|Year : 2016 | Volume
| Issue : 4 | Page : 172-181
Cohort event monitoring of patients treated for uncomplicated malaria with artemisinin-based combination therapies in selected hospitals and community pharmacies in Nigeria
PU Bassi1, AI Osakwe2, C Suku2, M Kalat2, C Elagbaje2, A Isah3, S Ayinbuomwan3, RD Wammanda4, II Bob-Okon5, J Ambe6, Y Mava6, AO Adesina7, CG Ugochukwu8, EE Nyong9, OO Ogunleye10, F Onuoha11, I Jalo12, VO Adegoke13, ST Balogun14, G Ntadom15, FN Ejiekpe16, R Tahir17, K Dabit18, AA Amodu19, S Nwaosu20, AT Habib21
1 Department of Pharmacology and Therapeutics, College of Health Sciences, University of Abuja, Abuja, Nigeria
2 National Agency for Food and Drug Administration and Control, Abuja, Nigeria
3 Department of Medicine, Clinical Pharmacology Unit, University of Benin Teaching Hospital, Benin City, Nigeria
4 Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
5 Department of Paediatrics, Federal Medical Centre, Yenagoa, Nigeria
6 Department of Paediatrics, University of Maiduguri Teaching Hospital, Maiduguri, Nigeria
7 Department of Obstetrics and Gynecology, University College Hospital, Ibadan, Nigeria
8 Department of Paediatrics, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria
9 Department of Paediatrics, University of Uyo Teaching Hospital, Akwa Ibom, Nigeria
10 Lagos State University Teaching Hospital, Lagos, Nigeria
11 Federal Medical Centre, Owerri, Nigeria
12 Department of Paediatrics, Federal Teaching Hospital, Gombe, Nigeria
13 NIPRD Research Clinic, National Institute for Pharmaceutical Research and Development, Abuja, Nigeria
14 Department of Clinical Pharmacology and Therapeutics, University of Maiduguri, Maiduguri, Nigeria
15 National Malaria Control Programme, FMoH, Abuja, Nigeria
16 Lafes Pharmacy Ltd, Enugu, Nigeria
17 Rata Pharmacy, Maiduguri, Nigeria
18 Skylark Pharmacy, Abuja, Nigeria
19 Federal Medical Center, Makurdi, Nigeria
20 Department of Mathematics, Federal University of Technology, Makurdi, Nigeria
21 Waziri Shehu Specialist Hospital, Kano, Nigeria
|Date of Web Publication||20-Dec-2016|
P U Bassi
Department of Pharmacology and Therapeutics, College of Health Sciences, University of Abuja, Abuja
Source of Support: None, Conflict of Interest: None
Aims and Objectives: The study was designed with the broad objective of determining the safety profile of artemisinin-based combination therapies amongst Nigerian population.
Patients and Methods: This was a cohort event monitoring (CEM) programme involving monitoring adverse events (AEs) in malaria patients treated with either artemether-lumefantrine (AL) or artesunate-amodiaquine (AA) in healthcare facilities in Nigeria. The study involved continuous enrolment of patients with malaria and treated with either AL or AA at the various sites until a total cohort of 600 patients were enrolled at each site. Patients were monitored from the onset of therapy, and on days 3 and 7 from the first day of treatment to identify AEs that may occur.
Results: A total of 6102 AEs were recorded in 10,259 patients monitored during the programme. Of 4896 patients who received AA, 4233 (86.5%) patients reported at least one AE while 1869 (34.8%) AEs out of 5363 patients who received AL were reported (P = 0.010). The predominant incidence of each specific AE reported in each group among the patients who received AA and AL includes body weakness 30.8%/7.5%, dizziness 10.3%/3.9%, restlessness 5.02/1.12%, vomiting 3.5/1.03% and drowsiness 3.1/1.5% for AA and AL, respectively. There were more AEs among patients with co-morbid conditions and patients in the younger age groups (9-<15 years), P = 0.000.
Conclusions: Various types of AEs were seen and documented during the CEM programme. The findings suggested that the AA/AL monitored during this programme was generally safe and remarkably well tolerated among the Nigerian populations.
