Rebetol

Rebetol is an antiviral drug.

Indications Rebetola

It is used exclusively in combination with α-2b interferon or α-2b peginterferon for the following disorders:

• chronic hepatitis C in individuals who have previously undergone a course of treatment with α-2b interferon/peginterferon and had a positive response to this therapy (stabilization of ALT levels) – in the event of a relapse of the disease;
• previously untreated hepatitis C in the chronic stage, which proceeds without the development of signs of liver decompensation, but with seropositivity for HCV RNA, as well as elevated ALT values - in the case of the presence of fibrosis or a pronounced inflammatory process against the background of the disease.

Release form

The product is released in capsules, in the amount of 140 pieces inside a separate box.

Pharmacodynamics

Rebetol is a synthetic drug, a member of a group of nucleoside analogues with in vitro activity against some DNA- or RNA-containing viruses. When used in standard doses, no specific symptoms of enzyme inhibition observed with HCV or signs of replication of this virus were detected – either under the influence of ribavirin or under the influence of its metabolites.

With monotherapy using ribavirin for a period of 0.5-1 year, and also during subsequent observation of the patient for 6 months, no improvement was found in the histological indicators of the liver, nor in the process of elimination of HCV RNA.

The use of ribavirin alone for therapy of hepatitis C (also its chronic stage) did not give the required result. At the same time, complex treatment in people with HCV, in which ribavirin was supplemented with α-2b interferon/peginterferon, demonstrated higher efficiency compared to monotherapy, in which the patient was prescribed only α-2b interferon/peginterferon.

The mechanism that promotes the development of antiviral effects with such a combination of drugs has not yet been identified.

Pharmacokinetics

When a single dose of ribavirin is administered orally, absorption is poor (peak levels are observed after 1.5 hours) with rapid subsequent distribution of the drug within the body. The drug is excreted quite slowly.

Absorption of ribavirin is almost complete, only 10% of the drug is excreted with feces. At the same time, the level of absolute bioavailability of the drug is within 45-65%, possibly due to the effect of the first liver pass. After taking single doses of the drug within 0.2-1 g, a linear relationship is observed between the dosage size and the AUC indicator. The distribution volume is about 5000 l. The drug is not synthesized with protein in the plasma.

A careful study of red blood cells during distribution of the drug from the systemic circulation demonstrated that the drug is primarily transported by equilibrium transmitters of the nucleoside form es. This element is found in virtually all cells of the body.

Ribavirin has 2 metabolic transformation pathways: hydrolytic processes (de-ribosylation and amide hydrolysis), during which excretion of the carboxyl degradation product of the triazole type occurs, as well as reversible phosphorylation. The degradation products of the medicinal element (triazole carboxylic acid together with triazole carboxamide), like the drug itself, are excreted in the urine.

With repeated administration of ribavirin, a noticeable accumulation of the drug within the plasma is observed. The bioavailability values for single and repeated use of the drug have a ratio of 1 to 6.

With daily oral administration of 1.2 g of the drug, at the end of the 1st month of the course, equilibrium values of the drug in the plasma are observed, which are about 2200 ng / ml. The half-life after stopping the use of Rebetol is about 298 hours. This indicates that the substance is slowly excreted from fluids with tissues (the only exception is plasma).

In patients with kidney disease (creatinine clearance level less than 90 ml/min), an increase in the maximum values of the drug in plasma, as well as its AUC values, is observed. The hemodialysis procedure has almost no effect on the peak values of the drug in plasma.

Dosing and administration

The capsules should be taken orally, 2 times per 24 hours (in the morning and in the evening) - with food. The range of daily doses of the drug fluctuates between 0.8-1.2 g. While taking the drug, subcutaneous administration of α-2b interferon in the amount of 3,000,000 IU three times per 7 days or α-2b peginterferon in the amount of 1.5 mg/kg once during the first week should be performed.

When used in combination with α-2b interferon, people weighing no more than 75 kg should take Rebetol according to the following schedule: 0.4 g in the morning and 0.6 g in the evening. People weighing more than 75 kg should take 0.6 g in the morning and 0.6 g in the evening.

