Adisa et al

Tropical Journal of Pharmaceutical Research, June 2008; 7 (2): 937-944 © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, Nigeria. All rights reserved .

Available online at http://www.tjpr.org Research Article

Evaluation of Adverse Drug Reactions to - based in a Nigeria University Community

R Adisa *, TO Fakeye and D Dike Department of Clinical Pharmacy & Pharmacy Administration, University of Ibadan, Ibadan, Nigeria.

Abstract

Purpose: The study was carried out to evaluate the incidence of adverse reactions to antimalarial drugs among residents of a Nigeria university community with a focus on artemisinin-based combination therapy (ACT). Specifically, the profile of use, and the reporting culture of people with respect to experienced reactions were noted. Method: Questionnaires were administered to respondents at the university health centre between November 2006 and January 2007. Information on demographic characteristics, nature of experienced adverse reactions and the most frequently used ACT, among other questions, were collected. Descriptive statistics and Fisher’s Exact test were used to evaluate the distribution of respondent’s opinion. Result: The study achieved a response rate of 86%. The results revealed that 210 (70.0 %) of respondents said they had used artemisinin-based combination drugs while 134 (44.7 %) said they used artemisinin derivatives alone as monotherapy for treatment. plus 94 (31.3%) as a co-packaged product was the most commonly used ACT. Incidence of the experienced adverse reactions to ACT was reported to be generally mild and well tolerated. Conclusion: Efforts to improve the use of ACT in the management of acute uncomplicated P. falciparum malaria is recommended. Furthermore, an effective mechanism to improve reporting of adverse effects of ACT is also recommended

Keywords: Adverse Drug Reaction, Artemisinin- combination therapy (ACT), malaria

*Corresponding author: Email: [email protected] & [email protected] Tel: 2348034226199

937 Trop J Pharm Res, June 2008; 7 (2) Adisa et al

INTRODUCTION Nigeria has successfully adopted the use of In many Africa countries, intensity of malaria artemisinin-based combination therapy for transmission is high and antimalarial drugs malaria treatment for more than two years are used frequently for presumptive treatment with WHO recommended drug-combinations of fever, even in the absence of laboratory available in the country under different confirmed malaria diagnosis 1, 2, 3, 4, 5 . Informal proprietary names. To the best of our use of antimalarial drugs may increase the knowledge, there are no substantial reports of risk of incorrect dosing, inappropriate incidence of adverse effects associated with treatment, occurrence of adverse drug the use of these medicines aside those reactions and interaction of different documented during clinical trials or pre- medicines, which could have a negative marketing phase. However, obtaining impact on antimalarial treatment safety 5, 6, 7, 8 . information on adverse reaction profile of ACT Increasing parasite resistance and failure of will be necessary in countries (such as single drug treatment of malaria in many Nigeria) where self-treatment with antimalarial endemic countries of Africa 9 has led to a drugs is pervasive. This is to ensure that the widespread promotion of artemisinin-based common and rare adverse drug events to ACT combination therapy (ACT) as a strategy for are documented and, also to ensure that effective management of patients are getting the desired therapeutic falciparum malaria 10 . World Health benefits rather than negative consequences Organization (WHO) has, since 2001, on account of such adverse drug effects. recommended that malaria endemic countries To detect such adverse events, monitoring the change their treatment policies and adopt use and evaluating patients’ response to combination therapy, and in particular antimalarial drugs, particularly the new artemisinin-based combination therapy as the combination therapies, outside of clinical trials first- line antimalarial treatment 11 . Artemeter- at the health facilities and community levels , artesunate (AS) plus becomes essential 14,15,16 . It is in line with amodiaquine (AQ), artesunate plus this background that this study was carried out sulphadoxine/ (SP), and to evaluate the incidence of adverse drug artesunate plus are some of the reactions to antimalarial drugs among ACT that have been recommended for use in residents of a Nigerian university community Africa based on available efficacy and safety with a focus on artemisinin-based combination data 11, 12. therapy (ACT). Information on the profile of The current plans for a wide- scale use and reporting culture of people with implementation of ACT across Africa offer an respect to experienced adverse reactions to opportunity to evaluate the occurrence of ACT were also obtained. adverse drug reactions to these medicines when used in the larger population or the METHODS community. Gabon and Sao Tome had The study area, University of Ibadan, is the implemented the use of artesunate plus oldest university community in the country. It amodiaquine, with report of minor side effects has all the necessary infrastructure and while Burundi and Zanzibar reported that the amenities that can be found in a typical safety of ACT for the last two years had been community including offices and housing good 1,12 . Other Africa countries are at various accommodation for staff, their families and stages of preparations to implement chosen students of the institution. The study site, the ACT. China, Thailand and South East Asia university health centre, has in its employment are also some of the countries that have used 10 physicians, 5 pharmacists, 22 nurses, 2 artemisinin-based combination therapy physiotherapists, 13 laboratory technologists extensively with no report of any serious and other ancillary health workers. It is also adverse reactions 13 . the only clinic within the university

