Application to 21st WHO Expert Committee on the Selection and Use of Essential Medicines to include the childhood TB fixed-dose combinations into the WHO model list of Essential Medicines for Children Summary This application is about inclusion of the following two childhood TB fixed dose combinations into the core list of the WHO model list of Essential Medicines for Children: For the intensive phase of TB treatment: Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150mg For the continuation phase of TB treatment: Rifampicin 75mg + Isoniazid 50 mg General items 1. Summary of statement of the proposal for inclusion, change or deletion At least 1 million children become ill with TB every year. In 2015, 210,000 children died of TB including 40,000 children who were HIV-infected. Children represent about 10- 11% of all TB cases annually (1). Researchers estimate that nearly 67 million children are globally infected with TB and therefore at risk of developing disease in the future (2) . Until recently, there were no appropriate first-line TB medicines designed for treatment of TB in children. Then, treatment of childhood TB faced two major challenges namely: i) inadequacy of the dosage of INH in the existing FDC (rifampicin60mg, isoniazid30mg, pyrazinamide150mg); and ii) difficulties in administering solid non-dispersible medications to children. However, updated WHO guideline development group recommendations as reflected in the WHO Guidance for national TB programmes on the management of tuberculosis in children: second edition, 2014 provided the framework for the dosage adjustment to the appropriate levels. Sustained advocacy for child-friendly formulations of anti-TB drugs resulted in the development of the new FDCs in recommended doses; and as dispersible formulations for easy administration through an initiative led by the TB Alliance and WHO (Essential Medicines and Health Products Department and the Global TB Programme), and funded by UNITAID and USAID. These child-friendly fixed dose combinations are therefore not new drugs, but rather reformulated version of already existing FDCs listed individually on the current EML albeit in different strengths and administration form. This application therefore seeks the listing of the two new formulations (strengths) of child-friendly fixed-dose combination medicines for the treatment of tuberculosis in children of less than 25kg body weight namely: 1 1. Rifampicin, pyrazinamide and isoniazid (rifampicin 75 mg + pyrazinamide 150mg + isoniazid 50 mg) For the intensive phase of childhood TB treatment: 2. Rifampicin and Isoniazid (Rifampicin 75mg + Isoniazid 50 mg) For the continuation phase of childhood TB treatment: In addition, the application seeks the deletion of the previous strengths from the EML namely: 1. Rifampicin, pyrazinamide and isoniazid (rifampicin 60 mg + pyrazinamide 150mg + isoniazid 60 mg) For the intensive phase of childhood TB treatment: 2. Rifampicin and Isoniazid (Rifampicin 60mg + Isoniazid 30 mg) For the continuation phase of childhood TB treatment: The development of newly formulate fixed-dose combinations (FDCs) was informed by evidence from pharmacokinetic studies supporting revised dosage recommendations of rifampicin, pyrazinamide and isoniazid to achieve the desired therapeutic blood levels in young children, including those under 2 years of age (3). Systematic review of the evidence also shows that the revised dosages have an excellent safety profile and are not associated with an increased risk of toxicity (including no increased risk of drug-induced hepatotoxicity due to isoniazid or pyrazinamide (4), (5), (6). The new FDCs addresses the most recent WHO recommendations requiring an isoniazid to rifampicin ratio of 2:3, i.e. isoniazid 10 mg/kg with rifampicin 15 mg/kg; as opposed to the previous recommendations which required a ratio of 1:2, i.e. isoniazid 5 mg/kg with rifampicin 10 mg/kg (7). This has enabled the possibility to achieve isoniazid dosages of 10-15 mg/kg while staying within the upper limit for dosages of rifampicin and pyrazinamide – which is critical to maintain a very low risk of hepatotoxicity. 