Ribavirin

General characteristics. Structure:

Active ingredient: 200 mg of a ribavirin.

 Excipients: sugar milk (lactose), starch corn, polyvinylpirrolidone (povidone), aerosil (silicon dioxide colloid), calcium октадеканоат (calcium stearate). Gelatinous solid capsules: gelatin, water, sodium lauryl sulfate, methylparaben, propylparaben, dye — titanium dioxide.

Synthetic antiviral drug with broad antiviral action.

Pharmacological properties:

Pharmacodynamics. Ribavirin easily gets into   the cells affected with a virus and is quickly phosphorylated by an intracellular adenosine kinasa in рибавирин mono - di - and triphosphate. These metabolites, especially рибавирин triphosphate, have the expressed antiviral activity.

The mechanism of action of a ribavirin is found out insufficiently. However it is known what рибавирин inhibits inosine monophosphate a dehydrogenase (IMF), this effect leads to the expressed decrease in level intracellular guanine riboside of triphosphate (GTF) that, in turn, also the virus of specific proteins is followed by suppression of synthesis of virus RNA. Ribavirin inhibits replication of new virions that provides decrease in virus loading. Ribavirin selectively inhibits synthesis of virus RNA, without suppressing synthesis of RNA in normally functioning cells.

Ribavirin is effective concerning many DNA and RNA of viruses. The viruses, most sensitive to DNA ribavirin, are: Simplex herpes virus, poks-virus, virus of Mareks illness. Viruses, insensitive to DNA ribavirin, are: Varicella Zoster, pseudorabies, cow smallpox. The viruses, most sensitive to a RNA ribavirin, are: influenza A, B, paramyxovirus (parainfluenza, epidemic parotite, Nucasls illness), reoviruses, RNA tumoral viruses. Viruses, insensitive to a RNA ribavirin, are: enteroviruses, rhinovirus, Semlicy Forest.

Ribavirin has activity against  the hepatitis C virus (HCV) . The mechanism of action of a ribavirin against VGS is completely not found out. It is supposed that the triphosphate collecting in process of phosphorylation рибавирин competitively suppresses education triphosphate guanine riboside, thereby reducing synthesis of virus RNA. It is considered also that the mechanism of synergy action of a ribavirin and an alpha of interferon against VGS is caused by strengthening of phosphorylation of a ribavirin interferon.

Pharmacokinetics. Absorption: at oral administration рибавирин it is quickly soaked up in digestive tract. At the same time its bioavailability makes more than 45%.

Distribution: рибавирин it is distributed in plasma, a secret mucous respiratory tracts and erythrocytes. A large number рибавирин triphosphate collects in erythrocytes, reaching the plateau by 4th day and remaining within several weeks after removal. The period of semi-distribution makes 3,7 h. The volume of distribution (Vd) — 647 — 802 l. At course reception рибавирин collects in plasma in large numbers. The ratio of indicators of bioavailability (AUC — the area under a curve "concentration/time") at a repeated and single dose is equal to 6. Considerable concentration of a ribavirin (more than 67%) can be found in cerebrospinal liquid after prolonged use. Slightly contacts proteins of plasma.

Time of achievement of the maximum concentration in plasma — from 1 to 1,5 hours.

Time of achievement of therapeutic concentration in plasma depends on the size of minute volume of blood.

The average size of the maximum concentration (Cmax) in plasma: about 5 µmol on liter at the end of 1 week of reception in a dose of 200 mg each 8 hours and about 11 µmol on liter at the end of 1 week of reception in a dose of 400 mg each 8 hours.

Biotransformation: рибавирин it is phosphorylated in liver cells in active metabolites in the form of mono - di - and triphosphate which then are metabolized in 1,2,4-triazolkarboksamid (amide hydrolysis in trikarboksilovy acid and a deribozilirovaniye with formation of a triazolny carboxyl metabolite).

Removal: рибавирин it is brought out of an organism slowly. Time of semi-removal (T1/2) after a single dose of a dose of 200 mg makes from 1 to 2 hours of plasma and up to 40 days of erythrocytes. After the termination of course reception of T1/2 Ribavirin makes about 300 h and his metabolites are generally brought out of an organism with urine. Only about 10% are removed with a stake. In an invariable look about 7% of a ribavirin are removed in 24 hours and about 10% — in 48 hours.

Pharmacokinetics at special clinical states: 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 patients with a liver failure (And, In and From degree) the pharmacokinetics of a ribavirin does not change. After reception of a single dose with the food containing fats, the pharmacokinetics of a ribavirin changes significantly (AUC and Cmax increase by 70%).

