Sirturo (Sirturo)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceBedakvilinBedakvilin
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  • Sirturo
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    PHARMSTANDART-UFIM VITAMIN FACTORY, OJSC     Russia
    • Dosage form: & nbspPills.
    Composition:

    Each tablet contains:

    Active substance: Bedakvilina fumarate - 120.89 mg, in terms of Bedakvilin - 100.0 mg.

    Excipients: lactose monohydrate 152.91 mg, corn starch - 66.0 mg, hypromellose 2910, 15 mPa-s to 8.00 mg, polysorbate 20 to 1.00 mg, microcrystalline cellulose 82.20 mg, croscarmellose sodium 23.00 mg, silicon colloidal dioxide 1.40 mg, magnesium stearate 4.60 mg.

    Description:

    Round biconvex tablets of white or almost white color, with a squeezed out inscription "T" above "207" on one side and "100" on the other side.

    Pharmacotherapeutic group:Anti-tuberculosis drug.
    ATX: & nbsp

    J.04.A.K   Other antituberculous drugs

    Pharmacodynamics:

    Bedakvilin belongs to the group of diaryl quinolines - a new class of antituberculous compounds. The bactericidal effect of the drug is due to specific inhibition of the proton pump ATP-synthase mycobacteria (adenosine 5'-triphosphate synthase) - an enzyme that plays a major role in the process of cellular respiration

    Mycobacterium tuberculosis. The inhibition of the synthesis of ATP leads to a disruption in the production of energy and, as a result, to the death of the microbial cell.

    Bedakvilin in vitro is active against drug-sensitive and drug-resistant (including multidrug-resistant and extensively drug-resistant) strains Mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) in the range <0.008-0.12 μg / ml (MIC50 - 0.03 μg / ml and MIC90 0.06 μg / ml).

    Mechanisms of development of resistance.

    Mechanisms that determine resistance Mycobacterium tuberculosis to poorakvilu, include at least 6 variants of mutations (replacement of the amino acid sequence) of the target gene atpE. Not all strains have gene mutations atpE, which presupposes the existence of at least one other mechanism for the development of resistance to the drug. In vitro the frequency of spontaneous mutations was 10-7 - 10-8 and decreased with increasing drug concentration. In low concentrations Bedakvilin can exhibit a bacteriostatic effect and potentiate the risk of developing resistance, in high concentrations - has a bactericidal effect.

    Pharmacokinetics:

    Suction.

    At oral intake, a high absorption of Bedakville was noted. The maximum concentration in plasma (Cmax) is achieved approximately 5 hours after taking the drug. FROMmax and the area under the "concentration-time" curve (AUC) increase in proportion to the increase in the dose up to the highest doses studied (700 mg per day single and 400 mg in several doses) without changing the time to reach the maximum concentration (Tmax) and half-life (T1/2). The greatest bioavailability is achieved when taken with food (up to 95%), which is about 2 times higher than bioavailability when taken on an empty stomach. Thus, to increase the bioavailability of Bedakville, the drug should be taken with food.

    Distribution.

    Bedakvinin and its active metabolite N(M2) are characterized by a high volume of distribution (approximately 164 L), a concentration ratio in tissues to a plasma concentration of 30. Binding to plasma proteins is> 99.9%. The highest concentrations are created in the lung tissue, lymph nodes, spleen, kidneys and liver. Penetration through the blood-brain barrier is insignificant.

    Metabolism

    Bedakvinin is metabolized primarily by oxidation, leading to the formation of M2. The main isoenzyme of the P450 family, involved in the metabolism of Bedakville and the formation of M2 in vitro is an CYP3A4.

    In studies in vitro Bedakvinin does not have a significant effect on the activity of known cytochrome P450 family isozymes (does not inhibit CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4 / 5, CYP4A and does not induce activity CYP1A2, CYP2C9, CYP2C19 and CYP3A4).

    Metabolite M2 does not have a significant clinical effect, taking into account its weaker antibacterial activity (4-6 times lower) compared with the original compound.

    Excretion.

    Bedakvinin is excreted from the body mainly by the intestine. In clinical studies, the excretion of unaltered Bedakwinin by the kidneys was <0.001% of the administered dose, which indicates a slight renal clearance of the unchanged drug. After reaching Cmax the concentration of the pooraclin in the plasma decreases in a three-exponential manner. Terminal half-life (T 1/2 term) Bedakvilina and M2 is about 5.5 months, which probably reflects the slow release of Bedaklavin and M2 from peripheral tissues.

