Research Article Pharmacovigilance and drug safety in Calabria (Italy): 2012 adverse events analysis Chiara Giofrè, Francesca Scicchitano, Caterina Palleria, Carmela Mazzitello, Miriam Ciriaco, Luca
Gallelli, Laura Paletta, Giuseppina Marrazzo, Christian Leporini, Pasquale Ventrice, Claudia Carbone,

Patanè, Stefania Esposito, Felisa Cilurzo, Orietta Staltari, Emilio Russo, Giovambattista De Sarro, and
Department of Science of Health, School of Medicine, University of Catanzaro, Italy and Pharmacovigilance's Centre Calabria Region,
University Hospital Mater Domini, Catanzaro, Italy

Introduction: Pharmacovigilance (PV) is designed to monitor drugs continuously after their
commercialization, assessing and improving their safety profile. The main objective is to increase the
spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information.
The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase
reporting. In Calabria, a PV information center has been created in 2010. Materials and Methods: We
obtained data using the database of the National Health Information System AIFA relatively to Italy and
Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs. Results: A total
number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011
(138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar®),
the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently
reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently
reported, whereas the age groups "41-65" (39.07%) and "over 65" (27.9%) were the most affected.
Conclusions: Calabria has had a positive increase in the number of ADRs reported, although it has
not yet reached the gold standard set by World Health Organization (about 600 reports), the data have
shown that PV culture is making inroads in this region and that PV projects stimulating and increasing
PV knowledge are needed.
Key words: Adverse drug reaction, Italy, ketoprofen, pharmacovigilance, safety
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caused by thalidomide in 1961, with the 16th World Health Quick Response Code:
reiterated the need for early intervention with regard to the rapid dissemination of information on adverse drug reactions Health Organization (WHO) of a pilot research project for international drug monitoring.[1] Address for correspondence:
Emilio Russo, Department of Science of Health, Chair of Pharmacology, School of Medicine, University of Catanzaro, Via T. Campanella,
115, 88100 Catanzaro, Italy. E-mail:
Journal of Pharmacology and Pharmacotherapeutics December 2013 Vol 4 Supplement 1 Giofrè, et al.: ADRs report year 2012 in Calabria (Italy) The purpose of this was to develop a system, applicable from the Uppsala Monitoring Centre in 1999 and various internationally, for detecting previously unknown or poorly understood adverse effects of medicines. From this, practice in different countries. Unfortunately not in all countries, the and science of PV emerged.
voluntary reporting reaches standard levels set by the WHO under-reporting, according to literature data, appear to be due to: Lack of detection, assessment, understanding and prevention of adverse knowledge (it is believed that only serious adverse reactions effects and of all other drug problems.[1] Furthermore, the WHO should be reported), lack of interest or time, the indifference program for international drug monitoring aims at developing to the problem, the uncertainty about the causal link between a a comprehensive global PV strategy that responds to the drug and an ADR; the mistaken belief that only safe drugs are health-care needs of all countries.[4] As previously stated by the marketed.[19] For these reasons, Agenzia Italiana del Farmaco (AIFA) has been promoting several projects on the whole program for international drug control. Under this program, national territory and managed at regional level, in order to systems have been created in Member States for the collection increase "PV Culture".
and evaluation of individual case safety reports (ICSRs).[5] One of these structures "Regional network of drug information: ADRs knowledge led to increased recognition and reporting caused by ADRs and these are the fourth and the sixth most "Mater Domini" University Hospital of Catanzaro, in order common cause of death.[6] Furthermore, the increase in the average age of the population is related to a proportional inform the community on PV issue, indirectly increasing the increase in the number of drugs used (due to the prevalence number of spontaneously reported ADRs in the region.
of chronic diseases, such as hypertension, heart failure, glaucoma, prostatic hyperplasia, diabetes, etc.) resulting in The components of this project are carrying out various an exponential increase of the ADRs. Other possible causes activities in the whole Calabria regional territory by involving are the rapid development of new molecules for diseases the various training health workers, doctors, pharmacists and previously intractable and new treatment alternatives for other structures health facilities. This collaboration has increased the quality and quantity of reports of suspected ADRs and of drugs commercially available. This can generate a lack of vaccines; AIFA projects by increasing awareness about PV health professionals knowledge about the potential adverse surely help in improving the status of ADRs reporting.
effects due to drug-drug interactions or contraindications of some dugs caused by improper use.
Furthermore, the In Italy, the actual situation of spontaneous reports of ADRs is introduction of generic drugs has also increased the number of patients not responding to treatments or with ADRs due to increased bioavailability.
In all countries, PV systems rely on spontaneous (or voluntary) communication, in which suspected ADRs are reported by the medical staff or by patients themselves to a national health In the present study, we report an analysis of the ADRs coordinating center. The spontaneous reporting systems provide the highest volume of information at the lowest maintenance cost and have established their value in the possible corrections to improve the system in Calabria or to early diagnosis of problems related to safety in patients or be used in other countries.
