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

Composition:Composition per one tablet:
Active substance: Ribavirin 0.2 g (200 mg).
Excipients: microcrystalline cellulose, potato starch, povidone, calcium stearate.

Description:Tablets are white or white with a yellowish tint of color, flat-cylindrical 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:An antiviral agent. Quickly penetrates into the cells and acts inside the virus-infected cells. Intracellularly ribavirin it is easily phosphorylated by adenosinase to mono-, di- and triphosphate metabolites. Ribavirin triphosphate - a strong competitive inhibitor of inosine monophosphate dehydrogenase, an RNA polymerase of influenza virus and guanylyltransferase messenger RNA, last seen capping inhibition of messenger RNA. These diverse effects lead to a significant reduction in the number of cellular guanosine and suppress the synthesis of viral RNA and protein. Ribavirin inhibits the replication of new virions, which reduces the viral load, selectively inhibits the synthesis of viral RNA, without suppressing the synthesis of RNA in normally functioning cells.
The activity of ribavirin against hepatitis C virus has been revealed. Although the mechanism of action is completely unclear, it is assumed that ribavirin triphosphate accumulating in the course of phosphorylation competitively suppresses the formation of guanosine triphosphate, thereby reducing the synthesis of viral RNAs. It is also believed that the mechanism of synergistic action of ribavirin and interferon alfa-2b or peginterferon alfa-2b against hepatitis C virus is due to the increased phosphorylation of ribavirin by interferon.
The most sensitive to ribavirin DNA viruses are herpes simplex virus, adenoviruses, cytomegalovirus, 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, Crimean-Congo hemorrhagic fever virus), hantaviruses (haemorrhagic fever virus with renal or pulmonary syndrome) paramyxoviruses, oncogenic RNA viruses.
Ribavirin-insensitive DNA viruses - Varicella zoster, pseudorabies virus, cowpox virus; RNA viruses - enteroviruses, rhinoviruses, encephalitis virus of the forest Semliki.

Pharmacokinetics:At intake absorption - high; bioavailability - 45-65% (has the effect of first passage through the liver and linear dependence on the dose in the range from.200 to 1200 mg).
The time to reach the maximum concentration in the blood plasma (TCam) with ingestion is 1-1.5 hours. It binds to plasma proteins in small amounts. The average maximum concentration (Cmax) at the end of 1 week with oral administration of 0.2 and 0.4 g every 8 h -5 and 11 μmol / l, respectively; when ingested 600 mg twice a day, the equilibrium concentration in blood plasma (Css) was reached by the end of 4 weeks and was 2200 ng / ml. The volume of distribution is 647-802 to 5000 liters. Distributed in plasma, respiratory secretions and erythrocytes. A large amount of the active metabolite of ribavirin triphosphate accumulates in the erythrocytes, reaching a constant level after about 4 days and remaining in them for several weeks after application. Significant concentration (after long-term use) can be detected in cerebrospinal fluid (CSF) - 67% of that in plasma.
Metabolized by reversible phosphorylation to form mono-, di- and triphosphate (active) metabolites; is also metabolized to 1,2,4-triazolecarboxamide.Inactivation is carried out by de-rososylation followed by hydrolysis and rupture of the triazole ring. Half-life (T1 / 2) with oral administration of a single dose: initial - 0.5-2 h from plasma and up to 40 days from erythrocytes; the final - 27-36 hours; when reaching a stable concentration of -151 h.
When administered orally, it is excreted by the kidneys: 7% unchanged for 24 hours; 10% unchanged for 48 hours. The metabolite 1,2,4-triazolecarboxamide is also characterized by a renal excretion pathway. Through the intestine, 10% is excreted.
It is not excreted by hemodialysis. In patients with renal failure, the area under the concentration / time curve (AUC) and the maximum concentration (Cmax) of ribavirin increase, which is due to a decrease in the true clearance. In patients with hepatic insufficiency, the pharmacokinetics of ribavirin does not change. After taking a single dose with food containing fats, the pharmacokinetics of ribavirin varies significantly (AUC and Cmax are increased by 70%).

Indications:Chronic hepatitis C (in combination with interferon alpha-2b or peginterferon alfa-2b): in patients previously untreated with interferon alpha-2b or peginterferon alfa-2b; when exacerbated after a course of monotherapy with interferon alpha-2b or peginterferon alfa-2b; in patients,refractory to monotherapy with interferon alpha-2b or peginterferon alfa-2b.

Contraindications:Hypersensitivity, pregnancy, lactation, chronic heart failure IIb-III st, myocardial infarction, renal failure (creatinine clearance less than 50 ml / min), severe anemia, severe hepatic insufficiency, decompensated liver cirrhosis, autoimmune diseases (incl. autoimmune hepatitis), non-treatable thyroid disease, severe depression with suicidal intent, children and adolescence (under 18 years of age).

Carefully:Women of reproductive age (the onset of pregnancy is undesirable), decompensated diabetes mellitus (with attacks of ketoacidosis); chronic obstructive pulmonary disease, pulmonary embolism, chronic heart failure I-IIa art, thyroid diseases (including hyperthyroidism), bleeding disorders, thrombosis, mielodeprescia, hemoglobinopathies (including thalassemia, sickle-cell anemia ), depression, suicidal tendencies (including history), concomitant HIV infection (against the background of a combination highly active antiretroviral therapy - the risk of lactic acidosis), advanced age.

Pregnancy and lactation:Data on the penetration of the drug into breast milk is not obtained. Due to the adverse effects of the drug on the baby's body, breastfeeding should be discontinued before therapy begins.

