Analysis of health care professionals' incident reports on medical devices in Croatia.

AIM: To assess the quantity and quality of incident reports on medical devices by health care professionals from 2012 to 2021 and evaluate the effect of reporting on manufacturers' post-market surveillance. METHODS: Eighty-five incident reports were scored according to a self-developed evaluation system, and categorized as excellent, good, medium, qualified, and unqualified. The completeness of data in critical fields was assessed. For each report, the type and city of the reporter, and medical device risk class were extracted to calculate the frequency of report occurrence per risk class and outcomes for reportable reports. RESULTS: The number of reports received from health care professionals was low; the highest number of reports in a year was 17. The majority of reports were deemed as unqualified (61.18%) and only 4.71% as excellent. Still, 67.65% of incident reports importantly affected the manufacturer's post-market surveillance, either as added information that contributes to risk monitoring or directly triggering a field safety corrective action. CONCLUSION: The number of total reports and reports per year shows extensive underreporting in Croatia, and the quality of the provided reports is insufficient.

REVIEW OF ADVERSE DRUG REACTIONS OF MEDICINES USED FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA REPORTED TO HALMED.

Benign prostatic hyperplasia is one of the most common diseases in men, with a prevalence rate of 50% in their 50s to 80% in their 80s, and is mostly treated with chronic drug therapy. The aim of this study was to analyze adverse drug reactions (ADR) to drugs used in benign prostate hyperplasia (BPH) treatment reported to HALMED from 2008 to 2021. Data on ADR reports in Croatia were obtained from the VigiFlow national database and on the use of drugs for BPH in Croatia from Drug Utilization Reports from HALMED. In the observed period, the number of reports on each BPH drug, total number of reports, seriousness of reported ADR, patient age and sex, type of reporter, and most reported ADRs were analyzed. Results showed that 438 ADR reports were received, of which 45.95% on tamsulosin as the most frequently used drug for BPH. Of all reports, 84% were non-serious, 96% were reported in men and 82% in patients older than 45 years. The most frequently reported ADRs were consistent with the known safety profile of BPH drugs. Pharmacists were the most common (47%) reporters of ADRs for BPH drugs, while 33% were reported by physicians. Analysis of the reported ADRs showed that most frequently reported ones were in line with the known safety profile of BPH drugs. However, given the prevalence of the disease and the extent of the use of BPH drugs, it could be argued that the number of reports could be higher (i.e., 34 reports/year). Reporting on ADRs is necessary to better understand the safety profile of drugs in the post-authorization period, and more information on the safe use of medicines could be collected by raising awareness of healthcare professionals.

Mutual recognition in the European system: A blueprint for increasing access to medicines?

The European regulatory system for approval of medicinal products is globally recognised as a unique platform for regulatory work-sharing and mutual recognition. As such, it potentially serves as a role model for regulatory capacity building worldwide. While focusing on mutual recognition and decentralised procedures, this paper illustrates key success factors and structures allowing for the reliance-based authorisation of medicines in the European Economic Area from the perspective of a national regulatory authority (NRA). This paper presents major challenges in fulfilling the requirements for joining the European Medicines Regulatory Network (EMRN) and the strategies regarding how those challenges could be successfully addressed based on the example of the Agency for Medicinal Products and Medical Devices of Croatia, the most recent NRA in the EMRN. It also discusses the hallmarks of successful implementation of the European system of reliance as a blueprint for increasing access to safe and efficacious medicines from the perspective of a NRA.

Membrane of Candida albicans as a target of berberine.

