The Role of a Pharmacist in Pharmacovigilance System A

The Role of a Pharmacist in Pharmacovigilance System A Marija M. Lučić1, Nastasija P. Milošević1, Nikola B. Martić1, Milica M. Paut Kusturica1, Vojin M. Jovančević2, Milan B. Ubavić3, Nemanja B. Todorović4, Dejan J. Krajačić5, Aleksandar L. Rašković1 A 1 Department of Pharmacology and Toxicology, Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia 2 Provincial Secretariat for Education, Regulations, Administration and National Minorities, Novi Sad, Serbia 3 Institute for Laboratory Diagnostics, Medlab, Novi Sad, Serbia 4 Department of Pharmacy, Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia 5 Genaral Hospital “Dr Radivoj Siminović” Sombor, Serbia


INTRODUCTION
No medicine is entirely safe.In other words, no medicine is risk free.Although many of the risks are known at the time of licensing a medicine, some information on its safety profi le comes to light later, aft er marketing a medicine, as medicine usage increase.Before a medicine is marketed, information on its safety is limited to its use in clinical trials under specifi c, ideal circumstances that do not necessarily refl ect the way the medicines are used in daily routine health practice, once they are marketed.Despite the extensive pre-marketing research, non-clinical trials in animals and clinical trials in humans, some adverse reactions may not be seen until a very large number of people have received the medicine.Th erefore it is very important that the safety of all medicines is monitored throughout their marketed life -known as pharmacovigilance [1].

Adverse drug reaction
Adverse reaction to the drug (ADR) is every noxious and unintended reaction to the drug which occurs aft er the usage of an usual dose of the drug by people and animals (for the purpose of therapy, prophylaxis, diagnosis, renewal, improvement or change of a physiological function) or aft er the usage of any dose of the drug during the clinical trial.
Serious adverse reaction to the drug implies any unfavorable medical event which results in death, endangering life, hospitalization of the patient or prolongation of stay in hospital or the one which causes permanent dysfunction or disability.
Adverse event is medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related.Adverse experience is any unmanaged or unwanted sign, symptom or disease, which has time relationship with drug usage.
ADRs can be expected or unexpected.Expected adverse reaction is the reaction which had been previously discovered and described in Summary of Product characteristics.Unexpected adverse reaction is the reac-tion to the drug whose nature, severity or outcome has never been described in Summary of Product characteristics.
According to mechanism of origin, ADRs are classifi ed in four types.Type A, dosedependent ADR with clear time relationship to drug intake, which are oft en discovered during the clinical trial and symptoms disappear aft er cessation of therapy.Type B or dose-independent ADR, are rare (0.01-0.1%) according to frequency.Th ey are unexpected, and it is hard to establish causal-consequential relationship and mechanism.Th ere is time relationship between using the drug and appearance of the adverse eff ect.Th ese reactions are oft en allergic, pseudo allergic or idiosyncratic reaction or congenital enzymatic defect -they are individual, and they depend on patient's characteristics; usually they are not discovered during the clinical trials, but they are discovered aft er the appearance of the drug in the market, so that is why they can cause death.Type C represent higher frequency of 'spontaneous diseases' in population.Usually there is long latent period between the beginning of using the drug and manifestation of ADR.Time relationship between using the drug and the adverse reaction is less clear but mechanism is hard to establish [2].Type D represent delayed ADR (e.g.cancer genesis, teratogenesis) [3].
It has been estimated that such ADRs are the 4th to 6th largest cause for mortality in the USA.Th ey result in the death of several thousands of patients each year, and many more suff er from ADRs [4].

