Bedakvilin diarilhinolinov refers to the group – a new class of anti-TB compounds. The bactericidal effect caused by the specific drug ingibirovanpem proton pump ATP synthase of Mycobacterium (adenosine 5’trifosfat synthase) – an enzyme that plays a pivotal role in cell respiration Mycobacterium tuberculosis. Inhibition of ATP synthesis leads to the disruption of power generation and, as a result, to the microbial cell death.
Bedakvilin in vitro activity against drug-sensitive and drug-resistant (including and extensively drug-resistant) Mycobacterium tuberculosis strains having the minimum inhibitory concentration (MIC) in the range < 0,008-0,12 mg / ml (MIK50 – 0.03 g / ml and MIC 90 – 0.06 ug / ml)
The mechanisms of the development of resistance
The mechanisms that determine resistance to Mycobacterium tuberculosis bedakvilinu include, at least 6 different mutations (replacement amino acid sequence) of a target gene atpE. Not all strains are atpE gene mutations, which suggests the existence of at least one more mechanism of resistance to the drug. In vitro spontaneous mutation frequency was 10-7-10-8 and decreased with increasing drug concentration. In low concentrations bedakvilin may exhibit a bacteriostatic effect and potentiate the risk of resistance, in high concentrations – has a bactericidal effect
1 tab .:
– bedakvilina fumarate 120.89 mg, respectively. bedakvilina content of 100 mg
Excipients: lactose monohydrate 152.91 mg Corn starch 66 mg Hypromellose 2910 8 mg, 1 mg polysorbate 20, microcrystalline cellulose 82.2 mg Croscarmellose sodium 23 mg Colloidal silicon dioxide 1.4 mg Magnesium stearate 4.6 mg
Tablets Sirturo white or almost white, round, biconvex, embossed with the words “T” over “207” on one side and “100” on the other.
– in a combination therapy of pulmonary tuberculosis caused by strains of Mycobacterium tuberculosis with multidrug resistance in adults (> 18)
– hypersensitivity to bedakvilinu and / or any other component of the product;
– lactation (breastfeeding);
– child and adolescence to 18 years;
– severe renal failure (creatinine clearance < 30 ml / min / 1.73 m2);
– severe hepatic insufficiency (in the absence of clinical data on the safety of the drug in this group);
– congenital lactose intolerance, lactase deficiency, glucose-galactose malabsorption
When extending the QT interval adjusted according to the formula Frederick (QTcF) > 450 msec (with confirmation by repeated ECG research); at dekomnensirovannoy heart failure; in patients with a personal or family history of congenital long interval QT, development of arrhythmia type “torsade de points”; in patients with clinically significant bradycardia, electrolyte disturbances (hypocalcemia, gipomagiiemiya, ginokaliemiya); indicating a history of hypothyroidism; while the use of drugs that prolong the interval QT; when combined with lopinavir / ritonavir; in elderly patients (65 years and older)
Clinical trials are conducted in a variety of settings, so the frequency of undesirable side reactions observed in clinical trials of the drug can not be directly compared with the frequency of adverse reactions in clinical trials of another drug and may not reflect the frequency observed in clinical practice. < / p>
Undesirable side reactions (NDP) Sirturo drug were determined based on pooled data for patients receiving the drug in the composition Sirturo antituberculous therapy combined regimen conducted in controlled clinical trials.
Adverse drug reactions pas Sirturo listed in accordance with the systems and organs of classes of the frequency (very frequent (> 1/10), frequent (from > 1/100 up to 1 / 1,000 < 1/100), rare ( from > 1/10000 to < 1/1000), very rare (
Disorders of the nervous system (CNS): very often – headache, dizziness
Disorders of the cardiovascular system: often – prolonged QT interval on an electrocardiogram
Disorders of the gastrointestinal tract: often – nausea, vomiting; often – diarrhea
Violations of the liver and zhelchevyvodyaischh tract: often – increasing the activity of transaminases (ALT, ACT)
Violations of the musculoskeletal and connective tissue disorders: often – pain in the joints, often – muscle pain
hemoptysis, anorexia, chest pain, skin rash <:
In controlled clinical studies, phase 2 in the group of patients receiving the drug Sirturo in combined mode of TB treatment more often, compared to placebo, the following adverse events were reported. / p>
How to accept, acceptance rate and dosage
The drug, taken orally Sirturo during meal time, as concomitant use with food increases the bioavailability (see. Pharmacokinetics section). Sirturo tablet formulation recommended swallowed whole with water. Sirturo drug should only be administered in a combination therapy for the treatment of multi-drug-resistant tuberculosis (MDR-TB) under the direct supervision of a specialist (see. Section Indications for use. See section Pharmacodynamics).
