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1 capsule includes 200 mg of a ribavirin – active agent.
Additional components: magnesium stearate, microcrystallic cellulose, monohydrate of lactose, sodium of a kroskarmelloz.
Capsule: titanium dioxide, gelatin, shellac, isopropanol, ethanol, butanol, ammonium hydroxide, propylene glycol, the aluminum blue varnish based on indigo carmine.
The Shering-Plau company lets out Rebetol in the form of capsules, 140 pieces in a pack.
Pharmacodynamics and pharmacokinetics
Rebetol is drug of a synthetic origin and treats analogs of nucleosides which in vitro are active in relation to some DNA — and to the RNA-containing viruses. Characteristic signs of suppression of the enzymes inherent in VGS (a hepatitis virus C) or oppressions of replication of this virus ribaviriny products of its intracellular metabolism in physiological dosages it is not revealed. Monotherapy ribaviriny for 6-12 months, and also further supervision over the patient within half a year, did not show improvement of histologic hepatic characteristics and did not lead to elimination VGS RNA. Purpose of one ribavirin for treatment of hepatitis C, including its chronic form, was inefficient. In too time the combination therapy of patients with VGS with use of a ribavirin and alpha 2b interferon or alpha 2b peginterferon was more effective in comparison with monotherapy alpha 2b interferon or alpha 2b peginterferon. The mechanism of antiviral efficiency of this combination of medicines is still unknown.
Oral administration of a single dose of a ribavirin leads to its easy absorption (Cmax is observed in 90 minutes) and the subsequent fast distribution in an organism. Drug is characterized by slow removal. Absorption of a ribavirin happens almost in full and only 10% of drug are allocated with a stake. Despite it, degree of absolute bioavailability of drug is at the level of 45-65%, it is probable because of effect of primary passing through a hepatic barrier. At reception of one-time dosages of a ribavirin in the range of 200-1200 mg, between its dose and AUC linear dependence is observed. The volume of distribution is equal to about 5000 liters. Linkng with plasma proteins is not revealed.
Distribution of a ribavirin from a circulatory bed was studied for erythrocytes in detail and showed that the main transportation of drug is carried out with the participation of a nukleozidny equilibrium carrier like es which is present almost at all cells.
Metabolic transformations of a ribavirin take place in two ways: hydrolytic reactions (amide hydrolysis and a deribozilirovaniye) with allocation of a carboxyl triazolny metabolite and reversible phosphorylation. Metabolites of a ribavirin (triazolcarboxylic acid and triazolkarboksamid), as well as drug, are removed with urine.
Repeated use of a ribavirin leads to significant plasma cumulation of drug. Indicators of bioavailability (AUC12h) of one-time and repeated reception of a ribavirin are observed in the ratio 1:6. Oral daily administration of 1200 mg of a ribavirin by the end of the first month of therapy results in the equilibrium plasma concentration of drug equaling about 2200 ng/ml. T1/2 after cancellation of treatment makes about 298 hours that speaks well for the slowed-down removal of a ribavirin from fabrics and liquids of an organism (excepting plasma).
At pathologies of a liver of changes of pharmacokinetic indicators of drug it is not revealed.
Indications to use
Rebetol's appointment practices only in a combination with alpha 2b interferon or alpha 2b peginterferon.
Treatment using the above-stated combination of drugs is shown at:
- chronic hepatitis C at the patients who were earlier passing therapy with use alpha 2b interferon or alpha 2b peginterferon and with an affirmative answer on the carried-out treatment (normalization of the ALT level) in case of recurrence of a disease;
- earlier not treated chronic hepatitis C, proceeding without symptoms of a decompensation of hepatic function, with a seropozitivnost to RNA of VGS and the increased ALT level, in the presence of the expressed inflammation or fibrosis.
Purpose of the combined treatment with Rebetol is contraindicated at:
- heavy cardiac pathologies (including steady against treatment and unstable forms of diseases) which were observed at least for half a year before Rebetol's appointment;
- hemoglobinopathies (including drepanocytic anemia and a thalassemia);
- pathologies of a thyroid gland, steady against treatment;
- serious renal illness (including at HPN with KK it is less than 50 ml/min. also with carrying out a hemodialysis);
- heavy depressions with suicide bents (also specified in the anamnesis);
- heavy disturbances of hepatic function;
- autoimmune diseases (including autoimmune hepatitis);
- dekompensirovanny cirrhosis;
- personal hypersensitivity to a ribavirin or other components of HP;
- aged till 18 years.
With respect for extra care purpose of a combination therapy is possible at:
- diseases of lungs of a heavy current (including obstructive chronic diseases);
- other heart diseases;
- diabetes mellitus with risk of forming of ketoacidosis;
- the suppressed marrowy hemopoiesis;
- the accompanying highly active anti-retrovirus treatment of HIV-positive patients (because of the increased risk of forming of lactic acidosis);
- disturbances of blood coagulability (thrombembolia, thrombophlebitis and so forth).
