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Year : 2012  |  Volume : 44  |  Issue : 2  |  Page : 257--260

A prospective study of adverse drug reactions to artemisinin-based combination therapy in a tertiary care hospital in India

Mahesh N Belhekar1, Manjari G Advani2, Sudhir R Pawar2,  
1 Department of Clinical Pharmacology, T.N. Medical College and B.Y.L. Nair Charitable Hospital, Mumbai Central, Mumbai, India
2 Department of Pharmacology, L.T.M. Medical College and L.T.M. General Hospital, Sion, Mumbai, India

Correspondence Address:
Mahesh N Belhekar
Department of Clinical Pharmacology, T.N. Medical College and B.Y.L. Nair Charitable Hospital, Mumbai Central, Mumbai


Objectives: Antimalarial drugs are commonly prescribed for the treatment of malaria and suspected cases of malaria in India. The recent trend is to prescribe ACT and the incidence of adverse reactions to this therapy is notwell-documented in Indian population. Therefore, this study was designed to assess ADR pattern of antimalarial drugs particularly ACT in India. Materials and Methods: Over a period of 1 year, 500 patients who were administered antimalarial drugs were enrolled in the study. The World Health Organization causality assessment scale was used for classifying the ADR. Results: In this study out of 500 patients, 251 complained of ADRs. The sex-wise difference in reporting of ADRs was statistically not significant (P=0.0943). The most common ADRs reported were nausea, anorexia and vomiting. ADRs were most commonly reported when chloroquine was coprescribed. Conclusions: This study indicates that ACT was commonlyused in the treatment of malaria. Results of the analysis suggest that all the ADRs were of moderate intensity and no serious ADR was observed. This baseline information will be useful to implement the ACT in India.

How to cite this article:
Belhekar MN, Advani MG, Pawar SR. A prospective study of adverse drug reactions to artemisinin-based combination therapy in a tertiary care hospital in India.Indian J Pharmacol 2012;44:257-260

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Belhekar MN, Advani MG, Pawar SR. A prospective study of adverse drug reactions to artemisinin-based combination therapy in a tertiary care hospital in India. Indian J Pharmacol [serial online] 2012 [cited 2021 Feb 28 ];44:257-260
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Malaria continues to be a major public health problem, in spite of enhanced control efforts, mostly in Africa and parts of Asia. In 2008, approximately 243 million people fell sick with malaria, with a majority of cases in the African region (85%), causing death of nearly one million people, 85% of whom were children under 5 years of age. [1] Malaria and poverty are connected. In the countries where malaria has an impact on public health, it is also severely hampering economic development. [2] As a consequence of increasing resistance of the malarial parasite to previously effective monotherapies including chloroquine (CQ) and sulphadoxine-pyrimethamine (SP), the World Health Organization (WHO) held a technical consultation in 2001 endorsing the potential of artemisinin-based combination therapy (ACT) for drug-resistantmalaria. [3] Antimalarial combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. [4] The objective of a national antimalarial treatment policy in India is to enable the population at risk of malaria infection to have access to safe, good quality, effective, affordable and acceptable antimalarial drugs. [5] By 2009, most malaria-endemic countries had introduced ACT in their national drug policy, as first-line treatment for uncomplicated Plasmodium falciparum malaria. The detection of adverse drug reactions (ADR) mainly depends on detailed and elaborate drug history of the patient. The diagnosis of ADR is by exclusion of other disease and assessment of the causal relationship. [6]

Inappropriate treatment, incorrect dosing, drug-drug interaction, administration in populations suffering from or being treated against concomitant diseases like HIV/AIDS, tuberculosis, malnutrition and anemia can all impact negatively on drug safety and efficacy. [7],[8] In general, safety information can be collected through two main pharmacovigilance channels: (a) spontaneous reporting and (b) systems using pharmacoepidemiological methods through phase IV clinical trials or cohorts. [7],[9] While spontaneous reporting is essential for signal detection of rare events, the pharmacoepidemiological methods provide additional information on both, the utilization and the extent of consumption that will permit the determination of frequency of ADRs in the studied population or the safety comparison between two or more products. [9] Although ACT isgenerally considered safe, there is still little structured information about their use in real-life settings and the published data are mainly from clinical trials. [10]

The present study analyses the ADRs to the ACT according to demographic distribution and to determine the causal relationship.

