Essential Medicines List (EML) 2015 Application for the inclusion of terizidone in the WHO Model List of Essential Medicines, as reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (complementary lists of anti‐tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section 6.2.4 Antituberculosis medicines in the 2013 editions of both the WHO Model List of Essential Medicines (18th list) and the WHO Model List of Essential Medicines for Children (4th list)(1),(2). The proposal is to add terizidone to both the complementary list of anti‐tuberculosis medicines for adults and in children. Terizidone is not on the EML, but its sister medication, cycloserine, is on the complementary list in section 6.2.4 Antituberculosis medicines The applicant considers that terizidone should be viewed as an essential medicine for patients with multidrug‐resistant (MDR‐TB) and extensively drug‐resistant (XDR‐TB) disease. In many low resource settings, patients with these forms of tuberculosis are inadequately treated and often die because not enough medications are available to compose a suitable regimen (3). Second‐line drugs for the treatment of M/XDR‐TB are frequently not available; and global stock outs occur regularly. Terizidone should become more widely available to specialized care centres of national TB programmes and other health care providers treating M/XDR‐TB patients. The inclusion of terizidone as an anti‐tuberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in its production and will facilitate its inclusion in the national EML and its registration in countries where MDR and XDR‐TB are a health threat. Additionally, this harmonization of treatment regimens is key to medication price reduction through an increase in the volume of medications purchased. A major initiative to help enhance the treatment of TB and MDR‐TB patients has recently attracted UNITAID funding up to USD 60 million and aims to create new regimens using combinations of both the new TB medicines and older medications such as terizidone (5). This request to the EML is thus very timely and in line with the position of WHO and its technical partners on the subject. If approved, it would synergise with their concerted efforts to improve outcomes and reduce avoidable mortality for the close to half a million patients estimated to develop MDR‐TB in the world every year. Globally, 30% (95%CI: 24%–35%) of patients with MDR‐TB have resistance to a fluoroquinolone, a second‐line injectable agent, or both i.e. XDR‐TB. These patients would be eligible to receive regimens containing new and repurposed TB drugs, when options to treat them with existing drugs have been exhausted [3] 2. Name of the focal point in WHO submitting or supporting the application (where relevant) The focal point is the Unit of Laboratories, Diagnostics and Drug‐resistance of the Global TB Programme of WHO Headquarters (WHO/HTM/GTB/LDR). The technical personnel directly concerned are Dennis FALZON, Linh Nhat NGUYEN and Ernesto JARAMILLO. This application was prepared in close collaboration with WHO/GTB by Elizabeth HARAUSZ and the GRADE Tables (Sections 10 and 11) by Dick MENZIES. The guidance of Nicola MAGRINI of WHO/EMP in this work is acknowledged. 3. Name of the organization(s) consulted and/or supporting the application Not applicable. 4. International Nonproprietary Name (INN, generic name) of the medicine The WHO INN (generic name) is terizidone (6, 22, 23). 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) (1,2,4) The proposed formulation is 250 mg capsule for both adults and children. A drug information sheet for terizidone is attached as Annex 1 [4]. 6. International availability – sources, of possible manufacturers and trade names (4 , 26) Generic Drug Trade Names Availability Logistics Terizidone Terivalidin, Terizidon, Fatol in Germany is the only quality assured Tablets: no special storage or Terizidona source (27). However, Sanofi pharmaceuticals administrative needs. Store at manufactures terizidone in South Africa under room temperature in airtight the name “Terivalidin” and exports to Zambia, container. Angola, Mozambique, Botswana, Namibia and Kenya, with plans for future expansion (36). 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Terizidone is applying as an individual medicine without a square box symbol. 