Pharmacovigilance
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse eff ects or any other possible drug-related problems.Re-cently, its concerns have been widened to include herbals, traditional and complementary medicines, blood products, biologicals, medical devices, vaccines [5].
Th e history of pharmacovigilance goes back more than 50 years [6].Th e beginning of the development of pharmacovigilance is linked to 'thalidomide catastrophe' .In early 1960s, thalidomide was the drug which was prescribed to pregnant women so that they can fall asleep easier and in order to reduce nausea.However, thalidomide caused between 10.000 -15.000 cases of severe deformation of the limbs (phocomelia) to the children whose mothers were using this drug [7].In 1965 the eighteenth World Health Assembly, WHA 18.42, drew attention to the problem of ADR monitoring and following further resolutions in 1966, 1967 and 1970 the International Drug Monitoring Programme came into being [6].
By 2016, 123 countries have joined the programme [8].Th e programme functions on the basis of national pharmacovigilance centers coordinated by the WHO Programme for International Drug Monitoring which consists of the WHO Collaborating Centre for International Drug Monitoring, Uppsala and the Pharmacovigilance Department of WHO, Geneva.
Th erefore, it is essential that new and medically still evolving treatments are monitored for their eff ectiveness and safety under real-life conditions post release.Experience has shown that many ADRs, interactions (i.e. with foods or other medicines) and risk factors come to light only during the years aft er the release of a medicine [9].
Th e success or failure of any pharmacovigilance activity depends on the reporting of suspected ADR.To date, the mainstay of pharmacovigilance has been spontaneous reporting by health professionals.To detect the full spectrum of complications from pharmaceutical treatment and to gain a representative picture, all sectors of the health-care system need to be involved.Th is includes public and private hospitals, general practice, pharmacies, nursing homes, retail dispensaries and providers of traditional medicine.Wherever medicines are being used, there should be a readiness to observe and report unwanted and unexpected medical events.Reports made by a health professional are an interpretation of information originally provided by a patient who has experienced the actual benefi t or harm of a medicine taken [6,10].
A pharmacist contributes to drug safety by preventing, identifi cation, documenting or reporting ADRs.Th e role of the pharmacist in pharmacovigilance system is diff erent in countries.Nowadays the pharmacist also frequently acts as a consultant on pharmacotherapy and in the UK and USA pharmacists are, to a degree, also authorized to write out prescriptions, which, incidentally, has been a long-standing practice in many countries where doctors are in short supply.Currently the role of the pharmacist in the reporting of ADRs is not appreciated everywhere.In the Scandinavian countries, for instance, pharmacists are not authorized to report ADRs and in the United Kingdom they have only recently been allowed to report independently.By contrast, in the Netherlands 40% of the reports on ADRs are submitted by pharmacists [11].
An important clinical responsibility of the pharmacist is in the early detection of ADRs and other drug-related problems as well as monitoring the eff ectiveness of medicines.Th e pharmacist, as a part of the healthcare team, is a source of both information and critical evaluation of drug information.Th e pharmacist's expertise is vital to the application of the safety profi le of a medicine to the needs of a particular patient [12].

Reporting of ADRs in Serbia
In Serbia, every medical worker is obligated to report an adverse reaction on the drug.Medicines and Medical Devices Agency of Serbia (ALIMS) and Nacional Pharmacovigilance Center (NPC) which works under this Agency are competent to follow and regulate reported adverse eff ect on drugs.
Reporting ADRs in Serbia is being done by fi lling in the form which is publicly available on site of ALIMS.Aft er fi lling it, the form is being forwarded to ALIMS and NPC.
Aft er the evaluation of collected data and identifi cation of new safety fi ndings, AL-IMS takes steps to ensure that the medicine is used in a manner which minimizes risks and maximizes the benefi ts.Th ese actions usually include changes to safety information in the Summary of Product Characteristics and Patient Information Leafl et In terms of adding new important warnings and precautions, and ADR, new contraindications, reduction of the recommended dose, limitations in the adminis-tration of a medicine.Other regulatory actions are also taken for risk management purposes, particularly in terms of risk minimization, and in rare cases, the decision can be made on termination of a marketing authorization, or to temporarily revoke a marketing authorization for safety reasons and to withdraw a medicine from the market, when it is demonstrated that the potential risk is greater than the expected benefi t in normal therapeutic administration of a medicine [1].
According to information about number of reported ADRs which ALIMS had collected in period from 2005.-2011.there is a steady rising trend in reporting ADRs.Total number of reports in 2011.was 962, or it was 128 reports per 1 million of residents in Serbia, and that number is still much smaller than 200 reports per 1 million of residents, which is expected number of reported ADRs according to advices, from World Health Organization (WHO), in order to achieve well developed national pharmacovigilance system.Th at means that Serbia needs 1400 ADRs per year.In 2015, NPC and ALIMS recorded 1170 reports.Number of reported reactions in 2015.was 15% bigger than in 2014 [13].
During 2017, there were 964 reported ADRs, and that number is 12.76% smaller than in 2016.
Even though the number of reported ADRs from patients was 86.6% bigger than number in 2016, amount of reports is still small, and according to that we can conclude that system of reporting ADRs by patients in Serbia is not developed enough [14].