 Materials and Methods


The study was conducted over a period of 1 year in a tertiary care hospital in India. Ethics Committee approval was obtained before commencing the study.

Study Population

Five hundred patients (318 males and182 females) hospitalized in medical ward receiving antimalarial agents for treatment of fever were enrolled in the study. Patients were enrolled in the study after obtaining the written informed consent.

Data Collection

The study was based on Cohort Event Monitoring (CEM) system. CEM records all clinical events and not just suspected ADRs. Event monitoring involves actively and systematically asking for reports of all the drug-related events. CEM is a prospective, observational, cohort study of adverse events associated with one or more medicines. [11]

Data Analysis

Information from patients was recorded in a case record form. WHO causality assessment scale [12] was used for classifying the adverse drug events as certain, probable, possible, unlikely, unclassified or unassessable.


Treatment with Antimalarial Drugs

As evident from the findings [Table 1], the most frequent drugs prescribed were ACT. Artesunate and doxycycline was administered to 279 (55.8%) patients, and artesunate and chloroquine was administered to 86 (17.2%) of patients. Twenty-six (5.2%) patients were prescribed chloroquine; however, 20 (4%) of these patients did not show clinical improvement for the next 2 days and were then administered artesunate with doxycycline instead of chloroquine [Table 1]. Concomitant drugs used were antiemetics, cytoprotective drugs and paracetamol.{Table 1}

Occurrence of ADRs

It is evident from the findings of [Table 2] (a) that out of 500 patients, 251 (50.2%) patients reported ADRs subsequent to antimalarial treatment. A total of 442 ADRs were reported, since many patients complained of more than one ADR. Out of 318 male patients 169 (53.15%) complained of ADRs and out of 182 female patients 82 (45.1%) complained of ADRs.{Table 2}

Statistical Analysis of Sex Distribution of ADRs

The observations for sex distribution of ADRs was analysed statistically using Fischer's exact test. The sex wise difference in reporting of ADRs was statistically not significant (P=0.0943) [Table 2].

Incidence of ADRs

It is evident from the findings [Table 3] that 169 male patients complained of 305 ADRs and that 82 female patients complained of 137 ADRs as more than one ADR was observed in most patients. The most common ADR reported was nausea (in 208 i.e., 41.6% patients), followed by anorexia (in 104 i.e., 20.8% patients), vomiting (in 75 i.e., 15% patients), bitterness in mouth (in 34 i.e., 6.8% patients) and other ADR events like giddiness and dizziness in (in 21 i.e., 4.2% patients) [Table 3].{Table 3}

Causality Assessment

Causality assessment of all the ADRs was done according to WHO causality assessment scale. [12] Almost all the adverse reactions were possibly due to the treatment and small percentages were unlikely due to the treatment [Table 4].{Table 4}


Pharmacovigilance deals with the vital mechanism for evaluating and monitoring the safety of medicines in clinical use. It is a division of patient care. It aims at getting the best outcome of treatment with medicines. No one wants to harm patients, but unfortunately, because of many different factors, any medicine will sometimes do this.

Malaria is the greatest killer disease of all time. Unfortunately, after a period of relatively good control in many countries with the use of insecticides and antimalarials such as chloroquine, there has been a resurgence of this disease. This is due to the development of resistance of mosquitoes to insecticides and resistance of parasites to antimalarials, thus producing an increase in morbidity and mortality due to malaria. WHO is promoting the use of ACTs as a therapeutic tool to treat uncomplicated acute falciparum malaria. [13]

In Thailand, Price et al., achieved a significant reduction in transmission with artesunate in combination with mefloquine, compared with mefloquine as monotherapy. [14] Studies have shown that Gambian children treated with sulphadoxine-pyrimethamine (SP)+artesunate (three doses) were five times less likely to produce infectious gametocytes as children treated with SP alone (Targett et al.). [15] ACT is known to be effective, but its safety under large-scale operational use has not been fully assessed. A range of ACTs is being recommended by WHO and it is important that these are carefully monitored. [13] ACT is also now prescribed for all suspected malaria patients who have severe symptoms for more than 2 days.

