Bedaquiline

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. 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.

Bedaquiline 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

Bedaquiline 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.

Hepatotoxic medicinal products and alcohol should be avoided while on bedaquiline, especially in patients with diminished hepatic reserve.

The short-term co-administration of bedaquiline and ketoconazole (strong CYP3A4 inhibitor) in healthy adults increased the mean bedaquiline exposure (AUC) by 22% [90% CI (12; 32)]. In healthy adults, 10 days of co-administration of another strong CYP3A4 inhibitor, clarithromycin, with single-dose bedaquiline increased the mean bedaquiline exposure (AUC) by 14% [90% CI (9; 19)]. A more pronounced effect on bedaquiline may be observed during prolonged co-administration of CYP3A4 inhibitors.

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.

In an interaction study of single-dose bedaquiline and once daily rifampicin (strong inducer) in healthy adults, the bedaquiline exposure (AUC) 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.

In patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis, bedaquiline should be used with caution.

Bedaquiline should be used with caution in patients with moderate hepatic impairment.

In the Phase III trial, long-term co-administration of bedaquiline as part of a combination therapy and lopinavir/ritonavir in patients co-infected with HIV resulted in a mild increase in mean bedaquiline exposure at Week 24 compared to a subgroup without HIV co-infection. No dose adjustment is required.

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.

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.

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.

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.

Summary of the safety profile

Adverse reactions for bedaquiline were identified from Phase IIb clinical trial data (both controlled and uncontrolled, C208 and C209) in 335 adult patients who received bedaquiline for 8 weeks or 24 weeks. No new adverse reactions were identified in the Phase III active-controlled trial including 354 patients who received bedaquiline for 40 weeks or 28 weeks. In these studies, patients received bedaquiline in combination with other antimycobacterial drugs.

The most frequent adverse reactions (>10.0% of patients) reported during treatment with bedaquiline in the open-label Phase III trial were QT prolongation (61% in the bedaquiline group vs 56% in the control group), nausea (54% vs 63%), vomiting (54% vs 62%), arthralgia (45% vs 33%), transaminases increased (30% vs 29%), dizziness (18% vs 21%) and headache (17% vs 18%). Refer to the Summary of Product Characteristics of the medicinal products used in combination with bedaquiline for their respective adverse reactions.

Tabulated list of adverse reactions

Adverse reactions to bedaquiline based on reported safety data from Phase II and Phase III trials in adult patients treated with bedaquiline are presented in the Table below.

Adverse 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).

^a Frequencies derived from Phase III trial STREAM Stage 2 40-week, all-oral treatment of bedaquiline, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase).
^b Terms represented by 'transaminases increased' included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, hypertransaminasaemia, and transaminases increased (see section below).
^c Incidence of transaminases increased in the controlled Phase IIb study was Common (6.9% in the bedaquiline group and 1% in placebo control).
^d Incidence of QT prolonged in Phase IIb study was Common (2.9% in the bedaquiline group and 3.8% in placebo control).

Description of selected adverse reactions

QT prolongation

Clinical trials of bedaquiline in adult TB patients collectively show a mild (<10 ms) QTcF increase throughout treatment attributable to M2, the major bedaquiline metabolite. In combination with other QT-prolonging drugs (e.g., clofazimine, delamanid, or fluoroquinolones), a prolongation of the QTc interval not more than additive was observed.

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 bedaquiline and 3.5 ms for placebo). The largest mean increase (at Week 18) in QTcF during the 24 weeks of treatment with bedaquiline was 15.7 ms, compared to 6.2 ms in the placebo group. After treatment with bedaquiline ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study Week 60.

In the Phase IIb, open-label study (C209), where patients with no treatment options received other QT-prolonging medicinal products used to treat pulmonary TB including clofazimine, concurrent use with bedaquiline resulted in additive QT prolongation. In patients taking bedaquiline with no other QT-prolonging drugs, there were no patients with QTcF interval durations above 480 ms, and in patients who were taking at least two other QT-prolonging drugs, there was one patient with a QTcF interval duration above 500 ms.

In the controlled Phase III study, in which the 40-week bedaquiline and active control treatment groups included both clofazimine and a fluoroquinolone, the mean QTcF gradually increased from baseline over the first 10 to 14 weeks, when a plateau was reached and additive QT prolongation was observed. The highest mean QTcF increase from baseline was 34.5 ms for the bedaquiline-containing group and 29.9 ms for the non-bedaquiline-containing control. Throughout treatment, mean QTcF increase was less than 10 ms higher in the bedaquiline-containing group compared to the control. Upon treatment completion mean QTcF decreased steadily. QTcF values ≥500 ms were observed in 5.2% of patients in the bedaquiline-containing group compared to 7.4% in the non-bedaquiline-containing control group.

Increased transaminases

In Study C208 (Stage 1 and 2), transaminase elevations of at least 3 x ULN developed more frequently in the bedaquiline treatment group (11/101 [10.9%] versus 6/104 [5.8%]) in the placebo treatment group. In the bedaquiline treatment group, the majority of these increases occurred throughout the 24 weeks of treatment and were reversible. During the investigational treatment phase in Stage 2 of Study C208, increased transaminases were reported in 7/78 (9.0%) patients in the bedaquiline treatment group compared to 1/80 (1.3%) in the placebo treatment group.

In the STREAM Stage 2 study, increased transaminases were reported in 63/211 (29.9%) patients in the 40-week bedaquiline treatment group versus 59/202 (29.2%) patients in the 40-week active control group.

Paediatric population

The safety assessment of bedaquiline is based on the Week 120 analyses for patients 12 years to less than 18 years of age and 5 years to less than 12 years of age, and the Week 24 analysis for patients 2 years to less than 5 years of age, from 45 paediatric patients greater than or equal to 2 years of age with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampicin in an ongoing, single-arm, open-label, multi-cohort trial.

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. No deaths were reported during the study.

In paediatric patients aged 5 years to less than 11 years (N=15), the most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), reported as ALT/AST increased and hepatotoxicity; hepatotoxicity led to discontinuation of bedaquiline in three patients. Elevations in liver enzymes were reversible upon discontinuation of bedaquiline and background regimen. No deaths were reported during the study.

In paediatric patients aged 2 years to less than 5 years (N=15), the most common adverse reaction was vomiting in 3/15 (20%) patients. QT prolongation and arthralgia were reported in one patient each. Among these 15 paediatric patients, no deaths were reported during treatment with bedaquiline (Week 24 analysis).