AIM
Th e aim of this research is that by collecting information about unexpected and ADRs, based on direct contact of pharmacists and patients, improve the role of a pharmacist in pharmacovigilance system.

SUBJECTS AND METHODS
Information about ADR were being collected in three private pharmacies in Inđija and one private pharmacy in Sombor.
Information was presented to patients in written forms and through them patients were informed about the importance of reporting unexpected and ADR.Th ey were in- formed that during the report data about them would be anonymous and that the survey was being held in purpose of making a scientifi c work.It was written in text that if they had experienced any kind of adverse reaction they can report it to the phone number (author's phone number) or they can report it directly to the pharmacist in the pharmacy (Annex 1).Needed information to fi ll in the form was about gender and age of the patient, description, result and duration of the adverse reaction, name, form and dose of the drug which lead to the adverse reaction, dosage regimen, method of application, indication and total usage time.Also, patients were asked if they had used some other drugs at the same time, and about some other relevant conditions in order to connect the adverse reaction to the suspect drug.
According to given information, forms available on site were fi lled and then sent to NPC.
NPC assessed reported ADRs in terms of expectation, seriousness and causalconsequential relationship between usage of the drug and the adverse eff ect.
For estimation of causal-consequential relationship NPC was using the World Health Organization's (WHO) methodology (Table 1) [15].
Suspect drugs are classifi ed in categories according to ATC classifi cation [16]: -Group A -Alimentary tract and metabolism; -Group B -Blood and blood forming organs; www.hophonline.org-Group C -Cardiovascular system; -Group D -Dermatologicals; -Group G -Genito-urinary system and sex hormones; -Group H -Systemic hormonal preparations, excluding sex hormones and insulins; -Group J -Antiinfectives for systemic use; -Group L -Antineoplastic and immunomodulating agents; -Group M -Musculo-skeletal system; -Group N -Nervous system; -Group P -Antiparasitic products, insecticides and repellents; -Group R -Respiratory system; -Group S -Sensory organs; -Group V -Various.

