Ribavirin

General characteristics. Structure:

Active agent: рибавирин - 200 mg;
excipients: sugar milk (lactose) - 181 mg, starch corn – 4 mg, cellulose microcrystallic – 8 mg, silicon dioxide colloid (aerosil) - 3 mg, calcium stearate – 4 mg.
Structure of the capsule: gelatin, titanium dioxide.

Description. Solid gelatin capsules of white color No. 0. Case of white color, lid of white color. Contents of capsules – powder of color, white or white with a yellowish shade.

Pharmacological properties:

Pharmacodynamics. Ribavirin - antiviral means of direct action, a synthetic analog of nucleosides. Ribavirin quickly gets into the cells infected with a virus and is easily phosphorylated by an intracellular adenosine kinasa to metabolites - mono - di - and three - phosphates. Ribavirintrifosfat is a powerful competitive inhibitor of an inozinmonofosfatdegidrogenaza, a virus RNA polymerase and virus мРНК-guanililtransferaza. The inhibition of the last stops capping of MRNK that leads to considerable exhaustion of intracellular stocks guanozintri-
phosphate, to inhibition of synthesis of virus-specific protein and virus RNA. Ribavirin is also built in a virus genome, causing lethal mutations. Ribavirin inhibits replication of new virions that leads to decrease in virus loading; drug selectively inhibits synthesis of virus RNA, without suppressing synthesis of RNA in healthy cells. The mechanism by means of which рибавирин in a combination with interferon alpha 2b or peginterferon alpha 2b realizes the antiviral action against the hepatitis C virus (HCV) finally is not found out. It is considered that a synergism of a ribavirin and interferon alpha 2b or peginterferon alpha 2b against VGS is caused by acceleration of phosphorylation of a ribavirin in the presence of interferon. Monotherapy of hepatitis C ribaviriny is inefficient. Ribavirin, as well as his metabolites, do not find signs of suppression of replication and/or inhibition of the enzymes specific to the hepatitis C virus (HCV). The DNA viruses, most sensitive to ribavirin, – a herpes simplex virus, adenoviruses, viruses of group of smallpox, Marek's disease; RNA viruses – influenza viruses And, In, paramyxoviruses (a parainfluenza, epidemic parotitis, the Newcastle disease), reoviruses, arenavirusa (a virus of fever of Lass, the Bolivian hemorrhagic fever), bunyavirusa (the Valley fever virus the Rift, a virus of Congo-Crimean
fevers), hantavirusa (a virus of hemorrhagic fever with a renal or pulmonic syndrome), paramyxoviruses; oncogenous RNA viruses, including TsMV and VPCh - DNA - viruses. DNA viruses, insensitive to a ribavirin, - Varicella zoster, a virus of pseudo-rage, a natural vaccinia; RNA viruses - enteroviruses, rhinoviruses, a virus of encephalitis of the wood of Semliki.

Pharmacokinetics. Absorption at oral administration bystry. Bioavailability at reception on an empty stomach makes 45%, at a concomitant use with food – 65 - 70%. The effect of "the first passing" through a liver takes place. Time of achievement of the maximum concentration – 1-1,5 h. The average size of the maximum concentration (Cmax) in plasma: about 5 µmol/l at the end of 1 week of reception in a dose of 200 mg each 8 hours and about 11 µmol/l at the end of 1 week of reception in a dose of 400 mg each 8 hours. Dependence of the area under pharmacokinetic curve (AUC) from a dose linear; from Cmax – nonlinear. рибавирин contacts proteins of plasma slightly. At intake on 600 mg 2 times a day equilibrium concentration (Css) is reached by the end 4 weeks and makes 2200 ng/ml. Ribavirin is intensively distributed on bodies and fabrics; gets through a blood-brain barrier, it is found in a brain, in cerebrospinal fluid, in a secret of respiratory tracts and erythrocytes. The period of semi-distribution makes 3,7 h. The volume of distribution (Vd) – from 647 to 5000 l. A large number of a ribavirintrifosfat collects in erythrocytes. Further it is practically not brought out of them; therefore, considering negative impact on reproductive system, before regeneration of a pool of erythrocytes (not less than 6 months) patients of reproductive age need to use reliable methods of contraception. Considerable concentration of a ribavirin (67% of that in plasma) is found in
cerebrospinal fluid. The ratio of indicators of bioavailability at a course and single dose is equal to 6:1. Metabolism of a ribavirin is carried out in two ways: reversible fosforilirova-
ny and splitting (a deribozilirovaniye and amide hydrolysis with formation of a triazolny carboxyl metabolite). Ribavirin is brought from an organism slowly. The elimination half-life (Т½) after a single dose of 200 mg makes from 1 to 2 hours of plasma and up to 40 days of erythrocytes. After the termination of reception Т½ Ribavirin makes about 300 h and his metabolites are brought out of an organism preferential through kidneys. For the first 24 h in not changed look about 7% of drug, for 48 h – about 10% are removed. Through intestines only 10% of not changed ribavirin are removed.
At administration of drug by patients with a renal failure of AUC and Cmax of a ribavirin increase that is caused by decrease in true clearance. At a liver failure (And, In and About classes on Chayld-Pyyu) the pharmacokinetics of a ribavirin does not change. рибавирин does not influence system of P450 cytochrome.

