ATC codes: J04AK06
Multi-drug resistant Mycobacterium tuberculosis ICD11 code: ML32.00
Medicines for the treatment of multidrug-resistant tuberculosis (MDR-TB) should be used in specialized centres adhering to WHO standards for TB contol.
Oral > Solid: 50 mg tablet ; 25 mg tablet (dispersible) (EMLc)
EML status history
Also recommended for children
50 mg tablet: ≥6 years / 25 mg dispersible tablet: ≥3 years
The recommendation is for this specific medicine
Expert Committee recommendation
The Expert Committee recognized the importance of the availability of age-appropriate, child-friendly formulations of medicines for the treatment of multidrug-resistant tuberculosis to meet the dosing and administration needs of children. The Expert Committee noted delamanid, as an oral 50 mg tablet formulation, has been included in the complementary list of the EML since 2015 and EMLc since 2017 for children aged 6 years and older. The Committee noted the acceptable pharmacokinetic data indicating therapeutic delamanid exposure at the recommended dose in children using the proposed 25 mg dispersible tablet formulation, and that there were no additional safety signals beyond those already known in adults. The Expert Committee therefore recommended the addition of the new formulation of delamanid (delamanid 25 mg dispersible tablets) to the complementary list of the EMLc for the treatment of multidrug-resistant tuberculosis in children aged 3 years and older, in line with the updated WHO treatment guidelines. The Committee noted that the availability of the proposed formulation was currently limited, but welcomed the intention of the manufacturer to make this formulation available through the Global Drug Facility.
Delamanid 50 mg tablets were added to the EMLc in 2017 for the treatment of multidrug-resistant tuberculosis in children aged 6–17 years (1). In 2019, a request to change the age restriction to ≥ 3 years was not recommended because it was noted that: the pharmacokinetic data used to inform WHO guideline recommendations used a 25 mg tablet formulation that differed from the formulation included in the Model Lists; the 25 mg formulation was not commercially available and had not been shown to be bioequivalent to the listed 50 mg formulation (2).
Public health relevance
It is estimated that 7.5 million children and young adolescents (0–14 years) are infected with Mycobacterium tuberculosis each year across the world (3). The estimated incidence of tuberculosis disease in children younger than 15 years was 1.2 million in 2019. Globally, the number of tuberculosis notifications among children and young adolescents aged 0–14 years increased from fewer than 400 000 in 2015 to 523 000 in 2019. It is estimated that 230 000 children 0–14 years died from tuberculosis in 2019, with 80% of these deaths happening in children under 5 years. Children treated for tuberculosis have excellent outcomes (84% treatment success rate in the 2018 patient cohort) but, without treatment, mortality from tuberculosis is as high as 43% among children under 5 years of age (4). More than 30 000 incident cases of multidrug-resistant tuberculosis in children are estimated globally each year. In 2020, for the first time, countries reported the number of children and young adolescents aged 0–14 years started on second-line treatment for multidrug-resistant tuberculosis and rifampicin-resistant tuberculosis: the numbers were 3398 in 2018 and 5586 in 2019 (4). These figures correspond to 2.2% and 3.2% of all people started on treatment for multidrug-resistant and rifampicin-resistant tuberculosis (4). In September 2018, heads of state agreed on the following main global targets: 40 million people with tuberculosis to be reached with care during 2018 to 2023 (including 3.5 million children), and 1.5 million people with drug-resistant tuberculosis (including 115 000 children) (5). However, data in the latest global tuberculosis report in 2020 show that we are far from reaching these targets, especially for children with tuberculosis The total number of children treated for multidrug-resistant and rifampicin-resistant tuberculosis in 2018–2019 was 8986, which corresponds to only 7.8% of the 5-year target of 115 000 (4). The roadmap towards ending tuberculosis in children and adolescents, launched just before the United Nations General Assembly High-Level Meeting on the Fight Against Tuberculosis, includes milestones to reaching these targets, including access to shorter and safer child-friendly regimens for prevention and treatment of drug-susceptible and drug-resistant tuberculosis. Child-friendly formulations of tuberculosis medicines are essential to facilitate correct implementation of WHO recommendations for the prevention and treatment of tuberculosis in younger children (6). Delamanid is an essential medicine for young children with multidrug-resistant and rifampicin-resistant tuberculosis and extensively-drug-resistant tuberculosis, a more severe form of drug-resistant-tuberculosis. In many low-resource settings, delamanid is often used to replace painful injectable agents, which have several side-effects, when designing all-oral regimens for young children (7). As shown by the results of a recent survey of policies and practice on tuberculosis prevention, testing and treatment in 37 countries with high tuberculosis burden, countries are transitioning to injectable-free, all-oral regimens for children with uncomplicated drug-resistant tuberculosis. Among the countries surveyed, 72% had policies indicating the use of oral regimens for children (7), with most of the regimens reported including delamanid (8).