Dosing and Administration:The drug is taken orally without squeezing and washing with water, along with a meal of 0.8-1.2 g per day in 2 divided doses (morning and evening). At the same time, interferon alfa-2b is administered, 3 times a week, 3 times a week, or peginterferon alfa-2b - subcutaneously, 1.5 mcg / kg once a week. When combined with interferon alpha-2b at a body weight of 75 kg, the dose of ribavirin is 1 g per day (0.4 g in the morning and 0.6 g in the evening); above 75 kg - 1.2 grams per day (0.6 g in the morning and 0.6 g in the evening). When combined with peginterferon alfa-2b at a body weight less than 65 kg, the dose of ribavirin is 0.8 g per day (0.4 g in the morning and 0.4 g in the evening); 65-85 kg - 1 g per day (0.4 g in the morning and 0.6 g in the evening); more than 85 kg - 1.2 grams per day (0.6 g in the morning and 0.6 g in the evening).
Duration of treatment is 24-48 weeks; while for previously untreated patients - not less than 24 weeks, in patients with the virus of genotype 1 - 48 weeks. In patients who are not susceptible to monotherapy with interferon alpha, and also during relapse, at least 6 months to 1 year (depending on the clinical course of the disease and response to ongoing therapy).

Side effects:From the nervous system: headache, dizziness, general weakness, malaise, insomnia, asthenia, depression, irritability, anxiety, emotional lability, nervousness, agitation, aggressive behavior, confused consciousness; rarely - suicidal tendencies, increased smooth muscle tone, tremor, paresthesia, hyperesthesia, hypoesthesia, fainting.
From the cardiovascular system: a decrease or increase in blood pressure, brady or tachycardia, palpitations, cardiac arrest.
From the hematopoiesis: Hemolytic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia; extremely rare - aplastic anemia.
From the respiratory system: cough, pharyngitis, dyspnea, bronchitis, otitis media, sinusitis, rhinitis.
From the digestive system: dry mouth, decreased appetite, nausea, vomiting, diarrhea, abdominal pain, constipation, taste distortion, pancreatitis, flatulence, stomatitis, glossitis, bleeding from the gums, hyperbilirubinemia.
From the sense organs: lesions of the lacrimal gland, conjunctivitis, visual impairment, hearing impairment / loss, tinnitus.
From the musculoskeletal system: arthralgia, myalgia.
From the genitourinary system: decreased libido, dysmenorrhea, amenorrhea, menorrhagia, prostatitis.
From the skin and subcutaneous fat: "tides".
Allergic reactions: skin rash, erythema, urticaria, hyperthermia, angioedema, bronchospasm, anaphylaxis, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Other: hair loss, alopecia, hair structure disorder, dry skin, hypothyroidism, chest pain, thirst, fungal infection, viral infection (including herpes), flu-like syndrome, sweating, lymphadenopathy.

Overdose:It is not revealed (one-stage oral administration in a dose of 10 g did not reveal the appearance of symptoms associated with overdose).
Treatment: withdrawal of the drug, symptomatic therapy.

Interaction:Medicines containing ions of salts of magnesium and aluminum, and also simethicone reduce the bioavailability (AUC decreases by 14%, has no clinical significance).
When combined with interferon alpha-2b or peginterferon alfa-2b-synergism action.
The appointment of ribavirin during treatment with zidovudine and / or stavudine is accompanied by a decrease in their phosphorylation, which can lead to HIV viremia and require a change in the treatment regimen.
Increases the concentration of phosphorylated metabolites of purine nucleosides (including didanosine, abacavir) and the associated risk of developing lactic acidosis.
Does not affect the enzymatic activity of the liver with the participation of cytochrome P450.
Simultaneous food intake with a high fat content increases the bioavailability of ribavirin (AUC and C max are increased by 70%).

Special instructions:It should take into account the teratogenicity of the drug, men and women of reproductive age during treatment and for 7 months after the end of therapy should use effective contraceptives.
Laboratory tests (clinical analysis of blood counting the leukocyte count and number of platelets, determination of electrolytes, creatinine concentration, functional liver tests) should be performed before the start of therapy, for 2 and 4 weeks and then regularly.
During treatment with ribavirin, the maximum reduction in hemoglobin in most cases occurs after 4-8 weeks from the start of treatment.With a decrease in hemoglobin below 110 g / l, the dose of ribavirin should be temporarily reduced by 400 mg per day, with a decrease in hemoglobin below 100 g / l, the dose should be reduced to 50% of the original dose. If the intolerance of ribavirin remains intact after dose adjustment, and if hemoglobin falls below 85 g / l, the drug should be discontinued.
In 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.
Before the onset of hepatitis C therapy, the need for histological confirmation of the diagnosis should be assessed (treatment of patients with the genotype of virus 2 or 3 can begin without prior biopsy of the liver).

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

Form release / dosage:Tablets 200 mg.

Packaging:For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.
3 or 6 contour packs together with the instruction for use are placed in a pack of cardboard.

Storage conditions:List B. Store in dry the dark place at a temperature of no higher than 25 0C. Keep out of the reach of children.

Shelf life:4 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-000413

Date of registration:04.02.2010

The owner of the registration certificate:VALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Manufacturer: & nbsp

VALENTA PHARMACEUTICS, JSC Russia

Representation: & nbspVALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Information update date: & nbsp13.08.2015

Illustrated instructions

Instructions

Ribavirin (Ribavirin)