Rebetol

General characteristics. Structure:

Active вещество:в to 1 capsule 200 mg of a ribavirin contain.

Auxiliary veshchestva:tsellyuloza microcrystallic, lactoses monohydrate, croscarmellose sodium, magnesium stearate. Capsule cover: gelatin, titanium dioxide. Structure of a text on the capsule: shellac, ethanol, isopropanol, butanol, propylene glycol, ammonium hydroxide, a blue aluminum varnish on the basis of indigo carmine.

Pharmacological properties:

Pharmacodynamics. Ribavirin is a synthetic analog of nucleosides, active in vitro concerning some RNA - and the DNA-containing viruses. Signs of inhibition of the enzymes specific to the hepatitis C virus (HCV), or suppression of replication of a virus of hepatitis C, ribaviriny, intracellular metabolites of a ribavirin in physiological concentration are not revealed. Monotherapy ribaviriny does not lead to elimination of a virus of hepatitis (a hepatitis RNA virus C) or to improvement of the histologic characteristic of a liver after 6-12 months of use of drug and within 6 months of the subsequent observations. Use of a ribavirin as only therapeutic cure for hepatitis C, including at its chronic form, inefficiently. The combined treatment ribaviriny and interferon alpha 2b or peginterferon alpha 2b patients with hepatitis C more effectively, than monotherapy by interferon alpha 2b or peginterferon alpha 2b.Механизм by means of which рибавирин in a combination with interferon alpha 2b or peginterferon alpha 2b shows the antiviral action, in particular against a hepatitis C virus, it is unknown.

Pharmacokinetics. Ribavirin is easily soaked up after intake of a single dose of drug (Tmax of =1,5 h) then it is quickly distributed in an organism. Removal of a ribavirin from an organism slow. Sizes of the periods of semi-absorption, distribution and removal of a single dose are made by 0,05, 3,73 and 79 h respectively. Ribavirin is soaked up almost completely; only about 10% of a marked dose are allocated through intestines. Nevertheless, absolute bioavailability makes about 45-65% that, apparently, is connected with effect of primary passing through a hepatic barrier. Between a dose and the area under a curve "concentration - time" (AUC) exists linear dependence at reception of a ribavirin in single doses from 200 to 1200 mg. The volume of distribution makes about 5000 l. Ribavirin does not contact proteins of plasma. Transfer of a ribavirin out of plasma was studied especially in detail for erythrocytes; it was shown that, generally transport happens to participation of an equilibrium nukleozidny carrier like es (nitrobenziltioinozinchuvstvitelny). This type of a carrier is present practically at all types of cells and can be the major factor influencing distribution of a ribavirin.

Metabolism of a ribavirin is carried out in two ways: 1) reversible phosphorylation and 2) hydrolytic reactions where the deribozilirovaniye and amide hydrolysis with formation of a triazolny carboxyl metabolite enter. Ribavirin and his metabolites триазолкарбоксамид and triazolcarboxylic acid - are brought out of an organism by kidneys.

At repeated use рибавирин collects in plasma in large numbers; the ratio of the areas under curves "concentration - time" (Auc12ch) at repeated reception and a single dose is equal to 6:1. At oral administration (600 mg twice a day) equilibrium concentration of a ribavirin in plasma was reached by the end 4 weeks; at the same time it made about 2200 ng/ml. After the reception termination the elimination half-life of a ribavirin made about 298 h that, apparently, speaks about its slowed-down removal from liquids and body tissues, except plasma.

At patients with a renal failure (clearance of creatinine> of 90 ml/min.), increase in AUC and the maximum concentration of drug in blood (Cmax) is noted. Concentration of a ribavirin in plasma at a hemodialysis significantly does not change.

The pharmacokinetics of a ribavirin at introduction of a single dose by the patient with a liver failure of easy, moderate or heavy severity (classes A, B or C on classification of Chayld-Pyyu), is similar to pharmacokinetics of a ribavirin at healthy faces.

