Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study.

INTRODUCTION: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. METHODS: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). RESULTS: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82-74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19--0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. CONCLUSION: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

Prevalence and Risk Factors Associated with Potentially Inappropriate Prescribing According to STOPP-2 Criteria among Discharged Older Patients-An Observational Retrospective Study.

Pharmacokinetic and pharmacodynamic changes associated with old age, along with multimorbidity and polypharmacy might lead to inappropriate prescribing and adverse reactions. Explicit criteria such as the Screening tool of older people's prescribing (STOPP) are useful to identify potential inappropriate prescribing's (PIPs). Our retrospective study included discharge papers from patients aged ≥65 years, from an internal medicine department in Romania (January-June 2018). A subset of the STOPP-2 criteria was used to assess the prevalence and characteristics of PIPs. Regression analysis was performed to evaluate the impact of associated risk factors (i.e., age, gender, polypharmacy and specific disease). Out of the 516 discharge papers analyzed, 417 were further assessed for PIPs. Patients' mean age was 75 years, 61.63% were female and 55.16% had at least one PIP, with 81.30% having one or two PIPs. Antithrombotic agents in patients with significant bleeding risk was the most prevalent PIP (23.98%), followed by the use of benzodiazepines (9.11%). Polypharmacy, extreme (>10 drugs) polypharmacy, hypertension and congestive heart failure were found as independent risk factors. PIP was prevalent and increased with (extreme) polypharmacy and specific cardiac disease. Comprehensive criteria like STOPP should be regularly used in clinical practice to identify PIPs to prevent potential harm.

Utilization of psychotropic medicines in Romania during 1998-2018.

Background: Mental disorders can have a significant impact on patients' life, including economic, social and individual consequences, and psychotropic medication is essential to treat these conditions. Psychotropic drug utilization studies contribute to a clearer picture of the management of these conditions. Data published from Romania on this topic is limited. The present study aims to characterize the utilization patterns of anxiolytics, antidepressants (ADs), and antipsychotics (APs) in Romania during 1998-2018. Methods: Drug utilization data were provided by Management Center for Documentation, Information and Marketing (CEGEDIM) Romania and quantitative data for each psychotropic medicine were converted to total defined daily doses (DDDs) and to DDD/1000inhabitants/day (DDD/TID). The total use of medicines in DDD/TID was computed in order to obtain the drug utilization 90% (DU90%) segment. Results: An increasing trend in total utilization of psychotropic medicines in Romania started in 2004. Anxiolytics use was predominant until 2013 and the yearly anxiolytic use over the entire study period remained between 10 and 15 DDD/TID. Diazepam lost popularity over time in detriment of the utilization of other anxiolytic benzodiazepines, such as alprazolam and lorazepam. ADs utilization markedly increased during the study period (the average annual growth rate was 13.66% starting 1999). Selective serotonin reuptake inhibitors (SSRIs) became present on the 2008 DU90% and was the dominant class of ADs, with sertraline being the most prescribed, followed by escitalopram and paroxetine. APs utilization showed an increasing trend from 2003 until 2018. Atypical APs became present on the 2008 DU90%, while typical APs were no longer included in the 2018 DU90%. Among atypical APs, olanzapine was the main agent prescribed, and starting 2010 was followed by quetiapine and risperidone. The uptake of APs long-acting formulations became more evident during the last analyzed years (2015-2018). Conclusion: We observed an increasing utilization of APs and a more prominent increase in ADs utilization in Romania during 1998-2018. The anxiolytic prescribing remained nearly stable during this time. Further research can bring more information on the various factors influencing psychotropic utilization in Romania.

A Description of Acute Renal Failure and Nephrolithiasis Associated With Sodium-Glucose Co-Transporter 2 Inhibitor Use: A VigiBase Study.

