Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs.

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too.

Financing and Reimbursement of Approved Advanced Therapies in Several European Countries.

OBJECTIVES: The uncertainty in the cost-benefit of advanced therapy medicinal products (ATMPs) is a current challenge for their reimbursement in health systems. This study aimed to provide a comparative analysis of the National Health Authorities (NHAs) reimbursement recommendations issued in different European countries. METHODS: The NHA reimbursement recommendations for the approved ATMPs were compared among 8 European Union (EU) Countries (EU8: Ireland, England/Wales, Scotland, The Netherlands, France, Germany, Spain, and Italy). The search was carried out until December 31, 2021. RESULTS: A total of 19 approved ATMPs and 76 appraisal reports were analyzed. The majority of the ATMPs were reimbursed, although with uncertainty in added therapeutic value. No relationship between the type of the European Medicines Agency approval and reimbursement was found. Managed entry agreements, such as payment by results, were necessary to ensure market access. The main issue during the evaluation was to base the cost-effectiveness analyses on assumptions because of the limited long-term data. The estimated incremental cost-effectiveness ratio among countries reveals high variability. Overall, the median time to NHA recommendation for the EU8 is in the range of 9 to 17 months. CONCLUSIONS: Transparent, harmonized, and systematic assessments across the EU NHAs in terms of cost-effectiveness, added therapeutic value, and grade of innovativeness are needed. This could lead to a more aligned access, increasing the EU market attractiveness and raising public fairness in terms of patient access and pricing.

Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). METHODS: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. FINDINGS: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. INTERPRETATION: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. FUNDING: Instituto de Salud Carlos III. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States.

BACKGROUND AIMS: Regulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions. METHODS: A retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions. RESULTS: In the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU. CONCLUSIONS: The current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study.

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-ß-exposed pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-ß group (odds ratio, 2.2; 95% confidence interval, 0.2-24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-ß-exposed pregnancies was 0.6 (95% confidence interval, 0.2-1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.

A case series of confusional states and other neurotoxic effects caused by ertapenem.

Ten cases of ertapenem neurotoxicity, mainly confusional states, are described, some of them with fatal outcomes. The majority of patients (90%) had a creatinine clearance (CrCl) < 50 mL/min/1.73m2 at some point during treatment and hypoalbuminaemia was always present when ertapenem treatment was started. The pharmacokinetic and pharmacodynamic properties of this carbapenem could favour a different profile, and approved doses can be excessive in some patients with moderate renal failure (CrCl 31-59 mL/min/1.73 m2 ). It may be necessary to re-evaluate renal function during treatment and adjust doses or reconsider the adequacy of treatment based on clinical judgement, especially if relevant changes in the CrCl occur (i.e. a reduction to ≤30 mL/min/1.73 m2 ) or unexplained behavioural disorders are detected. The onset of the symptoms of ertapenem neurotoxicity can be insidious and go unnoticed, and so a knowledge and early suspicion of confusional states are important to improve the patient prognosis.

Withdrawal of hospital outpatient treatments in severe diseases due to unacceptable toxicity: A retrospective study from the register of patients and treatments.

AIM: To retrospectively analyse hospital outpatient treatment (HOT) withdrawal due to unacceptable toxicity at our hospital. Information regarding unacceptable toxicity leading to treatment withdrawal was recorded. METHODS: HOT interruptions because of unacceptable toxicity were identified from the Register of Patients and Treatments (RPT) (January 2014 to December 2017). Information regarding the demographic and clinical characteristics of patients, adverse drug reactions (ADRs) and drug treatments was retrieved from electronic health records. Causality and previous knowledge of ADRs were assessed according to the Spanish Pharmacovigilance System algorithm. Information regarding HOT risk management plans (RMPs) and their classification as inverted black triangle medicines was obtained from the European Medicines Agency (EMA). RESULTS: HOTs were withdrawn due to unacceptable toxicity in 136 (1.5%) registries corresponding to 135 (1.7%) patients. Fifty-one different HOTs (38.6% of those registered) were involved in 240 ADR/HOT pairs: 24 (47%) were additional monitoring medicines and 37 (72.5%) were EMA RMPs. The most frequent medicines involved in ADRs were lenalidomide (30, 12.5%) (mainly neutropenia, thrombocytopenia and bicytopenia), bevacizumab (19, 7.9%) (mainly venous and pulmonary thromboembolism) and sunitinib (13, 5.4%) (mainly thromboembolic events, diarrhoea and worsening of chronic renal failure). Cytopenia (40, 17.3%), diarrhoea (15, 6.5%), asthenia (9, 3.9%) and neuropathy (6, 2.6%) were the most frequent ADRs. All ADRs were severe, 10 (6 patients) had been poorly described or were unknown and only 9 (5 patients) had been reported by spontaneous notification. CONCLUSIONS: Valuable information regarding severe and unknown ADRs was obtained from the RPT. Such registers are useful tools to complement spontaneous ADR notifications.

