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

Composition:One capsule contains active substance: ribavirin - 0.2 g; Excipients: lactose, corn starch, povidone (polyvinylpyrrolidone), silicon dioxide colloid (aerosil), calcium stearate. Hard gelatine capsules: gelatin, titanium dioxide, iron oxide, yellow oxide.

Description:Hard gelatin capsules No. 0 of yellow color. The contents of the capsules are a powder or compacted mass from white to white with a yellowish tint of color, disintegrating when pressed with a glass rod.

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-guanyltransferase. Inhibition of the latter stops capping mRNA, which leads to a significant depletion of the intracellular reserves of guanosine triphosphate,inhibition of the synthesis of the virus-specific protein and viral RNA. Ribavirin is also built into the viral genome, causing lethal 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, does not detect signs of suppression of replication and / or inhibition of enzymes specific for the hepatitis C virus (HCV).
The most sensitive to ribavirin DNA viruses are herpes simplex virus, adenoviruses, smallpox viruses, Marek's diseases, cytomegalovirus, human papillomavirus; RNA viruses - viruses of influenza A, B, paramyxoviruses (parainfluenza, mumps,New Zealand 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.
Ribavirin-insensitive DNA viruses - Varicella zoster, pseudorabies virus, cowpox; RNA viruses - enteroviruses, rhinoviruses, encephalitis virus of the forest Semliki.

Pharmacokinetics:

When administered orally ribavirin quickly absorbed in the gastrointestinal tract. 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 in the plasma - from 1 before 1,5 hours. 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.

FROM plasma proteins ribavirin binds slightly. When administered orally 600 mg 2 an equilibrium concentration (Css) 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. Volume of distribution (Vd) from 647 before 5000 l. A large amount of ribavirin triphosphate accumulates in the erythrocytes. Next, almost no output from them; Therefore, taking into account 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 use reliable methods of contraception. A significant concentration of ribavirin (67 % of 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).

Displayed ribavirin from the body slowly. 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 the termination of course reception T_1/2 is about 300 h. Ribavirin and its metabolites are mainly excreted from the body through the kidneys. Only about 10 % unchanged ribavirin is excreted through the intestine. For the first 24 h in unchanged form is displayed near 7 % of the drug, for 48 h - about 10 %.

Pharmacokinetics in special clinical conditions: when taking the drug in patients with renal insufficiency AUC (area under the pharmacokinetic curve "concentration / time") and C_max Ribavirin increase, which is due to a decrease in true clearance. In patients with hepatic insufficiency (A, B and C classes on Child-Pugh) the pharmacokinetics of ribavirin does not change.

On the cytochrome P45 system0 Ribavirin is not affected.

Indications:Chronic hepatitis C (in patients previously untreated with interferon alfa-2b or peginterferon alfa-2b, with exacerbation after the course of monotherapy with interferon alpha-2b or peginterferon alfa-2b, in patients not susceptible to monotherapy with interferon alpha-2b or peginterferon alfa-2b ). Treatment is performed in combination with interferon alpha-2b or peginterferon alfa-2b.

Contraindications:- hypersensitivity to ribavrin and / or to any of the excipients;
- pregnancy, lactation period;
- chronic heart failure IIb-III st. (according to Vasilenko-Strazhesko classification), myocardial infarction, severe heart diseases (including unstable and resistant to therapy forms);
- hemoglobinopathy (including thalassemia, sickle cell anemia);
- renal failure (creatinine clearance less than 50 ml / min, need for dialysis);
- liver failure, decompensated liver cirrhosis;
- autoimmune diseases (including autoimmune hepatitis);
- non-treatable thyroid disease;
- severe depression with suicidal intentions (including in history);
- lactose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption;
- Children's and adolescence (up to 18 years).

Carefully:- women of reproductive age (the onset of pregnancy is undesirable);
- Decompensated diabetes mellitus (with attacks of ketoacidosis);
- chronic obstructive pulmonary disease, thromboembolism of the pulmonary artery;
- chronic heart failure I-IIa st.(according to Vasilenko-Strazhesko classification);
- diseases of the thyroid gland (including hyperthyroidism);
- coagulation disorders, thrombophlebitis;
- Myelodepression;
- significant oppression of the hematopoietic function of the bone marrow;
- concomitant HIV infection (combined with antiretroviral therapy, risk of lactate-acidosis);
- elderly age.

Pregnancy and lactation:Contraindicated use of the drug during pregnancy and lactation (breastfeeding).
Treatment with ribavirin should not be started until a negative pregnancy test result is obtained, which should be performed immediately before starting the drug.
Data on the penetration of the drug into breast milk is not obtained. Due to 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 chewing and washing with water, while taking a meal at 800-1200 mg / day in 2 divided doses (morning and evening) at intervals of 12 hours. Simultaneously, interferon alfa-2b is administered subcutaneously (sc), 3 million IU 3 times a week or peginterferon alfa-2b-p / k, 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 capsules
<75 kg	1000 mg	5 (2 in the morning + 3 in the evening)
> 75 kg	1200 mg	6 (3 in the 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 capsules
<65 kg	800 mg	4 (2 in the morning + 2 in the evening)
65 to 85 kg	1000 mg	5 (2 in the morning + 3 in the evening)
> 85 kg	1200 mg	6 (3 in the morning + 3 in the evening)

