Ribavirin

General characteristics. Structure:

Active agent: рибавирин 200 mg.
excipients: starch the corn hydrophosphate modified 26 mg, calcium a dihydrate of 44 mg, cellulose of microcrystallic 34 mg, talc of 3 mg, magnesium stearate of 3 mg.

Description: Tablets of white or almost white color, round, a ploskotsilindrichesky form with a facet and risky.

Pharmacological properties:

Antiviral drug. Synthetic analog of nucleosides. Aktiveninvitrov the relation of various RNA - and the DNA-containing viruses. Oppresses replication of viruses — causative agents of especially dangerous hemorrhagic fevers both in vitro, and in vivo. It easily gets into the cells affected with a virus and is quickly phosphorylated by an intracellular adenosine kinasa in рибавирин mono - di - and triphosphate.
Ribavirin inhibits inosine monophosphate-dehydrogenase, this effect leads to the expressed decrease in level intracellular triphosphate guanine riboside that is followed by suppression of synthesis of virus RNA and virus-specific proteins.
The combination therapy ribaviriny and interferon alpha 2b at patients with the hepatitis C which had a disease recurrence against the background of monotherapy by interferon alpha 2b was by 10 times of more effective, than monotherapy interferon alpha 2b, iprimerno by 3 times of more effective at the patients who were earlier not treated by interferon alpha 2b.
The mechanism of antiviral action of a ribavirin in a combination with interferon alpha 2b, in particular concerning a hepatitis C virus, is unknown.

Pharmacokinetics. After intake рибавирин easily and almost it is completely soaked up from digestive tract. At reception of a single dose time of achievement of the maximum concentration of a ribavirin in a blood plasma makes from 1 to 1,5 hours. Absolute bioavailability makes about 45-65% that apparently, is connected with effect of "the first passing through a liver". Between a dose and an indicator of bioavailability (AUC) there is a linear dependence.

Time of achievement of therapeutic concentration in plasma depends on the size of minute volume of blood. The average size of the maximum concentration in plasma about 5 µmol/l at the end of 1 week of reception in a dose of 200 mg each 8 h and about 11 µmol/l at the end of 1 week of reception in a dose of 400 mg each 8 h.

Drug is distributed in plasma, a secret mucous respiratory tracts and erythrocytes. A large number рибавирин triphosphate collects in erythrocytes. The elimination half-life makes 3,7 h.

After achievement of the maximum concentration in plasma it is quickly distributed in an organism. The volume of distribution makes about 5000 l

At course use рибавирин collects in plasma in large numbers. Linkng with proteins of plasma is insignificant.

Metabolism. It is carried out by reversible phosphorylation in active metabolites which are split: amide hydrolysis and a deribozilirovaniye with formation of a triazolny carboxyl metabolite.

Removal. Ribavirin is brought from an organism slowly. After a single dose inside in a dose of 200 mg the elimination half-life makes from 1 to 2 hours of plasma and up to 40 days of erythrocytes. After the termination of course use the elimination half-life makes about 300 hours.

Ribavirin and his metabolites — триазолкарбоксамид and triazolcarboxylic acid — are brought out of an organism with urine. With a stake no more than 10% are removed.

Pharmacokinetics in special clinical cases
At patients with a renal failure the pharmacokinetics of a ribavirin at a single dose inside changes — the maximum concentration (Cmax) and an indicator of bioavailability (AUC) increase in comparison with control (clearance of creatine more than 90 ml/min.). Concentration of a ribavirin in plasma at a hemodialysis significantly does not change.

The pharmacokinetics of a ribavirin at introduction of a single dose does not change at the patients having a liver failure irrespective of its expressiveness (classes A, B or C on a scale of Chayld-Pyyu).

After intake of a single dose of drug together with food with the high content of fats bioavailability of a ribavirin increases (indicators of Cmax and AUC increased by 70%).