their products or their use.[14] Most important function of the signals[15] and the formulation of hypotheses, which leads to MATERIALS AND METHODS risks related to the use of a medication, any possible changes All reports of ADR relating to Calabria region were obtained in the package insert and give updated information product.[16] from the database through portal National Health Information System (NSIS) AIFA, a system specifically designed to In some cases, the withdrawal of marketing authorizations are handle the reporting of ADRs. These reports collected in the also based on ICSRs, for example, in the case of cerivastatin, an association (a "signal") among cerivastatin, myopathy and analysis including ADRs severity, the pharmacological class rhabdomyolysis has been published on the basis of ICSRs, causing ADRs and the kind of reporter. A total of 461 ADRs Journal of Pharmacology and Pharmacotherapeutics December 2013 Vol 4 Supplement 1 Giofrè, et al.: ADRs report year 2012 in Calabria (Italy) were present in the database in the period 1st a higher number of ADRs for women has been reported serious adverse events was reported for antibacterial agents ADRs analysis
The ADRs' reports present in the national network of PV via
Further analysis showed that the class of drugs, which caused analysis showed a higher incidence of ADRs in the age group between 41 and 65 years old, followed by the series "over 65" this age group. In fact, in the "age 41-65" group, 61 patients of The main class of reporters is represented by hospital doctors respectively. All health-care groups have reported more non-serious adverse reactions; the hospital doctors have reaction was severe [Figure 1]. Furthermore, in the age group of non-serious events comparing all reactions. Considering antibacterials, the association "amoxicillin/clavulanic acid" By comparing all age groups the minor onset of ADRs was in the globally considering ADRs the majority of adverse events were In the age group 41-65, drugs that have given more ADRs were [Figure 4].
From the comparison between brands and generics, it has pharmacological class of antimicrobial it is possible to observe generic drugs use while the rest was caused by brand drugs. a homogenous number of ADRs in all the range age; the The most frequently reported reactions were skin reactions antiepileptic drugs have caused the major number of ADRs showed gender differences for the reporting; ADRs in men Last analysis examined the occurrence of ADRs for each to the month of observation, the mean number of ADRs/month Figure 1: Frequency of adverse drug reactions in different age range
Figure 2: Number of adverse drug reactions caused by different drugs
and their related severity class in different range age Journal of Pharmacology and Pharmacotherapeutics December 2013 Vol 4 Supplement 1 Giofrè, et al.: ADRs report year 2012 in Calabria (Italy) Figure 3:
reactions considering different pharmacological classes
Figure 4: Distribution of adverse drug reactions relatively to every
single brand name. Nexavar = Sorafenib; OKI = Ketoprofene;
Augmentin = Amoxicillin/clavulanic acid; Keppra = Levetiracetam;
T e g r e t o l = C a r b a m a z e p i n e ; D e p a k i n = V a l p r o i c a c i d ;
Clavulin = Amoxicillin/clavulanic acid; Zimox = Amoxicillin Figure 5: Incidence of the most frequently reported type of adverse
drug reactions
January represent the months with the higher number of ADRs whereas, August and December are below the average/month.
Figure 6: Number of adverse drug reactions in the months of 2012
advertisement on the role of the PV center and the importance of PV has been pursued at all levels including brief meetings positive trend of spontaneous reporting in the Calabria region in hospitals or publications on newspapers. Finally, a strong collaboration based on selected local project has led to the creation of small professional networks paying particular reached; however, the mechanism set up has already collected attention to the development of ADRs and drug safety. th of May. Up to date, All together, the continuous feedback obtained by health the number is already very close to the previous year and very professionals increased the general knowledge on PV.
This result was achieved by an intensive activity of information a high participation of specialist doctors mainly working in to health professionals by the organization of 5 regional hospitals and general practitioners; very relevant is the increase Journal of Pharmacology and Pharmacotherapeutics December 2013 Vol 4 Supplement 1 Giofrè, et al.: ADRs report year 2012 in Calabria (Italy) observed for pharmacists in comparison to the previous year that the world medical-health is sensitive to the problem; surely all the interventions put in place in recent years have nurses remains very low despite the fact that them together with increased PV culture.
ADRs; furthermore, no spontaneous reports from patients were uploaded into the system. The reasons for such a result might be various (see below); however, in some cases nurses In conclusion, Italy at national level has reached and exceeded observed the ADR and then the physician reported it, whereas the GD pre-set by the WHO and has shown an important growth despite the increment in the number of reports by pharmacists, this class could undoubtedly increase their participation to the system. These data, although many measures have been put increase in the total number of ADRs. The region Calabria has in place to increase the PV culture at regional, national and global levels, it must be admitted that still more job has to be reached yet the GD it has shown one of the largest increase.
done in order to move out of this under-reporting condition.
The positive trend is encouraging and the work of the regional Under-reporting has many causes: The detectors often look center is reaching satisfactory levels. The activities organized for a certain temporality and causality between ADRs and drug before reporting the event; sometimes the reports are (CME) courses, have led to good results (the current ADRs count of poor quality or incomplete and cannot be inserted into the for this year is very encouraging). More generally, the role of PV system; there is an underutilization of the latest technological regional centers seems to be necessary to the correct functioning communication means; very often the reporters complain about of this machine. In the past, when such centers activities were stopped, due to lack of funding, the number of ADRs dropped down to unsatisfactory levels. Therefore, information and support must continue in the next coming years at least until PV culture gets a widespread diffusion starting to be self-sustained. In any case, the relevance of PV to patients' safety and pharmaco- inhabitants ADRs were reported keeping Italy beyond the economy should be a primary aim in all countries.
standard set by WHO. Although the gold standard (GD) has been achieved at national level, the number of reports is not homogenous in the country and there are regions that exceed the GD and other, which are far below.
Among the various Italian regions, a strong discrepancy and technical support.
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