The potential benefits of delamanid were extensively reviewed and summarized at the time of the original applications and the associated evidence is available in the technical reports of the meetings (1,9). Since the time of the original application in 2015, WHO assessed the relative effectiveness of second-line medicines for multidrug-resistant tuberculosis during a meeting of a guideline development group. As reported in the 2020 WHO consolidated guidelines on tuberculosis, the adjusted odds ratio (aOR) for delamanid was 1.1 (95% confidence interval (CI) 0.4–2.8) for treatment failure and relapse versus treatment success and aOR 1.2 (95% CI 0.5–3.0) for death versus treatment success (10). Based on the pharmacological and safety data reviewed by the WHO guideline development group in 2018, including cohorts of patients 3–5 years treated with delamanid 25 mg dispersible tablet (11), it was concluded that exposure profiles in children given this formulation were comparable to adults and no safety signs distinct from those reported in adults were observed (12).
The harms associated with delamanid were reviewed and summarized at the time of the original applications and the associated evidence is available in the technical reports of the meetings (1,9).
Cost / cost effectiveness
Since April 2019, delamanid 25 mg dispersible tablets have been made available for compassionate use and can be obtained from the manufacturer (Otsuka Pharmaceuticals) at no charge on a patient-by-patient basis (16). Delamanid 50 mg tablets are available via the Global Drug Facility at a price of US$ 1700 for 672 tablets (24 weeks treatment).
The 2020 WHO guidelines on tuberculosis recommend that delamanid may be included in the treatment of multidrug-resistant and rifampicin-resistant tuberculosis in children aged 3 years or older on longer regimens (conditional recommendation, moderate certainty in the estimates of effect) (10). Delamanid is currently classified by WHO as a Group C drug for the treatment of multidrug-resistant and rifampicin-resistant tuberculosis as part of longer regimens. Group C drugs are to be used in a treatment regimen when medicines from Groups A and B cannot be used (10). Delamanid is one of only a few new tuberculosis medicines that have been approved by stringent regulatory authorities in the past few years and was first recommended for use by WHO in 2014, when the Organization issued interim policy guidance on its use. The interim policy guidance stated that “delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB” (13). In 2016, the delamanid interim policy was extended to children aged 6–17 years, following a review of data from a 6-month safety, efficacy and pharmacokinetic trial of paediatric patients (14). In January 2018, WHO issued a position statement on the use of delamanid in the treatment of multidrug-resistant tuberculosis (15). Based on a review of data, an expert review panel concluded that the interim and conditional guidance on delamanid should remain in place. In 2018, additional paediatric data on the use of delamanid were reviewed to examine whether the recommendations for the use of delamanid in children could be further lowered to children younger than 6 years. The focus of this review was on safety and pharmacological exposure data available from ongoing paediatric studies. At this time, WHO convened a guideline development group which reviewed the data and recommended that delamanid could be safely used in children aged 3 years and older (11). However, at the time, the guideline development group also noted their concerns about the feasibility of administering the correct dose to children aged 3–5 years, given that the special formulation used in the trial (i.e. a 25 mg dispersible tablet formulation) would not be available in the foreseeable future. At that time, only the adult tablet was available (i.e. 50 mg tablet), and based on the data assessed, there were concerns that bioavailability may be altered if the 50 mg tablet was halved, crushed or dissolved. The delamanid 50 mg tablet and 25 mg dispersible tablet formulations are not bioequivalent. In a crossover bioequivalence study, neither Cmax (90% CI of the geometric mean ratio (GMR) 0.701 to 0.809) nor AUC (90% CI GMR 0.775 to 0.909) satisfied the criteria for bioequivalence as specified by regulatory agencies. As such, the formulations are not interchangeable (12). Substituting the adult formulation for the paediatric formulation will result in higher delamanid exposures than would be expected from the paediatric formulation. Delamanid 50 mg tablet is also susceptible to oxidation and heat. Therefore, retaining pill fragments for use at any time other than at the time of administration will likely result in the delivery of lower-than-expected active compound and unspecified oxidation by-products. Broken 50 mg tablets were also noted to be bitter and unpalatable (12). Despite these problems, clinicians and paediatric experts in the field have been manipulating the 50 mg delamanid formulation (either by splitting the tablet and then discarding the remaining part, or by giving the 50 mg tablet once a day so no manipulation of the tablet is required), as this is the only option currently available when delamanid is used in young children (Furin J, Garcia-Pratts AJ, Schaff S. Personal communication with Tiziana Masini, WHO, December 2020). Many countries are already using delamanid as part of short, all-oral regimens under operational research conditions (8).