Indications to use:

As a part of a combination therapy with interferon alpha 2b:
The recurrence of chronic hepatitis C at patients is more senior than 18 years which were earlier receiving treatment by interferon an alpha with long effect (normalization alanine of transferase (ALT) by the end of a medical course);
The chronic hepatitis C confirmed histologically earlier not treated, without signs of a decompensation of function of a liver, with the raised ALT, a seropozitivnost to a hepatitis C RNA virus, in the presence of fibrosis or the expressed inflammatory activity;
Viral infections;
Herpetic ginginostomatit, genital herpes, the surrounding herpes, flu of A and V type, measles and chicken pox, hepatitises A and B.

Route of administration and doses:

Pill is taken inside, without chewing and washing down with water, together with meal, on 0.8–1.2 g/days in 2 receptions (in the morning and in the evening).

Patients with a virus of a genotype have 1–48 weeks:

The average recommended dose for patients with body weight less than 75 kg makes 1000 mg/days (2 tab. in the morning and 3 tab. in the evening), for patients with body weight more than 75 kg the recommended dose makes 1200 mg/days (3 tab. in the morning and 3 tab. in the evening).

Duration of a course of a combination therapy ribaviriny with interferon the alpha, as a rule, makes 24 — 48 weeks (for earlier not treated patients — not less than 24 weeks, and at patients with a virus of a genotype of 1 — 48 weeks.). At immunity to monotherapy by interferon the alpha, or with a disease recurrence duration of a course makes not less than 6 months.

Features of use:

Men and women of reproductive age during treatment and within 7 months after the end of therapy have to use effective measures of contraception.
 In the course of treatment ribaviriny the maximum decrease in Hb is in most cases noted after 4–8 weeks from the beginning of therapy. At decrease in Hb lower than 11 g/dl it is necessary to reduce temporarily a dose of a ribavirin by 400 mg a day, at decrease in Hb it is lower than 100 mg/ml to reduce a dose to 50% of initial. At preservation of intolerance of a ribavirin after dose adjustment, and also when falling Hb 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.

Clinical blood test with calculation of a leukocytic formula and number of thrombocytes, definition of electrolytes, contents of creatinine, functional trials of a liver it is necessary to carry out before therapy, for 2 and 4 weeks of reception and further it is regular.

Due to the possible deterioration in function of kidneys at elderly people before use of drug it is necessary to check function of kidneys, including clearance of creatinine.
Before therapy of hepatitis C it is necessary to estimate need of histologic confirmation of the diagnosis (treatment of patients with a genotype of a virus 2 or 3 can be begun without preliminary biopsy of a liver).

During treatment the persons testing fatigue, drowsiness or a disorientation need to abstain from driving of motor transport and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

From the central nervous system: headache, sleeplessness, asthenic syndrome, depression,
From cardiovascular: lowering of arterial pressure, bradi-or tachycardia, heartbeat, cardiac standstill.
From system of a hemopoiesis: hemolitic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia.

From the alimentary system: loss of appetite, nausea, hyperbilirubinemia.
Allergic reactions: skin rash, erythema, small tortoiseshell, hyperthermia, bronchospasm, anaphylaxis,

Others: hair loss.

Interaction with other medicines:

The medicines containing ions of magnesium and aluminum and also симетикон reduce bioavailability (AUC decreases by 14%)
At combined use with interferon alpha 2b or peginterferon alpha 2b — a synergism of action, medicinal interaction it is not revealed.
Purpose of a ribavirin during treatment by a zidovudine and/or stavudiny is followed by decrease in their phosphorylation that can lead to increase in concentration of RNA - HIV — in plasma of patients and to demand change of the scheme of treatment.
Does not exert impact on enzymatic activity of a liver with P450 cytochrome participation.

The concomitant use of food with the high content of fats increases bioavailability of a ribavirin (AUC and Cmax increase by 70%).

Contraindications:

Hypersensitivity, pregnancy, the lactation period, chronic heart failure of IIB-III of a stage, myocardial infarction, renal failure (clearance of creatine — less than 50 ml/min.), the heavy anemia, a heavy 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).

Overdose:

It is not revealed (single-step introduction inside in a dose of 10 g did not reveal emergence of the symptoms connected with overdose).

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

Tablets on 200 mg. On 10, 30 tablets in a blister strip packaging. On 2, 3, 6, 9 blister strip packagings on 10 tablets, on 1, 2, 3 blister strip packagings on 30 tablets in a pack cardboard together with the application instruction.