938 Trop J Pharm Res, June 2008; 7 (2) Adisa et al environment that caters for the health care statistics were used to evaluate the needs of the entire university community. distribution of respondent opinions to other The study design was cross-sectional and questions. level significance (p) was set at involved the use of structured questionnaires 0.05. administered to the patients at the study site within a period of three months (November RESULTS 2006-January 2007). The questionnaire was Three hundred questionnaires which were designed to have two sections: the first properly filled were analysed. There were 160 section contained questions on demographic (53.3 %) male and 140 (46.7%) female characteristics of respondents while the respondents, out of which, 225 (75.0%) were second section contained open- and closed- single while 75 (25.0%) were married. ended questions to obtain relevant information Respondents in the age group of 21-30 years on the experienced adverse reactions to constituted the largest proportion 172 (57.3%), antimalarial drugs, particularly ACTs. while only 8.7% were 41 years and above; Information was also obtained on the profile of those in the age groups 12-20 and 31-40 use, adverse drug reaction reporting culture of years constituted 55 (18.3%) and 47(15.7%), respondents, among other questions. The respectively. Opinion on the frequency of use questionnaire was pre-tested among five of antimalarial drugs showed that a majority, experienced heath care workers (3 127 (42.3%) had used antimalarial pharmacists and 2 doctors) in the locality for for presumptive treatment of fever, 100 content validity and these individuals were (33.3%) took these drugs only when it was subsequently not included in the study. recommended in the hospital, while 48 Permission to conduct the study was obtained (16.0%) claimed to have taken antimalarial from the authorities of the University Health drugs occasionally for prophylactic treatment Services and approval to conduct the study at of malaria. the centre was granted. Subjects who One third of the respondents, 102 (34.0%), presented at the study site with symptoms believed that they have malaria whenever suggestive of malaria fever or history of recent there is high body temperature; 94 (31.3%) fever were approached for participation in the mentioned joint pains and loss of appetite as study, after they had seen their physicians. the symptoms that prompt them to self- The objective of the study was explained to treatment with antimalarial drugs. Eighty-four the subjects and those who were interested in (28.0%) said they do not take antimalarial the study consented to participate. Informed drugs until physician’s diagnosis indicate verbal consent was obtained from individual malaria illness, while only 20 (6.7%) claimed subject at every contact. Excluded from the that they do not treat malaria until they study were children, pregnant women, and undertake laboratory confirmation for malaria unconscious patients. Participating subjects parasites. The frequency profile of antimalarial were assured of their anonymity. drugs used by respondents is shown in Table Three hundred and fifty questionnaires were 1. administered directly to the subjects at the Two-thirds of the respondents, 206 (68.7%), study site within the three-month period. Each said they have access to artemisinin-based participant was given between 20 and 30 combination therapy since these medicines minutes to fill in their responses. Only the 300 are readily available for purchase in most questionnaires (85.7%) that were properly pharmacies and patent medicine shops, while filled were subjected to statistical analysis. 25 (8.3%) believed that both the branded and Data generated were analyzed using Graph generic products of artemisinin-based Pad InStat ® 3. Fisher’s Exact Test was used combination drugs are not accessible because to determine whether there was an they are expensive and unaffordable. Fifty association between certain variables and (16.7%) respondents would not allow the high some of the responses, while descriptive cost of ACTs to discourage them from

