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.

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

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.

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 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 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, bedaquiline 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.

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).

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.

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.

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 bedaquiline therapy taking into account the benefit of breast-feeding for the infant and the benefit of therapy for the mother.

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 drug reactions for bedaquiline were identified from pooled Phase IIb clinical trial data (both controlled and uncontrolled, C208 and C209) containing 335 adult patients who received bedaquiline in combination with a background regimen of tuberculosis medicinal products. The basis of assessment of causality between the adverse drug reactions and bedaquiline 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 bedaquiline in the controlled trials were nausea (35.3% in the bedaquiline 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 bedaquiline for their respective adverse reactions.

Tabulated list of adverse reactions

Adverse drug reactions to bedaquiline reported from controlled trials in 102 adult patients treated with bedaquiline 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).

^* Terms represented by ‘transaminases increased’ included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, and transaminases increased (see section below).

Description of selected adverse reactions

Cardiovascular

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 from baseline values in QTcF during the 24 weeks of bedaquiline treatment was 15.7 ms (at week 18). After the end of bedaquiline treatment (i.e. after week 24), QTcF increases in the bedaquiline 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).

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 bedaquiline resulted in additive QT prolongation, proportional to the number of QT prolonging medicinal products in the treatment regimen.

Patients receiving bedaquiline 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.

Increased transaminases

In study C208 (stage 1 and 2), aminotransferase elevations of at least 3 x ULN developed more frequently in the bedaquiline treatment group (11/102 [10.8%] versus 6/105 [5.7%]) 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 phase in Stage 2 of study C208, increased aminotransferases were reported in 7/79 (8.9%) patients in the bedaquiline treatment group compared to 1/81 (1.2%) in the placebo treatment group.

Paediatric population

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.

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 bedaquiline in three patients. Elevations in liver enzymes were reversible upon discontinuation of bedaquiline and background regimen. Among these 15 paediatric patients, no deaths occurred during treatment with bedaquiline.