RESULTS
In order to get the information about unexpected and adverse reactions to drugs, three private pharmacies in Inđija and one private pharmacy in Sombor were contacted in this survey.
In fi rst period, from 20.12.2017.un- Aft er that, when patients were additionally informed about the importance of reporting adverse reactions to the drugs, in period from 11.01.2018.until 01.02.2018., there were 33 reported cases (Figure 1).Exactly 21 patients (≈64%) reported their adverse reactions to the pharmacist, and 11 (≈36%) patients reported it to the author.Suspect drugs were classifi ed by ATC classifi cation, and their percentage share is shown in Figure 2.
Th e most of the reports of ADRs refer to drugs from group C according to ATC classifi cation (32.7%).Th ose drugs are used to treat cardiovascular diseases.Signifi cant number of ADRs are caused both by anti-infectives for systemic use, which belong to group J (15.4%) and drugs which are used for treating diseases of nervous system and which belong to group N (13.5%).
According to NPC, all of the reported reactions are expected, which means that they are related to their mechanism of action or that they had been already described in Summary of Drug Characteristics.3 out of 52 reported reactions were classifi ed as serious.Aft er estimating, it is concluded that causal-consequential relationship between ADR and used drug for drugs which caused serious ADRs is possible.
Drugs and adverse reactions which appeared aft er using them are classifi ed according to ATC classifi cation and shown in tables.
According to the collected information, fi ve drugs which belong to group A (9.6%), according to the ATC classifi cation caused ADRs.Th ree patients had diarrhea and cramps aft er using metformin chloride, while one patient had a problem with constipation aft er using granisetron, and one patient was tired and drowsy aft er using metoclopramide (Table 2).
According to the collected information, majority of reported ADRs referred to drugs which are from group C (32.7%), according to ATC classifi cation, where belong drugs which are used in treating cardiovascular diseases.Seventeen drugs from this group caused diff erent ADRs.Amlodipine, one of calcium channel blockers, caused redness and hock edema to three patients.Same ADRs appeared to patients who used nifedipine, felodipine, lercanidipine.Two patients reported that aft er using glyceryl trinitrate beside signifi cant decrease of blood pressure they felt strong headache.Aft er using propranolol, nonselective blocker of beta adrenergic receptors, one patient had insomnia and feeling of cold limbs, while another patient had problem with eye dryness.Metoprolol, selective blocker of beta 1 adrenergic receptors, caused dry cough and nightmares in one case, while bisoprolol, drug from same group of drugs, caused dry cough and impotence.One patient noticed strong palpitations aft er using spironolactone, aldosterone antagonist.Angiotensin converting enzyme inhibitors, either as monocomponent therapy or in combination with diuretics caused dry stimulant cough (Table 3).
According to the collected information, only one drug from group D(1.9%), according to ATC classifi cation, where belong the drugs used in treating skin diseases.Th is particular drug, isotretinoin, which is used for treating acnes, caused the feeling of dry mouth and eyes (Table 4).
According to the collected information, three drugs from group G (7.7%), according to ATC classifi cation, where belong drugs used in treating diseases of genito-urinary system caused ADRs.Two patients had orthostatic hypotension aft er using tamsulosine.One patient felt mood disorder aft er using drug which is consisted of cyproterone and estradiole, while one patient aft er using fi nasteride had problem with impotence (Table 5).
According to the information, one drug which from group H (1.9%), according to ATC classifi cation, where belong systemic hormonal preparations, caused ADR to one patient.Using of dexamethasone caused gaining weight to one patient (Table 6).
According to the information, nine drugs from group J (17.3%), according to ATC classifi cation, where belong anti-infective drugs for systemic use, caused ADRs.Two patients had gastrointestinal problems, nausea and vomiting, aft er using cephalexin.Erythromycin caused rash on the hands to the one patient.Two patients had hypersensitivity reactions aft er intramuscular application of procain benzylpenicillin.Tetracyclines for systemic use, caused two ADRs.Doxycycline caused photosensitivity reaction, while tetracycline caused nausea and diarrhea.One patient had nausea and metallic taste in the mouth aft er using metronidazole (Table 7).
According to information, three drugs from group M (5.8%), according to ATC classifi cation, where belong the drugs used for treatment of mucsulo-skeletal system diseases, caused ADRs.Using allopurinol caused in-creased blood pressure to one patient.Nausea and vomiting were reactions that happened aft er one patient used meloxicam, while glucosamine caused abdominal pain and nausea to the one patient (Table 8).
According to the collected information, six drugs from group N (13.5%), according to ATC classifi cation, where belong drugs used for treating diseases of central nervous system, caused ADRs.One patient had rash on the hands aft er using metamizol.Acetylsalicylic acid caused dyspepsia to two patients.One patient had hot fl ashes aft er using vinpocetine.Antiepileptic drugs, topiramate and carbamazepine, caused visual disorders, diplopia and nystagmus.One patient noticed that he had gained weight while using amitriptyline (Table 9).
According to the collected information, fi ve drugs from group R (9.6%), according to ATC classifi cation, where belong drugs for treating diseases of respiratory system,  caused ADRs.Acetylcysteine caused bronchospasm to the one patient.One patient, who has epilepsy, aft er using desloratadine had generalized contractions of skeletal muscles, which were identic to generalized epileptic seizure.Using of montelukast caused tremor in hands to the one patient.Two patients reported anxiety and tremor in hands aft er using salbutamol (Table 10).