All described below side effects can be shown at a combination therapy Rebetoly and alpha 2b by interferon or alpha 2b peginterferon.
System of a hemopoiesis:
- hemolysis (is the main toxic effect);
- aplastic anemia;
- agressive behavior;
- feeling of concern;
- emotional lability;
- decrease in concentration;
- confusion of consciousness;
- contagious excitation;
- suicide bents.
- food faddism;
- abdominal pain;
- fluctuations of level of thyritropic hormone, able to lead to dysfunctions of a thyroid gland and demanding carrying out therapy.
- rushes of blood;
- reduction of a libido;
- shifts in a menstrual cycle;
- increase in a tone of smooth muscles;
- defeats of the lacrimal glands;
- disturbance/hearing loss;
- visual disturbances.
- mnogoformny erythema;
- Stephens-Johnson's syndrome;
- dryness of integuments;
- damage of structure of hair;
- toxic epidermal necrolysis;
- herpes infection.
- the increase in maintenance of levels of an indirect bilirubin and uric acid connected with hemolysis (are normalized for a month after treatment cancellation).
- average otitis;
- virus/fungal infection;
- allergic manifestations;
- pain around an injection;
- grippopodobny syndrome;
- weight reduction;
- dryness in a mouth;
Rebetol, application instruction
Rebetol's capsules are intended for peroral (in) use twice at 24 o'clock (in the morning and in the evening) together with meal. Range of daily doses varies within 800-1200 mg. Carrying out p / to injections alpha 2b interferon in a dose 3000000 ME three times a week, or alpha 2b peginterferon in a dose of 1,5 mg on kilogram of weight once in 7 days is in parallel shown.
In case of the combined use with alpha 2b interferon appoint Rebetol to patients weighing up to 75 kilograms in doses 400 mg in the morning and 600 mg in the evening, sick weighing more than 75 kilograms – 600 mg in the morning and 600 mg in the evening.
At combined use with alpha 2b peginterferon the recommended Rebetol's dosages equal: weighing up to 65 kilograms – on 400 mg in the morning and in the evening; weighing 65-85 kilograms – 400 mg in the morning and 600 mg in the evening; weighing over 85 kilograms – on 600 mg in the morning and in the evening.
Therapy, as a rule, lasts till 1st year, with the individual restrictions depending on the course of a disease, portability of medicines and the response of the patient to effects of the used drugs.
After semi-annual therapy it is necessary to appoint purposeful inspection of the patient for the purpose of definition of the individual virologic answer. In case of its absence it is necessary to consider a question of the termination of the appointed treatment.
When diagnosing serious negative manifestations or deviations in indicators of laboratory researches it is necessary to carry out correction of the dosing mode or for a while to stop therapy.
In case of decrease in Hb (hemoglobin) more than na10 g/dl lower a daily dosage of Rebetol to 600 mg, with reception of 200 mg of drug in the morning and 400 mg in the evening. At reduction of maintenance of Hb to indicators lower than 8,5 g/dl stop therapy.
At stable pathologies of CCC resort to correction of the dosing mode in a case when for a month of treatment of Hb went down to 2 g/dl.
Hematologic changes with number of leukocytes/thrombocytes/neutrophils less than 1500/50000/750 mkl demands decrease in doses of interferon, and at quantity of leukocytes/thrombocytes/neutrophils less than 1000/25000/500 mkl – therapy cancellations.
Therapy also should be stopped with a growth of concentration of direct bilirubin by 2,5 times in comparison with VGN.
Increase in maintenance of an indirect bilirubin more than on 5 mg/dl needs decrease in daily doses of Rebetol to 600 mg, and in case of the constant increased level of this indicator more than on 4 mg/dl for a month, the treatment termination.
In case of growth of activity of transaminases of the liver exceeding norm more than in two time, or increase of KK it is more than on 2 mg/dl, therapy is cancelled.
If the carried-out corrections of the dosing mode did not lead to significant improvement, a combination of drugs also stop treatment.
The case of purposeful single-step overdose of a combination of Rebetol (in a dose of 10 grams) with alpha 2b interferon (in a dose 39000000 ME) for the purpose of suicide was described. In this case, finding of the patient for 2 days in department of emergency treatment did not reveal any negative phenomena.
Bioavailability of the single dose of Rebetol accepted inside increased in case of a concomitant use of greasy food, with increase in indicators of Cmax and AUC by 70%. Most likely, this increase of bioavailability is connected with delay of transportation of a ribavirin or deviations rn in a gastrointestinal tract. Pharmacokinetic value of these indicators is not defined. In the course of conduct of clinical trials of efficiency of Rebetol of an emphasis on administration of drug together with food or without it it was not carried out, but, despite it, reception of capsules is recommended during food, it is possible because of faster achievement of plasma Cmax of drug.