Indications to use:

Only in combination with interferon alpha 2b or peginterferon alpha 2b:
- treatment of patients with chronic hepatitis C by which earlier treatment was not carried out, not having liver disease decompensation signs, with a superactivity of ALT, seropositive to a hepatitis C RNA virus, in the presence of fibrosis or the expressed inflammatory activity.
- treatment of the patients with chronic hepatitis C who were earlier receiving treatment by interferon an alpha or peginterferon an alpha and having the favorable response to the carried-out therapy (with normalization of activity of ALT by the end of a medical course) who had afterwards a disease recurrence.

Only in combination with peginterferon alpha 2b:
- treatment of the patients with chronic hepatitis C who do not have liver disease decompensation signs with a superactivity of ALT, seropositive to a hepatitis C RNA virus, in the presence of fibrosis or the expressed inflammatory activity by which treatment was not carried out earlier, including patients with clinically stable HIV infection (coinfection) and also including patients to whom treatment was carried out earlier, and who have a previous combination therapy interferon an alpha (pegylated or not pegylated) and ribaviriny or monotherapy by interferon the alpha was inefficient.

Route of administration and doses:

Inside, during food, in the dose of 800-1400 mg a day divided into two receptions (in the morning and in the evening). Interferon alpha 2b in the form of subcutaneous injections 3 times a week on 3 million ME or peginterferon alpha 2b subcutaneously in a dose of 1,5 mkg is at the same time appointed to body weight kg once a week.

The recommended Rebetol's doses depending on the body weight of the patient:

Body weight, kg	Daily dose of Rebetol, mg	Number of capsules
<65	800	4a
65-85	1000	5b
86-105	1200	6v
> 105	1400	7 g

and - in the 2nd morning, in the 2nd evening
- in the 2nd morning, in the 3rd evening
in - in the 3rd morning, in the 3rd evening
- in the 3rd morning, in the 4th evening

The recommended treatment duration - till 1 year. The individual duration of a course of treatment depends on the clinical course of a disease, the response to the carried-out therapy and its portability.

The patients infected with VGS of a genotype 1: emergence of the resistant virologic answer at continuation of treatment is very improbable if after 12 weeks of treatment virus RNA elimination from blood serum is not noted. To the patients having the virologic answer after 12 weeks of treatment, it is necessary to continue treatment within 9 months (the general duration of treatment - 48 weeks). To patients with low virus loading (it is not higher than 600000 ME/ml), who after 4 weeks of treatment had an elimination of RNA of a virus and during the subsequent period it was not found - to 24 weeks of treatment, treatment after 24 weeks can be stopped (the general duration of a course - 24 weeks) or is continued for 24 weeks (the general duration of a course - 48 weeks). However it is necessary to consider that the risk of a recurrence after a 24 weeks course of treatment is higher, than after a 48 weeks course.

The patients infected with VGS of a genotype 2 or 3: the recommended treatment duration to all patients of this group - 24 weeks, excepting patients with coinfection of VGS/VICh which should carry out treatment within 48 weeks.

The patients infected with VGS of a genotype 4: in general it is noted that at patients of this group achievement of the steady virologic answer is improbable. Duration of therapy has to be same, as for the patients infected with a virus of a genotype 1.

Carrying out a repeated course of therapy at the patients who did not answer primary course of therapy
The recommended duration of treatment makes 48 weeks irrespective of a virus genotype.

Assessment of probability of the response to treatment at the patients with a recurrence of a disease receiving a repeated course of therapy:

