Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for inclusion in the WHO Model List of essential medicines November 2010 ___________________________________________________________________________________ APPLICATION FOR INCLUSION OF PYRONARIDINE TETRAPHOSPHATE / ARTESUNATE FIXED DOSE COMBINATION TABLETS AND GRANULES IN THE WHO MODEL LISTS OF ESSENTIAL MEDICINES ___________________________________________________________________________________ Pyronaridine tetraphosphate / artesunate tablets and granule 1/74 Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for inclusion in the WHO Model List of essential medicines November 2010 ___________________________________________________________________________________ TABLE OF CONTENT 1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION ................................ 5 Rationale on the proposed formulation: .............................................................. 6 Rationale on the proposed dosage form: ............................................................. 6 Dosage: ............................................................................................................... 7 PHARMACEUTICAL DEVELOPMENT ......................................................... 8 Proof of efficacy and safety: ............................................................................... 8 Overall comparative efficacy of pyronaridine /artesunate tablets and granules: 8 Overall comparative safety of pyronaridine /artesunate tablets and granules: ... 8 Rationale on cost: ................................................................................................ 9 Quality: ............................................................................................................... 9 2. NAME OF THE FOCAL POINT IN WHO SUBMITTING OR SUPPORTING THE APPLICATION .................................................................................. 10 3. NAME OF THE ORGANISATION(S) CONSULTED AND/OR SUPPORTING THE APPLICATION .................................................................................. 11 4. INTERNATIONAL NON-PROPRIETARY NAME (INN, GENERIC NAME) OF THE MEDICINE ............................................................................................................ 12 5. DOSAGE FORM OR STRENGTH PROPOSED FOR INCLUSION................................. 13 5.1 Chemical characteristics .................................................................................................... 13 5.2 The formulation proposed for inclusion: ............................................................................ 13 5.2.1 Summary of Efficacy ............................................................................. 14 5.2.2 Summary of Safety ................................................................................. 15 5.2.3 Posology ................................................................................................. 16 5.3 Stability of the formulations .............................................................................................. 17 6. INTERNATIONAL AVAILABILITY – SOURCES, IF POSSIBLE MANUFACTURERS ............................................................................................................ 18 6.1 Sources and manufacturers ................................................................................................ 18 6.2 History of the product ....................................................................................................... 18 6.2.1 Background on artemisinin-based combinations (ACTs) ...................... 18 6.2.2 Rationale for Development .................................................................... 19 6.3 International availability and production capacity .............................................................. 20 7. WHETHER LISTING IS REQUESTED AS AN INDIVIDUAL MEDICINE OR AS AN EXAMPLE OF A GROUP ................................................................................. 22 8. INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE (EPIDEMIOLOGICAL INFORMATION ON DISEASE BURDEN, ASSESSMENT OF CURRENT USE, TARGET POPULATION) ...................................... 23 TARGET POPULATION AND RATIONALE ON THE RATIO/DOSE ....... 24 9. TREATMENT DETAILS ..................................................................................................... 27 9.1 Method of administration .................................................................................................. 27 ___________________________________________________________________________________ Pyronaridine tetraphosphate / artesunate tablets and granule 2/74 Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for inclusion in the WHO Model List of essential medicines November 2010 ___________________________________________________________________________________ 9.2 Dosage .............................................................................................................................. 27 9.3 Duration ............................................................................................................................ 28 10. SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICAL SETTINGS ........................................................................................................ 29 Phase II Paediatric Study of pyronaridine /artesunate ...................................... 32 Overall conclusion from phase II studies.......................................................... 36 Phase III studies with pyronaridine /artesunate ................................................ 36 Conclusions on the overall comparative efficacy of pyronaridine / artesunate tablets and granules ........................................................................................... 53 11. SUMMARY OF COMPARATIVE EVIDENCE ON SAFETY ........................................... 54 11.1 Safety and tolerability ....................................................................................................... 54 Overview of Safety ........................................................................................... 54 Conclusions on Safety from Phase II/III ........................................................... 56 11.2 A Risk Management Plan for pyronaridine artesunate fixed-dose combination .................. 57 11.3 Use in pregnancy and lactation .......................................................................................... 57 11.4 Drug interactions ............................................................................................................... 58 12. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST - EFFECTIVENESS WITHIN THE PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP .............................................................................................. 59 13. SUMMARY OF REGULATORY STATUS OF THE MEDICINE (IN COUNTRY OF ORIGIN, AND PREFERABLY IN OTHER COUNTRIES AS WELL) ............................................................................................................................. 60 14. AVAILABILITY OF PHARMACEUTICAL STANDARDS .............................................. 61 15. PROPOSED TEXT FOR THE WHO MODEL FORMULARY ......................................... 62 15.1 NAME OF THE MEDICINAL PRODUCT ....................................................................... 62 15.2 QUALITATIVE AND QUANTITATIVE COMPOSITION .............................................. 62 15.3 PHARMACEUTICAL FORM .......................................................................................... 62 15.4 Clinical particulars ............................................................................................................ 62 15.4.1 Therapeutic indications .......................................................................... 62 15.4.2 Posology and method of administration ................................................. 63 15.4.3 Contraindications ................................................................................... 64 15.4.4 Special warnings and precautions for use .............................................. 64 15.4.5 Interaction with other medicinal products and other forms of interaction 65 15.4.6 Fertility, pregnancy and lactation ........................................................... 65 15.4.7 Undesirable effects ................................................................................. 66 15.4.8 Overdose................................................................................................. 68 15.5 PHARMACOLOGICAL PROPERTIES ........................................................................... 68 15.5.1 Pharmacodynamic properties ................................................................. 68 15.5.2 Pharmacokinetic properties .................................................................... 70 15.5.3 Preclinical safety data............................................................................. 72 ___________________________________________________________________________________ Pyronaridine tetraphosphate / artesunate tablets and granule 3/74 Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for inclusion in the WHO Model List of essential medicines November 2010 ___________________________________________________________________________________ 15.4 Shelf life ..........................................................................................................................