Pharmacovigilance : Empowering Healthcare Professionals A

Introduction: Spontaneous reporting of adverse reactions is of greatest importance for obtaining information about adverse drug reactions (ADRs) after granting the marketing authorization. The most important role and also the greatest responsibility belong to healthcare professionals. Their active participation is a prerequisite for the existence of an eff ective national drug safety monitoring. Methods: This paper examines the legislative framework concerning the pharmacovigilance system in Montenegro. The information was collected from scientifi c articles and the website of the Agency for Medicines and Medical Devices of Montenegro. Topic: Key segments of pharmacovigilance system are presented, with a special reference to the importance of spontaneous reporting of ADRs, results of spontaneous reporting of ADRs according to the latest Agency’s Annual report on the results of spontaneous reporting of adverse reactions to medicines, possible reasons for underreporting ADRs, as well as the new EU regulation on pharmacovigilance. Conclusions: Spontaneous reporting of ADRs remains the cornerstone of pharmacovigilance systems. Hence, continuous education of healthcare professionals is needed, with the aim of improving their awareness of the importance of ADRs and risk factors that lead to them, in order to reduce the incidence of ADRs and to increase the number of reported suspected ADRs.


INTRODUCTION
According to the defi nition of World Health Organization (WHO), pharmacovigilance is a science that comprises activities relating to the detection, assessment, understanding and prevention of adverse eff ects or any other possible drug-related problem [1].Th e specifi c aims of pharmacovigilance are to: improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions, improve public health and safety in relation to the use of medicines, contribute to the assessment of benefi t, harm, eff ectiveness and risk of medicines, encouraging their safe, rational and more eff ective (including costeff ective) use, and promote understanding, education and clinical training in pharmacovigilance and its eff ective communication to the public [2].
Adverse drug reactions (ADRs) are observed during the preclinical and clinical trials.Data collected during these phases of drug development cannot predict the possible ADRs that may manifest only aft er placing the medicinal product on the market.Th e reasons are diff erent.For example, animal studies are insuffi cient to predict the safety of the medi-cines in humans; limited number of selected patients is included in clinical trials, conditions of administration of medicine are different from those in normal clinical practice, and duration of trials is limited; only ADRs with higher incidence of manifestation could have been observed because less than 5000 patients would be exposed to medicine during clinical trials before its placing on the market; data on rare serious adverse events, toxic effects of chronic treatment, use of the medicine in specifi c categories of patients (children, the elderly, pregnant women) or interactions with other medicines are oft en incomplete or not available [3].
Pharmacovigilance is the need and obligation of every country, because there are diff erences in the incidence of ADRs (and other problems caused by medicines) among different communities.Causes may be as follows: diff erences in prevalence of certain diseases; genetic factors, diet, habits; diff erent practice of prescribing medicines; diff erent manufacturing process (using diff erent excipients, diluents, fi llers, preservatives, antioxidants...) which aff ects the quality and composition of medicines; diff erences in the use of the drug, including the therapeutic indication and the dosage regimen; co-administration of the traditional and herbal products which may cause specifi c toxicological problems, whether administered alone or in combination with other medicines [4].
Th erefore, post-marketing surveillance activities are important to allow the early detection of unexpected and/or serious adverse reactions.Important part of post-marketing surveillance is also related to detection of falsifi ed medicines.

METHODS
This paper examines the legislative framework concerning the pharmacovigilance system in Montenegro.The information was collected from scientifi c articles and the website of the Agency for Medicines and Medical Devices of Montenegro.

Importance of spontaneous reporting of ADRs
ADRs appear more frequently then what is actually reported and registered.According to the information that literature has provided, it has been estimated that 10-30% of hospitalized patients experience ADRs [5][6][7][8][9] and 0.3-10% of all hospital admissions are actually results of ADRs [10][11][12].In hospital environment, 3% of all fatal outcomes are caused by ADRs [7].ADRs also cause prolongation of the hospitalization period and increase of hospital costs [6].It is estimated that only 6-10% of all ADRs are reported: Th is underestimation is a major problem [13].Although the extent of underreporting is widely variable depending on the estimates, it is certain that the number of reported ADRs represents only a small percentage of the total number of occurring ADRs [14].
In consideration of aforementioned, spontaneous reporting of adverse reactions is of greatest importance for obtaining information about adverse drug reactions (ADRs) after granting the marketing authorization.
Th e most important role and also the greatest responsibility belong to healthcare professionals.Th eir active participation is a prerequisite for the existence of an eff ective national drug safety monitoring.
Reporting of adverse drug reactions is a legal obligation [15] for all healthcare professionals in Montenegro prescribing, issuing and handling drugs in clinical practice.It is very important to involve all, physicians as prescribers, pharmacists as experts in medicines, the last control of prescribers, healthcare professional who is the most important link between prescribers and patients, and finally the nurses involved and responsible for the proper preparation and administration of certain drugs.Th e Agency for Medicines and Medical Devices of Montenegro (CALIMS), as a full member of the WHO, in order to protect public health by monitoring the safety of medicines, collects, assesses and manages all reported suspected ADRs into a national database, and forwards them to the Uppsala Monitoring Centre.