    Pharmacokinetics in various groups

    Age, gender and ethnicity

    According to the results of the population pharmacokinetic analysis of patients diagnosed with pulmonary tuberculosis, age, sex and ethnic clinically significant differences in the pharmacokinetics of Bedakville are not established.

    Pediatric patients (<18 years)

    The pharmacokinetics of the preparation of Sirturo in pediatric practice was not evaluated.

    Elderly patients (> 65 years)

    Data on the pharmacokinetics of the preparation of Sirturo in patients with a diagnosis of pulmonary tuberculosis, at the age of 65 and older are limited.

    Patients with kidney failure

    The preparation of Sirturo was studied mainly among patients with normal renal function. Excretion of unaltered Bedakville through the kidneys is insignificant (<0.001%). According to the results of the population pharmacokinetic analysis of patients receiving 200 mg of the preparation of Sirturo three times a week, the creatinine clearance did not influence the pharmacokinetic parameters of the poorakwin. Therefore, it is assumed that renal failure of mild to moderate degree will not have a clinically significant effect on the pharmacokinetics of Bedakville. In patients with severe renal failure (creatinine clearance <30 mL / min / 1.73 m2) or terminal stage of renal failure with the need for hemodialysis or peritoneal dialysis, the concentration of Bedaklavin can increase due to changes in absorption, distribution and metabolism of the drug against a background of impaired renal function. As Bedakvilin largely binds to plasma proteins, the effectiveness of hemodialysis or peritoneal dialysis to remove the drug from the plasma will be low (see section Method of administration and dose, see section Special instructions).

    Patients with hepatic failure

    After a single administration of the preparation Sirturo (400 mg) in 8 patients with moderate impaired liver function (class B on the Child-Pugh scale), AUC672h for Bedakvilina and M2 was approximately 20% lower in comparison with healthy volunteers. The pharmacokinetics of Bedakville in patients with severe hepatic insufficiency has not been studied (see section Method of administration and dose, see section Special instructions).

    HIV-infected patients

    Data on the pharmacokinetics of the preparation of Sirturo in HIV-infected patients are limited (see section Special instructions).

    Indications:

    Bedakvilin is indicated for use in adults (> 18 years) as part of a combination therapy for pulmonary tuberculosis caused by strains Mycobacterium tuberculosis multidrug-resistant.

    Contraindications:

    - hypersensitivity to Bedakville and / or any other component of the drug;

    - pregnancy;

    - lactation period (breastfeeding);

    - children and adolescents under 18;

    - severe renal failure (creatinine clearance <30 mL / min / 1.73 m3);

    - severe hepatic insufficiency (due to the lack of clinical safety data for the drug in this group);

    - Congenital lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

    Carefully:

    When the interval is extended QT with correction according to Frederick's formula (QTcF) > 450 ms (with confirmation by repeated ECG examination); with decompensated heart failure; In patients with a personal or family history of congenital lengthening of the interval QT, the development of arrhythmia by type "torsade de points"; in patients with clinically significant bradycardia, electrolyte disorders (hypocalcemia, hypomagnesemia, hypokalemia); with an indication of a history of hypothyroidism; when used simultaneously with drugs that extend the interval QT; when combined with lopinavir / ritonavir; in elderly patients (65 years and older) (see section Special instructions).

    Pregnancy and lactation:

    Pregnancy

    Safety of the preparation Sirturo during pregnancy is not established, so the drug is contraindicated for use in pregnant women.

    Lactation period

    Data on the use of Bedakville in women during lactation are absent, therefore, the use of the drug during breastfeeding is contraindicated.

    Dosing and Administration:

    The drug should be taken orally during meals, since simultaneous ingestion with food increases the bioavailability of the drug (see section Pharmacokinetics).

    It is recommended to swallow the tablet of the preparation of Sirturo whole, washed down with water. The drug Sirtruro should be used only as part of a combination therapy for the treatment of multidrug-resistant tuberculosis (MDR-TB) under the direct supervision of a specialist (see section Indications for use, see section Pharmacodynamics).

    The preparation should be used only in combination with at least 3 drugs, to which the absence in vitro resistance of the strain isolated from the patient. If the results of the study in vitro there is no treatment, the treatment with Sirturo can be started in combination with no less than 4 other drugs to which the strain isolated from the patient may be sensitive. During the course of treatment with Sirto and after the last administration of the drug, it is necessary to continue therapy with anti-tuberculosis drugs in accordance with the standard regimens of chemotherapy for MDR TB.When choosing a scheme and the duration of taking antituberculous drugs of the reserve as part of the combination therapy, the attending physician should be guided by the state standards for the treatment of tuberculosis, the data on the drug resistance of mycobacteria in the region, taking into account the drug sensitivity of the strain isolated from the patient with tuberculosis and the clinical and radiological examination data.