Sirturo The drug should be used only in conjunction with at least three drugs, which prove the lack of in vitro resistance strain isolated from the patient. If the results of in vitro studies are not available, Sirturo drug treatment could be initiated in combination with at least 4 other drugs to which the strain isolated from the patient may be sensitive. During the course of treatment Sirturo and after the last dose must continue therapy with anti-TB drugs in accordance with standard regimens for MDR-TB chemotherapy. When selecting circuit and duration TB drugs provision of combination therapy the physician should be guided by the state standards of treatment of tuberculosis, data on drug resistance of Mycobacterium in the region with the drug sensitivity of the strain isolated from a patient with tuberculosis and data klinnko-radiological inspection.
The recommended dosing regimen Sirturo drug:
400 mg 1 time per day for the first 2 weeks, followed by (3-but 24 weeks) 200 mg 3 times a week (at break of at least 48 hours between doses) for the next 22 weeks (total dose 600 mg per week).
The total duration of treatment is 24 weeks Sirturo. Patients should be advised of the need for drugs Sirturo in accordance with the doctor’s instructions. It is necessary to emphasize the importance of taking the full course of therapy.
Omitting the drug during the first 2 weeks of treatment missed dose should be taken. It is necessary to continue the normal dosing regimen. When missed doses ranging from 3 weeks should take missed dose as soon as possible and to continue taking the drug in accordance with the recommended dosing regimen with a break after the received missed doses (at 3-times reception weekly at 200 mg per day) did not less than 24 hours, thus, the total dose of drug Sirturo 7 days should not exceed 600 mg.
Special groups of patients
Pediatric patients (
The safety and efficacy of the drug Sirturo in children and adolescents younger than 18 years have not been established (see. Section Cautions).
Older patients (> 65 years)
Data on the use Sirturo drug in elderly patients are limited (see. Section Cautions).
Patients with renal insufficiency
The drug Sirturo investigated mainly in patients with normal renal function. For patients with mild or moderate renal insufficiency dose adjustment is required. Patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis, Sirturo drug use is not recommended (see. Section Cautions).
Patients with hepatic insufficiency
bedakvilina pharmacokinetic properties were evaluated in single dose studies in patients with moderate hepatic failure (class B Child-Pugh) (see. Pharmacokinetics section).
In patients with mild or moderate hepatic insufficiency changes in drug dosing regimen Sirturo not required. In patients with severe hepatic insufficiency bedakvilina efficacy and safety has not been studied and applied Sirturo drug in these patients is not recommended (see. Section Cautions).
Data on the use Sirturo drug in HIV-infected patients are limited.
Bedakvilin in vitro has no significant impact on the activity of the known cytochrome P450 family izofermeptov (see. Metabolism).
CYP3A4 is the major isoenzyme cytochrome P450 family participating in metabolism bedakvilina and M2 formation in vitro. Therefore plasma bedakvilina content may be reduced when used together with inducers of CYP3A4 and increase when coadministered with CYP3A4 inhibitors.
Antibiotics rifampicin and other inducers of CYP3A4
The study of drug interaction bedakvilina (300 mg dose) and rifampicin (600 mg per day for 21 days) in healthy volunteers bedakvilina AUC decreased by 52%. In connection with the possibility of reducing the therapeutic effect bedakvilina due to reduce its systemic effects, you should avoid joint use bedakvilina and antibiotics group rifampicin (rifampin, rifapentine and rifabutin), or other strong inducers of CYP3A4, assigned by the system (see. Section Cautions).
Ketokonazop and other inhibitors of CYP3A4
In joint application of ketoconazole (400 mg, 4 days) and bedakvilina (400 mg per day for 14 days) in healthy volunteers bedakvilina AUC increased by 22%, Cmax and Cmin of 9% and 33%, respectively. Due to the potential risk of adverse reactions by increasing bedakvilina systemic action, should avoid prolonged joint application (14 days) bedakvilina with moderate or potent inhibitors of CYP3A4, assigned by the system (see. Specific guidance section).
