The Expert Committee recommended the addition of bedaquiline to the
complementary list of the EMLc for the treatment of MDR-TB in children
aged 6 years and older, in line with updated WHO treatment guidelines. The
Committee noted that the extrapolation of evidence from adult data to children
suggested therapeutic bedaquiline exposure in children and no increased
The application requested the addition of bedaquiline to the complementary list of the EMLc as a reserve second-line medicine for the treatment of multidrug resistant tuberculosis (MDR-TB) in children aged 6 years and older.
In 2015, bedaquiline was included on the complementary list of the EML as a
reserve second-line medicine for treatment of MDR-TB in adults (1).
Public health relevance
It is estimated that of the 10 million people who developed TB in 2017, 1 million
of them were children. Children aged <15 years accounted for 7.1% of the
6.4 million new or relapsed cases of TB notified to national TB programmes
and reported to WHO. Children aged <15 years accounted for 15% and 10%
of total TB deaths among HIV-negative and HIV-positive people, respectively –
higher than their share of estimated cases, suggesting poorer access to diagnosis
and treatment. In 2017, it was estimated that about 558,000 new MDR-TB/
RR‑TB cases emerged and about 230,000 MDR-TB/RR‐TB patients died (2).
The contribution of bedaquiline to MDR‐TB regimens is crucial to
compose regimens, particularly in frequent situations in which other effective
and safe medicines are not available. In a substantial proportion of MDR-TB/RRTB
patients the susceptibility to fluoroquinolones is lost and other TB medicines
cannot be given because of safety concerns. Reports of sporadic cases and
outbreaks of MDR-TB and XDR-TB among patients not previously treated for
TB attests to the transmissibility of such strains, an additional public health
concern, making the provision of effective treatment for all M/XDR‐TB patients
very important. The likelihood of treatment success in MDR‐TB patients
diminishes with the acquisition of additional drug resistance. Bedaquiline can
increase the prospects of lasting cure in these patients.
The WHO Global TB Programme considers that bedaquiline should also
be viewed as an essential medicine in children aged 6 years and older following
the update by WHO of its treatment recommendations for adults and children
with MDR-TB/RR‐TB in December 2018 (3).
As part of the WHO guideline development process, a meta-analysis of individual
patient data with 13 104 records from 53 studies in 40 countries was used to
evaluate treatment success of bedaquiline. This dataset was largely composed of
adult patients, with only 181 of the 13 104 (1.4%) cases being under 15 years
Paediatric data for bedaquiline were reviewed to explore the extent to
which adult data could be extrapolated to children. The focus of this review
was on safety and pharmacologic exposure data available from two ongoing
paediatric studies of bedaquiline: TMC207‐C211 and IMPAACT P1108 (4).
Assuming that bedaquiline exposure-response (efficacy) profiles could be
extrapolated from adults to children, the WHO Guideline Development Group
concluded that the bedaquiline doses evaluated in the trials did not appear to
produce bedaquiline exposures that would put children aged 6 to 17 years at
greater risk of therapeutic failure.
With regard to harms, the Guideline Development Group concluded that the
safety risk of bedaquiline in children aged 6 years and older did not appear to
exceed that observed in adults. However, it was noted that children included in
the trials were all HIV negative and had limited exposure to other QT-interval
prolonging medicines (4).
Cost / cost effectiveness
Bedaquiline is available via the Global Drug Facility (GDF), at a price of US$ 400
for a 6-month course of adult treatment (5). There is a marked differential in
the price of bedaquiline between HICs and countries eligible for concessional
pricing through the GDF. Prices for a 6-month course of adult treatment have
been reported as EUR 26 481 in Italy (6), £ 18 880 in the United Kingdom (7) and
US$ 26 500 in the Republic of Korea (8).
The 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment
(3) make the following recommendation with regard to bedaquiline:
“Bedaquiline should be included in longer MDR-TB regimens for
patients aged 18 years or more (strong recommendation, moderate certainty in
the estimates of effect). Bedaquiline may also be included in longer MDR-TB
regimens for patients aged 6–17 years (conditional recommendation, very low
certainty in the estimates of effect).”
The updated guidelines include a weight-based dosage regimen for
children 6–17 years:
15–29 kg: 2 x 100 mg tablets once daily for two weeks, then 1 x 100 mg tablet once
daily on Monday, Wednesday and Friday for 22 weeks;
>29 kg: 4 x 100 mg tablets once daily for 2 weeks then 1 x 100 mg tablets once
daily on Monday, Wednesday and Friday for 22 weeks (equivalent to the adult
Bedaquiline is manufactured by Janssen Pharmaceuticals. It is available to eligible
countries through the GDF.
The Committee recalled that bedaquiline is associated with an increased risk of
QT interval prolongation, which may be further increased when bedaquiline is
administered with other medicines that prolong the QT interval. The Committee
also noted the potential for drug–drug interactions between bedaquiline and
other commonly co-prescribed medicines. These factors should be taken into
consideration when bedaquiline is prescribed.
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015
(including the 19th WHO Model List of Essential Medicines and the 5rd WHO Model List of
Essential Medicines for Children) (WHO Technical Report Series, No. 994). Geneva: World Health
Organization; 2015. Available from https://apps.who.int/iris/bitstream/handle/10665/189763/
9789241209946_eng.pdf, accessed 30 October 2019.
2. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Available from
30 October 2019.
3. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health
Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/10665/311389/
9789241550529-eng.pdf, accessed 30 October 2019.
4. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Annexes 3–9. Geneva:
World Health Organization; 2019. Available from https://apps.who.int/iris/bitstream/handle/
10665/311389/9789241550529-eng.pdf, accessed 30 October 2019.
5. Stop TB Partnership - Global Drug Facility (GDF) - GDF Products List [website]. (http://www.
stoptb.org/gdf/drugsupply/bedaquiline.asp, accessed 22 February 2019).
6. Codecasa LR, Toumi M, D’Ausilio A, Aiello A, Damele F, Termini R, et al. Cost-effectiveness of
bedaquiline in MDR and XDR tuberculosis in Italy. J Mark Access Health Policy. 2017;5(1):1283105.
7. Wolfson LJ, Walker A, Hettle R, Lu X, Kambili C, Murungi A, et al. Cost-effectiveness of adding
bedaquiline to drug regimens for the treatment of multidrug-resistant tuberculosis in the UK.
PLoS One. 2015;10(3):e0120763.
8. Park HY, Ku HM, Sohn HS, Seo HS, Yung Lee H, Hwa Lim K, et al. Cost-effectiveness of Bedaquiline
for the Treatment of Multidrug-resistant Tuberculosis in the Republic of Korea. Clin Ther.