    The recommended dosing regimen of the preparation of Sirturo:

    400 mg once a day for the first 2 weeks, then (from 3 to 24 weeks) 200 mg 3 times a week (with a break of at least 48 hours between doses) for the next 22 weeks (at a total dose of 600 mg per week ).

    The total duration of the course of treatment with the drug Sirturo is 24 weeks. Patients should be warned about the need to take the drug Sirturo according to the instructions of the doctor. It is necessary to emphasize the importance of taking the full course of therapy.

    If you skip the drug during the first 2 weeks of treatment, the missed dose should not be taken. It is necessary to continue the usual dosing regimen.

    If you skip the drug, starting from the 3rd week (with a 3-time intake of 200 mg per day per day),should take the missed dose as soon as possible and continue taking the drug in accordance with the recommended dosing regimen with a break after taking the missed dose for at least 24 hours, while the total dose of the preparation of Sirturo for 7 days should not exceed 600 mg.

    Side effects:

    Clinical trials are conducted in a wide variety of settings, so the incidence of unwanted adverse reactions observed in clinical trials of a single drug can not be directly compared with the frequency of adverse reactions in clinical studies of another drug, and may not reflect the frequency observed in clinical practice.

    The adverse side reactions (CPR) to the preparation of Sirturo were determined on the basis of the combined data on patients who received the preparation of Sirturo as part of the combined regimen of antituberculous therapy in the conducted controlled clinical trials.

    Undesirable reactions to the preparation of Sirturo are listed according to the organ class systems and the frequency of development (very frequent (> 1/10), frequent (> 1/100 to <1/10), infrequent (> 1/1000 to <1 / 100), rare (from> 1/10000 to <1/1000), very rare (< 1/10000)):

    Disorders from the nervous system (CNS): Often - headache, dizziness;

    Disorders from the cardiovascular system: often - interval lengthening QT on the ECG;

    Disorders from the gastrointestinal tract: Often - nausea, vomiting; often - diarrhea;

    Disturbances from the liver and bile ducts: often - increased activity of transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT));

    Disturbances from the musculoskeletal and connective tissue: Often - joint pain, often - muscle pain.

    In the controlled clinical trials, 2 phases in the group of patients receiving the preparation of Sirturo in the combined regimen of anti-tuberculosis therapy were more often compared with the placebo group, the following adverse events were recorded: hemoptysis, anorexia, chest pain, skin rash (at> 1/100 to <1/10). These reactions were not identified by the researchers as adverse side reactions.

    Overdose:

    Information on cases of intentional or accidental acute overdose of Bedakville is absent.In a study involving 44 healthy volunteers who received a single dose of 800 mg of the preparation of Sirturo, the adverse reactions corresponded to those observed with the recommended dose (see section Side effect).

    Treatment. The experience of treatment of acute overdosage with the preparation of Sirturo is absent. In the case of a deliberate or accidental overdose, general measures should be taken to support vital vital functions and ECG monitoring of the interval QT. Unabsorbed Bedakvilin can be removed by washing the stomach and taking activated charcoal. As Bedakvilin largely associated with proteins, the effectiveness of dialysis to remove poorakvilina from the plasma will be low. If possible, clinical follow-up should continue.

    Interaction:

    Bedakvilin in vitro has no significant effect on the activity of known isoenzymes of the cytochrome P450 family (see Metabolism).

    CYP3A4 is the main isoenzyme of the family of cytochrome P-450, taking part in the metabolism of Bedakville and the formation of M2 in vitro. Therefore, the content of poorakvinina in blood plasma may decrease when combined with inducers CYP3A4 and increase with co-administration with inhibitors CYP3A4.

    Rifampicin group antibiotics and other inducers CYP3A4

    In a study of the drug interaction bedakvilina (300 mg once) and rifampicin (600 mg per day 21 days) in healthy volunteers AUC misfortune decreased by 52%. In connection with the possibility of reducing the therapeutic effect of Bedakville due to a decrease in its systemic effect, joint use of Bedaklin and antibiotics of the rifampicin group should be avoidedrifampicin, rifapentin and rifabutin) or other powerful inducers CYP3A4, assigned systemically (see section Special instructions).

    Ketoconazole and other inhibitors CYP3A4

    With the combined use of ketoconazole (400 mg for 4 days) and Bedaklavina (400 mg per day for 14 days) in healthy volunteers AUC Bedakvilina increased by 22%, Cmax and Cmin by 9% and 33%, respectively. In connection with the potential risk of adverse reactions due to an increase in the systemic action of Bedakville, prolonged joint use (more than 14 days) of poorakwin with moderate or potent inhibitors should be avoided CYP3A4, systematically (see Special instructions).