DISCUSSION
Th e success of pharmacovigilance system in Serbia depends on spontaneous reports of ADRs.In Serbia, number of spontaneous reports is getting bigger every year, which is proven by the data that number of reported ADRs in 2003 was 70, but in 2015.there were 1170 reported ADRs.According to the information about reported ADRs in 2015, 101 referred to vaccines, 993 referred to the other drugs.Th e largest number of ADRs were reported by license holders (553), then from health workers (526).From patients there were only 18 reported ADRs.Th e majority of reported ADRs by health workers were from doctors.Partition of pharmacists in reporting ADRs is growing every year, but still is not enough, compared to doctors [13,17].Th e risk of harm, however, is less when medicines are used by an informed health professionals and by patients who themselves understand and share responsibility for their drugs.When adverse eff ects and toxicity appear -particularly when previously unknown in association with the medicine -it is essential that they should be analyzed and communicated eff ectively to an audience that has the knowledge to interpret the information.Th erefore.we can conclude that the role of pharmacovigilance is fi rstly managing the risk of ADR in order to avoid their serious consequences [5,18].
In this research, there were total of 52 collected ADRs by active collecting in contact with pharmacists.In fi rst period, which lasted 21 days, pharmacists in all four pharmacies were collecting reports of ADRs.At the end of this period, there were 19 collected reports.
During the second period, which also lasted 21 days, pharmacists in collaboration with authors were informing patients about the importance of reporting ADRs through written form (Annex 1).Aft er this additional information, number of reported ADRs in-creased.Th ere were 33 reported ADRs, at the end of this period.Th at means that the number was increased almost twice.Th anks to this information, it can be concluded that additional information is really important in process of improving system of reporting ADRs, and also for upgrading the relationship between patients and pharmacists.Aft er the information, patients who were reporting ADRs were asking for an advice how to use that suspect drug further on.
Forms for reporting ADRs, were fi lled based on the collected reports and then sent to NPC.Later, NPC was analyzing reported ADRs and sending back the information to the authors, about reaction, if it was expected or unexpected, how serious it was and if there was causal-consequential relationship between ADR and used drug.
Th e largest number of reports refers to the drugs from group C (ATC classifi cation) (32.7%),where belong drugs which are used in treating cardiovascular diseases, which was expected considering the fact of incidence of cardiovascular diseases nowadays in our surrounding.Selective calcium channels blockers, amlodipine and nifedipine, caused hock edema and redness several times.Th ese adverse reactions are frequent, expected and don't meet the criteria of seriousness.Angiotensin converting enzyme inhibitors caused in several cases dry stimulant cough, which is characteristic for this group of drugs, so it was expected, doesn't meet the criteria of seriousness and it is also listed in summary of drug characteristics.Selective blockers of beta adrenergic receptors also caused reactions such as cold limbs, nightmares, insomnia, dry cough, but neither of them meets the criteria of seriousness.
Th e second place according to number of reported ADRs belongs to drugs from group J (ATC classifi cation), where belong antiinfective drugs (15.4%).Majority of these reports were also expected, considering the fact that those drugs are oft en used by patients without previous consulting with doctors.Problems with gastrointestinal system, such as nausea, vomiting and diarrhea are most common reactions and they don't meet the criteria of seriousness.Hypersensitivity reactions are also reactions which occurred aft er using drugs from this group, and they meet criteria of seriousness.
Drugs from group N (ATC classifi cation) according to number of reported ADRs are on third place in this research (13.5%).Considering the fact that cyclooxygenase type 1 takes part in synthesis of gastro protective prostaglandins, defi ciency of this enzyme causes diff erent gastrointestinal problems.In that manner, we can explain that acetylsalicylic acid, as non-selective cyclooxygenase type 1 and 2 inhibitor, causes gastric pain which is expected ADR and doesn't meet the criteria of seriousness [19].Visual disorder, diplopia, nystagmus are characteristic adverse reactions caused by antiepileptic drugs, so these reported reactions are expected and don't meet the criteria of seriousness [20].
NPC estimated that all of reported ADRs were expected, based on the information from summary of drug characteristics, relevant medical literature and criteria for estimating of seriousness of ADR.From total of 52 reported reactions, 49 of them don't meet the criteria of seriousness.Th e rate of reporting of these adverse reactions aft er using these drugs is in accordance with the frequency of reporting, and the safety profi les of these drugs remain unchanged [1].However, 3 reports were classifi ed as serious adverse reactions.Two of them were hypersensitive reactions, which were caused by usage od procaine-benzylpenicillin and benzylpenicillin.Th e third serious reaction was an epileptic seizure which was caused by usage of desloratadine.
In both cases, anaphylactic shock happened aft er intramuscular usage of procainebenzylpenicillin.Reaction appeared soon aft er administration of the drug.It started with erythema, pruritus, and then bronchospasm and hypotensive shock, aft er which patients were given the proper therapy.
Penicillin antibiotics are the drugs most frequently suspected in drug hypersensitivity reactions.Drug allergies are divided into immediate and delayed reactions with diff erent immunological mechanisms.Immediate reactions occur less than 1 hour aft er drug administration and clinical presentation varies from urticaria to life-threatening anaphylactic shock.Th e most common delayed reactions are maculopapular exanthema and delayedonset urticaria, which are non-severe and self-limiting diseases.Severe delayed reactions such as acute generalized pustulosis, Stevens-Johnson syndrome or toxic epidermal necrolysis are rare and are accompanied by danger signs such as fever, bullous lesions, and mucosal and other organ involvement [21].
In both reported cases appeared immediate reaction to intramuscular administration of procaine-benzylpenicillin.
Some clinical experiences indicate that H1-antihistamines, especially fi rst-generation H1-antagonists, which pass the blood brain barrier, occasionally provoke convulsions in healthy children as well as epileptic patients.Even though CNS ADRs are rare aft er using non-sedating H1 antihistamines, there are several noted cases when they caused epileptic seizures [22].
Safer use of modern and traditional medicines is an ambitious goal of pharmacovigilance.It depends on patients and health professionals, health ministries, regulators, and manufacturers working actively together.Th e priority of pharmacovigilance is to identify when patients suff er any kind of harm from their therapy and to reduce the risk of this happening in the future.
In our study, direct communication with pharmacists and additional informing of patients about the importance of reporting of ADRs, signifi cantly increased the participation of pharmacists in the total number of collected ADRs and their role in pharmacovigilance system in our country.

