Application for the inclusion of CLOFAZIMINE in the WHO Model List of Essential Medicines (“EML”), as a reserve second-line drug 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 2015 editions of both the 19th Model List of Essential Medicines of the World Health Organization (WHO) and the 5th WHO Model List of Essential Medicines for Children(1),(2). The proposal is to add clofazimine - a medicine which is already included on both lists for use in leprosy (6.2.3 Antileprosy medicines) - to the Complementary Lists of antituberculosis medicines in adults and children at the next revision of the Essential Medicines Lists (EMLs) in April 2017. The applicant considers that under the current circumstances clofazimine should be considered an essential medicine for national programmes to have as part of the treatment they offer to patients with rifampicin-resistant (RR-TB), multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) disease. In many low resource settings, patients with these forms of tuberculosis often die or are only partially treated as a result of the limited options in the medicines available to compose an adequate regimen(3). Agents like clofazimine are therefore needed more widely for health care providers to treat M/XDR-TB patients adequately. Unfortunately, access continues to be challenged by several factors, including the limited availability of quality-assured suppliers of the medicine as well as the fact that clofazimine is used either off-label (in countries where the manufacturer registered it with an indication for leprosy) or through other mechanism (when in place) to access non registered drugs. Its listing could encourage more pharmaceutical manufacturers to invest in its production, help counter the unfavourable conditions of the global market for such drugs as numbers of TB cases diminish in the world. The 2011 WHO guidelines on M/XDR-TB treatment included clofazimine in the Group 5 of second-line drugs and recommends its use when other treatment options are not possible(4). This reflects a WHO policy dating since at least 2006 to consider this drug as a reserve anti-tuberculosis agent for drug- resistant strains(5),(6). The role of clofazimine in MDR-TB regimen design has been reviewed by a WHO Guidelines Development Group in November 2015(7). The 2016 update of the WHO policy for the treatment of MDR-TB now conditionally recommends the use of a shorter MDR-TB regimen in which clofazimine is a mainstay second-line drug used throughout its 9 month duration(7). Clofazimine is a mainstay component of shorter regimens which have shown promise to reduce drastically the length of treatment for MDR-TB patients(8),(9),(10),(11); these novel regimens are currently being used in various treatment programmes and their effectiveness and safety are also being studied under randomized controlled (RCT) conditions(12),(13). Moreover, the 2016 update of the WHO treatment guidelines for MDR-TB includes clofazimine as one of the four medicines in “Group C”, making it a core-drug option even for conventional regimens for M/XDR-TB (Table 1). Clofazimine currently the only core second‐line medicine for the treatment of MDR-TB which does not yet feature in the EML as an antituberculosis agent1(7). A major multi-partner initiative to develop the treatment of TB and MDR-TB patients, supported by UNITAID funding up to USD60 million, is now being implemented: it aims to create new regimens using 1 Gatifloxacin is not yet listed either, but moxifloxacin - an alternative later generation fluoroquinolone - is included. A separate application for the inclusion of gatifloxacin in the 20th EML is being submitted concurrently 1 combinations of both new medicines and old ones such as clofazimine(14). This request to the EML is thus very timely and well aligned the position of WHO and the consensus achieved with technical partners and experts on the subject. If approved, it would synergise with their concerted efforts to improve patient access to treatment, ensure more favourable outcomes and reduce avoidable mortality for the 580,000 patients estimated to develop rifampicin-resistant or MDR-TB in the world every year and who would need second-line TB treatment regimens to increase their likelihood of a successful outcome(3). Table 1. Medicines recommended for the treatment of rifampicin-resistant and multidrug-resistant TB as per the 2016 update of WHO policy for the treatment of drug-resistant TB(7)1 A. Fluoroquinolones2 Levofloxacin Lfx Moxifloxacin Mfx Gatifloxacin Gfx B. Second-line injectable agents Amikacin Am Capreomycin Cm Kanamycin Km (Streptomycin)3 (S) C. Other core second-line agents2 Ethionamide / Prothionamide Eto / Pto Cycloserine / Terizidone Cs / Trd Linezolid Lzd Clofazimine Cfz D. Add-on agents Pyrazinamide Z (not part of the core MDR-TB regimen) D1 Ethambutol E High-dose isoniazid Hh Bedaquiline Bdq D2 Delamanid Dlm p-aminosalicylic acid PAS Imipenem-cilastatin4 Ipm D3 Meropenem4 Mpm Amoxicillin-clavulanate4 Amx-Clv (Thioacetazone)5 (T) Notes for Table 1 1. This regrouping is intended to guide the design of conventional regimens; for shorter regimens lasting 9-12 months the composition is usually standardised 2. Medicines in Group A and Group C are shown by decreasing order of usual preference for use (subject to other considerations; see Guidelines text) 3. Refer to the Guidelines text for the conditions under which streptomycin may substitute other injectable agents. Resistance to streptomycin alone does not qualify for the definition of extensively drug-resistant TB (XDR-TB) 4. Carbapenems (Imipenem-cilastatin or Meropenem) and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin 5. HIV-status must be tested and confirmed to be negative before thioacetazone is started 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, Tiziana MASINI and Ernesto JARAMILLO. 2 3. Name of the organization(s) consulted and/or supporting the application Dr Kaspars Lunte of Global Drug Facility (GDF) 4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine. The WHO INN (generic name) of the medicine concerned is clofazimine (15). The Anatomical Therapeutic Chemical (ATC) code of the medicine concerned is J04BA012. 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) The formulations proposed, for both adults and children, are the same as those listed in the EML for use in leprosy, namely soft gelatin capsules in dosages of 50 mg and 100 mg. A drug information sheet for clofazimine is at Annex 1. The product package insert is available online(16). Clofazimine has been marketed by its original producer Novartis under the proprietary name Lampren and Lamprene®(16). Other manufacturers produce the product under different trade names: Clofozine, Hansepran, and Lapren. Novartis has stopped the production of the active pharmaceutical ingredient (API) of clofazimine, but other manufacturers have been producing clofazimine API3. Clofazimine is one of three drugs making up the multidrug therapy (MDT) regimen recommended by WHO for the treatment of adults and children with multibacillary leprosy4. The drug is also useful in the management of erythema nodosum leprosum and reversal immunity reactions(17). Clofazimine is still available today for leprosy, its registered indication. As several other medicines under the The drug is also used outside of this indication for the treatment of M/XDR-TB (see above). In early 2012, in the wake of a much-publicized report from India of TB patients with broad patterns of resistance, WHO convened an technical consultation(18),(19). The experts at this meeting recommended that two “Group 5” drugs - clofazimine and linezolid - be made available by the Global Drug Facility (GDF) to countries as a matter of priority. Following this, the 50mg and 100mg formulation of clofazimine can now be purchased through GDF5. The gel capsules do not require extraordinary storage conditions. 6. Whether listing is requested as an individual medicine or as a representative of a pharmacological class This request is for the inclusion of clofazimine as an individual medicine without a square box symbol. Clofazimine is the only riminophenazine with a market authorization for use in the treatment of leprosy in several countries with stringent drug regulatory authorities: Australia, France, Netherlands, Spain, Switzerland, and USA. It is also the only member of this pharmacological class for which there is experience and published information on effectiveness and safety when used in the treatment of drug- resistant TB patients, although other candidates from the same family of medicines may become available in future(20),(21). 2 http://www.whocc.no/atc_ddd_index/?code=J04BA01; accessed 27.06.2016 3 For example : http://www.sangroselabs.com/home.html; accessed 27.06.2016 4 http://www.who.int/lep/mdt/regimens/en/; accessed 27.06.2016 5 http://www.stoptb.org/gdf/drugsupply/pc3.asp?PID=562; accessed 27.06.2016 3 Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) WHO guidelines recommend clofazimine in the treatment of MDR-TB patients as part of two treatment approaches: 1) Longer (individualized) regimens : A typical MDR-TB regimen is composed of at least 4 second- line anti-TB drugs considered to be effective, including a later-generation fluoroquinolones, a second-line injectable, and two or more of ethionamide (or prothionamide), cycloserine (or terizidone), clofazimine or linezolid(7).