    Other antimicrobials

    The combined use of Bedakville (400 mg / day) with isoniazid (300 mg / day for 5 days) / pyrazinamide (1000 mg / day for 5 days) did not cause clinically significant changes in healthy volunteers for 14 days AUC Bedakville, isoniazid or pyrazinamide. With the simultaneous use of the drug Sirturo with isoniazid or pyrazinamide, dose adjustment is not required. In a placebo-controlled clinical trial in patients with MDR-TB, there was no significant effect of the preparation of Sirturo on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin, or cycloserine when combined.

    Antiretroviral drugs

    In a study of the drug interaction between poorakillin (400 mg once) and the drug lopinavir (400 mg) / ritonavir (100 mg) in the regimen twice daily for 24 days in healthy volunteers AUC Bedakvilina increased by 22%. Care should be taken to administer the preparation of Sirturo together with the drug lopinavir / ritonavir only after assessing the risk relationship to the benefit of this combination of drugs (see section Special instructions).

    Joint use of nevirapine (200 mg twice a day for 4 weeks) with Bedakvil (400 mg once) did not cause clinically significant changes in the content of Bedakville in blood plasma.

    Clinical data on the joint use of antiretroviral drugs and the preparation of Sirturo in HIV-infected patients with MDR-TB are not available (see section Special instructions).

    Drugs that extend the interval QT

    Information on the possible pharmacodynamic interaction between Bedakville and drugs that extend the interval QT, is limited.

    An additive or synergistic effect was observed with respect to the extension of the interval QT when joint application of Bedaklavin with drugs that extend the interval QT. In a study of the drug interaction of ketoconazole and poorakwin, after repeated co-administration, a more significant effect was observed on QTc this combination, than after repeated taking each of these drugs separately.

    Special instructions:

    Treatment should be carried out under the direct supervision of a specialist. Strains of M. tuberculosis isolated from a patient who did not undergo sputum conversion on the background of therapy, or if a relapse occurred after completion of treatment, should be investigated for sensitivity to Bedakville (MIC).

    Effect on lethality

    In a 2-phase clinical study, a significant increase in the risk of death (9/79 (11.4%)) was observed in the poorakwin group over the 120-week follow-up period compared with the placebo group (2/81 (2.5%)). The median time of death for 9 out of 10 patients in the study drug group was 344 days after the last dose. The most frequent cause of death in the group of poorakvilina was tuberculosis (5 cases), in 4 cases, lethal outcomes from other causes were noted. The drug should be used in cases where no other effective treatment regimen can be prescribed.

    Effect on elongation interval QT

    A 2-phase clinical trial showed an average increase QT, with correction according to Frederick's formula (QTcF), beginning with 1 week of therapy (in the group of Sirto - by 9.9 ms and by 3.5 ms in the placebo group). The greatest increase in the mean value QTcF during 24 weeks of therapy was observed at the 18th week and was 15.7 ms in the group receiving the preparation of Sirturo compared with 6.2 ms in the placebo group. After the end of taking the preparation of Sirturo (ie after the 24th week), the interval QTcF did not reach the normal values ​​in this group. In the course of the clinical study, there was no clear correlation between the clinically significant lengthening of the interval QT or rhythm disturbances among patients with lethal outcome (see sections Side effect, Interaction with other medicinal products).

    Before the start of therapy with the preparation of Sirturo and after 2, 12 and 24 weeks of treatment, it is necessary to conduct an ECG study for dynamic interval control QTc.

    Before starting therapy with the preparation of Sirturo it is necessary to assess the concentration of potassium, magnesium and calcium of blood serum and adjust the parameters in case of deviation from normal values.

    The following conditions may increase the risk of lengthening the interval QT on the background of taking the preparation of Sirturo, which requires a more frequent ECG monitoring against the background of ongoing therapy Bedakvilinom:

    - interval QT with correction according to Frederick's formula (QTcF) > 450 ms (with confirmation by repeated ECG examination);

    - Decompensated heart failure;

    - personal or family history of congenital lengthening of the interval QT or arrhythmia development by type "torsade de points";

    - clinically significant bradycardia;

    - electrolyte disorders (hypocalcemia, hypomagnesemia, hypokalemia);

    - history of hypothyroidism.

    There are no data on the use of the preparation of Sirturo in patients with ventricular arrhythmias and recent myocardial infarction.

