Hydroxychloroquine safety in Covid-19 vs non-Covid-19 patients: analysis of differences and potential interactions.

BACKGROUND: The use of hydroxychloroquine (HCQ) in the first COVID-19 epidemic wave raised safety concerns. RESEARCH DESIGN AND METHODS: Adverse reactions (ADR) suspected to be induced by HCQ and submitted to the Spanish Pharmacovigilance Database were studied. A disproportionality analysis was performed to determine adverse effects reported in non-Covid and Covid patients. To explore potential drug-drug interactions, Omega (Ω) statistics was calculated. RESULTS: More severe cases were reported when used in COVID-19. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the COVID-19 pandemic, high disproportionality in reports was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischemic colitis, 8.9 (2.6). Myopathies, hemolytic disorders and suicidal behavior increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, hematopoietic cytopaenias and interstitial lung disease in the pre-COVID-19 period. Potential interactions were showed between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab. CONCLUSIONS: The use of HCQ during the Covid-19 pandemic changed its ADRs reporting profile. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide, but not ocular disorders. Some signals identified would require more detailed analyses.

Synergism interaction between genetic polymorphisms in drug metabolizing enzymes and NSAIDs on upper gastrointestinal haemorrhage: a multicenter case-control study.

BACKGROUND: Interindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH. MATERIALS AND METHODS: We conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin). RESULTS: We observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [ORaspirin(+),wild-type: 2.22 (95%CI: 0.69-7.17) vs. ORaspirin(+),genetic-variation: 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation. CONCLUSIONS: The joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption.KEY MESSAGESMulticenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin).There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects.Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs.

Haplotypes in the GC, CYP2R1 and CYP24A1 Genes and Biomarkers of Bone Mineral Metabolism in Older Adults.

Candidate gene studies have analyzed the effect of specific vitamin D pathway genes on vitamin D availability; however, it is not clear whether genetic variants also affect overall bone metabolism. This study evaluated the association between genetic polymorphisms in GC, CYP2R1 and CYP24A1 and serum levels of total 25(OH)D, iPTH and other mineral metabolism biomarkers (albumin, total calcium and phosphorus) in a sample of 273 older Spanish adults. We observed a significant difference between CYP2R1 rs10741657 codominant model and total 25(OH)D levels after adjusting them by gender (p = 0.024). In addition, the two SNPs in the GC gene (rs4588 and rs2282679) were identified significantly associated with iPTH and creatinine serum levels. In the case of phosphorus, we observed an association with GC SNPs in dominant model. We found a relationship between haplotype 2 and 25(OH)D levels, haplotype 4 and iPTH serum levels and haplotype 7 and phosphorus levels. In conclusion, genetic variants in CYP2R1 and GC could be predictive of 25(OH)D and iPTH serum levels, respectively, in older Caucasian adults. The current study confirmed the role of iPTH as one of the most sensitive biomarkers of vitamin D activity in vivo.

A multicenter case-control study of the effect of e-nos VNTR polymorphism on upper gastrointestinal hemorrhage in NSAID users.

Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case-control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): -1.35 (95% CI -5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: -2.68 (95% CI -6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype.

A cross-sectional study of psychotropic drug use in the elderly: Consuming patterns, risk factors and potentially inappropriate use.

OBJECTIVES: The aims of the present study were: (1) to describe psychotropic drug consumption patterns in an outpatient population aged 65 years and older; (2) to determine the impact of a number of demographic and clinical factors on psychotropic consumption; and (3) to determine the ratio of potentially inappropriate psychotropic agents prescribed to the above population. METHODS: Cross-sectional, observational study of outpatients aged 65 years and older. Data on sociodemographic and clinical variables were collected. Psychotropic drugs were classified into three categories: anxiolytics-hypnotics, antidepressants, and antipsychotics. To determine the risk factors for psychotropic drug use among these patients, a multivariate logistic regression model was developed and subsequently validated using bootstrap resampling techniques. To identify the psychotropic drugs to be avoided, a review of treatments received by the patients was performed based on the 2015 version of the Beers criteria. RESULTS: The study included 225 outpatients of whom 30.7% were on psychotropic drugs for chronic treatment. The highest likelihood of psychotropic utilisation corresponded to the following profile: female, living in a nursing home, having two or more prescribing physicians, and having received six or more different diagnoses. According to Beers criteria, 51 patients (22.7% of the sample and 73.9% of patients on psychotropic drugs) had been prescribed at least one potentially inappropriate psychotropic drug. CONCLUSION: Elderly patients commonly use psychotropic medications and are the most vulnerable to the adverse effects of these drugs. It is necessary to re-evaluate the pertinence and accuracy of these medical prescriptions.