Keywords: Artemisinin combination therapies, cohort event monitoring, uncomplicated malaria - Nigerians
|How to cite this article:|
Bassi P U, Osakwe A I, Suku C, Kalat M, Elagbaje C, Isah A, Ayinbuomwan S, Wammanda R D, Bob-Okon I I, Ambe J, Mava Y, Adesina A O, Ugochukwu C G, Nyong E E, Ogunleye O O, Onuoha F, Jalo I, Adegoke V O, Balogun S T, Ntadom G, Ejiekpe F N, Tahir R, Dabit K, Amodu A A, Nwaosu S, Habib A T. Cohort event monitoring of patients treated for uncomplicated malaria with artemisinin-based combination therapies in selected hospitals and community pharmacies in Nigeria. Niger Postgrad Med J 2016;23:172-81
|How to cite this URL:|
Bassi P U, Osakwe A I, Suku C, Kalat M, Elagbaje C, Isah A, Ayinbuomwan S, Wammanda R D, Bob-Okon I I, Ambe J, Mava Y, Adesina A O, Ugochukwu C G, Nyong E E, Ogunleye O O, Onuoha F, Jalo I, Adegoke V O, Balogun S T, Ntadom G, Ejiekpe F N, Tahir R, Dabit K, Amodu A A, Nwaosu S, Habib A T. Cohort event monitoring of patients treated for uncomplicated malaria with artemisinin-based combination therapies in selected hospitals and community pharmacies in Nigeria. Niger Postgrad Med J [serial online] 2016 [cited 2018 Jun 23];23:172-81. Available from: http://www.npmj.org/text.asp?2016/23/4/172/196246
| Introduction|| |
Malaria is still a major health problem in Nigeria despite several control measures, causing morbidity and mortality, especially among the most vulnerable groups which are: the under-five children, pregnant women and populations with low immunity.  One of the major strategies adopted to control the disease is chemotherapy using good quality, safe and efficacious medicines. Since medicines play a very important role in public health programmes, it becomes imperative for their safety and efficacy to be guaranteed. 
The artemisinin combination therapies (ACTs) recommended by the Federal Ministry of Health (FMoH) under the new malaria treatment policy are combinations of artemether 20 mg-lumefantrine 120 mg (AL) and artesunate 4 mg/kg + amodiaquine 10 mg/kg (AA).  Following this change, there have been safety concerns raised regarding the ACTs with little or no experience/information on the safety profile of ACTs in Nigeria apart from clinical trial studies. The few clinical trials of ACTs in different parts of Nigeria since its introduction have shown good efficacy and tolerability of ACTs in the treatment of uncomplicated malaria in children ,,, and are also consistent with the high cure rates that have been reported for ACT in other malaria-endemic areas of Africa.  No serious adverse effects were observed with these drugs, and they were well tolerated, with comparable profiles.  Although such trials are useful for product registration, they typically evaluate only a small number of specifically selected participants under ideal conditions and have limited statistical power to detect the rare side effects. As a result, clinical trials are inadequate for the full assessment of safety. Consequently, pharmacovigilance (PV), conducted continuously from the time a drug, is developed to the post-marketing phase, becomes critical in evaluating safety. ACTs are now categorised as over the counter medicines widely and readily available in Nigeria, therefore, can be procured from drug stores by all individuals, including the role model mothers who are being actively engaged in the treatment of malaria, without the necessity of a valid prescription from a medical doctor.  These concerns underscore the need for intensive and active monitoring of patients treated with ACTs to determine their safety profile.
Cohort event monitoring (CEM) is a form of active PV developed primarily for malaria-endemic countries where ACTs were introduced as the first-line malaria treatment.  It is recommended by the World Health Organization (WHO) and has already been used to monitor ACTs in many countries like Nigeria. , CEM is a modified version of prescription event monitoring, , a method of intensive post-marketing surveillance for medicines used in public health programmes. CEM is intended for monitoring the safety of a new chemical entity in the early post-marketing phase but is also suitable for monitoring older medicines with new indications.  It can produce more complete information on event profiles, frequencies and associated risk factors in real-life conditions than spontaneous reporting, which is presently the mainstay of safety monitoring of medicines in Nigeria. Initially, a pilot study was conducted in 3000 Nigerians with one centre in the six zones of Nigeria which has demonstrated the power of CEM to provide adverse event (AE) rates.  We observed that ACTs produced AEs among the Nigerian population that were similar to the AE profile of ACTs reported in the literature, including general body weaknesses, dizziness, vomiting, loss of appetite, abdominal pain, etc. These AEs might result in change of therapy among Nigerians. However, these AEs are generally short lived with a mean duration of illness of 3 days. In addition, serious life-threatening events are not common. These suggest that the ACTs monitored in the pilot programme were well tolerated among Nigerians. We anticipate that the scaling up of the programme aiming at assessing 10,000 patients will produce clearer and more complete information which will guide policy decisions. 