The combined use bedakvilina (400 mg daily) with isoniazid (300 mg a day for 5 days) / pyrazinamide (1000 mg a day for 5 days) in healthy volunteers for 14 days did not cause clinically significant changes in AUC bedakvilina, isoniazid and pyrazinamide . In joint use of the drug or Sirturo with isoniazid pyrazinamide dose adjustment is required. In placebo-controlled clinical trial in patients with MDR-TB was no significant effect on the pharmacokinetics of the drug Sirturo ethambutol, kanamycin, pyrazinamide, cycloserine or ofloxacin in their joint application.
The study of drug interaction between bedakvilinom (400 mg dose) and the drug lopinavir (400 mg / ritonavir (100 mg) in the reception mode 2 times a day for 24 days in healthy volunteers AUC bedakvilina increased by 22%. It is prescribed the drug Sirturo together with the drug lopinavir / ritonavir with caution only after an assessment of the risk related to the use of a combination of drugs (see. section Cautions).
The combined use of nevirapine (200 mg, 2 times a day 4 weeks) with bedakvilinom (400 mg dose) did not cause clinically significant changes in blood content bedakvilina plasma.
Clinical data on the joint use of antiretroviral drugs and drug Sirturo in HIV-infected patients with MDR-TB is not available (see. Section Cautions).
Drugs prolonging the interval QT
Information about a possible pharmacodynamic interaction between bedakvilinom and drugs prolong the QT interval, is limited.
There was an additive or synergistic effect on QT interval elongation when used together bedakvilina with drugs that prolong the interval QT. The study drug interaction and bedakvilina ketoconazole after repeated co-administration of drugs was observed a significant effect on QTc this combination than after repeated administration of each of these drugs alone.
The treatment should be carried out under the direct supervision of a specialist.
The strains of M. tuberculosis isolated from a patient who has not occurred sputum conversion on therapy or relapse event marked the end of treatment, should be tested for sensitivity to bedakvilipu (MIC).
The effect on mortality
In the clinical study phases 2 for 120 weeks of observation bedakvilina group showed a significant increase in the risk of death (9/79 (11.4%)) compared with the placebo group (2/81 (2.5%)). The median time to death of 9 of the 10 patients in the study drug was 344 days after the last dose. The most common cause of death in the group bedakvilina had tuberculosis (5 cases), in 4 cases observed deaths from other causes. The drug should be used in the case when it can not be assigned to another effective treatment regimen.
The effect on prolongation of the interval QT
In phase 2 clinical trial there was an average increase QT, with the correction of formula Frederick (QTcF), starting from 1 week of treatment (group Sirturo – 9.9 ms and 3.5 ms in the placebo group). The greatest increase in the average value QTcF within 24 weeks of treatment was observed on the 18th week was 15.7 ms and in the group receiving the drug Sirturo compared to 6.2 ms in the placebo group. After receiving Sirturo drug (i.e., after 24 weeks) interval QTcF I not reached normal values in this group. In the clinical studies have not indicated a clear correlation clinically significant lengthening QT interval or rhythm disorders in patients with a fatal outcome (see. Partitions Side effects, interaction with other drugs).
Before starting therapy with Sirturo and at 2, 12 and 24 weeks of treatment is necessary to conduct an ECG study for dynamic control of interval QTc.
Before therapy drug Sirturo need to assess the concentration of potassium, magnesium and calcium serum and adjusted figures in case of deviation from normal values.
The following conditions may increase the risk of QT prolongation in patients receiving the drug Sirturo that requires more frequent ECG monitoring on the background of the therapy bedakvilinom:
– QT interval adjusted according to the formula Frederick (QTcF) > 450 msec (with confirmation by repeated ECG study);
– decompensated heart failure;
– personal or family history of congenital QT prolongation or arrhythmia of type “torsade de points”;
– clinically significant bradycardia;
– electrolyte disturbances (hypocalcemia, hypomagnesemia, hypokalemia);
– indicate a history of hypothyroidism
There are no preparation for use Sirturo data in patients with ventricular arrhythmias and recent myocardial infarction.