BACKGROUND: We investigated the mechanisms of anti-Candida action of isoquinoline alkaloid berberine, active constituent of medically important plants of Barberry species. METHODS: The effects on membrane, morphological transition, synthesis of ergosterol and the consequent changes in membrane permeability have been studied. Polarization and lipid peroxidation level of the membrane following berberine treatment have been addressed. RESULTS: Minimal inhibitory concentration (MIC) of berberine against C. albicans was 17.75 µg/mL. Cytotoxic effect of berberine was concentration dependent, and in sub-MIC concentrations inhibit morphological transition of C. albicans cells to its filamentous form. Results showed that berberine affects synthesis of membrane ergosterol dose-dependently and induces increased membrane permeability causing loss of intracellular material to the outer space (DNA/protein leakage). Berberine also caused membrane depolarization and lipid peroxidation of membrane constituents indicating its direct effect on the membrane. Moreover, ROS levels were also increased following berberine treatment indicating further the possibility of membrane damage. CONCLUSION: Based on the obtained results it seems that berberine achieves its anti-Candida activity by affecting the cell membrane.

Antifungal Activity of Oleuropein against Candida albicans-The In Vitro Study.

In the present study we investigated activity of oleuropein, a complex phenol present in large quantities in olive tree products, against opportunistic fungal pathogen Candida albicans. Oleuropein was found to have in vitro antifungal activity with a minimal inhibitory concentration (MIC) value of 12.5 mg·mL-1. Morphological changes in the nuclei after staining with fluorescent DNA-binding dyes revealed that apoptosis was a primary mode of cell death in the analyzed samples treated with subinhibitory concentrations of oleuropein. Our results suggest that this antifungal agent targets virulence factors essential for establishment of the fungal infection. We noticed that oleuropein modulates morphogenetic conversion and inhibits filamentation of C. albicans. The hydrophobicity assay showed that oleuropein in sub-MIC values has significantly decreased, in both aerobic and anaerobic conditions, the cellular surface hydrophobicity (CSH) of C. albicans, a factor associated with adhesion to epithelial cells. It was also demonstrated that the tested compound inhibits the activity of SAPs, cellular enzymes secreted by C. albicans, which are reported to be related to the pathogenicity of the fungi. Additionally, we detected that oleuropein causes a reduction in total sterol content in the membrane of C. albicans cells, which might be involved in the mechanism of its antifungal activity.

Generic Medicines in Croatia--Regulatory Aspects and Statistics.

A generic medicine is an equivalent of an originator pharmaceutical product. It contains the same active substance as, is "essentially similar" to, and is therefore interchangeable with, the originator product. The objective of this study was to determine the share of generic medicines of the total received marketing authorization applications in Croatia, and the specificities in the approval of generic medicines with regard to assessments of their quality documentation. We collected the information from the Agency's medicinal products databases. Absolute numbers are shown for the applications for the authorizations of medicines in total and generics in particular in the period from 2005-2009. Data were analyzed using descriptive statistics. The annual number of marketing authorization applications for generic medicines received in Croatia increased from 148 applications in 2005 to 276 applications in 2009. In the period from 2005-2009, the number of applications for the approval of generic medicines accounted for 55% of all submitted applications. More than five generic medicines were approved for the following active compounds: amlodipine, lisinopril, atorvastatin, tamsulosin and omeprazole. In the following years, the number of applications from international manufacturers stagnated, while the number of applications by local manufacturers is on a steady climb, with the exception of 2008. From 2005-2009, an almost continual increase in the number of applications for the approval of generic medicines is evident. The largest number of generic medicines was approved for generic medicines intended for the treatment of cardiovascular disease (amlodipine, lisinopril, atorvastatin). A continual increase of applications from local manufacturers has been recorded. In the approval of these medicines, it is very important to develop a uniform approach to assessing the quality of each medicine, in order to guarantee a high quality product for the patient.

Analysis of purity profiles of generic lisinopril tablets marketed in Croatia.