The broad objective of the programme was, therefore, to determine the safety profile of ACTs amongst the Nigerian population using AL and AA. The specific objectives were to obtain information on AEs following the administration of AL and AA, establish causality relationship between observed AEs and use of ACTs, document the safety profile of AL and AA, identify risk factors for development of AEs to ACTs, provide evidence for intervention and generate data for decision-making in managing adverse effects of ACTs.
| Patients and Methods|| |
This study was a CEM which was a prospective, longitudinal, inceptional, dynamic and observational programme that monitored AEs in a cohort of patients treated with either AL or AA. The method is designed to capture all AEs that occur in a defined group of patients (the cohort) who are exposed to a specific, newly marketed medicine during the course of routine clinical practice. ,
For this study, a total cohort of 10,000 patients were enrolled. The rational is that generally, a cohort of 10,000 patients will give a 95% chance of identifying a specific event with an incidence of 1:3000 (uncommon or rare).  Patients were enrolled into the cohort as they started treatment on AL or AA on an alternate basis. Demographic information and medical information on the patient's disease status, pregnancy status, past medical history and medication were captured at this initial encounter. Any new medical event (change in clinical condition, new symptoms or diagnoses or significant changes in laboratory parameters) that occurred 7 days before starting the monitored medicine were also recorded at treatment initiation. Patients were then followed at days 3 and 7 after the commencement of treatment to record any new AE that began after starting treatment with the monitored medicines, regardless of whether or not the drug was suspected to have caused the event. Patient recruitment was done in 18 healthcare facilities spread across the six geopolitical zones. The study source population covered approximately 50 million inhabitants (approximately 30% of the Nigerian population at the time). In brief, the 18 healthcare facilities across Nigeria-recruited patients prescribed antimalarials consecutively from the clinics and community pharmacists. Twelve of these facilities were government specialist or teaching hospitals serving the six zones, while six pharmacy shops involved were private community pharmacists located at densely populated areas within the urban communities. Specifically, the sites include from North Central (Nigerian Institute for Pharmaceutical Research and Development Clinic, Federal Medical Center [FMC], Makurdi, Skylark Pharmacy, Gwagwalada Abuja), Northeast (FMC, Gombe, Umoru Shehu Ultra-modern Specialist Hospital, Maiduguri, Rata Pharmacy, Bama Road, Maiduguri), Northwest (General Hospital Kura, Kano, Waziri Shehu Hospital, Kano), South East (University Of Nigeria Teaching Hospital Enugu, FMC Owerri, Lafes Pharmacy Ltd, Enugu), South - South (University Of Uyo Teaching Hospital, Akwa-Ibom, University of Benin Teaching Hospital, FMC Yenaguoa, Ladith Pharm. Co. Ltd), Southwest (University College Hospital, Ibadan, Lagos State University Teaching Hospital, Rosec Pharmacy, Lagos) of Nigeria between January 2012 and May 2012 as a follow-up to the pilot programme carried out in 2009 at six centres.  Recognising that a considerable number of Nigerians seek treatment for malaria from the private sector through community pharmacies, patent medicine vendors and even other sources such as drug hawkers, community pharmacies were engaged for data collection in this programme so as to broaden the base of data collection and get a picture of what is happening in the community.
A total cohort of 10,260 patients were enrolled. All patients with a presumptive or laboratory confirmed diagnosis of malaria were enrolled. The programme involved continuous enrolment of patients treated with ACTs (AL and AA) on an alternate basis at the various sites irrespective of age, sex, co-morbidities or use of other medicines until a total cohort of 600 patients have been enrolled at each site (hospital and community pharmacy). The regimen was according to the malaria treatment guidelines. The only exclusion criteria were infants <2 months (based on the drug guideline) and women in the first trimester of pregnancy (based on medical history, drug guideline and clinical examination at enrolment). Women in the first trimester of pregnancy were excluded by interviewing all women of childbearing age about their last menstrual period to be sure that they were not in the first trimester of pregnancy. Enrolment of patients was carried out by trained on-site personnel at the healthcare facilities.
