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

Composition:1 capsule contains
active substance: ribavirin - 200 mg;
Excipients: sugar milk (lactose) - 181 mg, corn starch - 4 mg, microcrystalline cellulose - 8 mg, silicon dioxide colloid (aerosil) - 3 mg, calcium stearate -4 mg.
Composition of the capsule: gelatin, titanium dioxide.

Description:Hard gelatin capsules of white color number 0. The body is white, the lid is white. The contents of the capsules are white or white powder with a yellowish tint of color

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, 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 alpha-2 versus 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 CMV and HPV - DNA viruses.
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%, at simultaneous reception with nutrition - 65 - 70%. There is an effect of "first passage" through the liver. The time to reach the maximum concentration is 1-1.5 hours. The average maximum plasma concentration (Cmax) is about 5 μmol / L at the end of the 1 week dose at a dose of 200 mg every 8 hours and about 11 μmol / L at the end of 1 week of admission in a dose of 400 mg every 8 hours. Dependence of the area under the pharmacokinetic curve (AUC) on the dose is linear; from Cmax is nonlinear.
With plasma proteins ribavirin binds slightly. When ingesting 600 mg twice a day, the equilibrium concentration (Css) is reached by the end of 4 weeks and is 2200 ng / ml. Ribavirin intensively distributed to organs and tissues; penetrates the blood-brain barrier, is found in the brain, in cerebrospinal fluid,in the secretion of the respiratory tract and erythrocytes. The half-distribution period is 3.7 hours. The volume of distribution (Vd) -OT 647 to 5000 liters. 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 erythrocytes is fully updated (at least 6 months), reliable methods of contraception must be used for patients of reproductive age. 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 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 200 mg intake is 1 to 2 hours from plasma and up to 40 days from red blood cells.
After stopping the reception of T1 / 2 is about 300 h. Ribavirin and its metabolites are excreted primarily through the kidneys.For the first 24 hours in unchanged form, about 7% of the drug is withdrawn, in 48 hours - about 10%. Through the intestine, only 10% of unchanged ribavirin is excreted.
When taking the drug, patients with renal insufficiency AUC and Cmax ribavirin increase, which is due to a decrease in the true clearance. With hepatic insufficiency (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 (in patients previously untreated with interferon alfa-2b or peginterferon alfa-2b, with exacerbation after a 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 ).

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); heavykidney disease (including chronic renal failure [QC not less than 50 ml / min] the need for hemodialysis); severe liver dysfunction or decompensated hepatic cirrhosis; severe depression, suicidal intentions, or attempted suicide (including in anamnesis); autoimmune diseases (including autoimmune hepatitis); age to 18 years, lactose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption.

Carefully:Elderly age, chronic heart failure, I-IIa, heavy lung diseases (including chronic obstructive pulmonary disease), decompensated diabetes mellitus with a tendency to ketoacidosis, thyroid disease (including hyperthyroidism), blood clotting disorders (thrombophlebitis, embolism pulmonary artery), 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 administered by 400-600 mg, 2 once a day, with an interval of 12 h. Accept ribavirin follows with eating, without chewing, squeezed with enough water. Simultaneously appoint interferon alfa-2b, subcutaneously, 3 once a week for 3 million ME or peginterferon alfa-2b, subcutaneously, in a dose 1,5 mkg / kg body weight 1 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 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 capsules
<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-2b, is 24 - 48 weeks. At the same time for previously untreated patients, the duration of the course is at least 24 weeks, and in patients with genotype virus 1 the duration of the course is 48 weeks. In patients who are unresponsive to monotherapy with interferon alpha-2b, as well as when the disease recurs, the duration of the course is at least 6 months. Minimal course of treatment - 16 weeks, the maximum - 52 weeks (1 year).

If serious adverse events or laboratory abnormalities occur, adjust the dose in accordance with the following recommendations or suspend the drug until the disappearance of adverse events.

Modification of the dosing regimen
Laboratory indicators	Reduction of the dose of only ribavirin before 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 (continuous use reduced dose)		<12 g / dL through 4 weeks after dose reduction
Leukocytes	-	<1500 / μL	<1000 / μL
Neutrophils	-	<750 / μL	<500 / μL
Platelets	-	<50000 / μL	<25000 / μL
Total bilirubin	-	-	2,5xVGN **
Free bilirubin	>5 mg / dL	-	>4 mg / dL (for more 4 weeks)
Creatinine	-	-	>2 mg / dL
Activity ALT / AST	-	-	2x(basic value) and> 10xVGN **
* Patients who had reduced the dose of ribavirin before 600 mg / day should be taken 1 capsule 200 mg in the morning and 2 capsules for 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 hemoglobin content below 10 g / dl is observed only in 14% of patients. Perhaps the development of moderate anemia, leukopenia, neutropenia, granulocytopenia and thrombocytopenia. In some cases, development of aplastic anemia is possible.
From the skin and subcutaneous fat: alopecia, itching, dry skin, hair structure disorder, rash, erythema, eczema, 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, suicidal ideation 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 (change in 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," a decrease in libido, a disorder in the menstrual cycle,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: increase in the concentration of uric acid and indirect bilirubin due to hemolysis; the indicators normalize within 4 weeks after the end of therapy, clinical symptoms of gout are noted; 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 p / c at a dose of 39 million ME did not reveal the appearance of symptoms associated with overdose).

Interaction:When combined with ribavirin and interferon alfa-2b, synergism is observed.
Medicines containing magnesium and aluminum compounds, simethicone reduce the bioavailability of the drug.
Competitive interaction of ribavirin with zidovudine or stavudine may lead to a decrease in antiretroviral activity of both drugs, and an increase in the concentration of RNA-HIV in the 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 , etc.) - the concentration of phosphorylated metabolites increases and the associated risk of lactate acidosis development.
Studies on liver microsomes revealed that the enzymes of cytochrome P450 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 for 6 months. after the end of therapy should use reliable contraception.

Laboratory tests (clinical blood count, calculating the leukocyte count and number of platelets, determining electrolytes, creatinine content, functional liver samples) should be performed before 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 reduction in hemoglobin in most cases occurs 4 and more weeks after the start of treatment. With a decrease in hemoglobin, the dose of ribavirin should be temporarily reduced (see the table "Modification of the dosing regimen"). Typically, the recommended dose changes provide a recovery level of hemoglobin.
In acute manifestation of hypersensitivity (urticaria, 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 decline in the excretory function of the kidneys in elderly patients, it is necessary to determine the indicators of kidney function, in particular 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:Capsules of 200 mg.

Packaging:10 capsules per contour cell package. 3 contour squares with instructions for use in a cardboard pack.

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

Shelf life:2 years.
Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000153

Date of registration:13.01.2011

The owner of the registration certificate:FARMPROJECT, CJSC FARMPROJECT, CJSC Russia

Manufacturer: & nbsp

FARMPROJECT, CJSC Russia

Representation: & nbspFARM PROJECT CJSC FARM PROJECT CJSC Russia

Information update date: & nbsp10.08.2015

Illustrated instructions

Instructions

Ribavirin (Ribavirin)