Pharmacovigilance in Europe
Th e trigger for proposal, fi nal approval by the European Parliament and entry into the force of the new EU regulation on pharmacovigilance was appalling statistics at the level of EU countries, in which the pharmacovigilance system was building through decades, especially when it comes to proven fatalities caused by irrational use of medicines (200 000 deaths annually in the EU due to adverse eff ects of medicines) [16] and the enormous costs of their treatment (about 709 billion euros annually) [16][17][18].
On July 21, 2012, a new EU pharmacovigilance legislation came into force in order to strengthen and rationalize the EU pharmacovigilance system, with the overall objectives of better protection of public health, ensuring proper functioning of the internal market and simplifying the existing procedures [19].
At European level, government agencies responsible for pharmacovigilance in Member States are in contact with each other and with the European Medicines Agency (EMA) [20].EudraVigilance -a web-based European network has been established by EMA, for reporting and exchanging suspected ADRs reports, during the pre-authorization phase and following post-authorization phase of medicinal products in the European Economic Area.EudraVigilance is an European database, which supports:

Pharmacovigilance in Montenegro
Fulfi lled reporting form could be submitted to the Agency in one of the following manners: by post, in person, by fax or by e-mail [22].In 2013 the possibility of reporting through the information system of primary healthcare institutions and general hospitals was introduced.Th is is expected to be the principal method when it comes to report ADRs, because it is an easy, safe and fast way to transfer date from a healthcare institution to CALIMS.Results of spontaneous reporting of ADRs, according to the latest CALIMS annual report [23], indicate that the number of reports per million inhabitants is 156.Th at number is under recommendation of the World Health Organization of 200 reports per million inhabitants [24].
Th e largest number of reports, according to the ATC classifi cation of suspected drugs, related to drugs belonging to the group of antineoplastics and immunomodulators, and anti-infective drugs for systemic use [23].While in the EU and in many countries around the world, to the appropriate agency quality reports are sent by patients, which are oft en the reason for the adoption of measures by the competent authorities, in Montenegro, unfortunately, we cannot yet speak of a developed awareness among healthcare professionals about the importance of reporting adverse drug reactions, primarily to public health, and further the economic viability of the healthcare system.
A huge responsibility is on the national agencies and manufacturers of medicines, but the most important role and responsibility for the health of people is on healthcare professionals.Th e lack of appropriate statistics in Montenegro on adverse eff ects, in terms of treatment outcomes and fi nancial burden caused by their treatment does not mean that we as a country spared this, in today's conditions of global phenomena.Agency for Medicines and Medical Devices of Montenegro (CALIMS) recognized as a challenge to raise awareness of healthcare professionals about the importance of pharmacovigilance and development of this scientifi c discipline, through continuing education.Aware of its responsibility for the public health, CALIMS continues the education in the fi eld of pharmacovigilance.One of them is organizing workshops on pharmacovigilance for the development of a system for continuous monitoring of safety of medicines.

Possible reasons for not reporting ADRs
In prospective study conducted by the author, which included 200 patients, hospitalized at Cardiology Centre of the Clinical Centre of Montenegro last year, results showed that 34% of all patients experienced at least one ADRs.Considering high incidence of ADRs in our study and the fact that none observed suspicion of ADRs wasn't reported to the CALIMS by health workers, it can be concluded that in Montenegro system of spontaneous reporting of ADRs does not provide enough information about the safety drugs use.
It is possible that doctors and nurses don't report ADRs due to: preoccupation with everyday duties and otherwise oversized adwww.hophonline.orgministrative work they do, the lack of increased spontaneous reporting system, focusing on ADRs patients have had during hospitalization, with lower paying attention to ADRs that caused hospitalization, reluctance to report ADRs which were preventable, guilt incurred for ADRs, lack of motivation, etc.

CONCLUSION
National ADRs reporting system in Montenegro is organized by the Pharmacovigilance Department of the Agency for Medicines and Medical Devices of Montenegro.Number of reports coming from healthcare professionals is quite low [23].
For HCPs, the emphasis should be on education and training, both at the undergraduate and graduate level, to recognize ADRs and knowing what, how and where to report them, e.g. by practicing how to fi ll out a Report form.Healthcare professionals also have to stay informed about changing regulations and evolving procedures and/or techniques.Hence, continuous education of healthcare professionals is needed, with the aim of improving their awareness of the importance of ADRs and the risk factors that lead to them, in order to reduce the incidence of ADRs and to increase the number of reported suspected ADRs.

[21] 1 .
Th e early detection of possible safety signals associated with medicinal products for human use.2. Th e continual monitoring and evaluation of potential safety issues in relation to reported adverse reactions.Th e decision making process, based on a broader knowledge of the adverse reaction profi le of medicinal products.