Indications to use:

Chronic hepatitis C (at the patients who were earlier not treated by interferon alpha 2b or peginterferon alpha 2b; at an aggravation after a monotherapy course interferon alpha 2b or peginterferon alpha 2b; at patients, unreceptive to monotherapy by interferon alpha 2b or peginterferon alpha 2b).

Route of administration and doses:

Inside.
Ribavirin appoint 400-600 mg, 2 times a day, at an interval of 12 h. It is necessary to accept рибавирин during food, without chewing, washing down with enough water. At the same time appoint interferon alpha 2b, subcutaneously, 3 times a week on 3 million ME or peginterferon alpha 2b, subcutaneously, in a dose of 1,5 mkg/kg of body weight once a week. The recommended doses of a ribavirin depending on body weight (a combination with interferon alpha 2b)
Body weight Daily dose of a ribavirin Number of capsules
≤75 kg 1000 mg 5 (in the 2nd morning + in the 3rd evening)
> 75 kg 1200 mg 6 (in the 3rd morning + in the 3rd evening)
The recommended doses of a ribavirin depending on body weight
(a combination with peginterferon alpha 2b)
Body weight Daily dose of a ribavirin Number of capsules
<65 kg 800 mg 4 (in the 2nd morning + in the 2nd evening)
65-85 kg 1000 mg 5 (in the 2nd morning + in the 3rd evening)
> 85 kg 1200 mg 6 (in the 3rd morning + in the 3rd evening)
Duration of a course of a combination therapy ribaviriny with interferon alpha 2b, makes 24 - 48 weeks. At the same time for earlier not treated patients duration of a course makes not less than 24 weeks, and at patients with a genotype virus 1 duration of a course makes 48 weeks. At patients, unreceptive to monotherapy by interferon alpha 2b, and also at a disease recurrence course duration with -
stavlyat not less than 6 months. The minimum course of treatment – 16 weeks, maximum – 52 weeks (1 year).
At emergence of the serious undesirable phenomena or deviations in laboratory indicators during use it is necessary to correct a dose according to the following recommendations or to suspend administration of drug before disappearance of the undesirable phenomena.

 Renal                   Clearance of creatinine               Dosing
insufficiency        (ml/min.)
Norm                         > 80th                                     usual dose
Easy                                                           50-79 2/3 usual doses in 2-3 receptions
Average                                                        30-49 1/3 usual doses in 2 receptions
Heavy                       <                                     30 1/6 usual doses, once
Final
stage                          -                                         it is contraindicated

If after dose adjustment portability of a ribavirin does not improve, use of this medicine, and also interferon alpha 2b or peginterferon alpha 2b should be stopped.

Features of use:

Due to the proved teratogenecity of drug, the man and woman of reproductive age during treatment and within 6 months after the end of therapy have to use reliable contraceptions. Laboratory researches (clinical blood test with calculation of a leukocytic formula and number of thrombocytes, definition of electrolytes, contents of creatinine, functional trials of a liver) need to be conducted before therapy, on the 2 and 4 week, and further it is regular. In 6 months of therapy it is necessary to conduct examination of the patient for assessment of the virologic answer. In the absence of the virologic answer treatment ribaviriny in a combination with interferon alpha 2b or peginterferon alpha 2b should be stopped. In the course of treatment ribaviriny the maximum decrease in a hemoglobin content is in most cases noted in 4 and more weeks from an initiation of treatment. At decrease in hemoglobin it is necessary to reduce temporarily a dose of a ribavirin (see the table "Modification of the Mode of Dosing"). As a rule, the recommended changes of a dose provide recovery of level of hemoglobin. At acute manifestation of hypersensitivity (a small tortoiseshell, a Quincke's disease, a bronchospasm, an anaphylaxis) use of drug should be stopped immediately. Tranzitorny rashes do not form the basis for treatment interruption. During treatment the persons testing weakness, drowsiness or a disorientation need to abstain from driving of motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.
Due to the possible age decrease in secretory function of kidneys at elderly patients before use of drug it is necessary to define indicators of function of kidneys, in particular clearance of creatinine.