939 Trop J Pharm Res June 2008; 7 (2) Adisa et al purchasing the drug as long as they find the reporting were that most of the reactions were drug effective. tolerable and some respondents were not Out of the total number of respondents 210 knowledgeable on how and where to report (70.0%) that had used artemisinin-based such reactions. However, 17 (24.6%) of those combination drugs (namely artesunate plus that experienced adverse reactions claimed to amodiaquine, arthemether-lumefantrine, have reported these reactions to a health artesunate plus sulphadoxine/pyrimethamine, care provider and appropriate advice were and artesunate plus mefloquine), 69 (32.9%) given based on the reaction experienced. had experienced one form of reaction or the Fisher’s Exact statistical test showed that other with the administered ACT, while 137 sex did not appear to have any significant (65.2%) had not. The experienced reactions, relationship with the incidence of experienced summarized in Table 2, were mainly some of adverse reactions to the ACTs used (P=0.25) the common adverse effects documented in (Table 3) literature to be associated with the corresponding ACT. Respondents found these DISCUSSION reactions tolerable. More than two-third of the respondents in this Itching or pruritus was experienced by only study had used ACT, which is probably an 0.3% of the respondents that took artesunate indication of increased awareness by the plus amodiaquine and artesunate plus people on the use of ACT for treatment of mefloquine, whereas twenty-two percent uncomplicated falciparum malaria. However, experienced needle-prick sensation with almost half of the respondents used monotherapy. Rashes were antimalarial drugs including ACT for self- completely absent with most respondents that treatment of malaria indicating irrational use of used ACT except with 0.7% of the the antimalarial agents. Such an informal use respondents who combined artesunate with of drugs may increase the risk of drug sulphadoxine/pyrimethamine, a reaction that problems and consequently, could have a was also experienced by 3.3% of respondents negative impact on the continued on sulphadoxine/pyrimethamine monotherapy. effectiveness and safety of antimalarial Incidence of vomiting and abdominal pain was treatment 5, 6, 7, 8. more with artemeter-lmefantrine 1.7% and Despite the usefulness of artemisinin 4.0% respectively, while 1.3% and 2.3% of the derivatives, its use as monotherapy should not respondents that took artesunate plus be encouraged due to the possibility of amodiaquine experienced nausea and emergence of resistance strains to the single abdominal pain respectively. drug treatment on repeated and inappropriate General body weakness was experienced by use 9,10,17 . Close to half of the respondents in respondents who combined artesunate with this study were found using artemisinin amodiaquine (5.3%), artemeter-lumefantrine derivatives as monotherapy, a practice that (2.7%), artesunate plus mefloquine and may lead to the development of resistant artesunate plus sulphadoxine/pyrimethamine strains. There is a need to encourage had 2.3% each. Body weakness was also patients to combine an artemisinin derivative experienced by 5.0% of respondents on with another antimalarial drug that has a chloroquine monotherapy. Ear and eye longer half life such as amodiaquine, disturbances were experienced by 1.3% and lumefantrine, sulphadoxine/pyrimethamine 1.0% of the respondents that took artesunate and mefloquine, in order to ensure complete plus amodiaquine and artemeter-lumefantrine eradication of malaria parasites and allow for respectively. a reduction in the duration of antimalarial A majority, 52 (75.4%), of those that treatment 10,18,19,20 . experienced adverse reactions with ACTs did Artesunate plus amodiaquine was found to be not report the reactions to any health care the most commonly used ACT despite some professional. The reasons given for not of the adverse drug reactions experienced

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Table 1: Frequency profile of antimalarial drugs used by respondents

Drugs Frequency Percentage (%) Artesunate plus Amodiaquine 94 31.3 Artemeter- lumefantrin 47 15.7 Artesunate plus 41 13.7 Sulphadoxine/pyrimethamine Artesunate plus mefloquine 28 9.3 Artesunate alone 134 44.7 Sulphadoxine/pyrimethamine 202 67.3 Chloroquine 166 55.3 Amodiaquine 35 11.7 Halofantrin 5 1.7