Since ACTs are taken within 3 days, using site programme coordinators who are doctors or pharmacists, patients were monitored from the onset of therapy to 3-7 days after treatment to identify AEs that may occur. This involved reviewing the patients during their follow-up visits (FUVs) on days 3 and 7 following the day 1 which was the day of the administration of ACTs or following them up if they do not come for FUVs (at home or through phone calls). Within this period, it was expected that common AEs would manifest and patients can still clearly remember any AE they have experienced. However, patients were also advised to contact the sites on any day outside their scheduled visit following the development of any clinical problem.
Advocacy and permission for the programme
Advocacy visits were undertaken to various stakeholder groups including the FMoH, National Agency for Food and Drug Administration and Control (NAFDAC), heads of the healthcare facilities that were used, media houses and other development partners.
Ethical clearance was obtained from the National Health Research and Ethics Committee (NHREC) (Protocol Number NHREC/01/01/2007-23/04/2011, NHREC Approval Number NHREC/01/01/2007-26/04/2011. Date: 30 th April, 2011) of Nigeria, FMoH Abuja and the local Institutional Review Boards of the institutions involved in the programme through advocacy visits to heads of the institutions due to the public health importance of the programme, and verbal consent was obtained from the patients. Participants were informed that their participation was voluntary and they could choose not to participate without having to give any reason. They were informed that the ACTs are the medicines recommended by the national policy for the treatment of uncomplicated malaria and are widely used in the country. Patients were given some stipend to offset the cost of transportation for FUV. Insecticide-treated nets to prevent malaria were also distributed to participants as additional incentives.
Data collection and analysis
Data on patients including their demographic information, medical history including drug use and experiences following the use of ACTs were collected by trained on-site programme personnel using specially designed and pre-tested pre- and post-treatment questionnaires and patient hand-held cards. The study instrument was a well-structured WHO standard questionnaire, corrected and validated by a team of researchers, PV experts, malaria experts, clinicians and relevant professionals adapted the pre- and post-treatment questionnaires to develop the tools used for the pilot CEM in Nigeria.  The pilot CEM consequently served as a pre-test for the tools used in the scale-up programme. All completed questionnaires were forwarded to the National PV Centre from where the data were collated and entered into the CemFlow software (Uppsala Monitoring Centre, Uppsala, Sweden. CEMFlowTM 2013. www.who-umc.org.) for data management and analysis. Statistical Package for the Social Sciences [SPSS] IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.
All information obtained from patients were handled under strict confidentiality. Confidentiality of data was ensured using a number of means such as restricting access to the filled questionnaires to only those directly involved in the programme and keeping them locked in a cabinet at the NAFDAC office. All programme personnel at the sites were de-briefed on the importance of confidentiality. Filled questionnaires were only collected from the sites and sent to NAFDAC office by trained programme supervisors during supervisory visits. NAFDAC guidelines for maintaining the confidentiality of Individual Case Safety Reports, collected routinely from reporters across the country, were also followed in handling the questionnaires.
| Results|| |
All consecutive patients who had a presumptive or laboratory diagnosis of malaria and attended the 18 health facilities to collect medication consented to participate. However, one patient who was enrolled and collected medication could not take the drugs (no reason was given) and as such was not included in the three data analysis. [Table 1] shows the total number of patients recruited during the study programme. Of the 10,259 patients enrolled, 10,217 (99.6%) were reviewed at the first FUV while 9631 (93.9%) came for the second FUV, while 7321 (71.4%) attended only one of the FUVs. Furthermore, 380 (3.8%) patients were followed up at home or by phone calls. Only 15 (0.5%) patients were lost to follow-up at both first and second visits during the study.
[Table 2] shows the baseline demographic characteristics of the study population. It showed that 5931 (57.8%) of the cohort were in the 15-59 year age group. Overall, females comprised 5993 (58.5%) of the cohort, while male consists 4263 (42%). A total of 4896 (47.7%) patients received AA while 5363 (52.3%) received AL; the other demographic data as per age group are also highlighted in [Table 2]. Both groups were statistically comparable as regards to age, weight and sex. Although care was taken to avoid recruiting pregnant women, especially those in their first trimester, 217 (12%) of those who participated in the study were either pregnant or breastfeeding mothers. Of the 217 women, 151 (69.6%) were pregnant. Those in the first trimester/uncertain were 23 (7.1%), second trimester 56 (26%) or third trimester 32 (16%) and those breastfeeding were 89 (40%). In relation to drug taken and pregnancy, 52 (34.4%) were on AA (P = 1.0), while AL = 99 (65.7) group (P = 0.269). The two group are statistically comparable.