Hydrochlorothiazide use and risk of non-melanoma skin cancer in Spain: A case/non-case study.

OBJECTIVE: In 2018, the Pharmacological Risk Assessment Committee alerted to a potential relationship between accumulated hydrochlorothiazide dosage and the risk of non-melanoma skin cancer. To study this relationship we used data from the Spanish Pharmacovigilance System for Medicinal Products of Human Use. MATERIALS AND METHODS: Following a case search for every thiazide potentially associated with (SMQ/MedDRA) "Malignant Skin Neoplasms and not Otherwise Specified Skin Neoplasms", a series of disproportionality analyses were conducted by estimating the reporting odds ratio (95% confidence interval). Registered adverse drug reactions and disproportionality through the reported odds ratio were the main outcome measures. RESULTS: For basal cell carcinoma, reporting odds ratio was 4.8 (2.2 - 10.7); squamous cell carcinoma 3.2 (0.9 - 10.5); malignant melanoma, 0.8 (0.2 - 3.5). We found both disproportionality and association between hydrochlorothiazide and basal cell carcinoma, but none of these were found regarding malignant skin melanoma. In the case of squamous cell carcinoma, the lower confidence interval limit was below 1, thus the disproportionality value was not statistically significant. The accumulated hydrochlorothiazide dose was 36,714 mg for basal cell carcinoma; 98,288 mg for squamous cell carcinoma; and 38,444 mg for malignant melanoma. CONCLUSION: The results in Spain, where sun exposure is significant, are consistent with the data in the Pharmacological Risk Assessment Committee's alert, which were obtained in Denmark for both basal cell carcinoma and malignant melanoma. However, the results for squamous cell carcinoma did not reach statistical significance, although the reporting odds ratio value suggested a potential relationship between hydrochlorothiazide and squamous cell carcinoma.

Corrigendum: Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

[This corrects the article DOI: 10.3389/fphar.2020.00860.].

Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

Background: Despite the wide benefits of aspirin and its cost-effectiveness, aspirin prescriptions have been reduced due to idiosyncratic responses in susceptible individuals. Low-dose aspirin and single-nucleotide polymorphisms (SNPs) are independently associated with increased risk of gastrointestinal hemorrhage; however, to-date, no studies investigated the SNP-aspirin interaction effect on upper gastrointestinal hemorrhage (UGIH). Therefore, we aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH. Methods: A multicenter, full case-control study was conducted in patients exposed and unexposed to aspirin. Three hundred twenty-six cases diagnosed with UGIH were matched with 748 controls (1:3) by age, gender, health center, and recruitment date. Only adults of European origin were included. Participants were stratified by aspirin exposure and genotype [(Aspirin(-), wild-type), (Aspirin(+), wild-type), (Aspirin(+), genetic variation), (Aspirin(-), genetic variation)]. For each SNP, the Odds Ratio of UGIH and their 95% confidence intervals were estimated in each subgroup by using the generalized linear mixed models for dependent binomial variables. SNP-aspirin interaction effect was estimated through Relative Excess Risk due to Interaction (RERI) measures. Results: We observed two categories of SNPs that might modify the risk magnitude of UGIH in aspirin consumers. Seven SNPs (rs1387180 A > G, rs2238631 T > C, rs1799964 T > C, rs5050 T > C/T > G, rs689466 T > C, rs1799983 T > A/T > G, and rs7756935 C > A) were "positive modifiers" associated with an excess of risk from aspirin exposure and carrying that genetic variation (1.75 ≤ RERI ≤ 4.95). On the contrary, the following nine SNPs (rs2243086 G > T, rs1131882 G > A, rs4311994 C > T, rs10120688 G > A, rs4251961 T > C, rs3778355 G > C, rs1330344 C > T, rs5275 A > G/A > T, and rs3779647 C > T) were "negative modifiers" and associated with a reduced risk in aspirin users (-2.74 ≤ RERI ≤ -0.95). Conclusion: This preliminary study suggests that polymorphisms in genes involved in platelets activity, angiogenesis and inflammatory response might modify the risk of aspirin-related UGIH. Further studies with larger sample size and in different populations are needed to confirm our findings. If confirmed, this might have great impact on public health, thanks to aspirin's prophylactic properties in diseases of high incidence and severity.