In case of combination with α-2b peginterferon, the drug is taken according to the following scheme:

• persons weighing less than 65 kg – 0.4 g in the morning and in the evening;
• persons weighing between 65-85 kg – 0.4 g in the morning and 0.6 g in the evening;
• people weighing more than 85 kg – 0.6 g in the morning and in the evening.

Treatment usually lasts for a maximum of 12 months, with various individual restrictions determined by the course of the pathology, sensitivity to drugs and the patient's reaction to the effects of the drug.

After six months of treatment, the patient should be examined to determine his virological response. If there is no response, the option of discontinuing therapy should be considered.

If the examination reveals the presence of serious negative symptoms or abnormal laboratory test results, it is necessary to change the dosage regimen of the drug or stop treatment for a while.

If the Hb level decreases by more than 10 g/dl, the daily dose of the drug should be reduced to 0.6 g – take 0.2 g in the morning and 0.4 g in the evening. If the Hb level decreases to values less than 8.5 g/dl, treatment should be stopped.

If the patient has stable cardiovascular diseases, it is necessary to change the dose size of the drug in cases where the Hb level during the first month of therapy decreases to 2 g/dl.

In case of hematological disorders with the number of leukocytes, platelets or neutrophils less than 1500, 50,000 and 750 µl, respectively, it is necessary to reduce the dosage of interferons. If leukocytes, platelets and neutrophils have indicators less than 1000, 25,000 and 500 µl, respectively, it is necessary to stop treatment.

Treatment should also be stopped if the direct bilirubin level increases by 2.5 times (compared to the ULN).

If the indirect bilirubin level increases by more than 5 mg/dl, the daily dose of the drug should be reduced to 0.6 g, and if this value regularly increases by more than 4 mg/dl during the first month, therapy should be discontinued.

If there is an increase in liver transaminase activity that exceeds the normal level by more than twice, or if the level of CC increases by more than 2 mg/dL, it is necessary to stop taking the drug.

If there is no noticeable improvement after portion size adjustments, the combination therapy should be discontinued.

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Use Rebetola during pregnancy

It is prohibited to prescribe Rebetol to nursing mothers and pregnant women.

Contraindications

Main contraindications:

• severe heart disease (including therapy-resistant and unstable types of pathologies) observed in the patient for at least 6 months prior to the prescription of the drug;
• hemoglobinopathy (this also includes thalassemia and sickle cell anemia);
• therapy-resistant diseases in the thyroid gland;
• severe kidney disease (including chronic renal failure with a creatinine clearance level of less than 50 ml/minute, as well as with hemodialysis procedures);
• severe depression, which leads to suicidal tendencies (also present in the anamnesis);
• severe liver dysfunction;
• autoimmune pathologies (including autoimmune hepatitis);
• decompensated stage of liver cirrhosis;
• the presence of hypersensitivity to ribavirin or other components of the drug;
• children under 18 years of age.

Particular caution is required when using combination treatment for the following disorders:

• severe pulmonary diseases (including chronic stages of obstructive pathologies);
• other heart diseases;
• diabetes mellitus, which can lead to ketoacidosis;
• suppression of the hematopoietic function of the bone marrow;
• concomitant antiretroviral therapy for HIV with high activity (because this increases the likelihood of developing lactic acidosis);
• problems with blood clotting (presence of thrombophlebitis or thromboembolism, etc.).

Side effects Rebetola

The development of the following side effects is usually observed during the combined use of Rebetol with α-2b interferon/peginterferon:

• damage to the hematopoietic organs: development of neutro-, thrombocyto-, leukopenia- or granulocytopenia, as well as anemia (and its aplastic form) and hemolysis (this is the main side effect);
• disorders of the nervous system function: the appearance of tremor, headaches, suicidal thoughts, paresthesia, dizziness, as well as hypoesthesia or hyperesthesia. Aggression, a feeling of nervousness, anxiety, confusion, irritability, emotional instability and emotional arousal may be observed. In addition, insomnia or depression occurs, and concentration deteriorates;
• digestive disorders: vomiting or nausea, diarrhea or bloating, constipation and abdominal pain, as well as dyspeptic symptoms. At the same time, glossitis, stomatitis, anorexia or pancreatitis may develop, as well as taste disorders and bleeding in the gums;
• disorders in the functioning of the endocrine system: fluctuations in thyrotropin levels, against the background of which thyroid disorders may develop, which will require treatment, as well as the development of hypothyroidism;
• dysfunction of the cardiovascular system: development of tachycardia, the appearance of palpitations or pain behind the breastbone, and in addition, fainting and changes in blood pressure values (decrease or increase);
• damage to the respiratory system: development of pharyngitis, runny nose, cough, dyspnea, bronchitis or sinusitis;
• reactions of the genital organs: development of amenorrhea, prostatitis, menorrhagia, as well as decreased libido, the appearance of hot flashes and changes in the menstrual cycle;
• manifestations from the muscles and bones: development of myalgia or arthralgia, as well as increased smooth muscle tone;
• damage to the sense organs: tinnitus, visual disturbances, hearing problems or its complete loss, development of disorders affecting the lacrimal glands or conjunctivitis;
• disorders of the skin surface: rashes or itching, erythema multiforme, eczema, alopecia, as well as Stevens-Johnson syndrome, photosensitivity, damage to the hair structure, dry skin, erythema, TEN and herpes infection;
• laboratory test results: increased uric acid levels, as well as indirect bilirubin, which occurs due to hemolysis (normalization of these indicators occurs within 1 month after completion of therapy);
• others: development of infection (fungal or viral origin), lymphadenopathy, allergy symptoms, otitis media, asthenia, fever and hyperhidrosis, as well as flu-like syndrome. In addition, there is a feeling of thirst, malaise and weakness, as well as chills. Weight loss, pain at the injection site and dryness of the oral mucosa are possible.

Interactions with other drugs

When a single dose of the drug was taken orally, its bioavailability increased when taken with fatty foods. Cmax values also increased, and AUC levels increased by 70%. Most likely, this reaction was caused by a slowdown in the movement of ribavirin or by changes in gastric pH values. It was not possible to determine the pharmacokinetic significance of these data. Although clinical tests of the drug's effectiveness did not emphasize the use of the drug with or without food, it is recommended to take the capsules with food, possibly due to the acceleration of the process of achieving Cmax values in plasma.

The study of drug interactions with other drugs is limited to tests involving α-2b interferon/peginterferon, as well as antacids.

Taking 0.6 g Rebetol together with antacids containing simethicone or magnesium-aluminum synthesis resulted in a 14% decrease in the bioavailability of the main drug. As with use with fatty foods, this phenomenon can be attributed to reactions to changes in gastric pH values or to a deviation in the movement of the drug. These effects are of no clinical significance.

No significant pharmacokinetic interactions were observed when alpha-2b interferon/peginterferon was co-administered with Rebetol.

In vitro studies have shown that ribavirin can inhibit the phosphorylation of zidovudine with stavudine. It was not possible to fully clarify the picture of this interaction, but the information obtained allows us to conclude that when combining these drugs, an increase in HIV indicators in the plasma is possible. Therefore, when combining the drug with zidovudine or stavudine, it is necessary to regularly monitor plasma HIV RNA values. If their level increases, it is necessary to adjust the conditions of the complex treatment.

Ribavirin can increase the levels of phosphorylated metabolites of purine nucleosides, which increases the likelihood of developing the lactic acid form of acidosis caused by purine nucleosides (such as didanosine or abacavir, etc.).

Because the drug is excreted slowly, it may retain the potential to interact with other drugs for at least the next 2 months.

In vitro tests have shown that Rebetol has no effect on hemoprotein P450.

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Storage conditions

Rebetol should be kept in normal conditions for medicines. The temperature should not be higher than 30°C.

Shelf life

Rebetol can be used for 2 years from the date of release of the drug.

Reviews

Rebetol has quite limited information about its use - due to the specificity of the drug. Therefore, it is impossible to obtain complete information about its advantages and disadvantages. The small number of reviews available on the Internet makes it clear that the drug is highly effective, but at the same time it is quite dangerous, because it has many side effects.