Clinical characteristics of the cohort
The symptoms are in keeping with typical malaria symptoms as seen in clinics across the country (fever, headache, joint pains, weakness, vomiting, chill and rigors, etc.) that are seen among patients who received AA/AL. A total number of 3086 patients had at least one co-morbidity at presentation, before administration of monitored ACT. The most commonly reported co-morbidities were hypertension (HTN) 397 (13%), respiratory tract infection (RTI) 213 (7%), dyspepsia/peptic ulcer disease 203 (7%), HIV 117 (4%), arthritis and joint disorders 109 (4.0%). Some patients had both diabetes and HTN 13 (0.4%), epilepsy/seizure disorders 9 (0.3%) and sickle cell disorder 29 (0.9%).
Pattern of adverse events
[Table 3] shows the incidence of events recorded on the first FUV (day 3 of medication) and the second FUV (day 7 of medication). Six thousand one hundred and two AEs were recorded during the monitoring programme, 4233 events were recorded on day 3 and 1869 on day 7 and classified according to system organ classification. The incidence of most predominant specific events seen were from neuropsychiatry, autonomic nervous system and musculoskeletal systems with weakness predominating 1510/403 (22.214.171.124%), dizziness 502/207 (10.3/3.9%), restlessness 244/59 (5.02/1.12%), vomiting 170/55 (3.5/1.03%), drowsiness 151/78 (3.1/1.5), etc., for AA and AL on days 3 and 7, respectively. Of 4896 patients who received AA, 4233 patients reported at least one AE while 1869 AEs was reported out of the 5363 patients who received AL. The number and incidence rate for the reported AEs are provided in [Table 3].
|Table 3: Incidence of adverse drug events recorded at follow - up visits |
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Few patients presented during the programme with rare but life-threatening serious AEs. Ninety-eight (2.3%) patients in AA study group, presented with fainting attacks, 17 (0.4%) with tremors, other serious events include shock 5 (0.1%), convulsions 1 (0.02%), inability to stand 2 (0.05%), sudden collapse 1 (0.02%), hot flushes 1 (0.02%), palpitations 9 (0.2%), yellowish urine 4 (0.09%) and overt haematuria 2 (0.11%).
In the AL study group, the following serious life-threatening events were observed: fainting attack 5 (0.3%), tremors 5 (0.3%), dyspnoea 1 (0.05%), yellowish urine 2 (0.11%), pallor 1 (0.05%) and jaundice 1 (0. 05%). Causality assessment was done (according to the WHO-Uppsala Monitoring Center [UMC] causality categories)  on each to ascertain their probability of being an adverse drug reaction (ADR). The WHO-UMC causality assessment method includes the following four criteria: (a) time relationships between the drug use and the AE. (b) The absence of other competing causes (medications, disease process itself). (c) Response to drug withdrawal or dose reduction (de-challenge). (d) Response to drug re-administration (rechallenge).
The level of causal association is grouped into six categories which are based on a number of the above criteria being met. Causal category is 'certain' when all the four criteria are met. It is 'probable' when criteria a, b and c are met. When only criterion a is met, the event is categorised as 'possible' and it is 'unlikely' when criteria a and b are not met.
Although active efficacy protocol was not observed during the monitoring programme, clinical assessment of patient's response to therapy was observed [Table 4]. Ten thousand two hundred and thirty-nine (99.8%) patients recovered from the signs and symptoms of malaria completely by the second FUV at day 7. At first FUV (day 3), 1436 (14%) of the patients still had no change in clinical symptoms, however, by the second FUV (at day 7), only 14 (0.14%) patients still had some complaints.
During the programme, however, life-threatening serious AEs were observed and referred for further management. The reason for referrals includes acute dystonic reactions, extreme dizziness, convulsions, fainting attacks and progression of the disease. Some of these causality assessments have been carried out and confirmed to be drug related.