Background: The Food and Drug Administration issued a warning on the risk of acute kidney injury and a signal of nephrolithiasis for patients using sodium-glucose co-transporter 2 inhibitors (SGLT2i). We performed a descriptive analysis on acute renal failure (ARF) and nephrolithiasis cases reported to SGLT2i in the VigiBase®, in the scope of characterizing the patients and reactions and to report on the disproportionality analysis. Methods: We analyzed all ARF and nephrolithiasis reports for SGLT2i in VigiBase from inception to September 2021. ARF cases were defined as reports containing at least one of the preferred terms (PTs) included in the ARF narrow Medical Dictionary for Regulatory Activities Standardised Queries (MedDRA SMQ). SGLT2i exposure was considered for reports with at least one gliflozin as a suspected/interacting drug. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR). Results: Of 27,370,413 total reports in VigiBase, we found 3,972 ARF reactions to gliflozins as suspected/interacting drugs in 3,751 patients and 231 nephrolithiasis reactions in 227 patients. Most cases were reported from American regions (3057; 81.49%), for patients of age group 45-64 years (1590; 59%). About 30% (1156) of the ARF reports were registered in 2018, most from spontaneous reporting, and from consumers followed by healthcare professionals (2,235; 61% and 1440; 38%, respectively). Canagliflozin was the most involved gliflozin in the ARF and nephrolithiasis cases (2,640; 67% and 109; 47%, respectively). The great majority of ARF and nephrolithiasis reports were serious (3,761; 95% and 182; 79%, respectively). Of the total ARF cases reported, 51 had fatal outcome, while 152 had not recovered/not resolved outcome. No fatal outcome was reported for nephrolithiasis. Disproportionality analysis in full database showed a PRR of 4.68 (95% CI 4.53-4.83) for all gliflozins-ARF and a PRR of 3.44 (95% CI 3.00-3.95) for all gliflozins-nephrolithiasis. Conclusion: Most of ARF reports associated with gliflozins were serious, with an important number of cases with fatal outcome. A drug safety signal was found between ARF narrow SMQ and gliflozins. Also, gliflozins were associated with an increase in the proportion of nephrolithiasis reports compared to other medications.

A VigiBase Descriptive Study of Fluoroquinolone-Associated Peripheral Nervous System Disorders.

BACKGROUND: Recent drug safety concerns described fluoroquinolone (FQ)-induced peripheral nervous system reactions. The objective of this study was to characterize such reports from VigiBase. METHODS: The analysis included FQ-induced peripheral nervous system disorder adverse drug reaction (ADR) reports (up to July 2019). We looked into the disproportionality data in terms of proportional reporting ratio (PRR) and information component (IC) values, and descriptive analysis was performed for FQ-ADRs positive associations (ADRs, suspected FQs, potential risk factors, such as associated therapy and underlying disease). RESULTS: Disproportionality analysis revealed 4374 reports (3531 serious) with peripheral nervous system ADRs associated with at least three FQs (neuropathy peripheral, 5492; neuralgia, 481; polyneuropathy, 220; sensory loss, 99; peripheral sensorimotor neuropathy, 39). Among these, both time-to-onset and duration of reaction were mostly between 1-7 days and ≥30 days. Most of the ADRs were not recovered/resolved at the time of reporting. CONCLUSION: The results augment the existing data on FQ safety concerns, specifically their potential effect on the nervous system.

Effects of Branched-Chain Amino Acids on Parameters Evaluating Sarcopenia in Liver Cirrhosis: Systematic Review and Meta-Analysis.

INTRODUCTION: Sarcopenia is a major element of malnutrition in liver cirrhosis (LC) and is present in 30-70% of this population, being associated with a poor overall prognosis due to related complications such as hepatic encephalopathy, ascites, and portal hypertension. This systematic review and meta-analysis aimed to evaluate the effects of branched-chain amino acids (BCAA) supplementation on several parameters used to assess sarcopenia in LC. MATERIALS AND METHODS: A comprehensive systematic electronic search was performed in PubMed, EMBASE, Scopus, Cochrane Library, and ClinicalTrials.gov databases using predefined keywords. We included full articles that satisfied the inclusion and exclusion criteria. Quality assessment of included studies was conducted using Cochrane Collaboration's tool and NHLBI quality assessment tools for interventional and observational studies, respectively. The principal summary outcome was the mean difference (MD) in the evaluated parameters. We performed a pre- and post-intervention analysis and comparison between two intervention groups (BCAA vs. controls) of the evaluated parameters when applicable. RESULTS: A total of 12 studies involving 1,225 subjects were included in our qualitative synthesis and five in our quantitative synthesis. At baseline vs. post-intervention assessment, subjects receiving BCAA supplementation were found to have a significant improvement in skeletal muscle index (SMI) (-0.347 [95% CI -0.628-0.067; p-value 0.015]) and mid-arm muscle circumference (MAMC) (-1.273 [95% CI (-2.251-0.294; p-value 0.011]). However, no improvements were reported in handgrip (-0.616 [95% CI -2.818-1.586; p-value 0.584]) and triceps subcutaneous fat (1.10 [95% CI -0.814-3.014; p-value 0.263]). CONCLUSION: Following BCAA supplementation, several parameters used to evaluate sarcopenia in LC patients were found to be improved, including SMI and MAMC. Nevertheless, no improvements were seen in handgrip and triceps subcutaneous fat. Results should be interpreted with caution due to the limited methodological quality of the included studies.