Medicines under additional monitoring in the European Union.

OBJECTIVE: The objective of this study was to analyse the characteristics of  medicines subject to additional monitoring. We assessed the following aspects:  the criteria applied to approve a medicine as being subject to additional  monitoring; the authorized dispensing conditions; the pharmacological groups to which they belong; and their post-authorisation safety. METHOD: We analysed the list published by the European Medicines Agency in  January 2017 (EMA/245297/2013 Rev.41). Information for the analysis was  obtained from the web sites of the European Medicines Agency and the Spanish  Agency of Medicines and Medical Devices. RESULTS: We assessed 316 medicines subject to additional monitoring. The most  common criterion used to assign a medicine as being subject to additional  monitoring was it being a new active substance (n = 197 [62.3%]). Other  common criteria were requiring a post-authorisation safety study (n = 52  [16.5%]) and being a biologic medicine but not a new active substance (n = 49  [15.5%]). Regarding dispensing conditions, nearly 66% of these medicines were authorized under restricted conditions. Until January 2017, the Spanish Agency  of Medicines and Medical Device published 14 safety reports related to medicines subject to additional monitoring. CONCLUSIONS: The group of medicines subject to additional monitoring mainly  includes new active substances. The most common pharmacological group is antineoplastic and immunomodulating agents. The postauthorisation safety  study has already produced information published by the Spanish Agency of  Medicines and Medical Devices.

Objetivo: El objetivo de nuestro estudio fue analizar las características de los  medicamentos sujetos a seguimiento adicional. Para ello, estudiamos: los  criterios aplicados para su designación, los criterios de dispensación autorizados,  los grupos farmacológicos a los que pertenecen y su seguridad postcomercialización.Método: Se analizó la lista publicada por la Agencia Europea de Medicamentos en enero de 2017 (EMA/245297/2013 Rev.41). La información para el análisis se extrajo de las páginas web de la Agencia Europea  de Medicamentos y la Agencia Española de Medicamentos y Productos  Sanitarios.Resultados: Se estudiaron 316 medicamentos sujetos a seguimiento adicional.  El criterio de designación más común fue ser un nuevo principio activo (n = 197  [62,3%]). Otros criterios de designación comunes fueron: requerir un estudio  postautorización de seguridad (n = 52 [16,5%]) y ser un medicamento  biológico, aunque no un nuevo principio activo (n = 49 [15,5%]). Con respecto a las condiciones de dispensación, casi el 66% de estos medicamentos se  autorizaron con criterios de dispensación restringidos. Hasta enero de 2017, la  Agencia Española de Medicamentos y Productos Sanitarios había publicado 14  notas informativas de seguridad referidas a los medicamentos sujetos a  seguimiento adicional.Conclusiones: Los medicamentos sujetos a seguimiento adicional incluyen mayoritariamente nuevas sustancias activas. El grupo farmacológico más frecuente es el de los fármacos antineoplásicos e  nmunomoduladores. La revisión postcomercialización de su seguridad ha  generado ya alguna información publicada por la Agencia Española de  Medicamentos y Productos Sanitarios.

New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof.