Multinomial logistic regression was conducted to evaluate the effects of some risk factors on ACT-based combination therapy among Nigerian populations [Table 5]. Patients with co-morbid conditions and taking other drugs for chronic conditions such as epilepsy or seizure disorders, hypertensive diabetic patients and those on traditional medications, female gender and pregnant women appeared to be more susceptible to AEs than those without these conditions. Those taking AA, as combinations of ACT, are also more at risk of AEs than those on AL. The younger age groups and the very old are more susceptible to the AEs than the middle age group (9≤15 years) (P < 0.0001).
| Discussion|| |
The WHO Technical Report 498 (1972) defines AEs as any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment. ADR is defined as a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man. , The phrase 'response to a medicinal product' means that a causal relationship between an AE and a medicinal product is at least a reasonable possibility, i.e., a relationship cannot be ruled out. By this, therefore, a relationship between many of the reported AEs and the monitored medicines (ACT) cannot be ruled out although they may also be explained by the disease (malaria) being treated, and concomitant drugs used or co-morbid conditions can present with similar symptoms, the plausible time profile can make the events suspected ADRs as seen in this programme.
Evidence is now emerging from studies revealing that artemisinin and its derivatives are effective, safe and remarkably well tolerated, which generally is supported by findings of this CEM monitoring programme, ,,,,,, and even though severity is a subjective assessment made by the patient and/or the clinician using WHO severity guidelines and the literature, , most of the events recorded were of mild to moderate severity. The most predominant events seen were from central nervous system/neuropsychiatry, autonomic nervous system and musculoskeletal with weakness predominating such as dizziness, restlessness, vomiting and drowsiness. These findings confirm the relative safety of ACT use as reported by the previous studies. ,, Furthermore, most of the events were not unexpected as they are mentioned in the summary of product characteristics of the drugs.
During the programme, however, few serious events, some life-threatening AEs were observed and referred for specialist management. The observed serious AEs include acute dystonic reactions, extreme dizziness, convulsions, fainting attacks (suggestive of extrapyramidal tract reactions) and progression of the disease. Some of these were subjected to causality assessment and confirmed to be possibly causally related. This follows a similar pattern seen during the pilot programme  and findings in some clinical trials. A recent publication by McEwen J (2012), supports an "association of the use of AS-AQ combination therapy with acute extrapyramidal reactions, such reactions occurred with recommended, and in some instances reduced, daily doses. It is recommended since such reaction is unpleasant and frightening, the association warrant being more closely and clearly recorded in official treatment guidelines and summary product characteristics". 
Mild to moderate gastrointestinal disturbances, such as nausea, anorexia, vomiting and diarrhoea, with abdominal disturbances such as abdominal pain and discomfort including constipation were also reported almost twice as much with AA group than AL. The frequency of gastrointestinal symptoms more related to AA than AL as has been reported in others studies. , Most of the serious events observed during this programme were linked to AA.
Artemisinin and its derivatives inhibit erythropoiesis in the early foetus and cause foetal resorption in all experimental animals tested to date.  This can, in some circumstances, lead to developmental abnormalities in rodents and rabbits. ,,, Because these drugs have not been evaluated extensively in early pregnancy in humans, they should be avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more information is available.  Although up-to-date, there is no evidence for adverse effects on the foetus exposed in the second and third trimesters; when these drugs are recommended depending on the safety profile of the drug used, we observed this caution as a rule during the CEM programme. We assessed some risk factors which might influence the AEs in some individuals, making them to be more at risk of AEs than others in the Nigerian populations using multinomial logistic regression. Similar to what was observed in the pilot, some patients presented with co-morbidities, the most common being HTN, dyspepsia/peptic ulcer disease, HIV, arthritis and joint disorders. The study shows that there is a statistical difference in the occurrence of AEs between patients who had co-morbid conditions and took other drugs for chronic conditions such as epilepsy/or seizure disorders, hypertensive/diabetic patients and those who took traditional medications (P ≤ 0.05, 0.005, 0.001, respectively).
Women who were pregnant appeared to be more susceptible to AEs than those without these conditions. Those taking AA were also more at risk of AEs than those on AL (P < 0.010). Patients in the age group 15 years and above which includes the adults were more prone to AEs than children below 9 years of age probably due to awareness or previous experiences with side effects of antimalarial. In the age group of <5 years, gastrointestinal tract- and respiratory tract-related AEs are more predominant than adults. This is expected as malaria usually presents in children with upper RTI (URTI), and diarrhoea and vomiting are common presenting features of malaria in children.  This finding is similar to some earlier clinical trial in a Nigerian study of AA and AL  where cough as the most frequent AE was reported. Another study by Oguche et al.  in Ibadan, which compared AL with artesunate-mefloquine (AM), reported anaemia, cough, URTI, vomiting (early and late), bronchitis and diarrhoea as AEs that occurred in more than 5% of patients in the two treatment groups. 
