Composition, form of production and packaging
Capsules hard gelatinous, size 1, body and lid matte white; on the body of the inscription with blue ink "200 mg" and a blue strip; on the capsule caps of the letter "SP" and a blue strip; the contents of the capsules are white powder.
1 caps.
ribavirin 200 mg
[PRING] microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate.
The composition of the capsule shell: gelatin, titanium dioxide.
The composition of the inscription on the capsule: shellac, ethanol, isopropanol, n-butanol, propylene glycol, ammonium hydroxide, blue aluminum varnish FD & C No. 2.
10 pieces. - blisters (14) - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
PHARMACHOLOGIC EFFECT
Antiviral drug. It is a synthetic analogue of nucleosides, active in vitro for certain RNA and DNA-containing viruses.
Neither ribavirin nor Rebetol intracellular nucleotide metabolites in physiological concentrations show signs of inhibiting enzymes specific for hepatitis C virus or suppressing hepatitis C virus replication. Rebetol monotherapy does not lead to the elimination of RNA-containing hepatitis C virus or to improvement of liver histology after 6-12 months of application of the drug and for 6 months of follow-up. The use of Rebetol in monotherapy of hepatitis C (including its chronic form) is ineffective. However, combined treatment with Rebetol and interferon alpha-2b or peginterferon alpha-2b in patients with hepatitis C is more effective than monotherapy with interferon alpha-2b or peginterferon alfa-2b.
The mechanism by which Rebetol in combination with interferon alpha-2b or peginterferon alfa-2b shows its antiviral effect, in particular against the hepatitis C virus, is not known.
PHARMACOKINETICS
Suction
After taking a single dose of ribavirin easily and almost completely absorbed (only about 10% of the labeled dose is excreted with feces). Nevertheless, absolute bioavailability is approximately 45-65%, which, apparently, is due to the effect of "first passage" through the liver. C max is reached after 1.5 hours. The values ​​of half-periods of absorption, distribution and excretion of a single dose are 0.05 h, 3.73 h and 79 h respectively.
Distribution
After absorption, it is quickly distributed in the body. When taking Rebetol in single doses from 200 mg to 1.2 g between the dose and the bioavailability index there is a linear relationship. V d is approximately 5000 liters. Ribavirin does not bind to plasma proteins.
The transfer of ribavirin outside the plasma has been studied in particular for erythrocytes. It was shown that in the main transport occurs with the participation of an equalizing nucleoside carrier of the type e s . This type of transporter is present in almost all cell types and can be a factor responsible for large V d of ribavirin.
With repeated administration, ribavirin accumulates in plasma in large quantities; the ratio of bioavailability indicators with repeated admission and single admission was 6. When Rebetol was administered at a dose of 600 mg 2 times / day, C ss of ribavirin in the plasma was reached at the end of 4 weeks and was approximately 2200 ng / ml.
Metabolism
The metabolism of ribavirin occurs in two ways: reversible phosphorylation and cleavage (deibosylation and amide hydrolysis with the formation of a triazole carboxyl metabolite).
Excretion
Removing ribavirin from the body is slow. Ribavirin and its metabolites - triazolcarboxamide and triazolecarboxylic acid - are excreted from the body with urine. After discontinuation of T1 / 2, ribavirin was about 298 hours, which seems to indicate its delayed excretion from the body (except plasma).
Pharmacokinetics in special clinical cases
In patients with renal insufficiency, pharmacokinetics in a single admission changes (AUC tf and C max increase) in comparison with the control (for KK> 90 ml / min). The concentration of ribavirin in plasma during hemodialysis does not change significantly.
The pharmacokinetics of ribavirin for single dose administration to patients with mild, moderate or severe hepatic insufficiency (A, B or C on the Child-Pugh scale) is similar to the ribokirin pharmacokinetics in healthy individuals.
INDICATIONS
In the combination therapy with interferon alpha-2b or peginterferon alfa-2b:
- treatment of chronic hepatitis C in patients who had previously received interferon alfa-2b or peginterferon alfa-2b and had a favorable response to the therapy (normalizing ALT activity at the end of the course of treatment), who subsequently had a relapse of the disease;
- Treatment of chronic hepatitis C, previously untreated, without signs of liver function decompensation, with increased ALT activity, seropositivity to the hepatitis C RNA virus, with fibrosis or marked inflammatory activity.
DOSING MODE
Rebetol is administered inside at a daily dose of 800-1200 mg divided into 2 divided doses (morning and evening) and combined with a meal. At the same time, interferon alfa-2b is administered in the form of SC injections 3 times a week for 3 million ME or peginterferon alfa-2b at a dose of 1.5 Ојg / kg of body weight once a week.
