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Updates to the Tuberculosis (TB) Section of the Model List of Essential Medicines to align with formulation availability for TB programmes and current treatment recommendations in guidelines

Summary statement of the proposal for additions and changes to the EML, including medicines for children

There have been significant changes in the TB treatment landscape in 2017 and 2018. Specifically, the World Health Organization’s Global TB Programme has released updated clinical guidance on the treatment of drug-sensitive TB in 2017 (1), the treatment of latent TB infection in 2018 (2), the treatment of mono-resistant TB in 2018 (3) and the treatment of drug-resistant TB in 2018 (4).

In parallel to the changes in guidelines a number of new formulations, particularly for children, have become quality-assured and are now available for TB programmes. These formulations should enable programmes to more effectively prevent and treat tuberculosis. These are not new medicines, but new formulations of drugs that are already included in the WHO guidance documents and are already included in the Model List.

The proposed changes are:

Add the following six formulations to the tuberculosis section (6.4.2) of the Model List, recommending use for children.

1 125mg solid oral dosage form 2 100mg dispersible tablets 3 125mg dispersible tablets 4 Levofloxacin 100mg dispersible tablets 5 150mg dispersible tablets 6 100mg dispersible tablets

Change the following entries in the tuberculosis section (6.4.2) of the Model List.

Current Entry Proposed New Entry Clofazimine capsule 50mg, 100mg Clofazimine solid oral dosage form 50mg, 100mg capsule 150mg Rifabutin solid oral dosage form 150mg* *This product is only recommended for adults.

New, paediatric-friendly formulations of key medicines to prevent and treat tuberculosis

In 2007, the World Health Assembly (WHA) called for WHO to promote the development of child- friendly medicines with a particular focus on treatment for HIV, tuberculosis, malaria and chronic disease(5). Nearly ten years later, the first paediatric-friendly dispersible formulations for drug- sensitive TB became available(6). These formulations have now been implemented in many TB programmes throughout the world(7).

In keeping with the WHA resolution, and the WHO’s Roadmap to ending TB in children and adolescents, several new paediatric-friendly formulations of medicines used to prevent and treat tuberculosis have become available(8). These are not new medicines, but rather new formulations of medicines that are already included in the Essential Medicines Lists. These 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 also flavoured to overcome the bitterness associated with breaking, crushing and otherwise manipulating adult formulations.

These new formulations are at lower strengths, aligned with the dosing needs of children (Annex 6 of the WHO treatment guidelines for multidrug- and -resistant tuberculosis 2018 update, reported at the end of this application)(4). All of these formulations are already quality-assured, either through the World Health Organization’s Prequalification for Medicines Programme, or by the Global Fund’s Expert Review Panel Programme (except for the linezolid 150mg dispersible tablet which is still in development). The formulations are in the StopTB Partnership’s Global Drug Facility Product Catalogue and are being procured by programmes.

Table 1: Proposed additions to the Essential Medicines for Children and the corresponding WHO guidance documents for their use

Anti-TB Paediatric WHO Guideline where Product is Included Formulation Levofloxacin  WHO treatment guidelines for multidrug- and rifampicin-resistant 100mg dispersible tuberculosis, 2018 update [in press] tablet https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1  WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2018: http://apps.who.int/iris/bitstream/handle/10665/260494/9789241550 079-eng.pdf?sequence=1 Moxifloxacin  WHO treatment guidelines for multidrug- and rifampicin-resistant 100mg dispersible tuberculosis, 2018 update [in press] tablet https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1  WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2018: http://apps.who.int/iris/bitstream/handle/10665/260494/9789241550 079-eng.pdf?sequence=1 Linezolid 150mg  WHO treatment guidelines for multidrug- and rifampicin-resistant dispersible tablet tuberculosis, 2018 update [in press] https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1 Cycloserine  WHO treatment guidelines for multidrug- and rifampicin-resistant 125mg solid oral tuberculosis, 2018 update [in press] dosage form https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1 Ethambutol  WHO treatment guidelines for multidrug- and rifampicin-resistant 100mg dispersible tuberculosis, 2018 update [in press] tablet https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1  WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2018: http://apps.who.int/iris/bitstream/handle/10665/260494/9789241550 079-eng.pdf?sequence=1