- the early virologic answer (decrease in virus load at least of 2 log (by 100 times) or virus RNA elimination in 12 weeks) allows to predict achievement of the steady virologic answer. For the patients with a recurrence after the previous therapy course (using not pegylated and pegylated interferon) who reached the early virologic answer on the 12th week of therapy, the frequency of the steady virologic answer made 59% and 50%, respectively. At the patients with the 1 or 4 genotype of a virus who were receiving earlier therapy by not pegylated interferon, reached the early virologic answer on the 12th week of a repeated course of therapy, the frequency of the steady virologic answer reached 51%. At patients with decrease in level of virus loading> 2 log (more than by 100 times), but therapy with a defined level at 12 week, the frequency of achievement of the steady virologic answer approximately makes 6%. At the same time the patients with lack of the virologic answer (with the determined level of virus loading at 12 to week of therapy) receiving earlier therapy by pegylated interferon have less chances of achievement of the steady answer, than the patients who were earlier receiving therapy by not pegylated interferon in a combination with ribaviriny (12% in comparison with 29%).
- not determined level of virus loading on the 12th week of therapy is characteristic of 36% of patients. In this group of patients the frequency of achievement of the steady virologic answer made 56%.
- the patients who did not reach the early virologic answer on the 12th week of therapy have extremely low chance of achievement of the steady virologic answer. Such patients should consider a question of the termination of a current rate of therapy by peginterferon alpha 2b both ribaviriny and change of therapeutic tactics.
Patients with chronic hepatitis About the infected HIV: the recommended duration of treatment makes 48 weeks, irrespective of a virus genotype.

Assessment of probability of the response to treatment at patients with VGS/VICh coinfection
The early virologic answer (decrease at least on 2 log (by 100 times) virus loading or virus RNA elimination in 12 weeks) allows to predict the steady virologic answer.

Situations at which correction of the mode of dosing can be required:

After 6 months of therapy it is necessary to conduct examination of the patient for detection of the virologic answer. In the absence of the virologic answer it is necessary to make the decision on the termination of a combination therapy the drug Rebetol® and interferon alpha 2b or peginterferon alpha 2b.

At emergence of the serious undesirable phenomena or deviations in laboratory indicators during use of the drug Rebetol® it is necessary to correct a dose or to suspend administration of drug before the termination of the undesirable phenomena.

Correction of the mode of dosing

Laboratory indicators	Dose decline only the drug Rebetol® to 600 mg/day if:	Dose decline only interferon alpha 2b or peginterferon alpha 2b for 50%, if:	Therapy termination, if:
Hemoglobin content	<10g/dl	-	<8,5 g/dl
Hemoglobin content at patients with a heart disease in a stable form	The hemoglobin content decreased on> 2 g/dl within any 4 weeks during treatment (constant use of the lowered dose)		<12 g/dl in 4 weeks after a dose decline
Number of leukocytes	-	<1,5Õ109/l	<1,0x109/l
Number of neutrophils	-	<0,75Õ109/l	<0,5x109/l
Number of thrombocytes	-	<50x10%	<25Õ109/l
Content of the connected bilirubin	-	-	2,5 x VGN **
Content of free bilirubin	> 5 mg/dl	-	> 4 mg/dl (during> 4 weeks)
Content of creatinine	-	-	> 2,0 mg/dl
Alaninamino-transferaza/Aspartate aminotransferase	-	-	2 x (basic value) and> 10 x VGN **

 * - patients to whom reduced a drug Rebetol® dose to 600 mg a day have to accept one capsule of 200 mg in the morning and two capsules on 200 mg in the evening.
** - upper bound of norm.

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

At purpose of the drug Rebetol® in a combination with interferon alpha 2b and peginterferon alpha 2b to patients with reduced function of kidneys 50 years are also aged more senior, patients need to be observed carefully in connection with risk of development of anemia.

Features of use:

Safety and efficiency of a combination therapy was investigated only when using the drug Rebetol® in a combination with interferon alpha 2b or peginterferon alpha 2b. Data on efficiency and safety of the drug Rebetol® in a combination with other interferona (not alpha 2b) are not available.

Before purpose of a combination therapy it is also recommended to study the application instruction according to interferon alpha 2b or peginterferon alpha 2b, attached to each of these drugs.

In researches on animals рибавирин showed embriotoksichesky and teratogenic action in a dose, a component 1/20 part from the dose recommended for use for the person. Treatment by the drug Rebetol® should not be begun until the negative take of the test for pregnancy which should be carried out just before an initiation of treatment is received. Female patients of childbearing age, and also their male partners have to use effective contraceptive remedies during treatment and within 6 months after its termination; monthly during all this period it is necessary to carry out the test for pregnancy. If pregnancy after all occurs during treatment or during the 6-month period after the end of treatment, the patient should be informed on great risk of teratogenic impact of a ribavirin on a fruit.