In view of an increasing number of generic drugs emerging, a comparative study was performed including the approved lisinopril preparations in the form of tablets marketed in Croatia, to compare purity profiles of generic drugs versus the original medicinal product. Several batches of each individual medicinal product at different stages of their shelf life were analyzed. Impurities were determined by means of high performance liquid chromatography (HPLC). Impurity profiles were demonstrated to be specific for each individual drug. Original drug, as compared to its generic copies, had the lowest values and also the lowest variability of all the tested parameters--type, total number and content of impurities--suggesting that its manufacturing process is to certain degree better controlled compared to other manufacturers. A characteristic impurity C appearing in all the assessed preparations has the lowest levels in the original drug, whereas the amount of the highest unknown impurity does not exceed 0.10% in any of the analyzed preparations. Although the original drug stands out from all the generic preparations with its purity, it can be generally concluded that, as regarding impurities levels, all the analyzed medicinal products are within the ranges of specification limits; accordingly, it is therefore not expected that, in case of lisinopril tablets, administration of the original drug as compared to any of its generic drugs, will be safer for the patient.

The readiness of the spontaneous reporting system for COVID-19 vaccines safety monitoring in Croatia.

We aimed to identify whether a spontaneous reporting system (SRS) in Croatia could timely identify and confirm signals for COVID-19 vaccines. Post-marketing spontaneous reports of adverse drug reactions (ADRs) following COVID-19 immunisation reported to the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) were extracted and analysed. 6624 cases reporting 30 655 ADRs following COVID-19 immunisation were received from 27th December 2020 to 31st December 2021. Available data in those cases were compared with data available to the EU network at the time when signals were confirmed and minimisation measures were implemented. 5032 cases, reporting 22 524 ADRs, were assessed as non-serious, and 1,592 cases, reporting 8,131 ADRs as serious. The most reported serious ADRs, which were listed in the MedDRA Important medical events terms list, were syncope (n = 58), arrhythmia (n = 48), pulmonary embolism (n = 45), loss of consciousness (n = 43), and deep vein thrombosis (n = 36). The highest reporting rate had Vaxzevria (0.003), followed by Spikevax and Jcovden (0.002), and Comirnaty (0.001). Potential signals were identified, however, they couldn't be timely confirmed solely on cases retrieved by SRS. In order to overcome the limitations of SRS, active surveillance and post-authorisation safety studies of vaccines should be implemented in Croatia.

Quality analysis of manufacturer's incident reports regarding medical devices.

BACKGROUND: Medical devices provide a great number of medical treatments and have an important role in patients' healthcare; however, there are certain risks, sometimes even serious incidents, associated with their usage. To ensure that benefits of medical device usage always outweigh associated risks, it is necessary to closely monitor known risks post-market and detect new ones as early as possible. Among others, valuable instrument of post-market surveillance is manufacturer incident report. Yet to accomplish its intended use, such report must be sufficiently populated and supplied with correct information. Aim of this paper is to assess the quality of manufacturer's incident reports received in HALMED since 2012 to May 2021. METHODS: The study included 578 initial reports and 566 final reports that were scored according to the evaluating system we designed and categorized as Excellent, Good, Medium, Qualified and Unqualified. For each report medical device risk class was also extracted to calculate the frequency of report occurrence per risk class and time that passed between the initial and final report. Difference in quality of the reports between manufacturers based on EU countries and countries outside the EU was determined by Mann Whitney U test. RESULTS: Most of initial and final reports fall into two highest quality category level, which means that a sufficient amount of reports are of good/excellent quality and quality of reports prevails. However, the study's results indicate the need for higher scores, especially in critical fields of the form. CONCLUSIONS: Data obtained from the manufacturer can be scarce and insufficient, causing negative influence on Competent Authority's investigation procedure. Another issue we recognized is extensive underreporting in Croatia, which can seriously undermine the established system.

Medical devices as a source of phthalate exposure: a review of current knowledge and alternative solutions.