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Each year it is estimated that half a million new MDR‐TB cases emerge in the world and over 200,000 MDR‐TB patients die (3). Many MDR‐TB cases go undetected and are not placed on appropriate treatment, increasing the risk that they die and/or transmit drug‐resistant strains to others. In 2013, countries reported that about 100,000 patients started MDR‐TB treatment worldwide. The effectiveness of these efforts vary considerably and data on outcome reporting in recent years showed that only about half the MDR‐TB patients complete their treatment successfully (9). The rest die, fail treatment, interrupt treatment, or are otherwise lost to follow up. Given the low treatment success of MDR and XDR‐TB, every effort must be made to ensure that all possible medications used to treat MDR and XDR‐TB are widely available. This is particularly the case in about one third of MDR‐TB cases who have lost susceptibility to fluoroquinolones, second‐line injectable agents, or both (i.e. XDR‐TB) (3). XDR‐TB represents about 9 % of MDR‐TB cases and some 100 countries have now detected at least one such case (3). The transmissibility of XDR‐TB strains has been documented in outbreaks and regular reports of cases without a previous history of TB treatment (28‐34); this poses a formidable, additional public health concern making the proper treatment of M/XDR‐TB patients all the more important. The likelihood of treatment success in MDR‐TB patients diminishes with the acquisition of additional resistance and is particularly low in XDR‐TB patients. The availability of all available possible medications to treat MDR/XDR‐TB is therefore essential to successfully treat these patients. 9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills) There are two main indications for terizidone in the treatment of MDR‐TB patients: 1) MDR‐TB treatment regimens : A typical MDR‐TB regimen is composed of pyrazinamide plus at least 4 second‐line anti‐TB drugs considered to be effective, including a later‐generation fluoroquinolones, a second‐line injectable, ethionamide (or prothionamide) and cycloserine or PAS(10). When one or more of these drugs are considered ineffective, as a result of in vitro resistance, severe intolerance, or prolonged use in the same patient, the regimen should be bolstered by “Group 5” drugs. Terizidone, which is a Group 4 drug, can be used in the place of cycloserine. 2) XDR‐TB regimens : XDR‐TB is difficult to treat. WHO guidelines recommend using pyrazinamide and any other Group 1 medication that may be effective, an injectable agent and a higher generation fluoroquinolone (if the strain retains susceptibility)(4). However, often these medications are no longer effective. Therefore, use of all Group 4 agents that are likely to be effective, use of 2 or more Group 5 drugs and consideration of high dose isoniazid and investigational drugs are recommended (4). As stated above, terizidone can be used in the place of cycloserine. Drug Treatment Regimen (4) Duration of Special diagnostics, treatment treatment or monitoring facilities and skills Terizidone Adults: 10‐15 mg/kg/day, can divide into 2 doses Duration of TB Baseline and monthly treatment Child: (>3kg and >28 days of age): 10‐20 mg/kg/day divided depression screening. every 12 hours (25) 10. Summary of comparative effectiveness in a variety of clinical settings: [See Annex 2] 11. Summary of comparative evidence on safety: [See Annex 2] 12. Summary of available data on comparative cost and cost‐effectiveness within the pharmacological class or therapeutic group: Drug Source Price (US$) Terizidone Global Drug Facility 250 mg: 79.40‐83.30/50 capsules MSH International Drug Price Indicator Guide 250 mg: 0.9152/tab Médecins sans Frontières (15) 250 mg: 1.513‐1.666/tab Regulatory information 13. Summary of regulatory status of the medicine (in various countries) The table below summarizes the regulatory status of terizidone vis‐à‐vis the stringent regulatory authorities and WHO’s Prequalification Programme. Drug Authority Regulatory status and indications Terizidone First marketed in Germany 1 January 1978 (15). Only quality assured supplier if Fatol, in Germany (15). However, terizidone is a scheduled medication in South Africa, regulated by the Medicines Control Council (35). Sanofi pharmaceuticals manufactures terizidone in South Africa under the name “Terivalidin” (36). United States Food and Not found Drug Administration European Medicines Not found Agency WHO List of Not found Prequalified Medications Health Canada Not found Australian Government Not found Department of Health Pharmaceuticals and Not found Medical Devices Agency (Japan) 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) Drug Standard Reference (accessed 22.10.2014) Terizidone Not found in the British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia or European Pharmacopeia 15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary If this request is approved, it is proposed that identical modifications are made to the tabulations in the WHO Model List of Essential Medicines (18th list)(1), and the WHO Model List of Essential Medicines for Children (4th list)(2) to accommodate the new addition.