Non-commercial vs. commercial clinical trials: a retrospective study of the applications submitted to a research ethics committee.

There are many difficulties in undertaking independent clinical research without support from the pharmaceutical industry. In this retrospective observational study, some design characteristics, the clinical trial public register and the publication rate of noncommercial clinical trials were compared to those of commercial clinical trials. A total of 809 applications of drug-evaluation clinical trials were submitted from May 2004 to May 2009 to the research ethics committee of a tertiary hospital, and 16.3% of trials were noncommercial. They were mainly phase IV, multicentre national, and unmasked controlled trials, compared to the commercial trials that were mainly phase II or III, multicentre international, and double-blind masked trials. The commercial trials were registered and published more often than noncommercial trials. More funding for noncommercial research is still needed. The results of the research, commercial or noncommercial, should be disseminated in order not to compromise either its scientific or its social value.

Elderly patients treated with psychotropic medicines admitted to hospital: associated characteristics and inappropriate use.

PURPOSE: The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. METHODS: An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. RESULTS: A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and ≥10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). CONCLUSIONS: Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics.

Inappropriate prescribing to the oldest old patients admitted to hospital: prevalence, most frequently used medicines, and associated factors.

BACKGROUND: Scientific evidence on treatments of chronic diseases in patients 85 years old or older is very limited, as is available information on inappropriate prescription (IP) and its associated factors. The study aimed to describe medicine prescription, potentially inappropriate medicines (PIM) and potentially prescribing omissions (PPO) and their associated factors on this population. METHODS: In the context of an observational, prospective and multicentric study carried out in elderly patients admitted to seven Spanish hospitals for a year, a sub-analysis of those aged 85 years and over was performed. To assess PIMs, the Beers and STOPP criteria were used, and to assess PPOs, the START and the ACOVE-3 criteria were used. To assess factors associated with IP, a multivariate logistic regression analysis was performed. Patients were selected randomly every week on consecutive days from the hospitalization lists. RESULTS: A total of 336 patients were included in the sub-analysis with a median (Q1-Q3) age of 88 (86-90) years. The median medicines taken during the month prior to admission was 10 (7-13). Forty-seven point two per cent of patients had at least one Beers-listed PIM, 63.3% at least one STOPP-listed PIM, 53.6% at least one START-listed PPO, and 59.4% at least one ACOVE-3-listed PPO. Use of benzodiazepines in patients who are prone to falls (18.3%) and omission of calcium and vitamin D supplements in patients with osteoporosis (13.3%) were the most common PIM and PPO, respectively. The main factor associated with the Beers-listed and the STOPP-listed PIM was consumption of 10 or more medicines (OR = 5.7, 95% CI 1.8-17.9 and OR = 13.4, 95% CI 4.0-44.0, respectively). The main factors associated with the START-listed PPO was a non-community dwelling origin (OR 2.3, 95% CI 1.0-5.0), and multimorbidity (OR1.8, 95% CI 1.0-3.1). CONCLUSIONS: Prescribed medicines and PIM and PPO prevalence were high among patients 85 years and over. Benzodiazepine use in those who are prone to falls and omission of calcium and vitamin D in those with osteoporosis were the most frequent PIM and PPO, respectively. Factors associated with PIM and PPO differed with polypharmacy being the most important factor associated with PIM.

Women's health in focus: Real-world data on valproate prescriptions during pregnancy - a cohort study in Catalonia (Spain).

