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ATC codes: J04AK02
EMLc
Indication
Tuberculosis ICD11 code: 1B4Z
INN
Ethambutol
Medicine type
Chemical agent
List type
Core WHO recommends and endorses the use of fixed-dose combinations and the development of appropriate new fixed-dose combinations, including modified dosage forms, non-refrigerated products and paediatric dosage forms of assured pharmaceutical quality.
Formulations
Oral > Liquid: 25 mg per mL (EMLc)
Oral > Solid: 100 to 400 mg tablet (hydrochloride) ; 100 mg dispersible tablet (EMLc)
EML status history
First added in 1977 (TRS 615)
Changed in 1979 (TRS 641)
Changed in 1989 (TRS 796)
Changed in 2007 (TRS 950)
Changed in 2019 (TRS 1021)
Sex
All
Age
Also recommended for children
Therapeutic equivalence
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee recommended the addition of the proposed dispersible tablet formulations of ethambutol and isoniazid to the core list of the EMLc, and of cycloserine, ethionamide, levofloxacin, linezolid and moxifloxacin to the complementary list of the EMLc for the treatment of children with drug-sensitive and drug-resistant TB. The Committee considered that the availability of quality-assured, age-appropriate formulations will help improve access to effective treatment for children with TB. The Committee also recommended the requested amendments to the dosage form terminology for clofazimine and rifabutin.
Background
The application requested: – the addition of various new formulations of currently listed medicines for tuberculosis (TB) for use in children; – amendments to the dosage form terminology used to describe clofazimine and rifabutin. All of the medicines for which additional formulations are requested for listing are currently included on the Model Lists in various formulations and strengths. In 2007, the World Health Assembly called for WHO to promote the development of child-friendly medicines with a particular focus on treatment for HIV, tuberculosis, malaria and chronic disease (1). In 2017, the Expert Committee recommended the addition to the EMLc of two fixed-dose combination, child-friendly dispersible tablet formulations of isoniazid + rifampicin +/– pyrazinamide for use in children with drug-sensitive tuberculosis infection. The Committee considered that the availability of these age-appropriate formulations would offer benefits including appropriate dosing, ease of administration and reduced pill burden (2).
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 (3).
Benefits
Evidence for the clinical effectiveness of the medicines was evaluated at the time of their individual listings. Paediatric-friendly formulations The proposed new formulations are mostly dispersible formulations, meaning they can be mixed in liquid, making it easier to get the correct doses and for children to swallow. They are flavoured to overcome the bitterness associated with breaking, crushing and otherwise manipulating adult formulations. The proposed formulations are at lower strengths, aligned with the dosing needs of children according to the 2019 update of the WHO consolidated guidelines on drug-resistant tuberculosis treatment (4). With the exception of linezolid 150 mg dispersible tablet (which is still in development), the proposed formulations are all quality-assured, either through the WHO Prequalification for Medicines Programme, or by the Global Fund Expert Review Panel.
Harms
Evidence for the safety of the medicines was evaluated at the time of their individual listings.
Cost / cost effectiveness
No information was provided in the application.
WHO guidelines
These medicines are all recommended the most recent WHO guidelines for treatment of drug-sensitive tuberculosis (2017) (5), treatment of latent TB infection (2018) (6), treatment of isoniazid mono-resistant TB (2018) (7) and treatment of drug-resistant TB (2019) (4).
Availability
The proposed new formulations are in the Stop TB Partnership’s Global Drug Facility product catalogue and are reportedly being procured by programmes.
Other considerations
Comments on the application were received from the WHO Global TB Programme. The technical unit advised that it supported the application, which was developed in consultation with the Global TB Programme, and was fully in line with the latest WHO recommendations on the management of multidrug-resistant TB (MDR-TB), rifampicin-resistant TB (RR-TB) and isoniazid-resistant TB. The technical unit stated that the addition of child-friendly formulations of second-line antituberculosis medicines will greatly benefit children with drugresistant tuberculosis.
1. Resolution WHA60.20. Better medicines for children. In: Sixtieth World Health Assembly, Geneva, 14–23 May 2007. Resolutions and decisions. Geneva: World Health Organization; 2007. Available from: http://apps.who.int/gb/ebwha/pdf_files/WHASSA_WHA60-Rec1/E/reso-60-en. pdf, accessed 30 October 2019. 2. 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) (WHO Technical Report Series, No. 1006). Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/handle/10665/ 259481/9789241210157-eng.pdf, accessed 30 October 2019. 3. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf, accessed 30 October 2019. 4. 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. 5. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. Geneva: World Health Organization; 2017. Available from: https://apps.who.int/iris/bitstream/ handle/10665/255052/9789241550000-eng.pdf, accessed 30 October 2019). 6. Latent tuberculosis infection: Updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018. Available from https://www.who.int/ tb/publications/2018/latent-tuberculosis-infection/en/, accessed 30 October 2019. 7. WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng. pdf, accessed 30 October 2019.