The aim of this study was to evaluate the adverse drug reaction (ADR) incidence rate and new signals thereof for classic compared with new anticoagulants in real-life ambulatory settings. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs; acenocoumarol or warfarin) or nonvitamin K antagonist oral anticoagulants (NOACs; apixaban, edoxaban, rivaroxaban, dabigatran etexilate). Descriptive, clinical, and ADRs data were reported and analyzed through a bivariate analysis (odds ratio [OR]) to compare the ADRs incidence rate and an adaptation of Bayesian methodology (false discovery rate [FDR] < 0.05) to detect new signals. A total of 334 patients were surveyed-average international normalized ratio (INR) of 2.6-and 45.4% taking new anticoagulants. Note that 835 ADRs were reported; 2.5 per patient (2.8 in the VKA cohort, 2.1 in the NOAC cohort). The authors obtained higher risk of epistaxis (OR, 2.18; 95% confidence interval [CI], 1.01-4.74) and hematoma (OR, 2.43; 95% CI, 1.39-4.25) with VKAs and lower risk of global bleeding symptoms with NOACs (OR, 0.45; 95% CI, 0.28-0.71). After standardizing the data, a significant risk of diarrhea with VKAs was observed (OR, 3.37; 95% CI, 1.09-10.41). They also detected an intense positive signal regarding the use of VKAs and osteoporosis (FDR < 0.001), specifically acenocoumarol (FDR < 0.002). NOACs presented lower risk of bleeding, especially dabigatran (FDR < 0.031), and of dermatological pathologies with apixaban being the safest (FDR = 0.050). The lower risk of global bleeding and a potential protective effect against osteoporosis in patients treated with NOACs postulate them as safer than VKAs.

What can we learn from the public's understanding of drug information and safety? A population survey.

OBJECTIVE: The aim of our study was to analyse the perceptions of the public on medicine information and safety and on consumer reporting of suspected adverse drug reactions (ADR). METHODS: A voluntary survey was conducted in a population ≥18 years of age in Asturias, a region in northern Spain. The survey was designed to be completed in a face-to-face street interview or completed independently by the public. The survey consisted of structured questions organised in four sections: (1) demographic data, (2) use of medicines, (3) reading and understanding of the patient information leaflet (PIL) and (4) awareness and perception about consumer reporting of ADR. KEY FINDINGS: A total of 402 surveys were given and analysed; 295 were completed independently and 107 were completed in street interviews. Of the population surveyed, 82.3% had taken some drug(s) in the previous 3 months, although only 62.4% had performed so by medical prescription. A quarter of respondents claimed that they never read the PIL of medicines, 12.7% that they sometimes read it, and 61.4% that they always read this information. A high percentage (82.8%) of respondents reported that they were not aware of consumer reporting of ADR, and 86.1% stated their agreement with this option. CONCLUSIONS: The public has great interest in useful information about all aspects involved in the use of medicines. This includes consumer reporting of suspected ADR, which is still unknown to many people.

Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs and Classical and Selective Cyclooxygenase-2 Inhibitors: A Meta-analysis of Observational Studies.

The purpose of this study was to review the published evidence on the clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to assess the cardiovascular risk (CVR) of cyclooxygenase-2 inhibitors (coxibs), excluding aspirin, by means of a meta-analytic procedure. A search was conducted on MEDLINE and EMBASE databases between October 1999 and June 2018. Cohort and case-control studies showing CVR as relative risk (RR), odds ratio, hazard ratio, or incidence rate ratio associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Eighty-seven studies met the inclusion criteria. Overall, NSAIDs were found to be associated with a statistically significantly increased CVR (RR, 1.24 [95%CI, 1.19-1.28]). The risk was slightly higher for coxibs (RR, 1.22 [95%CI, 1.17-1.28]) as compared with nonselective NSAIDs (RR, 1.18 [95%CI, 1.12-1.24]). Data analysis by drug disclosed that rofecoxib (RR, 1.39 [95%CI, 1.31-1.47]), followed by diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR, 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Analysis by type of event showed that the highest risk corresponded to vascular events for both coxibs (RR, 2.18 [95%CI, 1.72-2.78]) and nonselective NSAIDs (RR, 2.46 [95%CI, 2.00-3.02]). The meta-analysis results suggest that the use of the marketed coxibs celecoxib and etoricoxib would be related to a statistically significant CVR increase. Etoricoxib CVR could be higher than that for celecoxib. This increment would be similar to classical NSAID CVR.

Gastrointestinal safety of coxibs: systematic review and meta-analysis of observational studies on selective inhibitors of cyclo-oxygenase 2.

Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65 years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

A polypharmacy risk prediction model for elderly patients based on sociodemographic and clinical factors.

