Sirturo

/ Janssen

bedaquiline should be used in combination with at least three medicinal products to which the patient’s isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment may be initiated with bedaquiline in combination with at least four medicinal products to which the patient’s isolate is likely to be susceptible.
The recommended dosage is:
Weeks 1-2: 400 mg (4 tablets of 100 mg) once daily
Weeks 3-24: 200 mg (2 tablets of 100 mg) three times per week (with at least 48 hours between doses).
The total duration of treatment with SIRTURO is 24 weeks.

This medical product is indicated for use as part of an appropriate combination regimen in adult patients with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampicin and isoniazid.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Hypersensitivity to the active substances or to any of the excipients.

Resistance to bedaquiline: Bedaquiline should only be used in an appropriate combination regimen for treatment of pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid as recommended by official guidelines, such as from the WHO, to prevent development of resistance to bedaquiline.
QT prolongation: This medicinal product may prolong the QT interval. An electrocardiogram should be obtained before initiation of treatment and at least monthly after starting treatment to monitor the QTc interval. 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. 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
• Hypokalemia When bedaquiline is co-administered with other medicinal products that prolong the QTc interval (including clofazimine, delamanid or fluoroquinolones ), an additive effect on QT prolongation is expected.
Treatment may be considered after a favourable benefit-risk assessment and with ECG monitoring.
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 accompanied by total bilirubin ≥ 2x ULN were seen in clinical trials during administration of bedaquiline with the background regimen. 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 bedaquiline and/or any hepatotoxic background medicinal product should be discontinued. Other hepatotoxic medicinal products and alcohol should be avoided while on bedaquiline, especially in patients with diminished hepatic reserve. Interactions with other medicinal products: CYP3A4 inducers bedaquiline is metabolised by CYP3A4. Co-administration of bedaquiline with moderate or strong CYP3A4 inducers decreases bedaquiline plasma concentrations and may reduce the therapeutic effect of bedaquiline. Co-administration with moderate or strong CYP3A4 inducers used systemically, such as efavirenz and rifamycins (i.e., rifampicin, rifapentine and rifabutin) should, therefore, be avoided.
Lactose intolerance and lactase deficiency: Bedaquiline contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take bedaquiline.
See prescribing information for full details.

Very Common: Headache, dizziness, nausea, vomiting, transaminases increased, arthralgia, electrocardiogram QT prolonged.
Common: Diarrhoea, myalgia.
See prescribing information for full details.

CYP3A4 inducers
Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4. In an interaction study of single-dose bedaquiline and once daily rifampicin (strong inducer) in healthy subjects, the exposure (AUC) to bedaquiline was reduced by 52% [90% CI (-57; -46)]. Due to the possibility of a reduction of the therapeutic effect of bedaquiline due to a decrease in systemic exposure, co-administration of bedaquiline and moderate or strong CYP3A4 inducers (e.g. efavirenz, etravirine, rifamycins including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)) used systemically should be avoided
CYP3A4 inhibitors
Bedaquiline exposure may be increased during co-administration with inhibitors of CYP3A4. The short-term co-administration of bedaquiline and ketoconazole (potent CYP3A4 inhibitor) in healthy subjects increased the exposure (AUC) to bedaquiline by 22% [90% CI (12; 32)]. A more pronounced effect on bedaquiline may be observed during prolonged co-administration of ketoconazole or other inhibitors of CYP3A4.
Other antituberculosis medicinal products
The short-term co-administration with isoniazid/pyrazinamide in healthy adults did not result in clinically relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide. No dose-adjustment of isoniazid or pyrazinamide is required during co-administration withthis medicinal product. In a placebo-controlled clinical study in adults with TB, no major impact of co-administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.
QT interval prolonging medicinal products
In an open-label Phase IIb trial in adults, additive increases in QTcF were observed in the 17 patients who were using concomitant clofazimine at Week 24 (mean change from reference QTcF 31.9 ms compared to 12.3 ms in patients who were not using concomitant clofazimine). In the Phase III trial, additive increases in QTcF were observed when combining clofazimine and levofloxacin with bedaquiline. In an interaction study of bedaquiline and ketoconazole in healthy adults, a greater effect on QTcF was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs.
See prescribing information for full details.

Pregnancy: There are limited data on the use in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, avoid the use of bedaquiline during pregnancy unless the benefit of therapy is considered to outweigh the risks.
Lactation: Bedaquiline is excreted in human milk. Limited published literature reports higher bedaquiline concentrations in human milk than in maternal plasma. In one breastfed infant, a single random plasma bedaquiline concentration was similar to maternal plasma concentration; the mother had a high concentration of bedaquiline in breast milk, with a milk to plasma ratio of 14:1. This is consistent with data from animal studies. Available information indicates that systemic exposure in breastfed infants may reach levels similar to those observed in the breastfeeding mothers treated with bedaquiline. The clinical consequence of this exposure is unknown. Women who are treated with bedaquiline should not breastfeed.

Cases of intentional or accidental acute overdose with bedaquiline were not reported during clinical trials. In a study in 44 healthy adults receiving a single 800 mg dose of bedaquiline, adverse reactions were consistent with those observed in clinical studies at the recommended dose. There is no experience with the treatment of acute overdose with bedaquiline. General measures to support basic vital functions including monitoring of vital signs and electrocardiogram (QT interval) monitoring should be taken in case of deliberate or accidental overdose. Further management should be as clinically indicated or as recommended by the national poisons center, where available. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. Clinical monitoring should be considered.

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.