Recommended doses Rebetol, depending on body weight when used in combination with interferon alpha-2b
Body weight Daily dose of Rebetol Number of capsules
? 75 kg 1000 mg 5 (2 in the morning + 3 in the evening)
> 75 kg 1200 mg 6 (3 in the morning + 3 in the evening)
Recommended doses Rebetol depending on body weight when used in combination with peginterferon alfa-2b
Body weight Daily dose of Rebetol Number of capsules
<65 kg 800 mg 4 (2 in the morning + 2 in the evening)
65-85 kg 1000 mg 5 (2 in the morning + 3 in the evening)
> 85 kg 1200 mg 6 (3 in the morning + 3 in the evening)
The recommended duration of treatment is up to 1 year. The individual duration of treatment depends on the clinical course of the disease, the response to the therapy and its tolerability.
After 6 months of therapy, a patient should be screened for a virologic response. In the absence of a virologic response, a decision should be made to discontinue combination therapy with Rebetol and interferon alpha-2b or peginterferon alfa-2b.
In the event of serious adverse events or abnormalities in laboratory indicators during the application of Rebetol, the dose should be adjusted or the drug should be stopped until the elimination of undesirable events.
Modification of the dosing regimen
Laboratory indices: Reduction of only Rebetol dose to 600 mg / day * if: Decrease in the dose of only interferon alpha-2b or peginterferon alfa-2b by 50% if:Discontinuation of Rebetol and interferon alfa-2b or peginterferon alfa-2b if:
The content of hemoglobin <10 g / dL - <8.5 g / dL
Hemoglobin content in patients with cardiac disease in stable form The hemoglobin content decreased by? 2 g / dL for any 4 weeks during treatment (continued use of a reduced dose) <12 g / dL 4 weeks after dose reduction
The number of leukocytes is <1500 / Ојl <1000 / Ојl
The number of neutrophils is <750 / ОјL <500 / ОјL
The number of platelets is <50,000 / ОјL <25,000 / ОјL
The content of bound bilirubin - - 2.5С…Р’РџРќ **
Free bilirubin content> 5 mg / dL> 4 mg / dL (for more than 4 weeks)
Creatinine content - -> 2 mg / dL
ALT / AST 2 x (basic value) and> 10xVGN **
* Patients who have reduced the dose of Rebetol to 600 mg / day should take 1 capsule 200 mg in the morning and 2 capsules at 200 mg in the evening.
** the upper limit of the norm.
If, after correction of the dose, the tolerability of Rebetol does not improve, the use of this drug, as well as interferon alfa-2b or peginterferon alfa-2b should be discontinued.
SIDE EFFECT
Adverse events with combined therapy may be associated with both Rebetol and interferon alfa-2b or peginterferon alfa-2b, as well as combinations thereof.
From the hemopoietic system : hemolysis is the main toxic effect of Rebetol. However, a decrease in hemoglobin content by itself is usually not a reason for discontinuing therapy. A decrease in hemoglobin due to hemolysis (a decrease in hemoglobin by> 4 g / dl was observed in 37% of patients receiving combination therapy with Rebetol and interferon alpha-2b, and in 30% of patients receiving combination therapy with Rebetol and peginterferon alfa-2b; hemoglobin below the level of 10 g / dl is observed only in 14% of patients); there may be a moderately severe anemia, leukopenia, neutropenia, granulocytopenia and thrombocytopenia; in some cases, the use of Rebetol in combination with interferon alpha-2b may develop aplastic anemia.
From the side of the nervous system : headache, dizziness, tremor, paresthesia, hyperesthesia, hypesthesia, depression, irritability, insomnia, anxiety, decreased concentration, emotional lability, nervousness, emotional arousal, aggressive behavior, confusion; rarely - suicidal thoughts and attempts (when used in combination with interferon alpha-2b or peginterferon alfa-2b).
On the part of the digestive system: nausea, vomiting, diarrhea, abdominal pain, anorexia, constipation, dyspepsia, taste perversion, pancreatitis (when used in combination with interferon alpha-2b), flatulence, stomatitis, glossitis, gum bleeding.
From the endocrine system: hypothyroidism; Thyroid dysfunction (change in thyroid-stimulating hormone content) requiring therapeutic measures is observed in 3% of cases in patients who did not previously have such disorders.
From the cardiovascular system: pain in the chest, tachycardia, a decrease or increase in blood pressure, palpitation, fainting.
On the part of the respiratory system: pharyngitis, cough, dyspnea, bronchitis, sinusitis, rhinitis.