Ethionamide  WHO treatment guidelines for multidrug- and rifampicin-resistant 125mg dispersible tuberculosis, 2018 update [in press] tablet https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1 Isoniazid 100mg  WHO treatment guidelines for multidrug- and rifampicin-resistant dispersible tablet tuberculosis, 2018 update https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1  Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018. http://apps.who.int/iris/bitstream/handle/10665/260233/9789241550 239-eng.pdf?sequence=1

Change the dosage form terminology

Clofazimine has been a critical drug in the treatment of drug-resistant TB for years and its importance has been growing. The WHO has recommended the use of clofazimine in the shorter regimen used to treat drug-resistant TB since 2016(9). The most recent WHO guidance on treatment of drug-resistant TB has prioritized clofazimine moving it into Group B for the longer DR-TB regimens(4).

Until recently there has been a single supplier of clofazimine in a capsule formulation. This creates a risk to the global supply security of this key TB medicine, especially as it is increasing in importance and will likely have greater use in national programmes. Many organizations have worked to improve the supply security and have new suppliers develop clofazimine; in 2018 a new tablet formulation of clofazimine was quality-assured and is now eligible for procurement by programmes.

However, the current listing on the Model List refers only to clofazimine capsules. The specificity of having the dosage form limited to only capsules could create a barrier to accessing the new tablet formulations. This situation also applies to other products, where it is possible that different manufacturing approaches could mean that products may be produced in tablet and/or capsule formulations. Having robust quality assurance approaches, such as the WHO’s Prequalification Programme, ensures that the efficacy of the medicines remains regardless of the formulation.

Product Requested Formulation Name Requested Change in WHO EMLs EML EMLc Clofazimine Solid oral dosage form 50mg, 100mg   Rifabutin Solid oral dosage form 150mg 

Annex: Dosing tables from WHO Guidance Documents

Table 1: Paediatric dosing table from WHO DR-TB Guidance 2018 (Annex 6) https://www.who.int/tb/publications/2018/WHO.2018.MDR-TB.Rx.Guidelines.prefinal.text.pdf?ua=1 page 62

Dosing of medicines used in second-line MDR-TB regimens by weight band in patients under 15 yearsa

Group Medicine Weight- Formulation Weight bands among patients not yet 15 years olda Usual Comments based daily upper doseb 5–6 kg 7–9 kg 10–15 16–23 24–30 31–34 >34 kg daily kg kg kg kg doseb Fluoroquinolones

A Levofloxacin 15–20 100 mg dt 1 1.5 2 or 3 3 or 4 (>14 y) (>14 y) (>14 y) 1.5 g mg/kg 250 mg tab 0.5 0.5 1 or 1.5 1.5 or 2 2 3 (>14 y) 1.5 g

Moxifloxacin 10–15 100 mg dt 0.8 1.5 2 3 4 (>14 y) (>14 y) 400 mg mg/kg 400 mg tabc 2 mlc 3 mlc 5 mlc 0.5 or 1 (>14 y) (>14 y) 400 mg Use 10 mg/kg in <6 0.75 months Bedaquiline - 100 mg tab - - - 2 tabs od for two 4 tabs od for 2 - Only in patients >5 weeks; then weeks; then years old (lower 1 tab od M/W/F 2 tabs od M/W/F dose from 15–29 for 22 weeks for 22 weeks kg; higher dose from >29 kg) Linezolid 15 mg/kg 20 mg /ml susp 4 ml 6 ml 8 ml 11 ml 14 ml 15 ml 20 mld 600 mg od in <16 kg c d 600 mg tab 0.25 0.25 0.25 0.5 0.5 0.5 0.75 10–12 mg/kg od in >15 kg

B Clofazimine 2–5 mg/kg 50 mg cap 1 alt days 1 alt 1 alt 1 2 2 (>14 y) 100 mg Give on alternate days days days if dose in mg/kg/day is too 100 mg cap M/W/F M/W/F 1 alt 1 alt 1 (>14 y) (>14 y) 100 mg high days days Cycloserine or 15–20 125 mg mini 1 1 2 3 4 (>14 y) (>14 y) 1 g mg/kg capsule (cycloserine) 250 mg capc 4–5 mlc 5–6 mlc 7–10 2 2 2 (>14 y) 1 g mlc