Phthalates are a group of phthalic acid esters used as plasticisers in a large number of products to improve their flexibility, softness, and extensibility. Their wide use in medical devices, however, raises a lot of concern, as they can enter the organism and have toxic effects on human liver, thyroid, kidneys, lungs, reproductive, endocrine, nervous, and respiratory system and are associated with asthma, obesity, autism, and diabetes. The aim of this review is to summarise current knowledge about phthalate migration from medical devices during different medical procedures and possible impact on patient health. It also looks at alternative plasticisers with supposedly lower migration rates and safer profile. Not enough is known about which and how many phthalates make part of medical devices or about the health impacts of alternative plasticisers or their migration rates.

Evaluation of antiaggregatory activity of flavonoid aglycone series.

BACKGROUND: Among natural compounds, present in every day diet, flavonoids have shown beneficial effect in prevention of cardiovascular diseases that can be attributed, at least partially to the described antiaggregatory activity i.e. antiplatelet effects of flavonoids. Due to the ever increasing pharmacological interest in antiplatelet agents a systematic experimental evaluation of large flavonoid series is needed. METHODS: A set of thirty flavonoid aglycones has been selected for the evaluation. All measurements of aggregation were done under standardized and firmly controlled in vitro conditions. The whole blood samples, multiple platelet functional analyzer and adenosine diphosphate (ADP) as a weak agonist of aggregation were selected for this purpose. RESULTS: The results were expressed as minimal concentration of flavonoid that can significantly lower the platelet aggregation compared to the corresponding untreated sample (minimal antiaggregatory concentration--MINaAC). All analyzed flavonoids exhibited antiaggregatory activity MINaAC ranging from 0.119 µM to 122 µM, while the most potent representatives were 3,6-dihydroxyflavone (0.119 µM) and syringetin (0.119 µM). CONCLUSIONS: Measurable antiplatelet activity established at submicromolar flavonoid concentrations suggests that even a dietary consumption of some flavonoids can make an impact on in vivo aggregation of platelets. These findings also point out a therapeutical potential of some flavonoids.

Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study.

AIM: To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence. METHODS: In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them. RESULTS: HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n=4) was significantly higher (P<0.001) than among the remaining reports (580 out of 1982; n=2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter. CONCLUSION: The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education.

A century of antivenom.

Because it primarily affects the poor in undeveloped parts of the world where medical care is often inadequate and insufficient, envenomation is considered a neglected public health issue, despite the existence of antivenom therapy for more than a century. This article provides an overview of the epidemiological situation for important venomous animals, together with achievements in the production, control, technological progress and safety of antivenoms since their discovery.

Presence of nitrosamine impurities in medicinal products.

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.

Protective effects of olive oil phenolics oleuropein and hydroxytyrosol against hydrogen peroxide-induced DNA damage in human peripheral lymphocytes.

This study investigates antioxidant capacity and protective effects of phenolic compounds oleuropein (OLP) and hydroxytyrosol (HT), present in olive oil and olive leaves, against H2O2-induced DNA damage in human peripheral lymphocytes. Antioxidant potency was determined using the measurement of radical-scavenging activity (ABTS∙+ assay), ferric reducing power (FRAP assay) and cupric reducing antioxidant capacity (CUPRAC assay). Both substances were found to be potent antioxidant agents due to their free radical-scavenging activities. Antigenotoxic effects of oleuropein and hydroxytyrosol against H2O2-induced damage in human lymphocytes were evaluated in vitro by alkaline comet assay. At tested concentrations (1, 5, 10 µmol L-1), oleuropein and hydroxytyrosol did not induce a significant increase of primary DNA damage in comparison with the negative control. Pretreatment of human lymphocytes with each of the substances for 120 min produced a dose-dependent reduction of primary DNA damage in the tested cell type. Hydroxytyrosol showed a better protective effect against H2O2-induced DNA breaks than oleuropein which could be associated with their free radical-scavenging efficacy.

Antimicrobial Resistance: Physicians' and Pharmacists' Perspective.