Concordance of pharmacist versus patient responses regarding counselling in community pharmacy.

RATIONALE AND OBJECTIVES: Patient counselling on medication is one of the activities that can and should be performed in community pharmacy. Patient counselling was proved to have a positive effect on clinical outcomes, quality of life, drug/disease knowledge, satisfaction and reduced health-service utilization. Our objective was to assess the degree of concordance between the responses of patient and pharmacist on the same questions regarding provided counselling. METHODS: Data from two questionnaires containing a common block of 14 questions regarding the counselling provided on the medications use, safety concerns, storage, validity term, disposal and disease monitoring was paired and analysed. Questionnaires were paired based on a code and Kappa Cohen coefficient (KCc) and the prevalence adjusted biased adjusted kappa (PABAK) were calculated to evaluate the degree of concordance between pharmacist versus patient responses. The values of the KCc and PABAK were interpreted as per Altman. RESULTS: For the 14 questions, data from 2047 to 2378 questionnaires collected from 520 community pharmacies in 10 of Romania's counties were analysed. The highest level of concordance ('very good') was achieved on the items regarding the counselling on the medicines' route of administration (PABAK = 0.88), time of administration (PABAK = 0.80) and dosage (PABAK = 0.82). The highest disagreement (week concordance) was found on the question regarding the counselling on the medicines adverse effects (PABAK = 0.01), where 44.8% of patients responded that they received counselling as compared to 93.1% of the pharmacists who responded that they offered counselling. For the rest of the questions, moderate concordance was found. CONCLUSION: Overall a moderate level of concordance between patient and pharmacist responses was found on the majority of the questions, with the highest level found for drug use (dosage, route and time of administration). The highest discrepancy was found for the counselling on the medicines adverse effects.

Drug utilisation study of antidiabetic medication during 2012-2019 in Romania.

BACKGROUND: To analyse the antidiabetic medication (ADM) market trends in Romania and to describe the utilisation of the new ADMs (glucagon-like peptide-1 receptor agonists [GLP-1 RA], dipeptidyl peptidase-4 inhibitors [DPP-4i] and sodium-glucose transport protein 2 inhibitors [SGLT-2i]). METHODS: We conducted an analysis of pharmacy claims data from IQVIA Romania. We analysed the reimbursed prescriptions that included at least one ADM as defined daily doses (DDDs)/1000 inhabitants/day and the number of prescriptions. RESULTS: The total number of ADMs DDDs/1000/day increased by 54.33% from 2012 (48.08) to 2019 (74.20). Biguanides, sulfonylureas and insulin were the most prescribed each year, with an increasing utilisation trend. In 2019 metformin represented 37.69% of the total market share, followed by sulfonylureas (29.94%) and insulin (23.93%). The newer antidiabetics uptake was low. In 2019 the number of DDDs/1000 inhabitants/day was 2.03 for DDP-4i, 2.39 for GLP-1 RA and 1.6 for SGLT2i. CONCLUSIONS: An overall trend of market increase was found for ADMs from 2012 to 2019, corresponding to the increasing prevalence of diabetes in Romania. Although the use of DPP-4i, GLP-1 RA and SGLT2i have increased steadily, the uptake remained low, with no more than 12.61% of the market share (alone or as fixed combinations with metformin or insulin) in 2019.

A VigiBase descriptive study of fluoroquinolone induced disabling and potentially permanent musculoskeletal and connective tissue disorders.