On the part of the reproductive system: hot flashes, decreased libido, menstrual irregularity, amenorrhea, menorrhagia, prostatitis.
From the musculoskeletal system: myalgia, smooth muscle tone, arthralgia.
From the sense organs: lesion of the lacrimal gland, conjunctivitis, visual disturbance, hearing loss / loss, tinnitus.
Dermatological reactions: alopecia, itching, dry skin, dyspepsia, rash, erythema, eczema, herpetic infection, reactions of increased photosensitivity; In some cases, when Rebetol is used in combination with interferon alpha-2b or peginterferon alfa-2b, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
On the part of laboratory indicators: in some cases - an increase in the level of uric acid and indirect bilirubin, associated with hemolysis. These indicators are normalized within 4 weeks after the end of therapy. Only a small number of patients with elevated uric acid levels had clinical symptoms of gout, but did not require modification of the dose or withdrawal of treatment.
Other: otitis media, allergic reactions, pain at the injection site, weakness, malaise, chills, fever, flu-like syndrome, increased sweating, asthenia, weight loss, dry mouth, thirst, fungal infection, viral infection, lymphadenopathy.
CONTRAINDICATIONS
- severe heart disease (including unstable and resistant to therapy forms) that existed for at least 6 months before the beginning of Rebetol therapy;
- Thyroid disease, resistant to therapy;
- hemoglobinopathy (including thalassemia, sickle cell anemia);
- severe kidney disease (including chronic renal failure / CC less than 50 ml / min / with the need for hemodialysis);
- pronounced impaired liver function or decompensated hepatic cirrhosis;
- severe depression, suicidal thoughts or suicide attempts (including in the anamnesis);
- autoimmune diseases (including autoimmune hepatitis);
- age up to 18 years;
- Pregnancy;
- the period of lactation (breastfeeding);
- Hypersensitivity to ribavirin and other components of the drug.
Caution should be given to the drug with other heart conditions, severe lung diseases (including chronic obstructive pulmonary disease), diabetes mellitus with a tendency to ketoacidosis, bleeding disorders (eg, thrombophlebitis, pulmonary embolism) or with significant depression hematopoietic function of the bone marrow, as well as in combination with highly active antiretroviral therapy (HAART) with concomitant HIV infection (due to the increased risk of developing lactic acidosis).
PREGNANCY AND LACTATION
Contraindicated the use of the drug Rebetol during pregnancy and lactation (breastfeeding).
Treatment with Rebetol should not be started until a negative pregnancy test result is obtained, which should be performed immediately before starting the drug.
Sick women of childbearing age who are taking Rebetol, as well as their sexual partners, should use effective methods of contraception during therapy and for at least 6 months after the end.
Monthly during this entire period it is necessary to conduct pregnancy tests. If the pregnancy occurs during treatment or within 6 months after its termination, the patient should be informed of the significant risk of teratogenic effects of ribavirin on the fetus.
Sick men and their sexual partners - women of childbearing age - should also use reliable methods of contraception. Ribavirin accumulates intracellularly and is excreted from the body very slowly. To exclude the possible teratogenic effects of ribavirin, each partner should use an effective contraceptive during treatment, and also for at least 6 months after the end. Men should use a condom.
It is not known whether any component of ribavirin is excreted in breast milk.
Due to the high risk of adverse effects of ribavirin on the baby, breastfeeding should be discontinued before the drug is started.
In experimental animal studies, ribavirin has been shown to have embryotoxic and teratogenic effects at doses significantly lower than those recommended for clinical use. In animals, ribavirin caused sperm changes at doses below the therapeutic dose.
APPLICATION FOR FUNCTIONS OF THE LIVER
The drug is contraindicated in cases of severe kidney disease, incl. chronic renal failure (CC less than 50 ml / min) with the need for hemodialysis).
In patients with renal insufficiency, the pharmacokinetics in a single admission changes (AUC and C max increase) compared with the control (with KK> 90 ml / min). The concentration of ribavirin in plasma during hemodialysis does not change significantly.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The drug is contraindicated in severe violations of liver function or decompensated cirrhosis of the liver.
The pharmacokinetics of ribavirin for single dose administration to patients with mild, moderate or severe hepatic insufficiency (A, B or C on the Child-Pugh scale) is similar to the ribokirin pharmacokinetics in healthy individuals.
SPECIAL INSTRUCTIONS
The safety and effectiveness of combination therapy has been studied only with the use of Rebetol with interferon alpha-2b or peginterferon alfa-2b. Data on the effectiveness and safety of the use of Rebetol in combination with other interferons are not available.