Male patients and their partners of childbearing age have to undertake special measures of protection from pregnancy. In animal experiments рибавирин caused changes of sperm in doses below therapeutic. Ribavirin collects intracellularly and is brought from an organism very slowly. For an exception of possible teratogenic action of a ribavirin each of partners has to use effective contraceptive remedy during treatment, and also within at least 6 months after its termination. Men have to use condoms.

It is not known whether any component of the drug Rebetol® with mother's milk is allocated. Owing to a possibility of an adverse effect of a ribavirin on the child, breastfeeding it has to be stopped prior to drug use.

Disturbances from mentality and TsNS. Serious mental violations, in particular a depression, suicide thoughts and attempts, psychosis, including hallucinations, an agressive behavior, including directed to other people are the known side effects of interferon an alpha. It is necessary to use with care drug at patients mental disorders in the anamnesis.

In case of development of changes from mentality and/or TsNS, including development of a depression, is recommended observation of the doctor of such patients during the entire period of treatment, and also within 6 months after its termination. The specified side effects usually are quickly reversible after the therapy termination, however in certain cases it was required up to 3 weeks for their full involution. If symptoms of frustration of mentality do not regress or there are suicide thoughts or the agressive behavior directed to other people, it is recommended to stop treatment by the drug Rebetol® and interferon alpha 2b and to consult with the psychiatrist.

Hemolysis. Hemolysis - the main toxic effect of a ribavirin. However decrease in a hemoglobin content in itself usually does not serve as the therapy termination reason. Decrease in a hemoglobin content at a size> 4 g/dl is noted at 37% of the patients receiving a combination therapy the drug Rebetol® and interferon alpha 2b and at 30% of the patients receiving a combination therapy the drug Rebetol® and peginterferon alpha 2b. Lower than 10 g/dl observed decrease in a hemoglobin content at 14% of the patients receiving the drug Rebetol® during clinical trials. The majority of deviations of laboratory indicators korrigirutsya by means of selection of a dose.

Disturbances from cardiovascular system. Though the drug Rebetol® does not possess immediate effect on cardiovascular system, the anemia connected with administration of drug of Rebetol® can cause strengthening of heart failure and/or an aggravation of symptoms of coronary heart disease. In this regard, therapy by the drug Rebetol® has to be appointed to patients with these diseases only after the corresponding inspection. During treatment such patients demand special observation. In case of any deterioration from cardiovascular system treatment has to be stopped.

Patients at whom even prior to performing this therapy disturbances from cardiovascular system came to light are recommended to conduct an electrocardiographic research to and during a therapy course. Disturbances of a heart rhythm (generally supraventricular arrhythmia) usually well give in to stopping by usual means, however cancellation of antiviral therapy in some cases can be required.

Acute hypersensitivity. At acute manifestation of hypersensitivity (a small tortoiseshell, a Quincke's disease, a bronchospasm, an anaphylaxis) use of the drug Rebetol® it is necessary to stop and appoint the corresponding treatment immediately. Tranzitorny skin rashes do not form the basis for treatment interruption.

Function of kidneys. Obvious changes of pharmacokinetics of a ribavirin depending on age are not revealed, however, as well as at patients of younger age, at patients 50 years prior to use of the drug Rebetol® are more senior it is necessary to define a condition of function of kidneys.

Function of a liver. All patients at whom against the background of treatment heavy abnormal liver functions develop have to be under careful observation. Treatment should be stopped if at the patient increase in a blood clotting time and change of other indicators of coagulant system of blood is noted that can indicate a liver decompensation.

The HIV-positive patients sick with chronic hepatitis C receiving at the same time anti-retrovirus therapy and therapy against hepatitis have to be under careful observation, and at them it is necessary to estimate periodically function of a liver on a scale of Chayld-Pyyu. If at the patient there came the liver decompensation, then administration of drugs against a viral hepatitis should be stopped immediately, and also to estimate a possibility of continuation of anti-retrovirus therapy.

