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).

This medical product indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

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

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. Caution is recommended when prescribing bedaquiline concomitantly with medicinal products with a known risk of QT prolongation.
It is not recommended to start treatment 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
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 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 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.
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. 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.
Lactose intolerance and lactase deficiency
This medical product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
See prescribing information for full.

Very common: Headache, dizziness, Nausea, vomiting, Arthralgia.
Common: Electrocardiogram QT prolonged, Diarrhoea, Transaminases increased, 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.
Antiretroviral medicinal products
If the benefit outweighs the risk, bedaquiline may be used with caution when co-administered with lopinavir/ritonavir. Increases in plasma exposure to bedaquiline would be expected when it is co-administered with other ritonavir-boosted HIV protease inhibitors. Of note, no change in bedaquiline dosing is recommended in case of co-treatment with lopinavir/ritonavir or other ritonavir-boosted HIV protease inhibitors. There are no data to support a lowered bedaquiline dose in such circumstances.
Co-administration of single-dose bedaquiline and multiple-dose nevirapine did not result in clinically relevant changes in the exposure to bedaquiline. Clinical data on co-administration of bedaquiline and antiretroviral agents in patients co-infected with human immunodeficiency virus and multi-drug resistant Mycobacterium tuberculosis are not available. Efavirenz is a moderate inducer of CYP3A4 activity and co-administration with bedaquiline may result in reduced bedaquiline exposure and loss of activity, and is, therefore, not recommended.
QT interval prolonging medicinal products
There is limited information available on the potential for a pharmacodynamic interaction between bedaquiline and medicinal products that prolong the QT interval. In an interaction study of bedaquiline and ketoconazole, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual medicinal products. An additive or synergistic effect on QT prolongation of bedaquiline when co-administered with other medicinal products that prolong the QT interval cannot be excluded and frequent monitoring is recommended
See prescribing information for full.

Pregnancy:
There are limited data on the use of Bedaquiline 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. 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.
Fertility:
No human data on the effect of bedaquiline on fertility are available. In female rats, there was no effect on mating or fertility with bedaquiline treatment, however some effects were observed in male rats.

There is no experience with the treatment of acute overdose with SIRTURO. 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.