i STUDIES ON THE RATIONAL USE OF CHLOROQUINE IN THE MANAGEMENT OF UNCOMPLICATED MALARIA IN LAGOS STATE GENERAL HOSPITALS. BY AINA, BOLAJOKO AJOKE B.Pharm(Ife); M.Sc (Ife) (979009081) November 2005 ii STUDIES ON THE RATIONAL USE OF CHLOROQUINE IN THE MANAGEMENT OF UNCOMPLICATED MALARIA IN LAGOS STATE GENERAL HOSPITALS. A THESIS SUBMITTED IN FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (PH.D.) IN THE DEPARTMENT OF CLINICAL PHARMACY & BIOPHARMACY, FACULTY OF PHARMACY, UNIVERSITY OF LAGOS, NIGERIA. BY AINA, BOLAJOKO AJOKE B.Pharm(Ife); M.Sc (Ife) iii DECLARATION We hereby declare that this thesis titled “studies on the rational use of chloroquine in the management of uncomplicated malaria in Lagos State General Hospitals” is a record of original research carried out by AINA, Bolajoko Ajoke in the department of Clinical Pharmacy and Biopharmacy, Faculty of Pharmacy, University of Lagos. Student: ……………………………………………….. AINA Bolajoko Ajoke 1st Supervisor: ………………………………………………………. Prof. Fola TAYO 2nd Supervisor: …………………………………………………….. Dr. (Mrs.) O.TAYLOR Senior Lecturer iv DEDICATION THIS WORK IS DEDICATED TO GOD ALMIGHTY FOR HIS PROVISION AND PROTECTION THROUGHOUT THE PERIOD OF THE STUDY. TO MY HUSBAND AND CHILDREN MR. M. A. AINA, OKUNOLA, OLANREWAJU AND OLAPOSI; AND MY WARD TOYIN OSOSANYA. AND TO MY PARENTS LATE MR. E.G. SOKALE AND MRS M.I. SOKALE v ACKNOWLEDGEMENTS Thanks be to God Almighty whose mercy endures forever. I acknowledge the contribution of my immediate and extended family. I thank my husband and my children for their understanding. I acknowledge with gratitude the contributions of my supervisors Professor Fola Tayo and Dr (Mrs.) Ogori Taylor. I thank my sisters, Mrs. Funke Ososanya and her family, Dupe Sokale and my brother Adebola Sokale for contributing to the successful completion of this work. My thanks also go to my cousins especially Yomi Rabiu and Yomi Oyejobi. I thank the entire staff of Clinical Pharmacy and Biopharmacy Department, Dr. Peters, Mr. Anyika, Mrs. Soremekun, Ms Dada, Mrs Joda, Mr. Erastus, Mr. Olusanya, Mr Fadare, Mrs Adams, Mr. Adesiyun, Mr. Ikpehae, Mrs Abe and Mrs Olele. I acknowledge the following members of the Faculty of Pharmacy for encouragement and help, Prof H.A.B. Coker, Prof Ifudu, Prof (Mrs.) Igwillo, Dr. Abioye, Dr. Adesegun, Dr Odukoya, Dr (Mrs.) Ukpo, Mrs Adepoju, Dr (Mrs) Owolabi, Mrs Ajayi, Mr. Dosa, Mrs Olanrewaju, Lucky, Kayode, Oyedele and Mrs. Olanrewaju. I also thank Dr (Mrs.) Agiobu-Kemmer of Department of Psychology, Dr (Mrs.) Adeyemi of Dept. of Pharmacology, Dr. Chukwu of Dept of Marine Biology, Dr Oghojafor of Dept. of Business Administration, Dr (Mrs.) N. Osarenren of Dept of Education Foundation and Dr. A. Abu of Dept. of Geography of University of Lagos for their support and advice . vi I say thank you to Mr. Thomas, Pastor Adefarakan and Ms Doyin Anifaleye of Unilag Postgraduate School for their support and words of encouragement. My thanks go to all pharmacists in all the General Hospitals in Lagos State especially the Controllers of Pharmaceutical Services/ Pharmacists in charge of these hospitals for their assistance during data collection. I am also grateful to the Medical Directors in all these General Hospitals. I am grateful to Dr. Eniojukan, Mrs Opoola and Mrs Iyamabo for their encouragement and support during the period of this study. I say thank you to all my brothers and sisters in Christ at Foursquare Gospel Church, Apata especially my pastors, Rev and Rev (Mrs.) A.O. Aina and Pastor and Pastor (Mrs.) Kunle Muraina. I say thank you to Mr. Sakiru Odunuga of Geography department for the maps. Special thanks go to Awokoya Family and Stephen Oluwole Awokoya Foundation for Science Education for giving me scholarship during this program. vii TABLE OF