Studying of interactions of Rebetol with other HP was limited to researches with participation alpha 2b interferon, alpha 2b peginterferon and antacids.
At the parallel reception of 600 mg of Rebetol and antiacid drugs including simetikon or compounds of aluminum and magnesium, decrease in bioavailability of the main medicine by 14% was observed. As well as in a case with reception of greasy food this phenomenon can be referred to effects of change rn a gastrointestinal tract or to drug transportation deviations which are not clinically significant.
Repeated use alpha 2b interferon and alpha 2b peginterferon together with Rebetol did not show any significant pharmacokinetic interactions.
The carried-out researches of in vitro proved ability of a ribavirin to oppression of phosphorylation of a stavudin and a zidovudine. The full clinical picture of this interaction is up to the end not found out, however the obtained data demonstrate that the combined use of these drugs can cause increase of plasma concentration of HIV. In this regard Rebetol's use together with stavudiny and/or a zidovudine demands continuous monitoring of indicators of plasma maintenance of RNK-VICh. In a case increase of these indicators the carried-out therapy should reconsider conditions jointly.
Ribavirin can increase concentration of fosforilirovanny products of a metabolism of purine nucleosides that leads to potentiation of risk of forming of the lactic acidosis provoked by purine nucleosides (Abakavir, Didanozin and so forth).
Due to the slow removal of a ribavirin the possibility of its interaction with other HP remains for at least 60 days.
Authentic proofs of medicinal interaction of a ribavirin with inhibitors of protease and nenukleozidny inhibitors of a revertaza do not exist.
Results of the researches in vitro showed lack of influence of Rebetol on P450 cytochrome.
Terms of sale
Rebetol is drug of the prescription list.
Temperature condition of storage of capsules should not exceed 30 °C.
Period of validity
Since production – 2 years.
Efficiency and Rebetol's safety was investigated only in a combination with alpha 2b interferon and alpha 2b peginterferon. Authentic these these parameters at a combination to other interferona or other drugs are not available.
At purpose of the combined treatment with Rebetol's use and alpha 2b interferon or alpha 2b peginterferon the doctor has to be guided by instructions of each of these drugs.
Teratogenic and embriotoksichesky influence of Rebetol was proved in researches on animals in this connection, you should not begin therapy by Rebetol for women before test for pregnancy, with receiving its negative take. Patients of childbearing age, as well as their male partners, throughout all treatment, and also within half a year after its termination are obliged to practice the sexual relations with use of well-tried contraceptive remedies. Control of possible pregnancy is recommended to carry out monthly. In case of approach of pregnancy in the above-stated period it is necessary to inform the patient on all possible risks for her future child.
Sick men also should be protected from possible conception as the conducted researches on animals showed essential changes in composition of sperm, even at reception of doses below therapeutic.
For certain penetration any of Rebetol's ingredients in milk of the nursing mother is not proved, however the risk of emergence of negative manifestations at the child is at rather high level owing to what breastfeeding has to be cancelled even prior to treatment.
During clinical researches reduction of a hemoglobin content to level below 10 g/dl was observed at 14% of the patients passing therapy with Rebetol's use. Though Rebetol is also not characterized by direct influence on cardiovascular system, the developing of anemia connected with its reception can lead to increase in symptomatology of heart failure and/or an aggravation of signs of a coronary disease state. For this reason treatment by Rebetol can be appointed to patients with heart pathologies only after comprehensive inspection of cordial function. In the course of therapy such patients need special supervision. At detection of any deteriorations connected with cardiovascular activity, treatment by Rebetol should be stopped.
At manifestations of personal hypersensitivity (including the small tortoiseshell, a bronchospasm, a Quincke's disease and an anaphylaxis) reception of capsules of Rebetol it is necessary to interrupt and appoint immediately adequate treatment in an observed case. The phenomena of tranzitorny rash cannot form the basis for the therapy termination.
Before Rebetol's appointment to patients of advanced age, it is necessary to study thoroughly functionality of their renal function as age changes of this parameter can influence the appointed dosing mode.
Before Rebetol's use it is necessary to estimate need for histologic research of a liver for the purpose of confirmation of the exact diagnosis. In case of display of a virus with a genotype 2 and 3 purpose of therapy without preliminary carrying out a biopsy of a liver is possible.
Research of laboratory indicators (including functional hepatic trials, the general blood test, content of electrolytes and serumal creatinine) should be executed prior to treatment, and also in 14 and 28 days after its appointment. In the subsequent this research is conducted regularly and/or as required.
Coincidence on the ATH code of the 4th level:
- Medical OVIR;
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