Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

There are no clinical data on the use of SIRTURO to treat:
•     extra-pulmonary tuberculosis (e.g. central nervous system, bone)
•     infections due to mycobacterial species other than Mycobacterium tuberculosis
•     latent infection with Mycobacterium tuberculosis 
There are no clinical data on the use of SIRTURO as part of combination regimens used to treat drug-susceptible Mycobacterium tuberculosis.

Resistance to bedaquiline
Bedaquiline must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by official guidelines, such as from WHO, to prevent development of resistance to bedaquiline.
Mortality

In the 120-week C208 trial where SIRTURO was administered for 24 weeks in combination with a background regimen, more deaths occurred in the SIRTURO treatment group than in the placebo group (see section 5.1). The imbalance in deaths is unexplained; no evidence has been found for a causal relationship with SIRTURO treatment. For additional information on deaths in the C209 trial, see section 5.1.

Cardiovascular safety

Bedaquiline prolongs the QTc interval. An electrocardiogram should be obtained before initiation of treatment and at least monthly after starting treatment with bedaquiline. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected (see sections 4.5 and 4.8).

When bedaquiline is co-administered with other medicinal products that prolong the QTc interval (including delamanid and levofloxacin), an additive or synergistic effect on QT prolongation cannot be excluded (see section 4.5). Caution is recommended when prescribing bedaquiline concomitantly with medicinal products with a known risk of QT prolongation. In the event that co-administration of such medicinal products with bedaquiline is necessary, clinical monitoring, including frequent electrocardiogram assessment, is recommended.

In the event that co-administration of clofazimine with bedaquiline is necessary, clinical monitoring, including frequent electrocardiogram assessment, is recommended (see section 4.5).

SIRTURO treatment initiation is not recommended in patients with the following, unless the benefits of bedaquiline are considered to outweigh the potential risks:
•     Heart failure;
•     QT interval as corrected by the Fridericia method (QTcF) > 450 ms (confirmed by repeat electrocardiogram);
•     A personal or family history of congenital QT prolongation;
•     A history of or ongoing hypothyroidism;
•     A history of or ongoing bradyarrhythmia;
•     A history of Torsade de Pointes;
•     Concomitant administration of fluoroquinolone antibiotics that have a potential for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin).
•     Hypokalemia 
SIRTURO treatment must be discontinued if the patient develops:
•    Clinically significant ventricular arrhythmia
•    A QTcF interval of > 500 ms (confirmed by repeat electrocardiogram).

If syncope occurs, an electrocardiogram should be obtained to detect any QT prolongation.

Hepatic safety

Increases in transaminases or aminotransferase elevations accompanied by total bilirubin ≥ 2x ULN were seen in clinical trials during administration of SIRTURO with the background regimen (see section 4.8). Patients should be monitored throughout the treatment course, since the increases in liver enzymes were slow to appear and increased gradually during the 24 weeks. Monitor symptoms and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. If AST or ALT exceeds 5 times the upper limit of normal then the regimen should be reviewed and SIRTURO and/or any hepatotoxic background medicinal product should be discontinued.

Other hepatotoxic medicinal products and alcohol should be avoided while on SIRTURO, especially in patients with diminished hepatic reserve.

Interactions with other medicinal products

CYP3A4 inducers
Bedaquiline is metabolised by CYP3A4. Co-administration of bedaquiline and medicinal products that induce CYP3A4 may decrease bedaquiline plasma concentrations and reduce its therapeutic effect.
Co-administration of bedaquiline and moderate or strong CYP3A4 inducers used systemically should, therefore, be avoided (see section 4.5).

CYP3A4 inhibitors
Co-administration of bedaquiline and moderate or strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions (see section 4.5). Therefore, the combination of bedaquiline and moderate or strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided. If co-administration is required, more frequent electrocardiogram monitoring and monitoring of transaminases is recommended.

Patients infected with human immunodeficiency virus (HIV)

There are no clinical data on the safety and efficacy of bedaquiline when co-administered with antiretroviral agents.

There are only limited clinical data on the efficacy of bedaquiline in HIV-infected patients not receiving antiretroviral (ARV) therapy. Those patients studied all had CD4+ cell counts greater than 250 x 106 cells/l (N = 22; see section 4.5).

Lactose intolerance and lactase deficiency

SIRTURO contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on Driving

4.7    Effects on ability to drive and use machines

Bedaquiline may have a minor influence on the ability to drive and use machines. Dizziness has been reported in some patients taking bedaquiline and should be considered when assessing a patient’s ability to drive or operate machinery (see section 4.8).