CONTENTS TITLE…………………………………………………………………………………..i DECLARATION……………………………………………………………………...iii CERTIFICATION…………………………………………………………………….NA DEDICATION ………………………………………………………………………iv ACKNOWLEDGEMENT …………………………………………………………....v TABLE OF CONTENT……………………………………………………………...vii LIST OF TABLES …………………………………………………………………...xi LIST OF FIGURES ………………………………………………………………….xiv ABSTRACT …………………………………………………………………. ……..xv CHAPTER ONE 1.0 Introduction ……………………………………………………………… 1 1.1 Background to the study ………………………………………….1 1.2 Problem statement ……………………………………… ………..4 1.3 Objectives of the study ……………………………………………5 1.4 Research questions/hypotheses …………………………………...5 1.4.1 Research questions ………………………………………..5 1.4.2 Research hypotheses………………………………………6 1.5 Significance of study …………………………………………….. 6 1.6.0 Theoretical framework ……………………………….. ………….7 1.6.1 Diffusion of innovation theory …………………………………... 7 1.6.2 Health education theory …………………………………………. 7 viii 1.6.3 Social influence theory ………………………………………….. 8 1.6.4 Transtheoretical model of behavioural change …………………...8 1.7 Conceptual framework ……………………………………………. 9 CHAPTER TWO 2.0 Literature Review………… ……………………………………………..11 2.1 Malaria …………………………………………………………..11 2.2 Roll back malaria ………………………………………………..17 2.3 Rational Use of Drugs ………………………………………….. 21 2.3.1 Rational use of drugs………………………………….....21 2.3.2 Irrational use of drugs …………………………………...23 2.3.3 Strategies to promote rational use of drugs …………….. 27 2.4.0 Drug Utilization Studies (DUS) …………………………………………27 2.4.1 Drug utilization studies ………………………………………… 27 2.4.2 Studying drug use in Health facilities using WHO indicators…………………………………………………………32 2.4.3 Surveying Private Sector Drug Use ……………………………. 34 2.4.4 Examining Drug use in the community ………………………... 35 2.5 Interventions …………………………………………………………… …..36 2.6 Pharmacoeconomics ………………………………………………………. .42 2.7 Quality of Medicines ………………………….. …………………………..,57 2.8 Statistics ……………………………………………………………….…… 63 ix CHAPTER THREE 3 Materials and Methodology………………………….. ………………………….…65 3.1 Study area ……………………………………………………………………65 3.2 Study population …………………………………………………………… 67 3.3 Research design ……………………………………………………………..67 3.3.1 Study 1: Intervention study …………….. ………………………67 3.3.2 Study 2: Quality assessment study …………………………….. 67 3.3.3 Study 3: Cost effectiveness analysis …………………………… 68 3.4 Research Instruments/materials ………………………………………... …..68 3.4.1. Study 1 …………………………………………………………………. 68 3.4.2. Study 2 ………………………………………………………………….68 3.5 Procedure for data collection ……………………………………………….69 3.5.1 Study 1………………………………………………………….. 69 3.5.1.1 Phase 1 (Preintervention phase) using “Free Eko Malaria” prescriptions ……………………………….69 3.5.1.2 Phase 1 using questionnaires to determine the KAP of the prescribers ……………………………………………… 72 3.5.1.3 Phase 2 (Intervention phase) ……….…….. ……………73 3.5.1.4 Phase 3 (Post intervention phase)…… …………………76 3.5.2 Assessment of quality of chloroquine tablets, syrups and injections from the hospitals …………………… ………………………….76 3.5.2.1 Physical assay of quality ……………………………...…76 3.5.2.2 Chemical assay of quality ……………………………….78 x 3.5.2.3 Microbiological assay of quality ……………………….80 3.5.3 Cost effectiveness analysis …………………………………….. 82 3.5.4 Data analysis …………………………………………………… 82 3.5.5 Statistical analysis ……………………………………………… 82 CHAPTER FOUR 4.0 Results ……………………………………………………………………………… 83 4.1a Results of study 1: Prescribing pattern at pre, 1, 3, 6 and 12 months post interventions ……………………………………………………………………….. 