Disturbances from teeth and a periodontium. Dryness in a mouth at a long combination therapy ribaviriny and interferon alpha 2b can promote injury of teeth and a mucous membrane of an oral cavity. Patients have to brush teeth a brush 2 times a day and regularly have examination at the stomatologist. Besides, at some patients vomiting can be observed.

Disturbances from an organ of sight. All patients before therapy by this drug have to have ophthalmologic examination. Each patient who during therapy will have complaints to decrease in visual acuity or loss of sight has to have full ophthalmologic examination immediately. Patients with the preexisting diseases of an organ of sight (for example, with a diabetic or azotemic retinitis) against the background of a combination therapy from interferona an alpha have to have ophthalmologic examination periodically. If at the patient emergence of new ophthalmologic disturbance is noted or the condition of already being available disease will worsen, then the combination therapy from interferona an alpha should be cancelled.

Laboratory researches. Before an initiation of treatment all patients should carry out clinical blood test with calculation of total quantity of leukocytes, a leukocytic formula and number of thrombocytes, the analysis of electrolytes, determination of content of creatinine and uric acid in serum, functional trials of a liver.

Normal values at which it is possible to begin therapy with the drug Rebetol® is the following: hemoglobin-> 12 g/dl (woman),> 13 g/dl (man); thrombocytes-> 100000/mm3; neutrophils-> 1500/mm3.

Then laboratory researches are recommended to be conducted on the 2nd and 4th weeks of treatment and further it is regular, as required.

Before an initiation of treatment it is necessary to estimate need of histologic confirmation of the diagnosis. In certain cases (patients with a genotype of a virus 2 and 3) treatment can be carried out without preliminary biopsy of a liver.

The patients testing fatigue, drowsiness or a disorientation at the combined treatment by the drug Rebetol® and interferon alpha 2b or peginterferon alpha 2b should refuse driving of the car or control of mechanisms.

Side effects:

The undesirable phenomena at a combination therapy when carrying out both primary, and repeated course of therapy are similar among themselves, and can be connected as with the drug Rebetol®, and interferon alpha 2b or peginterferon alpha 2b, and also their combination.

Further the following classification of frequency of the undesirable phenomena is used: very often-> 1/10, it is frequent-> 1/100 and <1/10, infrequently-> 1/1000 and <1/100, is rare-> 1/10000 and <1/1000, is very rare - <10000, frequency is not established. In each group created on frequency, side effects are listed in decreasing order of their gravity.

As рибавирин always appoint with any drug of interferon an alpha, and the given side reactions include also the reactions revealed during post-marketing use (are noted *), the exact frequency of reactions cannot be determined, therefore, the frequency specified below was received on the basis of results of clinical trials during which рибавирин it was applied in a combination with interferon alpha 2b (pegylated or not pegylated).

Infectious diseases: very often - viral infections, pharyngitis; often - a fungal infection, average otitis, the infection caused by a herpes simplex virus, an infection of uric ways; seldom - пневмония*.

The high-quality, malignant and not specified new growths (including cysts and polyps): often - not specified new growths.

Disturbances from system of blood and the hemopoietic bodies: very often - anemia, a neutropenia; often - a lymphopenia, a lymphadenopathy, thrombocytopenia; very seldom - aplastic anemia *; frequency is not established - a true erythrocyte aplasia, an idiopathic Werlhof's disease, a trombotichesky Werlhof's disease.

From immune system: very seldom - a sarcoidosis *; frequency is not established - a syndrome of Fogta-Koyanagi-Harady, a system lupus erythematosus, a pseudorheumatism (for the first time arisen or an aggravation of symptoms), a vasculitis, reactions of acute hypersensitivity, including a small tortoiseshell, a Quincke's disease, a bronchospasm, an anaphylaxis.

From endocrine system: often - a hypothyroidism, a hyperthyroidism; seldom - a diabetes mellitus of the II type.

From a metabolism and food: very often - anorexia; often - a hyperglycemia, a hyperuricemia, a hypocalcemia, dehydration, increase in appetite, thirst; very seldom - гипертриглицеридемия*.

