Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340, Beerse, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
There are no clinical data on the use of SIRTURO to treat:
There are no clinical data on the use of SIRTURO as part of combination regimens used to treat drug-susceptible Mycobacterium tuberculosis.
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.
In the 120-week C208 trial in adults 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.
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:
SIRTURO treatment must be discontinued if the patient develops:
If syncope occurs, an electrocardiogram should be obtained to detect any QT prolongation.
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.
In adolescents weighing between 30 and 40 kg, average exposure is predicted to be higher compared to adult patients (see section 5.2). This may be associated with an increased risk of QT prolongation or hepatotoxicity.
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).
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.
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 adult patients not receiving antiretroviral (ARV) therapy. Those patients studied all had CD4+ cell counts greater than 250 × 106 cells/l (N=22; see section 4.5).
SIRTURO 100 mg tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take SIRTURO 100 mg tablet.
The elimination of bedaquiline has not been fully characterised in vivo. CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2). Urinary excretion of bedaquiline is negligible. Bedaquiline and M2 are not substrates or inhibitors of P-glycoprotein.
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 adult 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.
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 adult 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.
There are no safety data from bedaquiline multiple dose trials which utilised a dose higher than the indicated dose. Due to the potential risk of adverse reactions due to an increase in systemic exposure, prolonged co-administration of bedaquiline and moderate or strong CYP3A4 inhibitors (e.g. ciprofloxacin, erythromycin, fluconazole, clarithromycin, ketoconazole, ritonavir) 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 (see section 4.4).
The short-term co-administration of bedaquiline with isoniazid/pyrazinamide in healthy adult subjects 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 with bedaquiline.
In a placebo-controlled clinical study in patients with multi-drug resistant Mycobacterium tuberculosis, no major impact of co-administration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.
In an interaction study of single-dose bedaquiline and multiple-dose lopinavir/ritonavir in adults, exposure (AUC) to bedaquiline was increased by 22% [90% CI (11; 34)]. A more pronounced effect on bedaquiline plasma exposures may be observed during prolonged co-administration with lopinavir/ritonavir. Published data on adult patients treated with bedaquiline as part of therapy for drug-resistant TB and lopinavir/ritonavir-based ART have shown that bedaquiline exposure (AUC) over 48 hours was increased approximately 2 fold. This increase is likely due to ritonavir. If the benefit outweighs the risk, SIRTURO may be used with caution when co-administered with lopinavir/ritonavir. Increases in plasma exposure to bedaquiline would be expected when it is coadministered 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 in adults did not result in clinically relevant changes in the exposure to bedaquiline. Clinical data on co-administration of bedaquiline and antiretroviral agents in adult patients co-infected with human immunodeficiency virus and multi-drug resistant Mycobacterium tuberculosis are not available (see section 4.4). 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.
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 in adults, 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 section 4.4).
In an open label Phase IIb trial, mean increases in QTcF were larger in the 17 adult subjects who were using concomitant clofazimine at week 24 (mean change from reference of 31.9 ms) than in subjects who were not using concomitant clofazimine at week 24 (mean change from reference of 12.3 ms) (see section 4.4).
Interaction studies have only been performed in adults.
There are limited data on the use of SIRTURO in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, avoid the use of SIRTURO during pregnancy unless the benefit of therapy is considered to outweigh the risks.
It is not known whether bedaquiline or its metabolites are excreted in human milk.
In rats, concentrations of bedaquiline in milk were 6- to 12-fold higher than the maximum concentration observed in maternal plasma. Body weight decreases in pups were noted in high dose groups during the lactation period (see section 5.3).
Because of the potential for adverse reactions in breastfed infants, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from SIRTURO therapy taking into account the benefit of breast-feeding for the infant and the benefit of therapy for the mother.
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 (see section 5.3).
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).
Adverse drug reactions for SIRTURO were identified from pooled Phase IIb clinical trial data (both controlled and uncontrolled, C208 and C209) containing 335 adult patients who received SIRTURO in combination with a background regimen of tuberculosis medicinal products. The basis of assessment of causality between the adverse drug reactions and SIRTURO was not restricted to these trials, but also on review of the pooled Phase I and Phase IIa safety data in adults. The most frequent adverse drug reactions (>10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea (35.3% in the SIRTURO group vs 25.7% in the placebo group), arthralgia (29.4% vs 20.0%), headache (23.5% vs 11.4%), vomiting (20.6% vs 22.9%) and dizziness (12.7% vs 11.4%). Refer to the Summary of Product Characteristics of the medicinal products used in combination with SIRTURO for their respective adverse reactions.
Adverse drug reactions to SIRTURO reported from controlled trials in 102 adult patients treated with SIRTURO are presented in the table below.
Adverse drug reactions are listed by system organ class (SOC) and frequency. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100).
| System Organ Class (SOC) | Frequency Category | ADRs |
|---|---|---|
| Nervous system disorders | Very Common | Headache, dizziness |
| Cardiac disorders | Common | Electrocardiogram QT prolonged |
| Gastrointestinal disorders | Very Common | Nausea, vomiting |
| Common | Diarrhoea | |
| Hepatobiliary disorders | Common | Transaminases increased* |
| Musculoskeletal and connective tissue disorders | Very Common | Arthralgia |
| Common | Myalgia |
* Terms represented by ‘transaminases increased’ included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, and transaminases increased (see section below).
In the controlled Phase IIb study (C208), mean increases from baseline values in QTcF were observed from the first on-treatment assessment onwards (9.9 ms at week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase from baseline values in QTcF during the 24 weeks of SIRTURO treatment was 15.7 ms (at week 18). After the end of SIRTURO treatment (i.e. after week 24), QTcF increases in the SIRTURO group gradually became less pronounced. The largest mean increase from baseline values in QTcF in the placebo group during the first 24 weeks was 6.2 ms (also at week 18) (see section 4.4).
In the Phase IIb, open label study (C209), where patients with no treatment options received other QT-prolonging medicinal products used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging medicinal products in the treatment regimen.
Patients receiving SIRTURO alone with no other QT prolonging medicinal product developed a maximal mean QTcF increase over baseline of 23.7 ms with no QT duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging medicinal products developed a maximal mean QTcF prolongation of 30.7 ms over baseline, resulting in a QTcF duration in excess of 500 ms in one patient.
There were no documented cases of Torsade de Pointes in the safety database (see section 4.4). See section 4.5, QT interval and concomitant clofazimine use, for further information regarding patients using clofazimine concomitantly.
In study C208 (stage 1 and 2), aminotransferase elevations of at least 3 x ULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] versus 6/105 [5.7%]) in the placebo treatment group. In the SIRTURO treatment group, the majority of these increases occurred throughout the 24 weeks of treatment and were reversible. During the investigational phase in Stage 2 of study C208, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) in the placebo treatment group.
The safety assessment of bedaquiline is based on data from 30 paediatric patients greater than or equal to 5 years of age with confirmed or probable MDR-TB infection (see section 5.1).
Overall, there was no indication of any differences in the safety profile in adolescents aged 14 years to less than 18 years (N=15) compared to that observed in the adult population.
In paediatric patients aged 5 years to less than 11 years (N=15), the most common adverse drug reactions were related to elevations in liver enzymes (5/15, 33%), reported as ALT/AST increased and hepatotoxicity; hepatotoxicity led to discontinuation of SIRTURO in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO and background regimen. Among these 15 paediatric patients, no deaths occurred during treatment with SIRTURO.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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