83 4.1b Results from the questionnaire ……………………………………………………..98 4.2 Results of quality assessment of chloroquine formulations ………………………..105 4.3 Cost effectiveness analysis results …………………………………………………111 4.4 Statistical results …………………………………………………………………...116 CHAPTER FIVE 5.1 Discussion ………………………………………………………………………….119 5.2 Conclussion ………………………………………………………………………...127 5.3 Recommendation …………………………………………………………………..128 REFERENCES ……………………………………………………………………..129 Appendix I Questionnaire to determine KAP……………………………………….144 Appendix II Label on plastic box…………………………………………………….148 Appendix III Label on poster………………………………………………………….149 xi LIST OF TABLES Tables Page 1. Treatment of non-severe malaria with Chloroquine…………………. …16 2. Pharmacoeconomic Methods………………………………………….. 49 3. An example of a Decision Table ……………………………………. ….51 4. Average number of drugs and injections and average cost per prescription in the different health facilities at pre, 1,3,6 and 12 months post intervention …………………………………..86 5. Percentage of prescriptions with at least one injection, dipyrone and chloroquine in the different health facilities at pre, 1, 3, 6 and 12 months post intervention …………………………87 6. Percentage of prescriptions with halofantrine, sulphadoxine- pyrimethamine (S-P) and quinine in the different health facilities at pre, 1,3, 6 and 12 months post intervention ………………..88 7. Dosage of chloroquine prescribed in the different health facilities at pre, 1, 3, 6 and 12 months post intervention …………………………89 8. Dosage of chloroquine prescribed in the different intervention groups at pre, 1, 3, 6 and 12 months post intervention …………………90 9. Dosage of chloroquine in the different dosage forms prescribed at pre, 1, 3, 6 and 12 months post intervention …………………… …...96 10. Dosage of chloroquine in the different dosage forms prescribed for the intervention groups ……………………… ……………………..97 11. Dosage of chloroquine in the different dosage forms prescribed xii for adults and children ………………………………………………..97 12. The number of patients with chloroquine resistant malaria out of 10 patients …………………………………………….................100 13. Reasons given for chloroquine resistant malaria ………………………100 14. Percentage response of prescribers’ first and second choice of antimalarial …………………………………………………………101 15. Percentage response of prescribers’ first and second reasons for choice of chloroquine ………………………………………………101 16. Percentage response of prescribers’ choice of chloroquine dosage forms ………………………………………………………..…102 17. Percentage response of prescribers’ correct dosage of chloroquine in adult and children ………………………………...……102 18. Percentage response of prescribers’ number of dose of injection chloroquine only, adequate to treat malaria…………….……103 19. Percentage of prescribers who would prescribe 2 antimalarials together ………………………………………………………………. 103 20. Percentage response of the prescribers to the combination of the 2 antimalarials prescribed together………………..……………………...103 21. Source of information for chloroquine dosage ………………………...104 22. Results of quality assessment of chloroquine tablets ………………. …107 23. Results of quality assessment of chloroquine tablets ………………. ...108 24. Results of quality assessment of chloroquine syrups ………………. ...109 xiii 25. Results of quality assessment of chloroquine injections……………...110 26. Decision Table for cost effectiveness analysis of tablet chloroquine and injection chloroquine …………………………..111 27. Effectiveness Rating …………………………………………………...112 28. Calculation of costs …………………………………………………….113 29. Healthcare personnel costs………………………………………….. …114 30. multiple comparison between intervention times using Tukey’s honesty significant difference (HSD)……………………………………………118 xiv LIST OF FIGURES Figures Page 1. Framework for Formative and Intervention Studies……………………..10 2. Spatial distribution of General Hospitals in Lagos state…………………66 3. Map showing the different experimental groups………………………...75 4. Dosage of chloroquine prescribed at pre, 1, 3, 6 and 12 months post intervention …………………………………………….91 5. Correct dosage of