CONCLUSION
Even though reporting ADRs is duty for all the health professionals, in Serbia, number of spontaneous ADRs is still not enough for establishment a developed national pharmacovigilance system, in accordance with recommendations of WHO.
In this study, an active collecting of ADRs and additional informing of patients about the importance of reporting of ADRs, signifi cantly contribute to improve the pharmacovigilance system and the safety of pharmacotherapy in our country.

Figure 1 .Figure 2 .
Figure 1.Contribution of collected ADRs before and after additional notifi cation in regard to the number of all collected reports

Causality term Assessment criteria Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event defi nitive pharmacologically or phenomenologically (i.e. an objective and specifi c medical disorder or a recognised pharmacological phenomenon) • Rechallenge satisfactory, if necessary Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations Unclassifi ed • Event or laboratory test abnormality • More data for proper assessment needed, or • Additional data under examination Unclassifi able • Report suggesting an adverse reaction • Cannot be judged because information is insuffi cient or contradictory • Data cannot be supplemented or verifi edTable 1 .
Categories

Table 4 .
Group D according to ATC classifi cation

Table 5 .
Group G according to ATC classifi cation

Table 7 .
Group J according to ATC classifi cation

Table 8 .
Group M according to ATC classifi cation

Table 10 .
Group R according to ATC classifi cation