Aims: The aim of this study was to evaluate pharmacists' and physicians' attitudes and knowledge about antimicrobial treatment and resistance and based on the results to identify possible gaps and suggest opportunities for collaboration between the two professions. Methods: The physician's questionnaire consisted of 47 items and the pharmacists' questionnaire consisted of 50 items. Participants were asked to identify situations in which they were more likely to prescribe/dispense an antimicrobial without a firm indication, to identify the greatest contributors to antimicrobial resistance (AMR) among health care workers, to rate statements related to AMR, how frequently they used different sources of information and to rate the possible causes of AMR. Furthermore, preparedness for specific actions in practice was self-rated and knowledge was evaluated. The questionnaires were anonymous and participation in the study was voluntary. Results: This research included 180 community pharmacists and 181 physicians. As many as 76 (42.0%) physicians stated they would prescribe an antimicrobial when unsure whether the infection was of viral or bacterial etiology. More than half of the participants considered family medicine doctors the greatest contributors to AMR (N = 216, 59.8%), followed by patients (N = 175, 48.5%). In questions focusing on knowledge, physicians scored significantly higher compared with pharmacists (4.06 ± 1.01 vs. 3.71 ± 1.08, p = 0.001). Conclusion: This research revealed practices among pharmacists and physicians that should be improved and it highlighted gaps in knowledge by both professions. More attention should be given to patient consultation when dispensing and prescribing an antimicrobial as this may reduce their contribution to AMR.

Community pharmacists' use, perception and knowledge on dietary supplements: a cross sectional study.

BACKGROUND: Pharmacists are commonly tasked with recommending the appropriate dietary supplement and advising the patients of their correct and safe use. Previous research, conducted on pharmacy students, showed that they did not always use the evidence based sources of information, with personal use identified as a significant predictor influencing the decision to recommend a supplement. OBJECTIVES: To compare use, perceptions and knowledge of dietary supplements of pharmacists with different years of work experience and to explore factors that could influence their recommendation of supplements. METHODS: A questionnaire based cross-sectional study was conducted on Croatian community pharmacists in September 2017. The questionnaire explored pharmacists' demographic characteristics, use, perceptions and knowledge of dietary supplements. Pharmacists (N=102) were divided in two groups based on their work experience: P0 (<10 years) and P1 (≥10 years). RESULTS: All included pharmacists had high knowledge scores without differences between groups (P0=10, IQR 9-12 vs P1=11, IQR 9-12, expressed as median and interquartile range (IQR), p=0.275). Less experienced pharmacists perceived there was less research conducted on the dietary supplements compared to their more experienced counterparts (P0=1, IQR 1-2 vs P1=2, IQR 2-3, expressed as median and interquartile range, p<0.001). Groups differed in sources used when choosing the appropriate supplement with P0 using higher quality sources such as systematic reviews in comparison to P1 (32.1% vs 8.7%, p=0.004). Pharmacists' decision to recommend a dietary supplement was influenced by their personal use (odds ratio 0.216, 95%CI 0.068:0.689, p=0.01) and work experience (odds ratio 0.154, 95%CI 0.045:0.530, p=0.003). CONCLUSIONS: Pharmacists did not use the high quality sources when recommending dietary supplements and their decision to recommend the supplement was not based on objective evaluation of evidence. Further education about the practice of evidence-based pharmacy is necessary, with special emphasis on senior pharmacists who might have missed that aspect during their formal education.

Granting marketing authorisation for medicines in South East European countries: the point of view of the authority.