Recent drug safety concerns described fluoroquinolone (FQ)-induced serious musculoskeletal reactions. The objective of this study was to characterize reports with FQ-associated disabling musculoskeletal disorders, from VigiBase. The analysis included all FQ-induced musculoskeletal and connective tissue disorders adverse drug reaction (ADR) reports (up to July-2019), (disabling/incapacitating, or recovered/resolved with sequelae or fatal). We described aspects like reporter, suspected FQs, ADRs, associated corticosteroid therapy. We also looked into the disproportionality data in terms of proportional reporting ratio (PRR) and information component (IC) values. A total of 5355 reports with 13,563 ADRs and 5558 FQs were reported. The majority of reports were for patients aged 18-64 (62.67%), and the female gender prevailed (61.76%). Consumers reported almost half (45.99%), with a peak in reporting rates in 2017. Top reported ADRs were arthralgia (16.34%), tendonitis (11.04%), pain in extremity (9.98%), tendon pain (7.63%), and myalgia (7.17%). Top suspected FQs were levofloxacin (50.04%), ciprofloxacin (38.41%), moxifloxacin (5.16%), ofloxacin (3.17%) and norfloxacin (1.01%). For these, FQs-ADR association was supported by the disproportionality analysis. Corticosteroids were associated with about 7% of tendon related reports. The results augment the existing data on FQs safety concerns, specifically their potential effect on the musculoskeletal system.

Second-Generation Cephalosporins-Associated Drug-Induced Liver Disease: A Study in VigiBase with a Focus on the Elderly.

BACKGROUND: The objective of this study was to characterize individual case safety reports (ICSRs) and adverse drug reactions (ADRs) related to second-generation cephalosporins and resulting in hepatobiliary disorders, in VigiBase, WHO global database. METHODS: All second-generation cephalosporins hepatobiliary ADRs reported up to July 2019 were included. Characteristic of cephalosporins and ADRs, aside from disproportionality data were evaluated. RESULTS: A total of 1343 ICSRs containing 1585 ADRs were analyzed. Cefuroxime was suspected to have caused hepatobiliary disorders in most cases-in 38% of adults and in 35% of elderly. Abnormal hepatic function was the most frequent ADR, followed by jaundice and hepatitis. For 49% of the ADRs reported in the elderly and 51% in the adult population, the outcome was favorable, with fatal outcome for 2% of the adults and 10% of the elderly. Higher proportional reporting ration (PRR) values were reported in the elderly for cefotetan-associated jaundice, cefuroxime-associated acute hepatitis and hepatitis cholestatic as well as for cefotiam and cefmetazole-associated liver disorder. CONCLUSION: Hepatobiliary ADRs were reported for 2nd generation cephalosporins, with over 50% of cases in adults, without gender differences. Cholestatic hepatitis was predominately reported in the elderly and this category was more prone to specific hepatic reactions.

An investigation on the association between sodium glucose co-transporter 2 inhibitors use and acute pancreatitis: A VigiBase study.

PURPOSE: To characterize acute pancreatitis (AP) related to sodium glucose co-transporter 2 inhibitors and to investigate this relationship through disproportionality analysis in an international pharmacovigilance database. METHODS: We analyzed all AP reports for canagliflozin, dapagliflozin and/or empagliflozin from the WHOs Global adverse drug reactions database VigiBase® up to July 2019. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR) and information component (IC) for each of the gliflozins. AP cases were reports containing at least one of 11 previously selected preferred terms. Gliflozin exposure was considered for all reports with at least one gliflozin as suspected/ interacting drug. RESULTS: Of the 19 834 180 individual case safety reports in VigiBase, in 600 reports containing 618 AP group reactions, gliflozins were suspected/ interacting drugs. Men were affected in 52.3% of the cases and 59.6% of the patients were in the 45-64 years age group. The reporters were in 417 cases healthcare professionals. Most of the reactions were reported for canagliflozin (59.7%), followed by empagliflozin (21%) and dapagliflozin (19.2%) and were serious (98.6%). Most of the reactions' outcomes (84% of the patients) were favorable. Ketoacidosis was frequently associated with the AP (21.3%). Significant PRR and IC were found for pancreatitis and pancreatitis acute for all three gliflozins, pancreatitis necrotizing for canagliflozin and empagliflozin and pancreatitis relapsing for empagliflozin. CONCLUSIONS: Most of the AP cases were serious and with favorable outcome. We identified possible alternative causes for AP, like concomitant medication, hypertriglyceridemia, and cholelithiasis and a frequent association with ketoacidosis. We found a significant association between AP and the use of canagliflozin, dapagliflozin, and empagliflozin that would need further investigation.

Survery of healthcare professionals to assess the awareness, knowledge and self-reported behavior regarding recent fluoroquinolones safety issues.