From mentality: very often - a depression, sleeplessness, emotional lability, uneasiness; often - suicide thoughts, psychosis, an agressive behavior, confusion of consciousness, agitation, nervousness, sleep disorders, alarming dreams, apathy, decrease in a libido; infrequently - suicide attempts; seldom - hallucinations, it is very rare - a suicide *; frequency is not established - change of the mental status.

From a nervous system: very often - a headache, dizziness, disturbances of concentration of attention; often - an ataxy, a tremor, paresthesias, a dysphonia, a hypesthesia, a hyperesthesia, drowsiness, migraine, a hyper tone, food faddisms; seldom - convulsive attacks (spasms) *, peripheral neuropathy; very seldom - a hematencephalon *, cerebrovascular ischemia *, encephalopathy *, polyneuropathy *; frequency is not established - paralysis of a facial nerve, neuropathy (including mononeuropathy).

From an organ of sight: often - a sight illegibility, conjunctivitis, eye pain, a vision disorder, pathology of the lacrimal glands; seldom - retinal apoplexies *, retinopathies (including swelled a macula lutea) *, thrombosis of arteries of a retina *, a retina vein thrombosis *, an optic neuritis *, a papilledema *, decrease in visual acuity or loss of fields of vision *, the blackout centers in the form of lumps ваты*.

From acoustic organs and balance: often - вертиго, disturbance or a hearing loss, a ring in ears, ear pain.

From cardiovascular system: often - heartbeat, tachycardia, lowering of arterial pressure, increase in arterial pressure, a syncope, "inflows"; seldom - a cardiomyopathy *, arrhythmia *; very seldom - a myocardial infarction *, myocardium ischemia *; very seldom - ischemia of peripheral fabrics *.

From respiratory organs, a thorax and mediastinum: very often - short wind, cough; often - sinusitis, bronchitis, nasal bleeding, rhinitis, respiratory disturbances, a rhinedema, a rhinorrhea, unproductive cough; very seldom - pulmonary infiltrates *, a pneumonitis *, intersticial пневмонит*.

From digestive tract: very often - diarrhea, nausea, vomiting, dryness in a mouth, an abdominal pain; often - a stomacace, stomatitis, colitis, pain in the right upper quadrant of a stomach, dyspepsia, a gastrointestinal reflux *, a glossitis, bleeding of gums, an ulitis, weakening of flavoring feelings, a frequent liquid chair, a lock, a meteorism; seldom - pancreatitis *; very seldom - ischemic colitis *, ulcer colitis *; frequency is not established - disturbances from a periodontium, disturbances from teeth.

From gepatobiliarny system: often - a hepatomegalia, jaundice, a hyperbilirubinemia *; very seldom - a hepatotoxic (including with a lethal outcome) *.

From skin and a hypodermic fatty tissue: very often - an alopecia, an itch, a xeroderma, rash; often - psoriasis, deterioration in a course of already existing psoriasis, eczema, photosensitivity reaction, makulopapulyozny rash, erythematic rash, dermatitis, an acne, a furunculosis *, disturbances from skin, a hematoma, the increased perspiration, disturbance of structure of hair, disturbances from nails *; very seldom - Stephens's syndrome - Johnson *, a toxic epidermal necrolysis *, multiformny exudative эритема*.

From a musculoskeletal system and connecting fabric: very often - an arthralgia, a mialgiya, muscle and bones pains; often - arthritis; seldom - рабдомиолиз *, миозит*.

From kidneys and urinary system: often - a frequent urination, a polyuria; seldom - an impaired renal function *, a renal failure *; very seldom - nephrotic синдром*.

From system of reproductive organs and mammary glands: often - women - an amenorrhea, a hypermenorrhea, a dysmenorrhea, mammary gland pain, dysfunction of ovaries, disturbances from a vagina, men - impotence, prostatitis, disturbances of sexual function (without indication of the exact diagnosis) *.

From an organism in general, and also reactions in an injection site: very often - fatigue, a fever, fever, grippopodobny symptoms, an adynamy, irritability; often - thorax pain, swelled persons.