European legislation for medicines places the emphasis on an assessment of quality, safety and efficacy during the procedure for the granting of marketing authorisations for medicines, in order to protect patient health. The integrated European regulatory system involves the participation of a network of experts from the agencies of the member states that takes part in the European procedures for the authorisation of medicines. On the way to full membership in the EU, candidate countries and potential candidates have to transpose and implement the European directives for medicinal products; they must also strengthen their scientific and administrative capacities. Croatia acquired good experience in implementing the simplified marketing authorisation procedure for medicines authorised in the EU pursuant to the New Collaboration Agreement between Drug Regulatory Authorities in Central and East European Countries (nCADREAC), which helps it to exchange information and prepare for the implementation of European procedures. However, there are still some provisions to transpose before actual full membership, and also dossier upgrading, in which the marketing authorisation holder has to harmonise its documentation about a medicinal product with the requirements of the directives, if a product already on the market was not previously approved in line with current European legislation. Collaboration with the European Medicines Agency (EMA) through an Instrument for Pre-Accession (IPA) provides candidate countries and potential candidates the opportunity for education and training in some regulatory activities as well as the participation of their representatives as observers in some EMA committees and working groups. Some characteristics of the national regulatory frameworks of the countries of South East Europe in their efforts to achieve harmonisation with EU legislation are presented in this paper.

Regulating medicines in Croatia: five-year experience of Agency for Medicinal Products and Medical Devices.

AIM: To present the activities of the Agency for Medicinal Products and Medical Devices in the first 5 years of its existence and to define its future challenges. METHODS: Main activities within the scope of the Agency as a regulatory authority were retrospectively analyzed for the period from 2004-2008. Data were collected from the Agency's database and analyzed by descriptive statistics. RESULTS: The number of issued medicine authorizations rose from 240 in 2004 to 580 in 2008. The greatest number of new chemical and biological entities was approved in 2005. The greatest number of regular quality controls (n=5833) and special quality controls was performed in 2008 (n=589), while the greatest number of off-shelf quality controls (n=132) was performed in 2007. The greatest number of medicine labeling irregularities was found in 2007 (n=19) and of quality irregularities in 2004 (n=9). The greatest number of adverse reactions was reported in 2008 (n=1393). The number of registered medical devices rose from 213 in 2004 to 565 in 2008. CONCLUSION: Over its 5 years of existence, the Agency has successfully coped with the constant increase in workload. In the future, as Croatia enters the European Union, the Agency will have to face the challenge of joining the integrated European regulatory framework.

Preliminary investigation of metal and metalloid contamination of homeopathic products marketed in Croatia.

BACKGROUND: Due to their popularity as a complementary therapy in many diseases, homeopathic products of animal, vegetable, mineral and chemical origin should be tested for the presence of contaminants to prevent eventual toxic effects. OBJECTIVE: Thirty samples of homeopathic products were analyzed to estimate possible contamination with potentially toxic elements: Pb, Cd, As, Hg, Cr, Ni and Zn, and to assess human exposure to these metals/metalloid as a consequence of their consumption. METHODS: Atomic absorption spectrometry was used to determine metal and metalloid concentrations. RESULTS: Most tested products had very low metal/metalloid levels (below the limit of quantification of the method), but the metal/metalloid levels in the remaining products were in the following ranges (in microg g(-1)): Pb 0.33-1.29 (6 samples), Cd 2.78 (1 sample), As 0.22 (1 sample), Hg 0.02-0.12 (24 samples), Cr 0.40-10.27 (10 samples), Ni 0.43-55.00 (19 samples), and Zn 2.20-27.80 (11 samples). In the absence of regulatory standards for homeopathic products, the obtained results were compared to maximum allowable levels (MALs) as proposed by USP Ad Hoc Advisory Panel. Some analyzed preparations had metal levels above MALs (Pb: 2 samples; Cd: 1 sample; Ni: 2 samples). However, estimated cumulative daily intakes from tested homeopathic products were in all cases lower than permitted daily exposures for all dosage forms. CONCLUSION: The risk of bioaccumulation of metals/metalloid from the homeopathic medicines seems to be rather low, due to small quantities of those products prescribed to be applied per day, as well as insignificant metal contamination of the majority of tested products. However, the fact that particular formulations were contaminated by metals above MALs indicates potential risk and points to the necessity of regular monitoring of homeopathic products for metal contamination, due to their frequent and mostly unsupervised use.