Background and aims: The impact of fluoroquinolone (FQ)-induced long-lasting, disabling, and potentially irreversible serious adverse drug reactions (ADRs) on the overall benefit-risk balance and the need for adequate risk minimization measures has been recently assessed. The present study aims to evaluate physicians and pharmacists' awareness and knowledge of the recent safety issues communicated through a direct healthcare professional communication (DHPC), regarding FQs, at a national level, in Romania, as well as healthcare professionals (HPs) self-reported behavior regarding the management of the risk. Methods: Cross-sectional, online survey study, conducted in Romania. Results: A total of 127 participants responded to the survey. Six (4.7%) were physicians and 121 (95.3%) were pharmacists. The predominant age was 31-40 years (N=52, 40.9%), and most respondents were females (N=117, 92.1%). A majority of 101 (79.5%) were reportedly aware of the existence of the new safety issues associated with FQs, and slightly less were aware of the DHPC (N=86, 67.7%) issued in 2019. In terms of knowledge, slightly more than half of the respondents had correctly selected the responses regarding key safety messages on most important ADRs and restrictions / cautions for use. The impact of the communication on HPs self-reported behavior was high or very high in almost half of the participants (N=63, 49.6%). Conclusions: A high percentage of participants were aware of the FQ-associated safety concerns. Knowledge was relatively good for the key safety concerns among HPs. A notable impact on behavior was observed, mostly in terms of counselling of the patient and disseminating the information to colleagues.

Relationship between beliefs about medicines and adherence in elderly patients with cardiovascular and respiratory diseases: A cross-sectional study in Romania.

OBJECTIVES: The aim of this study was to explore elderly patients' beliefs about medicines in general, and specific towards their treatment and the relationship between beliefs and adherence. METHODS: A cross-sectional study was performed by administering a questionnaire developed to meet the study's objectives. Elderly patients were recruited from three different settings. RESULTS: 167 patients agreed to participate to our study, having a mean age of 73 years. Patients were aware of the necessity for treatment, but they also showed concern over the potential for the adverse outcomes. Only 15% of the patients were completely accepting their treatment having high necessity and low concerns, while 40% were ambivalent, having high necessity beliefs, but also high concerns, with 89% being adherent in this group. Overall, higher adherence was significantly correlated with higher necessity and with higher necessity-concern differential. CONCLUSION: Patients beliefs have an impact on adherence, thus patients' concerns and necessities should be addressed in order to improve adherence and treatment outcome. PRACTICE IMPLICATIONS: Higher necessity positively influenced adherence to treatment, suggesting the fact that healthcare professionals could improve patients' adherence by outlining and educating the patients on the necessity of the treatment, while also managing patients' concerns.

Safety Profile of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Hepatitis C in Romania: an Analysis Conducted in VigiBase®/ WHO.

BACKGROUND AND AIMS: Due to the increasing number of hepatitis C virus (HCV)-infected patients being treated with direct antiviral agents (DAAs) in Romania, we aimed to conduct a pharmacovigilance study in order to comprehensively evaluate the safety profile for the ombitasvir/paritaprevir/ritonavir and dasabuvir (Om/Pa/Ri+Da) regimen. METHODS: A retrospective analysis was conducted on the individual case safety reports (ICSRs), extracted from VigiBase® on 1 st February 2018, which included the Om/Pa/Ri+Da regimen as suspected for causing adverse drug reactions (ADRs). Potential drug-drug interactions (DDIs) were checked for all concomitant medication using the IBM Micromedex® tool. RESULTS: Among the 1,102 ICSRs retrieved, 260 were serious (23.5%). Ribavirin was significantly associated with more ADRs reported per case (on average 5.1 vs. 3.2 ADRs/case, p<0.001). Most commonly reported ADRs were pruritus (6.8%), fatigue (5.4%), dizziness (4.3%) and headache (3.8%). For the serious ICSRs, a significant relationship was found between age and renal and urinary disorders, and between gender and neoplasms, injury, poisonings and procedural complications. Hepatotoxicity was identified in six ICSRs, four of them being serious. Potential contraindicated DDIs were identified in 1.9% of all ICSRs and major DDIs in 20.4%. CONCLUSIONS: About a third of the ICSRs related to Om/Pa/Ri+Da regimen were serious. Pruritus, fatigue, dizziness and headache were the most commonly reported ADRs. The frequent use of multiple co- medications in HCV-infected patients requires the consideration of potential DDIs when using the Om/ Pa/Ri+Da regimen.

A description of medicines-related safety issues evaluated through a referral procedure at the EU level after 2012.