In September 2020, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion on the use of delamanid to treat pulmonary multidrug-resistant tuberculosis in adolescents and children weighing at least 30 kg (17). Otsuka is expecting an opinion from the Committee for Medicinal Products for Human Use for children weighing less than 30 kg in the coming months and approval of the delamanid 25 mg dispersible tablet formulation in late 2021 (Destito M, Otsuka. Personal communication with Tiziana Masini, WHO, December 2020). Delamanid 25 mg dispersible tablets are included in the 23rd Invitation to Manufacturers of the Global Fund’s Expert Review Panel to submit an expression of interest for product evaluation (18). Otsuka is exploring potential submission to the Global Fund ERP in 2021 (Destito M, Otsuka. Personal communication with Tiziana Masini, WHO, December 2020).
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2017 (WHO Technical Report Series, No. 1006; https://apps.who.int/iris/handle/10665/259481, accessed 19 August 2021). 2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2019 (WHO Technical Report Series, No. 1021; https://apps.who.int/iris/handle/10665/330668, accessed 19 August 2021). 3. Dodd PJ, Gardiner E, Coghlan R, Seddon JA. Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study. The Lancet Global health. 2014;2(8):e453–9. 4. Global tuberculosis report 2020. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/336069, accessed 19 August 2021). 5. A/RES/73/3. Political declaration of the high-level meeting of the General Assembly on the fight against tuberculosis. New York: United Nations General Assembly; 2018 (https://undocs.org/en/A/RES/73/3, accessed 19 August 2021). 6. Roadmap towards ending TB in children and adolescents. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/274374, accessed 19 August 2021). 7. Step up for TB: TB policies in 37 countries. A survey of prevention, testing and treatment policies and practices. Geneva: Médecins Sans Frontières, Stop TB Partnership; 2020 (https://msfaccess.org/step-tb-tb-policies-37-countries-4th-ed, accessed 19 August 2021). 8. Step Up for TB: TB policies in 37 countries. Full dataset. Geneva: Médecins Sans Frontières, Stop TB Partnership; 2020 (https://msfaccess.org/sites/default/files/2020-12/StepUpForTB_OnlineDatabase.xls, accessed 19 August 2021). 9. 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 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2015 (WHO Technical Report Series, No. 994; https://apps.who.int/iris/handle/10665/189763, accessed 19 August 2021). 10. WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/332397, accessed 19 August 2021). 11. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/311389, accessed 19 August 2021). 12. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Annexes 8–10. Geneva, World Health Organization. 2019:181–4 (https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf, accessed 19 August 2021). 13. The use of delamanid in the treatment of multidrug-resistant tuberculosis: interim policy guidance. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/137334, accessed 20 August 2021). 14. The use of delamanid in the treatment of multidrug-resistant tuberculosis in children and adolescents: interim policy guidance. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/250614, accessed 20 August 2021). 15. WHO position statement on the use of delamanid for multidrug-resistant tuberculosis. Geneva: World Health Organization; 2018 (https://www.who.int/publications/m/item/WHO-CDS-TB-2018.1, accessed 20 August 2021). 16. Delamanid compassionate use patient access form [internet]. Boston, MA: Sentinel Project on Pediatric Drug-Resistant Tuberculosis; 2019 (https://sentinel-project.org/2019/04/10/delamanid-compassionate-use-patient-access-form/, accessed 20 August 2021). 17. Deltyba. Summary of opinion (post authorisation) [internet]. Amsterdam: European Medicines Agency; 2020 (https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-deltyba-ii-40_en.pdf, accessed 20 August 2021). 18. Invitation to manufacturer. Geneva: Global Fund to Fight AIDS, Tuberculosis and Malaria; 2020 (https://www.theglobalfund.org/media/10377/psm_2020-11-20_invitation-to-manufacturers_en.pdf, accessed 20 August 2021).