chloroquine prescribed in adult and children at pre, 1, 3, 6 and 12 months post intervention …………………………92 6. Correct dosage of chloroquine prescribed in each health facility at pre, 1, 3 , 6 and 12 months post intervention ………………………...93 7. Percentage of chloroquine dosage forms prescribed at pre, 1, 3, 6 and 12 months post intervention ………………………………...94 8. Correct dosage of chloroquine for the different mode of intervention at pre, 1, 3, 6 and 12 months post intervention …………………………95 9. Standard curve of absorbance versus concentration for chloroquine phosphate …………………………………………….106 xv ABSTRACT Malaria is a curable and preventable disease and it is a major public health problem in Nigeria and Chloroquine is still the first line drug in its treatment in Nigeria. Inappropriate prescribing which is the failure to prescribe drugs in accordance with guidelines based on scientific evidence to ensure safe, effective, and economic use, is an irrational drug use behavior. Increased benefits from chloroquine or a slow down of progression to resistance could be achieved by improving prescribing practice, drug quality, and patient compliance. The objectives of the study were to determine the impact of two modes of educational intervention on chloroquine prescribing pattern of prescribers in Lagos State General Hospitals, to determine the quality of chloroquine dosage forms available in these hospitals and to undertake cost effectiveness analysis of chloroquine tablet and injection. The study was carried out in all the ten General Hospitals under Lagos State Hospitals Management Board. One hundred prescriptions each for adults and children at each hospital were systematically sampled between January and December 2000. Where there were fewer than 100 prescriptions all the prescriptions available were sampled for quantitative analysis. Questionnaires were distributed to prescribers between November and December 2001 for quantitative and qualitative analysis. Quality of the chloroquine dosage forms available in these hospitals was determined using British Pharmacopoeiea methods. The cost effectiveness analysis of chloroquine tablet and injection chloroquine was calculated Educational intervention took place between January and February 2002. Seminars were presented in 8 out of the 10 hospitals. Among the 8 that had seminars, 4 hospitals had xvi educational posters while the other 4 had plastic boxes describing correct doses of chloroquine left behind. Two hospitals served as control. There was significant increase in the percentage of prescriptions with correct dosage of chloroquine post-intervention compared with pre-intervention (p< 0.01). There was association between intervention and correctness of dosage of chloroquine prescribed (p<0.001). There was association between the mode of intervention and dosage of chloroquine prescribed (p<0.001). There was also association between the dosage of chloroquine and the different dosage forms of chloroquine prescribed (p<0.001). There was no significant difference between the group with plastic box and the group with poster in percentage of correct prescriptions (p>0.05). There was no statistically significant difference in percentage of correct prescriptions between 1 month, 3 months, 6 months and 12 months post intervention hence outcome of intervention was sustained. The tablets passed the quality tests more than the two other dosage forms. Tablet chloroquine was more cost effective than injection chloroquine The conclusion from this study is that educational intervention improved the prescribing pattern of chloroquine. Tablet should be encouraged more than injection because it is safer and more cost effective. There is need to determine the quality of chloroquine available in our hospitals.