Side effects:

By-effects at a combination therapy can be connected as with reception of a ribavirin, and interferon alpha 2b or peginterferon alpha 2b, and also their combinations. From system of blood and bodies of a hemopoiesis: hemolysis - the main toxic effect of a ribavirin. Decrease in level of hemoglobin (hemolitic anemia) at a size> 4 g/dl is noted at 37% of the patients receiving a combination therapy рибавирин + interferon alpha 2b and at 30% of the patients receiving a lump -
binirovanny therapy рибавирин + peginterferon alpha 2b; decrease in a hemoglobin content lower than 10 g/dl is noted only at 14% of patients. Perhaps, development of moderately expressed anemia, leukopenias, neutropenias, a granulocytopenia and thrombocytopenia. Development of aplastic anemia is in some cases possible.
From skin and a hypodermic fatty tissue: alopecia, itch, xeroderma, disturbance of structure of hair, rash, erythema, eczema, mnogoformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis.
From a nervous system: headache, dizziness, tremor, paresthesias, hyperesthesia, depression, irritability, sleeplessness, drowsiness, concern, decrease in concentration of attention, disorientation, emotional lability, nervousness, agressive behavior, confusion of consciousness, suicide intentions and attempts.
From the alimentary system: dryness in a mouth, nausea, vomiting, diarrhea, an abdominal pain, anorexia, a lock, dyspepsia, a food faddism, pancreatitis (at use in a combination with interferon alpha 2b), a meteorism, stomatitis, a glossitis, bleeding of gums.
From endocrine system: dysfunction of a thyroid gland (change of content of thyritropic hormone) demanding therapeutic measures; it is observed at 3% of the patients who earlier did not have such disturbances.
From cardiovascular system: thorax pain, tachycardia, decrease or increase in arterial pressure, heart consciousness, syncope.
From respiratory system and ENT organs: pharyngitis, cough, short wind, bronchitis, sinusitis, rhinitis.
From urinogenital system: "inflows", decrease in a libido, disturbance of a menstrual cycle, amenorrhea, menorrhagia, prostatitis.
From a musculoskeletal system: mialgiya, arthralgia, increase in a tone of unstriated muscles.
From sense bodys: defeat of the lacrimal gland, conjunctivitis, visual disturbance, disturbance/hearing loss, sonitus.
Laboratory indicators: increase in concentration of uric acid and an indirect bilirubin owing to hemolysis; indicators are normalized within 4 weeks after the end of therapy, clinical symptoms of gout are noted; at the same time dose adjustment or cancellation of treatment is not required.
Others: average otitis, allergic reactions, weakness, an indisposition, a fever, fever, a grippopodobny syndrome, the increased sweating, an adynamy, decrease in body weight, thirst, a fungal infection, a lymphadenopathy, a herpes infection.

Interaction with other medicines:

At combined use of a ribavirin and interferon alpha 2b a synergism of their action is noted.
The medicines containing compounds of magnesium and aluminum симетикон reduce bioavailability of drug. Competitive interaction of a ribavirin with a zidovudine or stavudiny can lead to decrease in anti-retrovirus activity of both drugs, and to increase in concentration of RNK-VICh in a blood plasma. Therefore careful monitoring of concentration of RNK-VICh in blood of patients which carries out treatment ribaviriny to combinations with one of these two means is recommended. In case of increase of a viremiya the scheme of therapy should be revised. Besides, at combined use with a zidovudine the risk of development of hemolitic anemia increases; and with didanoziny the risk of development of mitochondrial toxicity increases. In a combination with purine nucleosides (диданозин, абакавир, etc.) – concentration of fosforilirovanny metabolites and the related risk of development of a lactacidemia increases.
Researches on microsomes of a liver revealed that enzymes of P450 cytochrome do not participate in metabolic transformations of a ribavirin; just as рибавирин does not influence system of P450 cytochrome. The possibility of medicinal or other interaction with ribaviriny can remain to 2 months after phase-out in connection with the slowed-down its removal.

Contraindications:

Hypersensitivity to a ribavirin and/or to any of excipients; pregnancy and period of a lactation; chronic heart failure of IIB-III of the Art., myocardial infarction; a serious illness of heart (including forms, unstable and steady against therapy); diseases of a thyroid gland steady against therapy; hemoglobinopathies (including thalassemia, sickemia); heavy
diseases of kidneys (including chronic renal failure [KK not less than 50 ml/min.] need of carrying out hemodialysis); the expressed abnormal liver functions or dekompensirovanny cirrhosis; a heavy depression, suicide intentions or attempts of a suicide (including in the anamnesis); autoimmune diseases (including autoimmune hepatitis); age up to 18 years; lactose intolerance, insufficiency of lactase, galactosemia, glyukozo-galaktozny malabsorption.
With care
Advanced age, chronic heart failure of I-IIa of the Art., serious illness of lungs (including a chronic obstructive pulmonary disease), a dekompensirovany diabetes mellitus with tendency to ketoacidosis, diseases of a thyroid gland (including a hyperthyroidism), disturbances of coagulability of blood (thrombophlebitis, an embolism of a pulmonary artery), considerable oppression of the hemopoietic function of marrow,
miyelodepressiya, hemoglobinopathy (including thalassemia, sickemia); a combination with highly active anti-retrovirus therapy (VAART) at the accompanying HIV infection (the risk of development of a lactacidemia increases).

Overdose:

It is not revealed (single-step introduction inside in a dose of 10 g and п / to in a dose of 39 million ME did not reveal emergence of the symptoms connected with overdose).

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the places unavailable to children. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Capsules on 200 mg.
On 10 capsules in a blister strip packaging. 3 blister strip packagings together with the application instruction in a pack cardboard.