OBJECTIVES: To characterise the exposure to valproate within a cohort of pregnant women using electronic health records (EHRs) from Catalonia (System for the Development of Research in Primary Care, SIDIAP). DESIGN: Drug-utilisation cohort study covering the period from January 2011 to June 2020. The study included pregnancy episodes of women from Catalonia identified by the algorithm. SETTING: Data were sourced from SIDIAP, a comprehensive EHR repository that includes information from various data sources: recorded prescriptions (both hospital and primary care), diagnoses and sociodemographic characteristics identified by primary care physicians, and sexual and reproductive health data from ASSIR (used by gynaecologists and midwives). PARTICIPANTS: Women aged 12-50 with at least one pregnancy episode occurred during January 2011-June 2020 and at least a prescription of valproate during pregnancy. PRIMARY AND SECONDARY OUTCOMES: Primary outcomes included valproate exposure, measured through prevalence and cumulative incidence in pregnancy episodes and by trimester. The impact of regulatory measures (risk mitigation measures, RMMs) was assessed, and prescriptions over time were analysed using interrupted time series analysis. Secondary outcomes included health issues, pregnancy outcomes, smoking habits and socioeconomic characteristics. RESULTS: A total of 99 605 pregnancies were identified, with at least 3.03‰ (95% CI 2.69‰ to 3.39‰) exposed to valproate at some point (302 pregnancies, 276 women). The median pregnancy duration was 38.30 weeks (IQR 12.6-40.1), and the median age at pregnancy was 32.37 years (IQR 27.20-36.56). Epilepsy was the most frequent health issue. The prevalence and cumulative incidence of valproate prescriptions decreased during pregnancy and increased postpregnancy. The RMMs implemented in 2014 led to a reduction in monthly valproate prescriptions during pregnancy in this cohort. CONCLUSIONS: The study highlights the decline in valproate prescriptions during pregnancy due to RMMs and underscores the need for standardised methodologies in future studies to ensure the safety of pregnant patients and optimise scientific evidence.

Effectiveness and safety of alirocumab and evolocumab for hypercholesterolemia in a population with high cardiovascular risk.

BACKGROUND AND AIMS: The criteria for the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) more restrictive than those approved were established in Catalonia by the Health System (CatSalut) to improve their efficiency, with different LDL-C values from which to start treatment according to risk factors. The aim of the study is to analyse adherence to these criteria and results. METHODS: A retrospective study of patients treated with PCSK9i at Vall d'Hebron University Hospital between 2016 and 2021 was performed using data from the Registry of Patients and Treatments and medical records. The degree of agreement with the CatSalut criteria, LDL-C-responders (decrease ≥30%), cardiovascular events and discontinuations were analysed. RESULTS: A total of 193 patients treated with PCSK9i were followed for a median of 27 months (IQR 23). The median age was 61 (IQR 15); 62.7% were men. Seventy percent of the patients had non-familial hypercholesterolemia. Treatment was for secondary prevention of cardiovascular disease in 82.4% of cases. The median LDL-C decreased from 139 (IQR 52) to 59 (IQR 45) mg/dL. The percentage of LDL-C reduction was 61.0% (IQR 30). In 72.5% of patients, all CatSalut criteria for starting treatment were met. The rate of responders was 85.4%. During follow-up, 19 patients (9.8%) had a cardiovascular event, and 15 (7.7%) discontinued treatment, in two cases due to toxicity. CONCLUSION: PCSK9i were used according to CatSalut criteria in three out of four cases. In this high-risk population, incidence of cardiovascular events was similar to that in clinical trials.

Delabelling beta-lactam allergy.

Background: Hypersensitivity to beta-lactam (BL) antibiotics is one of the most frequent reported drug allergies. In our population, it is common to find labels of BL allergy in electronic medical records (EMRs) that have not been assessed. The objective of our study was to detect patients with beta-lactam allergy labels in their EMRs and to assess how many of them are false after a correct diagnostic evaluation. Methods: A multicentre prospective study was performed with patients labelled as allergic to BLs in their EMRs in the previous 5 years. Demographical and clinical data, as well as variables regarding the BL allergy label and the characteristics of the index reaction from clinical history and EMRs, were recorded. Then, diagnostic assessments including clinical history, skin tests (STs), and drug provocation tests (DPTs) were conducted in order to confirm or exclude the diagnosis of BL allergy. Results: A total of 249 patients completed the study, of which 160 (64.3%) were women with a median age of 57 years (interquartile range [IQR], 45-68). The most frequent BL allergy labels detected were for penicillin (124), amoxicillin/clavulanic acid (61), and amoxicillin (54). Of the 204 patients who underwent STs, 20.1% were positive. DPTs were performed in 224 patients, showing good tolerance in 87.1% of cases. After the allergy diagnosis work-up, 186 patients (74.7%) were diagnosed as non-allergic to BL antibiotics. Conclusion: In our study population, the number of patients labelled as allergic to BLs in their EMRs was similar to that in previously published studies, with proportions near to 75%-80% being falsely labelled as allergic to BLs.