OBJECTIVE: Elderly people take increasing amounts of medication. The aim of our study was to determine the effects of different sociodemographic and clinical factors on polypharmacy and to develop a risk prediction model in outpatients aged 65 years and older. MATERIALS AND METHODS: Cross-sectional, observational, descriptive study of outpatients aged 65 years and older scheduled for a specialist visit. Data on sociodemographic (age, sex, place of residence, and institutionalization) as well as on clinical variables (number of prescribing physicians and number of diagnoses) were collected. Polypharmacy was defined as the uninterrupted use of more than 5 medications within the last 3 months. To determine the risk factors for polypharmacy among these patients, a multivariate logistic regression model was developed and subsequently validated using bootstrap resampling techniques. The model was assessed for its discrimination accuracy using the area under the curve (ROC AUC). RESULTS: A total of 225 outpatients were included for development of the model. Polypharmacy was found in 46.7% of patients. The determinants that best predicted polypharmacy included: age, institutionalization, number of prescribing physicians, and number of diagnoses. The ROC AUC was 0.85. CONCLUSION: The predictive model developed in this study, which consists of 4 readily obtainable variables, may be a useful tool for identifying and monitoring elderly patients at risk for polypharmacy.
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Cardiovascular and gastrointestinal safety of selective cyclooxygenase-2 inhibitors: a case/non-case study.

Background Coxibs cardiovascular (CV) safety continues being a current issue after rofecoxib worldwide withdrawal in 2004. Objective To evaluate the cardiovascular and gastrointestinal (GI) risk of coxibs through case/non-case study. Setting The Spanish Pharmacovigilance System for Human Use Drugs (FEDRA) and the Uppsala Monitoring Centre (VigiBase) databases. Method We identified adverse drug reactions (ADRs) cases reported under the MedDRA system organ classes of "cardiac disorders", "vascular disorders", "nervous system disorder" and "gastrointestinal disorders". Disproportionality was considered when the following criteria were met simultaneously: proportional reporting ratio (PRR) ≥ 2, 95% confidence interval lower limit of reporting odds ratio (ROR) > 1, Chi square test (χ2) ≥ 4; and number of ADR reports (n rep.) > 3. Main outcome measure Potential disproportionality between cardiovascular and GI ADRs as reported to FEDRA and VigiBase and the use of coxibs. Results We found association between coxibs and CV-ADRs in FEDRA [PRR 2.11 (95% CI 1.97-2.27); ROR 2.53 (95% CI 2.29-2.89); χ2 367.81; n rep., 561] and VigiBase [PRR 2.67 (95% CI 2.64-2.71); ROR 3.26 (95% CI 3.20-3.31); χ2 23,950.93; n rep., 21,047]; and between coxibs and GI-ADRs in VigiBase [PRR 2.91 (95% CI 2.84-2.97); ROR 3.08 (95% CI 3.01-3.16); χ2 8762.82; n rep. 6954]. No association was found between coxibs and GI-ADRs in FEDRA. Conclusion The association found support a potential coxibs class effect in terms of cardiovascular safety. Classical NSAIDs GI risk may be higher than that for coxibs.

Atypical Fracture of the Sternum After Long-Term Alendronate Plus Cholecalciferol Treatment: A Case Report.

A 55-year-old woman developed an atraumatic sternum fracture during treatment with alendronate for osteoporosis. The woman received alendronate 70 mg in combination with cholecalciferol 5600 IU once weekly, as well as nonsteroidal anti-inflammatory drugs. After 4 years of treatment, following a dorsal flexion with no direct thoracic trauma, the patient suffered a fracture of the sternum, with an X-ray revealing sternal body fracture. This fracture was seen to be transverse, noncomminuted and without displacement. Magnetic resonance imaging was carried out to rule out the presence of either a pathological fracture or a fracture resulting from osteoporotic fragility, and showed a triple sternal fracture involving the body, as well as the upper and lower manubrium of the sternum. This fracture presented the features of an atypical femur fracture, except for the location. The alendronate and cholecalciferol combination was discontinued and denosumab was prescribed. After the withdrawal of alendronate, the patient showed clinical improvement, with a decrease in pain, and is currently having routine checkups. The causality algorithm of the Spanish Pharmacovigilance System shows a score of 5, indicating a possible relationship between the patient's sternum fracture and her use of the suspect drug (Naranjo scale 6 = probable).

Risk excess of mortality and use of antipsychotics: a case-noncase study.