From laboratory and tool data: very often - decrease in body weight; often - cordial noise, disturbances in the analysis of urine (increase in level of bilirubin).

In certain cases - increase in level of uric acid and an indirect bilirubin, owing to hemolysis. These indicators are normalized within 4 weeks after the end of therapy. Only at insignificant number of patients at the increased level of uric acid the clinical symptoms of gout which were not demanding correction of a dose or cancellation of treatment were noted.

At the HIV-positive people sick with chronic hepatitis C receiving the drug Rebetol® in a combination with peginterferon alpha 2b also other side effects were noted (which were not registered at patients with monoinfection); with a frequency> 5% were revealed the following side effects: oral cavity candidiasis (14%), the acquired lipodystrophy (13%), decrease in the CO+ level - lymphocytes (8%), a loss of appetite (8%), increase in level gamma глутамилтранспептидазы (9%), pain in a back (5%), increase in level of amylase in blood (6%), increase in level of lactic acid in blood (5%), cytolytic hepatitis (6%), increase in level of a lipase (6%) both upper and lower extremity pains (6%).

Toxic influence on mitochondrions.
At the HIV-positive people sick with chronic hepatitis C receiving nukleozidny inhibitors of the return transcriptase in combination with ribaviriny mitochondrial toxicity and a lactacidemia were observed.

Laboratory indicators at patients with VGS/VICh coinfection.
In most cases anemia, a leukopenia, a neutropenia, a granulocytopenia and thrombocytopenia are moderately expressed (by criteria of WHO).

Though the neutropenia, thrombocytopenia and anemia met more often at HIV-positive patients with chronic hepatitis C, in most cases changes of blood managed to be eliminated by a dose decline therefore they seldom led to the early termination of treatment. At treatment by the drug Rebetol® with peginterferon alpha 2b changes of blood developed in combinations more often than at treatment by the drug Rebetol® and interferon alpha 2b: decrease in absolute number of neutrophils <500/mm3, decrease in number of thrombocytes <50000/mm3, anemia (hemoglobin <9,4 g/dl).

Decrease in the C04 lymphocytes level.
Treatment by the drug Rebetol® in a combination with peginterferon alpha 2b was followed by reversible decrease in absolute number of SB4+ cells within the first 4 weeks which was not combined with reduction of percent of these cells. The number of SB4+ cells increased after a dose decline or the termination of therapy. The combination therapy the drug Rebetol® and peginterferon alpha 2b did not exert an explicit negative impact on the HIV RNA level both during treatment, and after its end. The treatments given about safety at HIV-positive patients with hepatitis C with C04+ cells number <200/mkl are limited.

Interaction with other medicines:

Bioavailability of a single peroral dose of a ribavirin increased at meal with the high content of fats (indicators of AUC and Cmax increased by 70%). It is possible that increase in bioavailability in this research was caused by delay of transport of a ribavirin or change рН. For the purpose of achievement of the maximum concentration of a ribavirin in plasma it is recommended to accept drug together with food.

The research of medicinal interaction of a ribavirin was conducted only with participation of interferon alpha 2b, peginterferon alpha 2b and antacids.

Interferon alpha 2b: according to a pharmacokinetic research, at repeated combined use pharmacokinetic interaction between ribaviriny both interferon alpha 2b and peginterferon alpha 2b was not noted.

Antacids: bioavailability of a ribavirin in a dose of 600 mg decreased at joint reception of the antiacid drug containing compounds of magnesium and aluminum or симетикон; the indicator of AUC decreased by 14%. It is possible that decrease in bioavailability in this research was caused by delay of transport of a ribavirin or change рН. It is represented that this interaction is not clinically significant.

Analogs of nucleosides: рибавирин in vitro showed ability to inhibit phosphorylation of a zidovudine and stavudin. The clinical importance of these data is up to the end not clear. However, they give the grounds to believe that simultaneous use of the drug Rebetol® with a zidovudine or stavudiny can result in the increased concentration of HIV in a blood plasma. Therefore careful monitoring of indicators of concentration of HIV RNA in plasma at patients to whom treatment by the drug Rebetol® is carried out to combinations with one of these two drugs is recommended. At increase in level of concentration of HIV RNA in plasma, use of the drug Rebetol® in combination with inhibitors of the return transcriptase should be reconsidered.