Duration of treatment is 24-48 weeks. At the same time for previously untreated patients, the duration of the course is at least 24 weeks, in patients with the virus of genotype 1, the course duration is 48 weeks. In patients who are not susceptible to monotherapy with interferon alpha-2b, and when the disease recurs - at least 6 months.
The minimum course of treatment is 16 weeks, the maximum is 52 weeks (1 year).
If serious adverse events or laboratory abnormalities occur during the use of ribavirin, the dose should be adjusted or the drug should be stopped until the elimination of adverse events.
Modification of the dosing regimen

Laboratory indicators	Dose reduction only ribavirin before 600 mg / day *, if:	Dose reduction only interferon alpha-2b or peginterferon alfa-2b on 50 %, if:	Termination of admission ribavirin and interferon alfa-2b or peginterferon alfa-2b, if:
Content hemoglobin	<100 mg / ml	-	<85 mg / ml
The content of hemoglobin in patients with heart disease in stable form	The content of hemoglobin decreased on ≥20 mg / ml for any 4 weeks in during the treatment (continuous use of a reduced dose)		<120 mg / ml through 4 weeks after dose reduction
Number of leukocytes	-	<1500 / μL	<1000/ μl
Number of neutrophils	-	<750 / μL	<500 / μL
Platelet count	-	<50000 / μL	<25000 / μL
The content of total bilirubin	-	-	2,5хVHN **
Content free bilirubin	>5 mg / dL	-	>4 mg / dL (for more 4 weeks)
Content creatinine	-	-	>2 mg / dL
ALT / AST activity	-	-	2 х (basic value) and> 10хВГН **

* Patients who had reduced the dose of ribavirin to 600 mg / day should take 1 200 mg capsule in the morning and 2 200 mg capsules 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 be discontinued.

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 due to hemolysis (a decrease in hemoglobin by> 4 g / dl was observed in 37% of patients receiving combination therapy with ribavirin and interferon alpha-2b, and in 30% of patients receiving combination therapy with ribavirin and peginterferon alfa-2b, a decrease in hemoglobin below 10 g / dl is observed only in 14% of patients); there may be a moderately severe anemia, leukopenia, neutropenia, granulocytopenia and thrombocytopenia; in some cases, development of aplastic anemia is possible.
From the nervous system: headache, dizziness, tremor, paresthesia, hyperesthesia, depression, irritability, insomnia, drowsiness, anxiety, decreased concentration, disorientation, emotional lability, nervousness, aggressive behavior, confusion. In some cases, suicidal intentions and attempts.
From the skin and subcutaneous tissues: alopecia, itching, dry skin, hair structure disorder, rash, erythema, eczema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
From the cardiovascular system: pain in the chest, decrease or increase in blood pressure, tachycardia, palpitations, fainting.
From the respiratory system and ENT organs: cough, pharyngitis, dyspnea, bronchitis, otitis media, sinusitis, rhinitis.
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 genitourinary system: "hot flashes", a decrease in libido, a disorder of the menstrual cycle, amenorrhea, menorrhagia, prostatitis.
From the musculoskeletal system:myalgia, increased smooth muscle tone, arthralgia.
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, associated with hemolysis.These indicators are normalized within 4 weeks after the end of therapy. Only a small number of patients with elevated uric acid concentrations had clinical symptoms of gout, but did not require modification of the dose or withdrawal of treatment.
Other: weakness, allergic reactions, malaise, chills, fever, flu-like syndrome, increased sweating, asthenia, weight loss, thirst, fungal infection, herpetic infection, lymphadenopathy.

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:When combined with interferon alpha-2b or peginterferon alfa-2b - synergism of action.

Drugs containing magnesium and aluminum compounds, as well as simethicone reduce the bioavailability of the drug (AUC decreases by 14%, has no clinical significance).

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.In addition, when combined with zidovudine, the risk of hemolytic anemia increases.

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.

The possibility of drug or other interaction with ribavirin may persist for up to 2 months after discontinuation due to delayed excretion.

Simultaneous food intake with a high fat content increases the bioavailability of ribavirin (AUC and Cmax increase by 70%).

Special instructions:It should take into account the teratogenicity of the drug, men and women of reproductive age during treatment and for 6 months after the end of therapy should use reliable methods of contraception.

Laboratory tests (clinical analysis of blood counting the leukocyte count and number of platelets, 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.
During treatment with ribavirin, the maximum reduction in hemoglobin in most cases occurs after 4-8 weeks from the start of treatment. If the hemoglobin falls below 100 mg / ml, the dose of ribavirin should be temporarily reduced (see Section "Dosage and Administration"). Typically, the recommended dose changes ensure the recovery of hemoglobin.
In case of acute manifestation of hypersensitivity (hives, angioedema, bronchospasm, anaphylaxis), the drug should be stopped immediately.
Transient rashes do not serve as a basis for interrupting treatment.
In connection with the possible deterioration of kidney function in elderly patients, the use of the kidney function, in particular creatinine clearance, is necessary before using the drug.
Before the initiation 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:Patients experiencing fatigue, drowsiness, or disorientation when combined with ribavirin and interferon alfa-2b or peginterferon alfa-2b should stop doing work that requires increased attention and speed of psychomotor reactions (including driving, driving).

Form release / dosage:Capsules of 200 mg.

Packaging:10 capsules in a planar cell package. 30, 60, 90 or 120 capsules in a polymer can. 3 or 6 contour squares or one plastic can with instructions for use in a pack of cardboard.

Storage conditions:In dry, dark place at a temperature of no higher than 25 0C.
Keep out of the reach of children.

Shelf life:3 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LS-000206

Date of registration:31.08.2010

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp12,08.2015

Illustrated instructions

Instructions

Ribavirin (Ribavirin)