Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for Inclusion in WHO Model List of Essential Medicine November 2016 ___________________________________________________________________________________ APPLICATION FOR INCLUSION OF PYRONARIDINE TETRAPHOSPHATE / ARTESUNATE FIXED DOSE COMBINATION TABLETS AND GRANULES IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES (EML) AND MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN (EMLc) ___________________________________________________________________________________ Pyronaridine tetraphosphate / artesunate tablets and granule 1/116 Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for Inclusion in WHO Model List of Essential Medicine November 2016 ___________________________________________________________________________________ TABLE OF CONTENTS 1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION ................................................. 5 Proof of efficacy and safety: ......................................................................................................... 6 Overall comparative efficacy of PYRAMAX® tablets and granules: ..................................... 7 Overall comparative safety of PYRAMAX® tablets and granules: ......................................... 8 Quality: ...................................................................................................................................... 9 2. NAME OF THE WHO TECHNICAL DEPARTMENT AND FOCAL POINT 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) AND ATC CODE OF THE MEDICINE .................................................................................................................... 12 5. FORMULATION AND STRENGTH PROPOSED FOR INCLUSION INCLUDING ADULT AND PAEDIATRIC ................................................................................................................... 13 5.1 Rationale on the PYRAMAX® formulation ......................................................................................... 13 5.2 Chemical characteristics ....................................................................................................................... 14 5.3 The formulation for inclusion: .............................................................................................................. 14 5.4 Stability of the formulations ................................................................................................................. 16 5.5 PYRAMAX® Manufacturer .................................................................................................................. 17 6. LISTING AS AN INDIVIDUAL MEDICINE OR A PHARMACOLOGICAL CLASS .................... 19 7. TREATMENT DETAILS: PYRAMAX® TABLETS AND GRANULES ............................................. 21 7.1 Therapeutic Indications ........................................................................................................................ 21 7.2 Posology and method of administration ............................................................................................... 21 7.3 Duration ................................................................................................................................................ 23 7.4 WHO Guidelines .................................................................................................................................. 23 7.5 Additional requirements ....................................................................................................................... 24 7.6 Core Listing .......................................................................................................................................... 24 8. INFORMATION SUPPORTING PUBLIC HEALTH RELEVANCE................................................. 25 9. REVIEW OF BENEFITS: SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICAL SETTINGS .................................................................................................. 29 Phase II Paediatric Study of PYRAMAX® ...................................................................................... 33 Overall conclusion from phase II studies ........................................................................................ 37 Phase III studies with PYRAMAX® ................................................................................................ 37 Overall conclusions from Phase III studies supporting registration .............................................. 54 10. REVIEW OF HARMS AND TOXICITY: SUMMARY OF EVIDENCE ON SAFETY .................... 61 10.1 Total patient exposure to date ............................................................................................................................... 61 10.2 Safety and tolerability ........................................................................................................................................... 64 10.2.1 Overview of PYRAMAX Safety ................................................................................ 64 10.2.2 Common Adverse Events Phase II/III ........................................................................ 64 10.2.3 Conclusions on PYRAMAX Safety from Phase II/III ................................................ 67 10.2.4 PYRAMAX Repeated Dosing .................................................................................... 67 10.3 Management of potential risks PYRAMAX® tablets and granules ....................................................................... 72 10.4 Variation in safety that may relate to health systems and patient factors ............................................. 72 ___________________________________________________________________________________ Pyronaridine tetraphosphate / artesunate tablets and granule 2/116 Shin Poong Pharmaceuticals Co. Ltd pyronaridine tetraphosphate/artesunate Application for Inclusion in WHO Model List of Essential Medicine November 2016 ___________________________________________________________________________________ 10.4.1 Use in pregnancy and lactation ................................................................................... 72 10.4.2 Drug interactions ........................................................................................................ 73 10.4.3 Other populations ....................................................................................................... 73 10.5 Summaries of Evidence for Safety and Efficacy ................................................................................................... 74 11. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST - EFFECTIVENESS WITHIN THE PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP ....................................................................................................................................................... 75 Rationale on cost: ............................................................................................................................ 75 12. REGULATORY INFORMATION .......................................................................................................... 77 12.1 Summary of Regulatory status ............................................................................................................. 77 12.2 Proposed text for the WHO Model Formulary ..................................................................................... 79 NAME OF THE MEDICINAL PRODUCT ..................................................................................................... 79 QUALITATIVE AND QUANTITATIVE COMPOSITION ........................................................................... 80 PHARMACEUTICAL FORM ......................................................................................................................... 80 Clinical particulars ............................................................................................................................................ 80 Therapeutic indications ................................................................................................................... 80 Posology and method of administration .......................................................................................... 80 Contraindications............................................................................................................................. 82 Special warnings and precautions for use ........................................................................................ 82 Interaction with other medicinal products and other forms of interaction ....................................... 84 Fertility, pregnancy and lactation .................................................................................................... 85 Effects on ability to drive and use machines ................................................................................... 85 Undesirable effects .......................................................................................................................... 86 Overdose ...................................................................................................................................