For all medications, there is a trade-off between the benefits and the potential for harm; these factors should be analyzed and communicated effectively as part of an effective approach towards pharmacovigilance.6
Anecdotal reports can identify the occurrence of an AE that may be coincidental23
rather than actual harm. It is important for patient safety to detect drug-event combinations and analyze these events using appropriate statistical methods.24
The present study provides information regarding the safety level of MFQ in adult travelers in the context of pharmacovigilance. As the ROR estimates and the lower limits of the corresponding 95% CI were <2 in both database sources in the present analysis, a safety signal was not detected.
Upon comparison of MFQ with the single comparator quinine or a combination drug (ie, chloroquine plus proguanil) in the present analysis, “signal dilution”26
was not observed. As data collection is expensive, data-mining processes are often performed using existing databases for the purpose of pharmacovigilance.6
Regarding the methodology of the data-mining process, measures of disproportionality are the only techniques which have been used to identify AEs.27
The current analysis followed this approach as well.
Spontaneous reporting to the World Health Organization or to the Food and Drug Administration may provide data on a broad spectrum of patients. Moreover, ADRs that occur after prolonged exposure or ADRs that are extremely rare can be detected through spontaneous reports. However, the absence of a control group and the lack of a denominator indicate that the attributable rate of the ADR cannot be calculated.28
Case reports are the main source of information used to withdraw a drug from the market for safety reasons.29
In assessing the culprit drug, it is difficult to determine whether the report is a genuine alert or a false alarm.30
The aim of the present study was not to examine the reporting system, but to highlight the usefulness of other published data sources for signal detection.
The risk of malaria during travel is determined by immunological characteristics of the individual traveler (the person), the travel destination (the place), and the use of preventive anti-mosquito measures and adequate chemoprophylaxis (prevention without and with drugs).4
In the present study, based on two different data sources, signals for neuropsychiatric event were not detected. Importantly, if a signal is not detected, it is impossible to determine whether no AEs (neuropsychiatric event in our case) exist or whether the data are insufficient.27
Further studies are needed to substantiate this hypothesis. Nevertheless, as our data pertinent to the second database were rooted in RCTs, our estimation of signal detection is less likely to exhibit bias. Additionally, approximately one in seven individuals with neuropsychiatric contraindications received a prescription for MFQ prior to combat deployment.15
Travelers and the deployment groups cannot necessarily be equated. Deployment may result in psychiatric casualties that are either the result of inadequate coping with deployment stressors or acute stress reactions caused by battle trauma or combat stress reactions.31
Stress-inducing factors compounded to the effect of MFQ may be a likely cause of neuropsychiatric events in this population. In pharmacovigilance and in medicine in general, it is important to be cognizant of interactions, not only between drugs but also between drugs and diseases as well as environmental factors. As such, nondrug interactions may act as confounders when they are actually co-precipitating factors25
in this special population.
We were unable to identify a signal for detection based on two datasets in which study time and participants were not the same. Thus, whether drug-events were related to MFQ-related neuropsychiatric effects did not vary significantly over time. Second, there was a relatively higher frequency of neuropsychiatric AEs related to MFQ than to comparator drugs although they were not related to SAEs. This highlights the need for clinical surveillance of MFQ chemoprophylaxis with stratification by gender or age group.
Notably, no individual approach to detect signals (ROR in our case) is adequate and the concurrent use of other methods is therefore essential.32
Further incorporation of pharmacovigilance principles into clinical practice and academic medicine is necessary.6
As such, published studies have postulated that neurologic syndromes in patients induced by MFQ were likely due to a central anticholinergic syndrome.32
Although multiple factors may have contributed to cognitive impairment, the temporal relationship between symptom onset and MFQ use suggests a high likelihood that MFQ was the causal factor;33
hence, further studies are warranted. There may be important differences between the pharmacokinetic properties of MFQ in pregnancy and nonpregnant adults.34
Moreover, we recommend future studies assessing SAE of MFQ for preventing malaria in pregnant women.