C Ethambutol 15–25 100 mg dt 1 2 3 4 - - (>14 y) - mg/kg 400 mg tabc 3 mlc 4 mlc 6 mlc 1 1 or 1.5 2 (>14 y)

Delamanid - 50 mg tab - -e -e -e 1 bd 1 bd 2 bd 200 mg Only in patients >2 years old (25 mg bd in 3–5 years; 50 mg bd in 6–11 years; 100 mg bd in 12–17 years) 30–40 150 mg dt 1 2 3 4 or 5 - - (>14 y) - mg/kg 400 mg tab 0.5 0.75 1 1.5 or 2 2.5 3 (>14 y)

500 mg tab 0.5 0.5 0.75 or 1.5 2 2.5 (>14 y) 1 Imipenem- - 0.5 g + 0.5 g vial ------Not used in patients cilastatin <15 years (use meropenem) Meropenem 20–40 1 g vial (20 ml) 2 ml 4 ml 6 ml 8-9 ml 11 ml (>14 y) (>14 y) - To be used with mg/kg iv clavulanic acid every 8 hours

Amikacin 15–20 500 mg/2 ml 0.4 ml 0.6 ml 0.8 - 1.0 1.2 - 1.5 2.0 ml (>14 y) (>14 y) 1 g mg/kg vialf ml ml 20–40 1 g vialf Calculate according to the dilution used (>14 y) (>14 y) 1 g mg/kg Ethionamide or 15–20 125 mg dt 1 1 2 3 4 4 (>14 y) 1 g mg/kg (ethionamide) 250 mg tab 0.5 0.5 1 2 2 2 (>14 y) 1 g

p-aminosalicylic 200–300 PAS acid (4 g) 0.5– 0.75–1 g 1–2 g 2–3 g 3–3.5 g (>14 y) (>14 y) - Full dose can be acid mg/kg in 2 sachet 0.75 g bd bd bd bd given once daily if divided bd tolerated doses PAS sodium salt 0.5– 0.75–1 g 1–2 g 2–3 g 3–3.5 g (>14 y) (>14 y) (4 g) sachet 0.75 g bd bd bd bd bd PAS sodium salt 1.5 g 2–3 g bd 3–4 g 4 or 6 g 6 or 8 g 8–12 g 8–12 g - 60% (9.2 g) bd bd bd bd bd bd sachet Isoniazid 15–20 50 mg/5 ml soln 8–10 15 ml 20 ml - - - - - 300 mg isoniazid mg/kg ml tablet can be used (high dose) in patients >20 kg 100 mg tab 1 1.5 2 3 4 4 (>14 y) Pyridoxine is always given with high- dose isoniazid in children (12.5 mg

od in <5 y olds and g 25 mg od in >4 y olds) Clavulanic acidh - 250 mg 2 ml 3 ml bdh 5 ml 8 ml 10 ml (>14 y) (>14 y) - Only to be used amoxicillin/62.5 bdh bdh bdh bdh with carbapenems mg clavulanic