Use of nukleozidny analogs - in monotherapy or in a combination with other nucleosides - led to development of a lactacidemia. Ribavirin of in vitro increases the maintenance of fosforilirovanny metabolites of purine nucleosides. This effect can exponentiate risk of development of the lactacidemia caused by purine analogs of nucleosides (for example, didanoziny, abakaviry). Joint introduction of a ribavirin and didanozin is not recommended. Simultaneous use of a ribavirin and zidovudine is also not recommended owing to the increasing risk of anemia. If the patient already receives the combined anti-retrovirus therapy, then the zidovudine should be replaced with other drug. It is especially important concerning patients who in the anamnesis have instructions on the postponed anemia caused by a zidovudine.

At the patients infected at the same time with a virus of hepatitis C and HIV and receiving highly active anti-retrovirus therapy (VAART) the lactacidemia can develop. At purpose of a combination therapy with the drug Rebetol® in addition with VAART it is necessary to show the increased care. The possibility of medicinal or other type of interaction with ribaviriny can remain up to two months (5 elimination half-lives of a ribavirin) after phase-out - in connection with its slowed-down removal.

Proofs of interaction of a ribavirin with nenukleozidny inhibitors of the return transcriptase or inhibitors of proteases are not available.

By results of the researches in vitro on microsomal drugs of a liver of the person and a rat, isoenzymes of P450 cytochrome do not participate in metabolic transformations of a ribavirin. Ribavirin is not inhibitor of isoenzymes of P450 cytochrome. Toxicological researches do not give the grounds to believe what рибавирин stimulates fermental activity of a liver. Thus, emergence of any interaction with participation of P450 cytochrome is improbable.

Contraindications:

- hypersensitivity to a ribavirin or any other component of drug;
- pregnancy and period of a lactation;
- children's age up to 18 years;
- a serious illness of heart, including the unstable and uncontrollable forms existing, at least, within 6 months preceding treatment;
- diseases of a thyroid gland if they do not give in to medicamentous correction;
- hemoglobinopathies (for example, thalassemia, sickemia);
- the chronic renal failure, clearance of creatinine is lower than 50 ml/min., need of carrying out a hemodialysis;
- considerable abnormal liver function or dekompensirovanny cirrhosis;
- the expressed depression, suicide thoughts or attempts, including according to the anamnesis;
- autoimmune hepatitis or other autoimmune diseases;
- cirrhosis with existence of a liver failure at patients with VGS/VICh coinfection (the Chayld-Pyyu index> 6);
- rare hereditary diseases, such as lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption.

WITH CARE:

- the diseases of cardiovascular system (which are not belonging to the categories specified in contraindications);
- serious illness of lungs (for example, chronic obstructive diseases of lungs);
- a diabetes mellitus with a ketoatsidotichesky coma;
- the disturbances connected with coagulant system of blood (for example, at thrombophlebitis, an embolism of a pulmonary artery) or considerable oppression of the hemopoietic function of marrow;
- the combined treatment with use VAART (highly active anti-retrovirus therapy) at the accompanying HIV infection (in connection with toxic impact on the mitochondrial device and the increased risk of development of a lactacidemia).

Overdose:

The known maximum accepted dose of the drug Rebetol® made 10 g of a ribavirin in capsules (50 capsules on 200 mg) and 39 million ME drug in the form of solution for injections (13 subcutaneous injections on 3 million ME); these quantities were entered to himself by one patient for the purpose of suicide within one day. The patient was within 2 days in department of emergency treatment; during this time no undesirable phenomena connected with overdose were noted.

The antidote is not known, a hemodialysis and peritoneal dialysises are not effective, lecheniyesimptomatichesky.

Storage conditions:

To store at a temperature not above 30 °C in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 200 mg, on 10 capsules in the blister manufactured of a polyvinyl chloride film and aluminum foil. On 14 blisters together with the application instruction in a cardboard pack.