Patterns of adverse drug reaction signals in NAFDAC pharmacovigilance activities from January to June 2015: safety of drug use in Nigeria

Abstract Adverse drug reactions (ADRs) are expected to be associated with an economic drain on the healthcare systems. The study was carried out to determine the occurrence of ADRs reported to NAFDAC Pharmacovigilance from January to June 2015, to illustrate the pattern of organ system affected by ADRs, to assess the completeness of ADR report, to determine the relationship between the occurrence of ADRs with suspect drugs and the use of concomitant drugs as well as to generate possible signals from the reported ADRs. A total number of 921 ADR cases reported from January to June 2015 were analyzed using SPSS version 22. A higher percentage of ADR reports were seen in females (65.5%). The highest percentages of reports (45.6%) were from the age range of 21‐40 years, most of the suspected drugs reported had both NAFDAC (50.2%) and batch number identification (65.6%). HIV (56.9%) was the most prevalent indication reported for using the suspected drug; Zidovudine/Lamivudine/Nevirapine combination (16.9%) was reported as the suspected drug with the highest occurrences of ADRs and generalized body itching (6.9%) as the most prevalent ADR. “General disorders” (47.3%) was the most predominant organ system affected by ADRs and Pharmacists were revealed as the highest reporters of ADRs (80.2%). Overall, patients on ARVs should be vigilantly followed up as they are mostly prone to ADRs. Adverse drug reaction reporting systems need to be robust and complete in order to be able to detect new drug alerts, possible signals and improve pharmacovigilance


| INTRODUCTION
The repeated occurrence of unexpected, serious adverse drug reactions (ADRs) over the years has attracted wide professional and public attention. This has cast doubt on the effectiveness and quality of drug safety surveillance systems. 1 Adverse drug reactions (ADRs) represent an important risk for patients as they could cause significant disability and mortality, and are expected to be associated with an economic drain on the healthcare systems. 2 Adverse drug reaction signals are reported information on possible causal relationships between an adverse event and a drug. 3 A group of scientists proposed that the assessment of ADRs, therefore, is likely to be the most important aspect of drug treatment. 4 ADRs are, in fact, responsible for around 4.9% of hospital admissions worldwide, and, in some cases, this number can be as high as 41.3%. 5 There is thus no doubt that drug safety is an important public health problem.
Spontaneous reporting of suspected adverse drug reactions has long been the cornerstone of pharmacovigilance for the identification of early signals of problems of drug safety related to the use of medicines worldwide. 6 Health professionals have contributed significantly to successful pharmacovigilance through spontaneous reporting. This enormously significant contribution has encouraged ongoing ascertainment of the benefit-risk ratio of some drugs 7,8 , as well as contributed to signal detection of unsuspected and unusual ADRs previously undetected during the initial evaluation of a drug. 9,10 Pharmacovigilance is an important and integral part of clinical research. 11 It continues to play a crucial role in meeting the challenges posed by the ever increasing range and potency of medicines as it is a well-known fact that no drug is completely free from adverse effects.
In Nigeria, the National Pharmacovigilance Centre (NPC) is domicile in National Agency for Food and Drugs Administration and Control (NAFDAC) and has the data bank of all reported adverse drug reactions in Nigeria. 3 There are a bunch of examples of drugs, which have been detached as well as outlawed from the Nigerian market owing to reported adverse effects of drugs. 12 Spontaneous reporting of ADRs to the NPC in Nigeria has prompted the timely withdrawal of toxic paracetamol adulterated with diethylene glycol that claimed the lives of some infants and young children in 2008. 13,14 It has also led to the ban of dipyrone in 2005 due to the frequent injection abscess and unexplained deaths associated with its use. 15,16 Hence, continuous postmarketing surveillance and signal detection from NAFDAC Pharmacovigilance database is important to guaranty the safety of patients.
The review of adverse drug reactions reported to NAFDAC in order to determine the patterns of adverse drug reaction signals in NAFDAC pharmacovigilance activities as well as explore information about new and unexpected adverse drug reactions reported is essential in safety of medicine assessment. This study is therefore aimed at determining the occurrence of ADRs reported to NAFDAC Pharmacovigilance, illustrating the pattern of organ system affected by ADRs reported, assessing the completeness of ADR reported data in NAFDAC Pharmacovigilance, determining the relationship between the occurrences of ADRs with suspect drugs as well as generate possible signals from the reported ADRs.
The outcome of this study will add to the pool of information available as regards ADRs and signals in NAFDAC and Uppsala Monitoring Centre (UMC). It will also form the epidemiological basis for certain regulatory decisions as affects the use of drugs.

| METHODOLOGY
Spontaneous reporting of ADRs is practiced in Nigeria using a stan- in Sweden. The five general components of the form are patient's details, adverse drug reaction details, suspected drug details, concomitant medicines details, and sources of report. Healthcare providers and patients can send ADR reports to either the NPC, zonal pharmacovigilance centers (ZPCs), or NAFDAC state offices nationwide. All completed adverse drug reaction forms are submitted to NPC for documentation and analysis is done by experts. A filled yellow/adverse reaction form is known as the individual case study report (ICSR). The ADRs are coded on the basis of the WHO Adverse Reaction Terminology (WHO-ART). 17 The reports concluded to be ADRs are sent to UMC excluding the names of the patient and names of reporters for entry into the WHO Global Individual Case Safety Report database, VigiBase ® .