    Therapy with a preparation of Sirturo and any other drugs extending the interval QT should be discontinued if the patient develops a clinically significant ventricular arrhythmia or interval QT with correction according to Frederick's formula (QTcF) > 500 ms (with confirmation by repeated ECG study). Frequent ECG monitoring should be performed until the interval value QT will not return to normal. In case of development of an attack of short-term loss of consciousness, it is necessary to conduct an ECG study to confirm the lengthening of the interval QT.

    With the combined use of Bedakville with drugs that cause lengthening of the interval QT (in particular with the antibiotics of the group of fluoroquinolones, macrolides, clofazimine), caution should be exercised, since an additive or synergistic effect can not be excluded which can lead to a significant lengthening of the interval QT. In the event that the joint use of such medications with Bedakwin is necessary, clinical observation of the patient is recommended, including regular monitoring of the ECG (see section Interaction with other medicinal products).

    Combined use with inducers / inhibitors CYP3A4

    It is necessary to avoid the combined use of poorakvilina and antibiotics group rifampicin (rifampicin, rifapentin and rifabutin) or other powerful inducers CYP3A4, assigned systemically, since it is possible to reduce its systemic action (see section Interaction with other medicinal products).

    It is necessary to avoid simultaneous reception bedakvilina with moderate or powerful inhibitors CYP3A4, administered systemically for more than 14 consecutive days, since it is possible to increase the time of systemic action of Bedakville and the risk of adverse reactions. If necessary, a longer (> 14 days) intake of inhibitors CYP3A4 with the preparation of Sirturo should assess the risk ratio to the benefits of this combination of drugs and adequate monitoring of possible adverse reactions associated with the use of Sirturo.

    It is necessary to prescribe the preparation of Sirturo together with lopinavir / ritonavir with caution - only after assessing the risk-to-benefit ratio of such a combination of drugs and with the regular monitoring of possible adverse reactions associated with the use of Sirturo.

    Effects on liver function

    Against the backdrop of Syrturo therapy (in combination with other antituberculosis drugs), more frequent adverse reactions from the liver were noted in clinical studies compared with the combined regimen of anti-tuberculosis drugs without the addition of Certuro (placebo): an increase in the level of transaminases was documented in 7/79 (8.9%) of patients in the Sirroturo group and in 1/81 (1.2%) patients in the placebo group (see section Side effect). In this regard, it is necessary to monitor the clinical condition of the patient and a biochemical blood test with the determination of the activity of "hepatic" enzymes (ACT, ALT) and cholestasis (the level of alkaline phosphatase, bilirubin) before the start of therapy with the drug Sirturo, monthly during treatment and, if necessary, more often. With an increase in the activity of aminotransferases (ALT, ACT) more than 3 times it is necessary to re-examine the indicators no later than 48 hours later, to examine the blood for markers of viral hepatitis and stop taking other drugs that have hepatotoxicity.

    In patients taking the preparation of Sirturo, with the appearance of previously not documented clinically significant changes in the functional performance of the liver or further deterioration of its function (assessed by the level ACT, ALT and / or bilirubin), as well as the presence of clinical symptoms (such as fatigue, anorexia, nausea, jaundice, darkening of the urine, hepatomegaly), careful monitoring of the patient is necessary.

    Therapy with Sirturo should be discontinued if the patient's aminotransferase activity is combined with an increase in total bilirubin by more than 2-fold or an increase in ALT and / or ACT more than 8 times, or the persistence of increased aminotransferase activity is observed for more than 2 weeks.

    During the period of treatment, Syrturo should avoid the use of alcohol and drugs that have a hepatotoxic effect.

    There is no experience of the joint use of antiretroviral drugs and the preparation of Sirturo in HIV-infected patients with MDR-TB, and there are limited clinical data on the use of the drug Sirturo in patients (n = 22) with HIV infection and MDR-TB not taking antiretroviral therapy.

    Patients of different ethnic groups do not need dose adjustment.

    Effect on the ability to drive transp. cf. and fur:

    If there are side effects from the central nervous system when the drug is used, patients are advised to refrain from managementmotor transport and employment by other potentially dangerous kinds of activity demanding the raised concentration of attention, speed of psychomotor and motor reactions.

    Form release / dosage:

    Tablets of 100 mg.

    Packaging:

    For 188 tablets in a bottle of high density polyethylene, sealed with a polypropylene lid with a system to protect children from opening and control the first autopsy.

    1 bottle with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep in original packaging in the dark place.

    Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002281
    Date of registration:22.10.2013
    The owner of the registration certificate:PHARMSTANDART-UFIM VITAMIN FACTORY, OJSC PHARMSTANDART-UFIM VITAMIN FACTORY, OJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp22.10.2013
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