such as general body weakness, ear and eye general weakness , blurred vision and disturbances, abdominal pain and dizziness. fatigue 12. Some of these reactions could have been due Artemeter-lumefantrin recorded the highest to the amodiaquine component of the number of respondents with incidence of combination. The preference of artesunate abdominal pain. Abdominal pain has been combined with amodiaquine by most people documented in literature as one of the for the treatment of malaria may probably be bothersome side effects of artemeter- due to availability of several branded lumefantrine that may affect adherence 21 , products of artesunate plus amodiaquine in though none of the respondents claimed to the country and its relatively low cost when have stopped the use of this combination compared with artemeter-lumefantrine. because of abdominal pain. Itching/pruritis which has been known to be It is encouraging to note that though most of one of the worrisome side effects of the respondents had experienced incidences chloroquine and sometimes amodiaquine of adverse drug reactions with the use of ACT, rarely occurred in most respondents that took the general inference that could be drawn ACT. This is encouraging since needle-prick from their responses was that they found the sensation is one of the side effects that reactions tolerable. There was no report of discourage patient adherence to treatment life-threatening adverse drug reactions that using 4-aminoquinoline antimalarial agents. could warrant termination of treatment or drug Rash was not found to occur in most use. This has confirmed reports from China, respondents that took artemisinin-based Thailand, South East Asia and other Africa combination drugs except for a few of the countries where ACTs have been used respondents that took artesunate plus extensively and were found to be relatively sulphadoxine/pyrimethamine, a reaction which safe and well tolerated 5, 6, 7, 8 . was probably due to the Most respondents that experienced adverse sulphadoxine/pyrimethamine component of reactions with ACT did not report those the combination. reactions to any health care professional. General body weakness, blurred vision or However, a few that did were not given any dizziness which were experienced by some adverse drug reactions (ADR) form to fill but respondents that took artesunate plus were given appropriate counsel. This finding amodiaquine, could also have been due to the indicates the poor reporting habit of ADR by amodiaquine component since some of the health care providers 22 , and is one of the documented side effects of 4-aminoquinoline issues that need to be addressed by the body antimalarial agents includes dizziness, in charge of pharmacovigilance.

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Artesunate Artesunate Table2: ethamine ethamine Sulphadoxine/pyrim + Artesunate Mefloquine + Artesunate lumefantrin Artemeter- (AQ) Amodiaquine + Artesunate(AS) (as monotherapy) Amodiaquine ethamine Sulphadoxine/pyrim Chloroquine DRUGS Adversedrug reactions experienced byrespondents and thean - 1(0.3) - 1(0.3) 1(0.3) 1(0.3) 3(1.0) 65(21.7) Itching/Urticaria/ Pruritus N (%) 3(1.0) 3(1.0) 1(0.3) 1(0.3) 4(1.3) 3(1.0) 3(1.0) 4(1.3) 3(1.0) Nausea N (%) 1(0.3) 1(0.3) 2(0.7) 5(1.37 3(1.0) 2(0.7) 3(1.0) 1(0.3) 1(0.3) Vomiting N (%) 2(0.7) 2(0.7) - - - - - 10(3.3) - Blistered Rash N (%) 7(2.3) 7(2.3) 7(2.3) 8(2.7) 16(5.3) 10(3.3) 8(2.7) 13(4.3) 15(5.0) General Weakness N (%) 1(0.3) 1(0.3) 1(0.3) 3(1.0) 4(1.3) 1(0.3) - - 4(1.3) Ear/eye Disturbance N (%) 1(0.3) 1(0.3) 3(1.0) 5(1.7) 6(2.0) 2(0.7) 2(0.7) 3(1.0) 6(2.0)

Headache timalarialdrugs implicated N (%) 4(1.3) 4(1.3) 3(1.0) 12(4.0) 7(2.3) - - 1(0.3) - Abdominal Upset N (%) 1(0.3) 1(0.3) 3(1.0) 3(1.0) 5(1.7) 6(2.7) 1(0.3) 7(2.3) 13(4.3) Dizziness N (%) - 1(0.3) 1(0.3) - - - 1(0.3) - Diarrhea N (%) - - - 1(0.3) 1(0.3) - 2(0.7) 1(0.3) Drowsiness N (%) 3(1.0) 3(1.0) - 3(1.0) - - 1(0.3) 1(0.3) - Palpitation N (%)

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Table 3: Fisher’s Exact Test to show the relationship between sexes and respondent’s experience of adverse reactions to artemisinin based combination therapy (ACT).

ADR(YES) ADR(NO) 2 95% CI Remark N (%) N (%) sided P value Sex Male 35(17.0) 75(36.0) 0.5580- 0.2525 1.157 Not significant Female 40(19.0) 61(29.0)

Level of significance was set at 0.05 C I = Confidential interval

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