The younger age groups (9-<15 years), are more susceptible to the AEs than middle age group P = 0.000. This appears also to support the study in Senegal by Brasseur et al. 2009, in which low weight was an independent risk factor for overdosing with AS-AQ, and hence, more reactions are seen. This is probably because the younger and very old as they may not fit well into age and weight group dosing in the national malaria treatment guidelines.
Finally, although active efficacy protocol was not observed during the monitoring programme, clinical assessment of patient response to therapy was observed as seen in 99.8% (10,239) of the patients recovered from the signs and symptoms of malaria completely by the second FUV at day 7. At the first FUV (day 3), 1436 (14%) of the patients reported no change in their clinical symptoms or just slight improvement; at the second FUV (at day 7), only 14 (0.14%) patients still had some complaints.
Experience with large-scale, long-term deployments of ACT is now becoming available as data exist from areas of moderate or high transmission. AA (AS + AQ) is one ACT that has been used in several African countries and is on the national policy in Senegal since 2006. Although its efficacy varies across regions in Senegal, in chloroquine-resistant Casamance, Southern Senegal, both AQ alone and AS + AQ have consistently resulted in high cure rates (>90%) in recent years. ,,,,,, In South Africa-Mozambique border, AM and AL, respectively,  have also resulted in large reductions of the malaria burden, where AM and AL, respectively,  have resulted in large reductions of the malaria burden. , Olusola et al. 2013,  demonstrate that 5 years after being introduced in Nigeria, both AL (Coartem) and fixed dose AA (Larimal) have been shown to be safe and highly effective in Nigerian children. 
| Conclusions|| |
Various types and degree of AEs were observed and documented with ACTs monitored among Nigerians. The pattern of AEs is similar to AEs observed in the pilot study and other literature. The majority, 99.8% (10,239), of the patients recovered completely from the signs and symptoms of malaria by the second FUV at day 7, suggesting that artemisinin is effective in the treatment of uncomplicated malaria among Nigerians. In summary, the artemisinin derivatives AA/AL, monitored during this programme are generally safe, effective and remarkably well tolerated among Nigerian populations.
Limitation of the study
In this study, events were actively assessed at all FUVs, with interviews, and a standard physical examination at standard intervals, pre-study training and onsite reviews was done. However, reporting events related to drug tolerability, such as anorexia and weakness, by relying on reporting of symptoms by participants, or assessing only for objective measures, such as serious AEs may not be assessed same way across all the centres. There might have differences in tolerability. Understanding and reporting of the symptoms also may depend on knowledge and skills of the attending clinician, which may differ and introduce bias.
CEM study is supposed to be under real-life situation without the gadgets of clinical trials to allow observation in real-life setting, and although as much as possible clinic settings were not interfered with in this study, patients were briefed and events were actively assessed at all FUVs, with interviews, and a standard physical examination at standard intervals may have given the patients an impression of being enrolled in clinical trials, and symptoms may have been exaggerated.
The principal investigator and coordinators of this CEM scale-up programme are grateful to all the healthcare personnel (doctors, pharmacists, nurses and other healthcare provider), patients and the leadership of the 18 healthcare facilities for their support and/or involvement in this work.
Special appreciation goes to Dr. Paul Ohii MBBS, MD, PhD OON, Former Director General NAFDAC, Nigeria, the host agency for the financial supplement that facilitates completion of the scaling programme.
The CEM scale-up programme was made possible by grant and training from the WHO, Department of Essential Medicine and Health Products, WHO, Geneva, Switzerland, The National Malaria Control Programme, Federal Ministry of Health, Abuja and Society for Family Health, Abuja. The Yakubu Gowon Centre, Nigeria, Novartis Pharmaceuticals, Lagos, Nigeria assisted the programme with drugs and long lasting insecticides - treated mosquitoes net, plus travel subsidies for patients.
We appreciate the chairman and staff of the National Health Research and Ethics Committee for the expedited ethical approval for the programme.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]