| Data abstraction
The ICSR of patients who experienced adverse drug reaction(s) from January 2015 to June 2015 were sourced from the NPC in Nigeria (NAFDAC) and data mining was done to obtain the following information: Demographic distribution of patients, batch and NAFDAC number identification for suspect drugs with ADRs, suspect drugs with ADRs (dosage form, specific indication for use, specific name, specific manufacturer), and ADR (specific type, duration, system organ classification, and outcome), reporter of ADR (institution and profession).

| ADR outcome rating
Outcome of the ADR refers to the extent of resolution of the signs and symptoms of ADR as at the time the report was submitted to NPC. The outcomes were categorized as resolved, ongoing, resolving, life-threatening, resolved with disability, and death.

| Ethical considerations
The National Agency for Food and Drug Administration and Control (NAFDAC) approved the study.

| Analysis
The data were analyzed with IBM SPSS statistics software, version 22. Descriptive statistics was used to summarize demographic distribution of patients, batch and NAFDAC number identification for suspect drugs with ADRs, suspect drugs with ADRs (dosage form, specific indication for use, specific name, specific manufacturer, country of manufacture), and ADR (specific type, duration, system organ classification, and outcome), reporter of ADR (institution and profession). Chi-square test was used to test the statistical significance of categorical variables.

| Specific indication for using the suspected drug(s)
The profile of specific indication for using the suspected drugs (Table 2) reveal that HIV (56.9%) was the most prevalent indication reported for using the suspected drug, followed by fever/malaria (6.9%), tuberculosis (5.7%), prevention of one ailment or the other (3.1%), etc. 'Others' represent a classification of indications only reported once.

| Suspected drugs causing ADRs
The profile of suspected drugs with ADRs (

| Reported ADRs with suspected drugs
It was observed from the study ( Table 4) that the most prevalent ADR was "generalized body itching" being reported 65 times (6.9%), "rash all over the body" was reported 49 times (5.3%), and "anemia" was reported 35 times (3.8%). "Others" category was reserved for ADRs with frequencies less than four. Table 5 shows a detailed list of system organ classification for the reported ADRs. Findings from the study revealed that, "general disorders" was the most predominant organ system affected by ADRs,

| Source of suspected drug and nature of outcome of ADRs reported
The findings of the study revealed that most of the suspected drugs reported were sourced from the Hospital Pharmacy (Table 6)

| Profession of reporter of ADRs
The findings in this study showed that Pharmacists (Table 7) reported ADRs the most. The "others" category refer to the pharmacy focal person, pharmacovigilance officer, human resource practitioner, media organization, house wife, self-employed person, hematolgist, engineer, teacher, as well as medical social work officer which each reported once.

| DISCUSSION
The biological differences of males and females can affect the action of many drugs. The anatomical and physiological differences are body weight, body composition, gastrointestinal tract factors, liver metabolism, and renal function. Women in comparison to men have lower bodyweight and organ size, more body fat, different gastric motility and lower glomerular filtration rate. These differences can affect the way the body deals with drugs by altering the pharmacokinetics and pharmacodynamics of the drugs including drug absorption, distribution, metabolism and elimination. 18 The findings revealed that females (65.5%) were reported to have more ADRs.
This is in line with several other studies which have suggested that a female preponderance in the overall frequency of adverse drug reactions may be present, in that female patients have more ADRs. [19][20][21] Gender may influence drug utilization and susceptibility to, presentation of, and detection of adverse drug reactions, although the results of this study showed that the influence is not statistically significant (P > 0.05). The lack of association may be due to a large proportion of reports from females that were neither pregnant nor breastfeeding as pregnancy is a known risk factor for ADRs occurrence. 18,22 Age has a significant effect on development of ADRs, especially the extreme ages that is pediatric and geriatric patients as these categories of patients are not usually studied extensively during clinical trials. 4 The findings in this study are however not in tandem with the aforementioned. The study revealed age range of 21-40 (45.6%) as T A B L E 1 0 Adverse drug reactions reported with artemesinin-based combination therapy (ACT)  37 There has not yet been any research into why this has occurred although speculation might pin point increased workload and administration or a presumption that others are reporting as possible reasons for this decline.

Suspected drug Adverse reactions Concomitant drug(s) Outcome of ADR
"General disorders" was the organ system (51.1%) reported to be most affected by ADRs, this is followed by skin and subcutaneous skin disorders (24.9%) and gastrointestinal disorders (7.6%).
This result is consistent with documented studies carried out in Sweden, which states that ADRs were most frequently gastrointestinal (21.6%) or general disorders (12.3%). 38 It is worth mentioning that most of the reports submitted to NAFDAC Pharmacovigilance were incomplete as they lacked neces- and Saudi Arabia, 40 and those submitted to a pharmaceutical company in Italy. 41 Incomplete ADR information may limit the effectiveness and full potential of analysis of reports. The NPC local database is used to store all reports received irrespective of their completeness status. Since the NPC has no rejection policy for incomplete suspected ADR reports, timely evaluation of the received suspected ADR reports should be considered as a means of early identification of incomplete reports. Reporters should be reached via repeated email, phone calls, or visits, and encouraged with incentives to providing missing details from the reports. Continuous pharmacovigilance education for healthcare professionals should emphasize the importance of completing the ADR report forms when reporting. 28

DISCLOSURE
None declared.