Indications to use:

Chronic hepatitis C (at primary patients who were earlier not treated by alpha interferon; at an aggravation after a monotherapy course alpha interferon, at patients, unreceptive to monotherapy by alpha interferon), treatment is carried out to combinations with alpha interferon.

Route of administration and doses:

Drug is accepted inside without chewing and washing down with water, along with meal.

Patients with hepatitis C are recommended to accept рибавирин at the rate of 15 mg on 1 kg of body weight that corresponds to 800-1200 mg a day, i.e. 2-3 capsules or tablets in the morning and 2-3 capsules or tablets in the evening. Usually recommended dosage for patients with body weight  less than 75 kg makes 1000 mg a day (2 capsules or tablets in the morning and 3 capsules or tablets in the evening), the patient with body weight more than 75 kg are recommended to accept 1200 mg a day (3 capsules or tablets in the morning and 3 capsules or tablets in the evening).

Duration  of a course of a combination therapy ribaviriny and alpha interferon, as a rule, 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 alpha interferon, and also at a disease recurrence duration of a course makes not less than 6 months.

Features of use:

It is necessary to consider teratogenecity of drug, the man and woman of reproductive age during treatment and within 7 months after the end of therapy have to use effective contraceptive remedies.

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 2 and 4 weeks, and further it is regular.

In the course of treatment ribaviriny the maximum decrease in a hemoglobin content is in most cases noted after 4-8 weeks from an initiation of treatment. At decrease in hemoglobin lower than 110 mg/ml it is necessary to reduce temporarily a dose of a ribavirin by 400 mg a day, at decrease in hemoglobin lower than 100 mg/ml it is necessary to reduce a dose to 50% of initial. In most cases the recommended changes of a dose provide recovery of level of hemoglobin. At decrease in hemoglobin lower than 85 mg/ml administration of drug should be stopped.

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 fatigue, 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 deterioration in function of kidneys at elderly patients before use of drug definition of function of kidneys, in particular clearance of creatinine is necessary.

Side effects:

 From a nervous system: headache, sleeplessness, asthenic syndrome, depression.

 From cardiovascular system: lowering of arterial pressure, bradycardia, cardiac standstill.

From bodies of a hemopoiesis: hemolitic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia.

 From the alimentary system: loss of appetite, nausea, hyperbilirubinemia.

Allergic reactions: urticaria, angionevrontichesky hypostasis, bronchospasm, anaphylaxis, skin rash.

Others: hair loss.

Interaction with other medicines:

At combined use of a ribavirin and alpha interferon a synergism of their action is noted.

At a clinical use of various drugs in therapeutic doses in a combination with ribaviriny significant interactions were not revealed.

Purpose of a ribavirin during treatment by the Zidovudine and/or Stavudin at at the same time available HIV infection is followed by decrease in phosphorylation of these drugs that brings to VICh-viremii and demands change of the scheme of treatment. Interaction of a ribavirin and nenukleozidny inhibitors of the return transcriptase or inhibitors of proteases is not revealed. Therefore perhaps combined use of a ribavirin and the specified drugs for treatment of patients with the combined infection of HIV with hepatitis C.

The medicines containing compounds of magnesium and aluminum симетикон reduce bioavailability of drug.

Contraindications:

Hypersensitivity, pregnancy, the lactation period, chronic heart failure of IIB-III of St,  myocardial infarction, renal failure (clearance of creatinine — less than 50 ml/min.), the heavy anemia, a liver failure, dekompensirovanny cirrhosis, autoimmune diseases (including autoimmune hepatitis) which are not giving in to treatment of a disease of a thyroid gland, a heavy depression with suicide intentions, children's and youthful age (up to 18 years).

With care. Women of reproductive age (approach of pregnancy is undesirable), a dekompensirovanny diabetes mellitus (with ketoacidosis attacks); a chronic obstructive pulmonary disease, a thrombembolia of a pulmonary artery, chronic heart failure, diseases of a thyroid gland (including a thyrotoxicosis), disturbances of coagulability of blood, thrombophlebitis, a miyelodepressiya, a hemoglobinopathy (including a thalassemia, a sickemia), a depression, tendency to a suicide (including in the anamnesis).

Overdose:

Strengthening of expressiveness of side effect is possible. Treatment: drug withdrawal, symptomatic therapy.

Storage conditions:

List B. In dry, protected from light, the place, unavailable to children, at a temperature not over 25 ºС. Period of validity 2 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Capsules on 200 mg. On 10 capsules in a blister strip packaging. On 30 capsules in bank polymeric. On 3 blister strip packagings or to one bank polymeric together with the application instruction in a pack from a cardboard.