Before the appointment of a combination therapy, it is also recommended that you read the instructions for the use of interferon alfa-2b or peginterferon alfa-2b, respectively, attached to each of these drugs.
With caution, after an appropriate examination and only under the supervision of a cardiologist, Rebetol should be prescribed to patients with heart disease, t. anemia that occurs when the drug is taken (a decrease in hemoglobin levels below 10 g / dl was observed in 14% of patients receiving ribavirin during clinical trials), may worsen heart failure and / or worsening of the symptoms of the disease. If symptoms of worsening of the cardiovascular system appear, treatment should be stopped.
In case of allergic reactions (hives, angioedema, bronchospasm, anaphylaxis) Rebetol should be immediately canceled and appropriate treatment should be prescribed. Transient skin rash is not a reason to interrupt treatment.
Since the functional capabilities of the kidneys may decrease with age, older patients need to investigate their function before using Rebetol.
Before the start of treatment should assess the need for histological confirmation of the diagnosis. In some cases (patients infected with the genotype 2 or 3 virus), treatment can be performed without a prior liver biopsy.
Control of laboratory indicators
Laboratory tests (clinical blood count with calculating the leukocyte count and platelet count, electrolyte analysis, determination of serum creatinine content, functional liver tests) should be performed before treatment, then at the 2nd and 4th week of treatment, and then regularly, as needed.
Impact on the ability to drive vehicles and manage mechanisms
Patients experiencing fatigue, drowsiness, or disorientation when combined with Rebetol and interferon alfa-2b or peginterferon alfa-2b should stop doing work that requires increased attention and speed of psychomotor reactions (including driving, controlling the mechanisms).
OVERDOSE
A case of Rebetol overdose is known when a patient for a single day took 10 grams of ribavirin in capsules (50 capsules in 200 mg) and 39 million ME in a solution for injection (13 injections of 3 million ME ). The patient stayed for 2 days in the emergency department; during which time no adverse events associated with overdose have been reported.
DRUG INTERACTION
Rebetola drug interaction study was conducted with only interferon alpha-2b, peginterferon alfa-2b and antacids.
When co-administered antacid preparation comprising a compound of magnesium and aluminum or simethicone Rebetola and 600 mg ribavirin decreased bioavailability, AUC index decreased by 14%. It is possible that a decrease in bioavailability was due to the slowdown of transport in this study ribavirin, or a change in pH. It appears that this interaction is not clinically significant.
According to pharmacokinetic study at repeated application of the joint were noted pharmacokinetic interaction between Ribavirin and interferon alpha-2b or pegylated interferon alpha-2b.
Ribavirin in vitro He has shown the ability to inhibit the phosphorylation of AZT and stavudine. The clinical significance of these data is not clear until the end. However, they suggest that the concurrent use Rebetola with zidovudine or stavudine might lead to increased concentrations of HIV in the blood plasma. Therefore, careful monitoring is recommended concentration indicators of HIV RNA in the plasma of patients undergoing treatment Rebetol in combination with one of these two means. At higher levels of HIV RNA in plasma Rebetola use in combination with reverse transcriptase inhibitors should be reconsidered.
Ribavirin in vitro It increases the amount of phosphorylated metabolites of purine nucleosides. This effect may potentiate the risk of lactic acidosis induced by purine nucleoside analogs (for example, didanosine, abacavir). Patients infected with both hepatitis C and HIV and HAART may develop lactic acidosis. With combination therapy with Rebetol in addition to HAART should exercise extreme caution.
Ability medicament or other type interaction with Rebetol may persist for up to 2 months (5 half-lives ribavirin) after termination of its use in connection with its delayed breeding.
No evidence of drug interactions with ribavirin non-nucleoside reverse transcriptase inhibitors or protease inhibitors are not available.
According to the results of in vitro studies in human liver microsomal preparations and rat isoenzymes of cytochrome P 450 are not involved in the metabolic conversions of ribavirin. Ribavirin is not an inhibitor of cytochrome P 450 . Toxicological tests do not suggest that Ribavirin promotes the enzymatic activity of the liver. Thus, the occurrence of any interaction with cytochrome P 450 is unlikely.
The bioavailability of a single oral dose Rebetola increased when eating a high-fat (parameters AUC and C maxincreased by 70%). It is possible that an increase in bioavailability was due to the slowdown of transport in this study, ribavirin, or a change in pH. The value of this study is not defined for the clinic. When the clinical efficacy trial, patients were not given any instructions about the time of the drug in relation to food intake. However, in order to achieve maximum plasma concentration of ribavirin is recommended to take the drug with food.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 2 years. Do not use after expiry date.