Sirturo drug therapy and any other drugs prolong the QT interval should be discontinued if the patient develops clinically significant ventricular arrhythmia or QT interval adjusted according to the formula Frederick (QTcF) > 500 ms (with confirmation by repeated ECG research). It is common to conduct an ECG monitoring as long as the value QT interval will not return to normal. In the case of short-term loss of consciousness attack, a study of ECG is required to confirm the extension of the interval QT.
bedakvilina When combined with drugs that cause lengthening of the interval QT (in particular fluoroquinolone antibiotics, macrolides, clofazimine), caution should be exercised, since one can not exclude the additive or synergistic effect which can lead to a significant lengthening of the interval QT. In case of such combined use of drugs with bedakvilinom necessary clinical observation of the patient is recommended, including regular ECG monitoring (see. Section Interaction with other drugs).
The combined use of inducers / inhibitors of CYP3A4
Avoid joint application bedakvilina group and antibiotics rifampicin (rifampin, rifapentine and rifabutin), or other potent inducers of CYP3A4, designated systemically because it may decrease systemic effects (see. Section Interaction with other drugs). Avoid simultaneous reception bedakvilina with moderate or potent inhibitors of CYP3A4, assigned by the system, more than 14 consecutive days, as may increase systemic bedakvilina time and risk of adverse reactions. If necessary, a longer (> 14 days) receiving a CYP3A4 inhibitor with a drug Sirturo risk ratio should be evaluated to the use of such combination preparations and adequate monitoring of possible adverse reactions associated with the use Sirturo
It is prescribed the drug together with Sirturo lopinavir / ritonavir with caution – only after assessing risk related to use of such combination preparations and regular monitoring of possible adverse reactions associated with the use Sirturo
The effect on liver function
The therapy Sirturo (in combination with other anti-TB drugs) observed in clinical trials more frequent adverse reactions by the liver in comparison with a combined treatment regime without the addition of anti-TB drugs Sirturo (placebo): transaminase elevation documented in 7/79 ( 8.9%) patients in Sirturo group and 1/81 (1.2%) patients in the placebo group (see. section Side effects). In this connection, it should monitor the patient’s clinical condition and biochemical blood tests, “liver” enzymes (ACT, ALT) and indicators cholestasis (serum alkaline phosphatase, bilirubin) before therapy with Sirturo monthly during treatment and, if necessary more often. By increasing the activity of aminotransferases (ALT, ACT) is more than 3 times should be carried out repeated research indicators not later than 48 hours, to examine the blood markers of viral hepatitis and stop taking other drugs with hepatotoxicity.
The patients taking the drug Sirturo, when a previously documented clinically significant changes in the functional parameters of the liver or further deterioration of its function (estimated from the ACT level of ALT and / or bilirubin), as well as the presence of clinical symptoms (such as fatigue , anorexia, nausea, jaundice, dark urine, hepatomegaly) should be particularly careful monitoring of the patient.
Treatment with Sirturo should be discontinued if the patient increase amiiotransferaz activity combined with an increase in total bilirubin more than 2 times, or an increase of ALT indicators and / or ACT more than 8 times, or retention of elevated aminotransferase activity observed for more than 2 weeks. During treatment Sirturo should avoid taking alcohol and drugs with hepatotoxic effect.
There is no experience of joint use of antiretroviral drugs and drug Sirturo in HIV-infected patients with MDR-TB, and there are limited clinical data on the use of Sirturo drug in patients (n = 22) with HIV infection and MDR-TB who are not taking antiretroviral therapy. Patients of different ethnic groups, the correction dose is not required.
The effect on the ability to drive vehicles and other mechanisms
In the event of adverse reactions from the central nervous system against the background of the use of the drug for patients to refrain from road management and other activities potentially hazardous activities that require high concentration of attention, psychomotor speed and motor responses.
Information on cases of intentional or accidental overdose there is no acute bedakvilinom. In a study of 44 healthy volunteers who received 800 mg once Sirturo drug, adverse events consistent with those observed at the recommended doses (see. Side effect profile).
Treatment. Experience in the treatment of acute overdose of the drug Sirturo absent. In the case of intentional or accidental overdose should take general measures to support basic vital functions and perform ECG monitoring interval QT. Unabsorbed bedakvilin may be removed using lavage and activated charcoal. Since bedakvilin largely associated with protein, the efficiency of dialysis to remove bedakvilina from plasma is low. If possible, continue the clinical observation of the patient.