ADRs to individual drugs are well documented but very little information is available of the ADR profile when these drugs are combined. Therefore, this study was planned to observe the incidence of ADRs occurring with antimalarials particularly with the ACTs. WHO causality assessment scale was chosen as it is a simple method for causality analysis in large number of subjects. Also in this study no other interventions were done.

No rechallenge or dechallenge with drug was studied since discontinuation of treatment would have adversely affected the treatment and increased susceptibility to the development of resistance to antimalarial drugs. Also ADRs observed were not serious and hence did not merit discontinuation of the drug.

Out of 500 patients 402 (80.4%) patients were administered ACT, whereas the remaining were administered either chloroquine and doxycycline or only artesunate or only chloroquine. The most frequently used ACT was artesunate and doxycycline in 56% of patients as it not only provides symptomatic relief but prevents recrudesce as well as drug resistance. [16]

The other ACTs prescribed were artesunate and chloroquine in 17%, artesunate and mefloquine in 2.2%, artesunate and sulfadoxine-pyrimethamine in 1.2% of patients. The rationale for all these combinations is the same as discussed above.

Chloroquine and doxycycline were combined in 10% of patients. 5.2% (26) patients were prescribed chloroquine; however, 77% of these patients did not show clinical improvement for the next 2 days and were then administered artesunate with doxycycline instead of chloroquine. These patients were considered to be clinically resistant to chloroquine.

For symptomatic treatment of fever, patients were administered paracetamol; for patients with anemia, multivitamin B complex and ferrous sulfate and folic acid tablets were given during the hospitalization. For prophylaxis and treatment of gastrointestinal side effects associated with the use of doxycycline and chloroquine, majority of the patients (88.6%) were given inhibitors of gastric acid secretion like ranitidine or pantoprazole and to prevent vomiting patients were given ondansetron. In addition some patients received other antibiotics along with the antimalarial treatment for the treatment of associated upper respiratory tract infection, diarrhea and for fever not responding to antimalarial drugs. Primaquine was given to almost all patients (98.4%) who were Plasmodium vivax-positive to prevent relapse.

In the present study, we observed a holistic approach to the treatment of malaria which included ACT to reduce the infectivity and resistance to malaria and prevention of expected adverse effects of antimalarials and hematinic therapy to overcome anemia of malaria.

Majority of the reported ADRs were related to gastrointestinal effects. In both the sexes most common ADR was nausea followed by anorexia, vomiting and bitterness in mouth. In the present study we observed that all the patients were prophylactically coadministered either ranitidine or pantoprazole with the ACTs. This in our opinion has markedly reduced the incidence of severe gastrointestinal system related adverse effects. Despite this almost 50% of the patients on antimalarial drugs complained of the above-mentioned gastrointestinal system related adverse effects, but did not require discontinuation of antimalarial drug therapy or reduction in the dose of the antimalarials.

The difference in the occurrence of adverse drug events between male and female patients was statistically insignificant, hence gender does not seem be associated with the reporting or occurrence of ADR.

The occurrence of ADRs with artesunate and chloroquine combination was statistically highly significant when compared with artesunate and doxycycline combination. However the efficacy of the two treatments as reflected in the recovery of symptoms and duration of hospitalization was comparable. Therefore, in this study we observed that artesunate and doxycycline combination is as effective as artesunate and chloroquine in the treatment of P. vivax as well as P. falciparum malaria. But the adverse events with artesunate and chloroquine were significantly higher. All the patients responded to treatment with ranitidine, pantoprazole and ondansetron.

The causality analysis of ADRs in this study showed almost all ADRs as possibly and only few as unlikely related to the antimalarial drugs. The scale used for the causality analysis of ADRs was the WHO assessment scale. Here, most of the ADRs followed a reasonable time sequence after drug administration and according to literature they could be possibly attributed to antimalarial drugs.

There were no exaggerations of adverse reactions in the combination therapies. There were no obvious drug interactions and no new adverse reactions were observed other than those mentioned in the literature. This study was an attempt to generate more systematic knowledge about ADRs to antimalarial drugs in particular ACTs with the ultimate aim of doing something good for human beings.

Therefore, our study concludes that the ADRs associated with ACT based regimens are less severe and tolerable when doxycycline is prescribed instead of chloroquine, alongwith asuitable antacid or antiemetic cover.


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