acid/5 ml susph Othermedicines

Kanamycin 15–20 500 mg/2 ml 0.4 ml 0.6 ml 0.8–1.0 1.2–1.5 2.0 ml (>14 y) (>14 y) 1 g 1 g vials (3 ml) also mg/kg vialf ml ml available 15–20 500 mg/2 ml 0.4 ml 0.6 ml 0.8–1.0 1.2–1.5 2.0 ml (>14 y) (>14 y) 1 g 1 g vials (2 ml) also mg/kg vialf ml ml available - 400 mg tab ------Not used in <18 y olds (no quality assured product currently available) ------Not used in <18 y olds (no quality assured product currently available) (>14 y) = follow the separate dose schedule for patients older than 14 years of age; alt = alternate; bd = two times a day; cap = capsule; dt = dispersible tablet; g = gram; im = intramuscular; iv = intravenous; kg = kilogram; ml = millilitre; mg = milligram; M/W/F = Monday, Wednesday, Friday; soln = solution; susp = suspension; tab = tablet Footnotes a Dosages were established by the Guideline Development Group for the WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update and the WHO Global task force on the and pharmacodynamics (PK/PD) of TB medicines and other experts. They are based on the most recent reviews and best practices in the treatment of MDR/RR-TB. For certain agents the dosages were informed by pharmacokinetic modelling results based on the principle of allometric scaling (Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008;48:303–32). Due to the pharmacokinetic properties of certain medicines the doses proposed may exceed the mg/kg/day ranges shown here in order to achieve blood concentrations similar to target levels in an average adult patient. In patients >30 kg follow the schedule for >14 year olds unless otherwise indicated. If multiple dose options are given for one weight band select the lower or higher option depending on whether the patient is at the lower or higher limit of the body weight range. Dosing more closely to the target mg/kg/day should be aimed for, and is more feasible with oral or parenteral fluids and when solid forms of different dosage are available. Fractioning of tablets into halves or less should be avoided if possible. Therapeutic drug monitoring is advised when the dose is at the upper and lower ends of the range to minimize the adverse therapeutic consequences of over- and under-exposure respectively (especially for injectable agents, linezolid and fluoroquinolones). b Clinicians may decide to exceed these values in particular cases to improve therapeutic effect. c Dissolving in 10 ml of water may facilitate administration in patients in lower weight-bands and avoids fractioning solid formulations, although bioavailability is uncertain (use of dispersible tablets is preferred if available). d In individuals >44 kg a dose of 600 mg od is proposed. e May be used in children 3–5 years of age. Giving half a 50 mg adult tablet in these children does not result in the same blood levels observed in trials using the special 25 mg paediatric tablet. Bioavailability may further be altered when the 50 mg tablet is split, crushed or dissolved. f Weight-based daily dose is for 6 or 7 days/week administration (M/W/F scheduling may permit higher dosing). Volumes shown may differ by preparation. Streptomycin may be diluted in three different ways. Dosing closer to the upper limit of the mg/kg/day is more desirable. For iv use, the volume may be increased. g In the 2018 WHO treatment guidelines, these agents are either no longer recommended (kanamycin, capreomycin), only recommended as a companion agent (amoxicillin/clavulanic acid) or not included because of lack of data from the latest analysis on longer MDR-TB regimens in adults (gatifloxacin, isoniazid and thioacetazone). h Only available in combination with amoxicillin as co-amoxyclav. Only to be used with carbapenems, in which case they are given together, e.g. 125 mg bd or 125 mg 3 times daily in the 24– 30 kg weight band.

Table 2: Dosing table from WHO LTBI Guidance 2018

Table 3: Paediatric dosing table WHO isoniazid mono-resistant Guidance 2018

References

1. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update [Internet]. Geneva: World Health Organization; 2017 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000- eng.pdf?sequence=1 2. Latent Tuberculosis Infection: updated and consolidated guidelines for programmatic management [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/260233/9789241550239- eng.pdf?sequence=1 3. WHO treatment guidelines for isoniazid-resistant tuberculosis: Supplement to the WHO treatment guidelines for drug-resistant tuberculosis [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079- eng.pdf?sequence=1 4. World Health Organization. WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 16]. Available from: https://www.who.int/tb/publications/2018/WHO.2018.MDR- TB.Rx.Guidelines.prefinal.text.pdf?ua=1 5. Sixtieth World Health Assembly resolution 60.20. Better medicines for children [Internet]. 2007. Available from: http://apps.who.int/medicinedocs/documents/s21455en/s21455en.pdf 6. Fixed-dose combinations for the treatment of TB in children [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 17]. Available from: http://www.who.int/tb/areas-of- work/children/ 7. Best practices in child and adolescent tuberculosis [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/274373/9789241514651-eng.pdf?ua=1 8. Roadmap towards ending TB in children and adolescents, second edition [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/275422/9789241514798-eng.pdf?ua=1 9. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. October 2016 revision [Internet]. Geneva: World Health Organization; 2016 [cited 2019 Jan 16]. Available from: http://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639- eng.pdf?sequence=1