The challenges of access to innovative medicines with limited evidence in the European Union.

The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems' concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement.

Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review.

Introduction: Off-label rituximab is commonly used for patients with systemic lupus erythematosus (SLE) with extrarenal disease activity. Methods: The outcomes and tolerability of rituximab in adult patients with non-renal SLE treated at our hospital from 2013 to 2020 were described. Patients were followed-up until December 2021. Data were retrieved from electronic medical records. Response was classified into complete, partial or no response according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2 K)-based definitions. Results: A total of 44 cycles were administered to 33 patients. Median age was 45 years and 97% were female. Median follow-up was 5.9 years (IQR 3.7-7.2). The most frequent symptoms that motivated rituximab use were thrombocytopenia (30.3%), arthritis (30.3%), neurological manifestations (24.2%) and cutaneous lupus (15.2%). After most treatment cycles a partial remission was achieved. The median SLEDAI-2 K score declined from 9 (IQR 5-13) to 1.5 (IQR 0-4) (p < 0.00001). The median number of flares significantly declined after receiving rituximab. Platelet counts significantly improved in patients with thrombocytopenia and patients with skin disorders or neurological manifestations also had a partial or complete response. Only 50% of patients with a predominant joint involvement had either a complete or a partial response. The median time to relapse after the first cycle was 1.6 years (95% CI, 0.6-3.1). Anti-dsDNA levels decreased significantly after rituximab from a median of 64.3 (IQR 12-373.9) to 32.7 (IQR 10-173), p = 0.00338. The most frequent adverse events were infusion-related reactions (18.2%) and infections (57.6%). All patients needed further treatment to maintain remission or to treat new flares. Conclusion: A partial or complete response was documented after most rituximab cycles in patients with non-renal SLE. Patients with thrombocytopenia, neurolupus, and cutaneous lupus had better response than those with a predominant joint involvement.

Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Reactogenicity to the mRNA-1273 Booster According to Previous mRNA COVID-19 Vaccination.

The objective of this study was to assess the local and systemic adverse reactions after the administration of a COVID-19 mRNA-1273 booster between December 2021 and February 2022 by comparing the type of mRNA vaccine used as primary series (mRNA-1273 or BNT162b2) and homologous versus heterologous booster in health care workers (HCW). A cross-sectional study was performed in HCW at a tertiary hospital in Barcelona, Spain. A total of 17% of booster recipients responded to the questionnaire. The frequency of reactogenicity after the mRNA-1273 booster (88.5%) was similar to the mRNA-1273 primary doses (85.8%), and higher than the BNT162b2 primary doses (71.1%). The reactogenicity was similar after receiving a heterologous booster compared to a homologous booster (88.0% vs. 90.2%, p = 0.3), and no statistically significant differences were identified in any local or systemic reactions. A higher frequency of medical leave was identified in the homologous booster dose group vs. the heterologous booster dose group (AOR 1.45; 95% CI: 1.00-2.07; p = 0.045). Our findings could be helpful in improving vaccine confidence toward heterologous combinations in the general population and in health care workers.

Review on the management of cardiovascular risk factors in the elderly.

Cardiovascular risk factors (CVRF) are very prevalent in the elderly population and in addition to predisposing to cardiovascular disease they are related to functional decline, which limits the quality of life in this population. The objective of this work is to offer a review of the current evidence in the management of CVRF in the elderly population. The search strategy was executed in PubMed, Clinicalstrials.org and Embase, to search for clinical trials, observational cohort or cross-sectional studies, reviews, and clinical practice guidelines focused or including elderly population. The results provided were refined after reading the title and abstract, as well as elimination of duplicates, and were finally identified and assessed following the GRADE methodology. A total of 136 studies were obtained for all predefined risk factors, such as sedentary lifestyle, smoking, obesity and metabolic syndrome, hypertension, diabetes mellitus, dyslipidemia and alcohol. We described the results of the studies identified and assessed according to their methodological quality in different recommendation sections: diagnostic and prevention, intervention, or treatment in the elderly population. As the main limitation to the results of this review, there is the lack of quality studies whose target population is elderly patients. This issue limits the recommendations that can be made in this population. Due to this reason, comprehensive geriatric assessment seems the best tool currently available to implement the most appropriate treatment plans based on the baseline situation and comorbidity of each elderly patient.

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial.

OBJECTIVES: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. METHODS: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400mg q12h the first day followed by200mg q12h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. RESULT: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0-35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. CONCLUSIONS: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19.