZ-PHARMA, LLC Russia

Representation: & nbspMAKIZ-PHARMA, LLCMAKIZ-PHARMA, LLCRussia

Information update date: & nbsp16.08.2015

Illustrated instructions

Instructions

Ribapeg® (Ribapeg®)