Severe mental disorders are associated with an increased mortality risk and the use of antipsychotic drugs may be one of the causes. In this study, we addressed the potential association of the reported mortality among patients on antipsychotics compared to other drugs from a pharmacovigilance database with the aim of evaluating the drug-induced mortality risk. A database containing 189 441 entries of suspected adverse reactions reported from 1 January 1995 to 31 December 2012 was explored for fatal outcomes. Potential disproportionality was estimated using the reporting odds ratio, proportional reporting ratio, and the χ-test. Two-hundred fatal outcomes were reported in patients on antipsychotics, which indicated the occurrence of disproportionality for this pharmacological class compared with any other drugs. When data were analysed by antipsychotic subclass, disproportionality was found only for atypical but not for typical antipsychotics. When individually analysed by active substances and routes, only a few substances were found to show disproportionality. The disproportionality encountered in this study compared with the mortality associated with other drugs suggests that the active substances under study may be associated with a mortality risk higher than what is assumed currently. Also, it suggests that atypical antipsychotics are likely to have a mortality risk higher than the risk of typical antipsychotics. The disproportionality found for zuclopentixol, in both oral and depot formulations, can be considered to be a drug surveillance signal.

Carpal Tunnel Syndrome Associated with Oral Bisphosphonates. A Population-Based Cohort Study.

BACKGROUND: Bisphosphonates are widely used to prevent osteoporotic fractures. Some severe musculoskeletal reactions have been described with this medication; among them, some cases of carpal tunnel syndrome. Thus, the aim of this study was to explore whether bisphosphonates may be associated with this syndrome. METHODS: A cohort study was conducted to compare exposed to unexposed women; the exposed group was that composed of women having received at least one prescription of an oral bisphosphonate. For the purpose, we used information from The Health Improvement Network (THIN) database. The outcome of interest was defined as those women diagnosed with carpal tunnel syndrome. A survival analysis was performed; the Cox proportional hazard model was used to calculate hazard ratios and 95% confidence intervals, and to adjust for identified confounding variables. RESULTS: Out of a sample of 59,475 women older than 51 years, 19,825 were treated with bisphosphonates during the period studied. No differences in age distribution or mean follow-up time were observed between the two groups in comparison. Overall, there were 572 women diagnosed with carpal tunnel syndrome, 242 (1.2%) in the group exposed to bisphosphonates, and 330 (0.8%) in the unexposed. An adjusted hazard ratio of developing carpal tunnel syndrome of 1.38 (95%CI, 1.15-1.64) was found for women exposed to bisphosphonates; no significant changes in the hazard ratios were found when considering different levels of bisphosphonate exposure. CONCLUSIONS: An increased risk of carpal tunnel syndrome is associated with the use of bisphosphonates in postmenopausal women.

Emergency contraceptive pill safety profile. Comparison of the results of a follow-up study to those coming from spontaneous reporting.

BACKGROUND: The emergency contraceptive pill (ECP) containing levonorgestrel is dispensed without a prescription in Spain since 2009. An easy access could diminish unwanted pregnancies; however, there is a risk of misuse and, in any case, of developing some adverse events. The aim of the present study is to further learn the adverse effects of this ECP. METHODS: An ad hoc follow-up study was carried out in three community pharmacies in a city of Central Spain; the sample was composed of those women asking for the ECP; they were interviewed by telephone after at least a month since the last menses. We completed the safety profile obtained with that coming from spontaneous reporting in Spain. RESULTS: Out of 139 women surveyed, 113 developed any adverse event--two considered as severe; the most frequently reported events were menstrual disturbances, which accounted for 21% of all events. Through spontaneous reporting, 36 cases of whatever adverse events related to levonorgestrel as ECP were identified. Twenty-five cases were considered as severe. Both types of reaction and severity were significantly different in the follow-up study and in the spontaneous reporting. Some of the reactions identified, such as miscarriage, febrile neutropenia, and porphyria, are not included in the Summary of Product Characteristics. CONCLUSIONS: Levonorgestrel as an ECP is mostly safe. Attention should be paid to some severe events and particularly to those risk factors for them to appear. Combining spontaneous reporting with an ad hoc follow-up study, the whole safety profile of a given medication can be obtained.