INTRODUCTION: Important drug safety issues are evaluated through a referral procedure in the EU by the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency. We aim to describe all safety-related referrals assessed by the PRAC by June 2019. METHODS: Publicly available data on safety issues assessed through referral procedures that reached a final decision during July 2012-June 2019 were identified, analyzed and classified according to predefined criteria. RESULTS: Fifty-one safety issues were assessed by PRAC for 45 medicines/combinations/therapeutic classes during this timeframe. Referrals were initiated mostly by the European Commission (16) and France (8). Nine medicines were authorized in the last five years, the rest being well-established drugs. In four cases (flupirtine, hydroxyethyl-starch, valproate, codeine) PRAC re-assessed the same risks as previous recommendations have not been effective. Post-referral recommendations consisted of updates of the summary of product characteristics and package leaflet (42), Direct Healthcare Professional Communication (32), and other additional risk minimization measures (RMMs). Withdrawal was recommended for seven active substances. CONCLUSIONS: PRAC recommended routine or additional RMMs for most referrals. Complete withdrawal of a drug or withdrawal of certain pharmaceutical forms or concentrations was advised only when the risk could not be managed by RMMs.

The economic burden of constipation therapy.

BACKGROUND AND AIM: Constipation is a widespread condition that requires adequate therapy. Given the large use of laxatives, it is important to know the burden of the treatment of this condition on the healthcare budget. METHODS: We collected information on the number of therapeutic units (boxes) of five frequently used laxatives delivered by prescription or over the counter in 30 pharmacies randomly selected in two adjacent counties from Romania for two consecutive years. We calculated also the cost value of the laxatives delivered. RESULTS: The total cost of laxatives in the group of pharmacies investigated was on average 62,500 euros per year. We extrapolated that the laxative consumption in Romania should be over 15 million Euro. CONCLUSIONS: To our knowledge this is the first study on the burden of constipation in this country. Although therapeutic units of laxatives are not expensive, the wide use of these drugs represents an economic burden for the patient.

An overview of the common methods used to measure treatment adherence.

BACKGROUND AND AIMS: The success of a treatment depends on the effectiveness of the medication regimen, provided that patients take the medicines as prescribed. A low rate of adherence in chronic conditions is associated with poor outcome and decreased quality of life, which constitutes an additional burden for the healthcare systems. To correctly identify the dimension of this problem may be a challenge, as there are numerous methods, definitions, patient settings and factors, each with their specific roles. Our aim was to give an appropriate overview of the most common validated methods that can be used to identify non-adherent patients. METHODS: This overview is based on an online search of PubMed database and includes the relevant articles in this field. RESULTS: We included both direct and indirect methods for measuring treatment adherence and presented concise information that can help researchers and clinicians when choosing an appropriate method. Both subjective and objective methods have advantages and disadvantages that should be fully understood and taken into consideration. CONCLUSIONS: Choosing a simple, accurate and inexpensive method that can give supplementary information about the patterns, beliefs and barriers of adherence would be desirable. But because this perfect method to measure treatment adherence does not exist, the best solution seems to be the combined use of at least two methods.

Study design, process and outcome indicators of post-authorization studies aimed at evaluating the effectiveness of risk minimization measures in the EU PAS Register.

Risk minimization measures (RMMs) represent an essential tool for preventing the occurrence of safety-related outcomes. The evaluation of RMMs effectiveness is essential to prove their success and ensure protection of public health. The aim of this qualitative review was to assess the design, process and outcome indicators used for attesting successful implementation of RMMs. We searched the EU Post-Authorization Studies Register up to 30 June 2018 for studies having the scope defined as 'effectiveness evaluation'. Study titles and objectives were screened to select the ones evaluating the effectiveness of RMMs. We described and assessed the extent to which these studies aligned with Good Pharmacovigilance Practices guidelines recommendations. Out of 360 registered studies, we identified 35 studies on evaluation of RMMs effectiveness, 29 being eligible for review. Twenty-six studies evaluated additional RMMs, employed in case routine interventions are considered insufficient. All studies assessed process indicators, five also assessing outcome indicators, thus using a dual-evidence approach as recommended by the guidelines. However, none of the latter used a pre-post design, comparing the frequency of the adverse outcome before and after the implementation of RMMs. Behaviour and knowledge were the most often assessed process indicators. Outcome indicators included occurrence of adverse reactions, pregnancy, off-label use and medication errors. Only four studies had an established threshold, all for process indicators. Stricter adherence to existing recommendations would allow for a more robust design for reaching established endpoints for RMM effectiveness evaluation. It would also infer harmonization, facilitate review and further more detailed guidance on conducting these studies.