2. Name of the WHO Technical Department and focal points for supporting the application (where relevant) WHO Global TB Programme: Dr Malgorzata Grzemska, Dr Kefas Samson & Ms Annemieke Brands 3. Name of organization(s) consulted and/or supporting the application Global Alliance for TB Drug Development (TB Alliance) Global Drug Facility, Stop TB Partnership, UNOPS 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine The WHO INN (generic name) of the medicines concerned is the generic name for the two fixed dose combinations (which are generic products): For the intensive phase of treatment: Rifampicin 75mg + Isoniazid 50mg + Pyrazinamide 150 mg 2 For the continuation phase of treatment: Rifampicin 75 mg + Isoniazid 50 mg. The two FDCs are listed under the classification anti-mycobacterials (ATC index Code J04); sub-class: Combination drugs for the treatment of tuberculosis with the following ATC names and index codes: 1. J04 AM05: Rifampicin, pyrazinamide and isoniazid 2. J04 AM02: Rifampicin and isoniazid 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) The FDC formulations are for the treatment of childhood tuberculosis cases presented as follows: 1. Rifampicin, Pyrazinamide and Isoniazid fixed-dose combination (FDC) – meant for intensive phase of the current WHO-recommended childhood TB treatment regimen. Solid tablets dispersible in water: dosage rifampicin:75mg, pyrazinamide:150mg and isoniazid:50mg 2. Rifampicin and Isoniazid fixed-dose combination (FDC) – meant for continuation phase of the current WHO-recommended childhood TB treatment regimen. Solid tablets dispersible in water: dosage R:75mg and H:50mg 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class This request is for the listing on the EMLc of two fixed-dose combinations for the treatment of childhood TB namely: For the intensive phase of TB treatment: Rifampicin 75mg + Isoniazid 50mg + Pyrazinamide 150 mg For the continuation phase of TB treatment: Rifampicin 75 mg + Isoniazid 50 mg. These fixed-dose combinations are within the same pharmacological class antimycobacterial agents (ATC index code J04) – drugs for treatment of tuberculosis with ATC index codes J04 AM 05 and 02 already listed in the 19th edition of the WHO EML for adults. Individual constituent drugs namely: Rifampicin, Isoniazid and Pyrazinamide are all listed in the 5th edition (April 2015) of the WHO EML for children (please refer to section 6.2.4 on page 8). The current request for listing is being made for inclusion of the child TB FDC formulations in section 6.2.4 of anti-tuberculosis medicines in the 6th WHO Model List of Essential Medicines for Children. 3 Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) The diagnosis of TB in children is made through a combination of approaches consisting of a careful history (including history of TB contact and symptoms consistent with TB); a thorough clinical examination (including growth assessment), tuberculin skin testing in some settings, chest X-ray (if available) as well as laboratory or other investigations relevant for suspected pulmonary TB and suspected extra-pulmonary TB including HIV testing (8). WHO recommends bacteriological confirmation of TB in children whenever possible and that it should be sought through microscopy, culture or WHO-endorsed genotypic (molecular) testing (i.e. Xpert MTB/RIF) of respiratory or non-respiratory samples as indicated by clinical presentation. WHO does not recommend a trial therapy as a method of diagnosing TB in children. An assessment of the key risk factors for TB in children namely: household or other close contact with a case of pulmonary TB (especially bacteriologically confirmed cases, age less than 5 years, HIV infection, and severe malnutrition; is also recommended as an essential component of the diagnostic process. Tuberculosis in children is treated in line with the principles and drug regimens as in adults. The first line treatment regimen is of a 6-month duration administered in two phases namely intensive and continuation phases. A distinction was made in WHO recommendations to cater for various settings based on HIV prevalence. Based on the current WHO recommendation, children with suspected or confirmed pulmonary TB or tuberculous peripheral lymphadenitis who live in settings with low HIV prevalence or low prevalence of isoniazid resistance and children who are HIV-negative can be treated with a three-drug regimen (HRZ) for 2 months (Intensive phase); followed by a two-drug (HR) regimen for 4 months (Continuation phase) at the recommended dosages (7). On the other hand, children with suspected or confirmed pulmonary TB or tuberculosis peripheral lymphadenitis and/or children with extensive pulmonary disease, living in settings where the prevalence of HIV is high and/or the prevalence of isoniazid resistance is high should be treated with a four-drug regimen (HRZE) for 2 months (intensive phase); followed by a two-drug regimen (HR) for 4 months (continuation phase) at the recommended dosages. The recommended dosage regimes (please refer to table below) are reflected on pages 33- 37 of the WHO guidance for national tuberculosis