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Current guidelines recommend the treatment of hormone receptor-positive breast cancer with aromatase inhibitors (AIs) and tamoxifen in the adjuvant setting. Some observational studies have raised concerns that tamoxifen may be associated with an increased risk of Parkinson disease (PD). However, no studies have directly compared the risk of PD between AIs and tamoxifen in women diagnosed with breast cancer.Using the UK Clinical Practice Research Datalink, the authors assembled a cohort of women newly diagnosed with breast cancer and newly treated with either AIs or tamoxifen between January 1, 1995, and December 31, 2017. Patients were followed 1 year after treatment initiation (ie, a 1-year lag) until an incident diagnosis of PD or were censored at death from any cause, the date of transfer out of the practice, or the end of the study period (December 31, 2018). Cox proportional hazards models with inverse probability of treatment weights were used to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for PD comparing AIs with tamoxifen and accounting for more than 30 confounders.In all, 30,140 women with nonmetastatic breast cancer were identified: 13,838 initiated AIs, and 16,302 initiated tamoxifen. Compared with tamoxifen, AIs were not associated with an increased risk of PD (HR, 0.94; 95% CI, 0.60-1.47). Consistent results were observed across all secondary and sensitivity analyses.In this large observational study, the use of AIs, in comparison with tamoxifen, was not associated with an increased risk of PD in women diagnosed with nonmetastatic breast cancer in a real-world setting.Previous studies have indicated that tamoxifen may increase the risk of Parkinson disease in the treatment of breast cancer. However, no studies have directly compared the risk of Parkinson disease between aromatase inhibitors and tamoxifen. This study included 30,140 women diagnosed with breast cancer and treated with aromatase inhibitors or tamoxifen. Overall, compared with tamoxifen, aromatase inhibitors were not associated with an increased risk of Parkinson disease in women diagnosed with breast cancer. This study provides an important addition to the comparative safety profile of aromatase inhibitors and tamoxifen in the treatment of breast cancer.

Diarrhea is an adverse drug reaction (ADR) widely reported with olmesartan, an angiotensin II receptor blocker (ARB). Isolated case reports described this ADR with other ARBs. The present study was performed to investigate if, among the different ARBs, some drugs are more at risk of diarrhea than others. Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/noncase study). Cases were reports with the MedDRA PT term « diarrhea » and noncases all other reports registered during the same period in Vigibase® from April 6, 1995 to December 31, 2020. After comparison of ARBs and angiotensin converting enzyme inhibitors (ACEIs), the main analysis was a comparison of the diarrhea reporting risk between each ARB and the seven other ARBs. Results are reported as reporting odds ratio (ROR) adjusted on age, gender, exposure to antihypertensive, and antidiabetic drugs with their 95% confidence interval. Among the 22,429,334 deduplicated reports registered in VigiBase® during the study period, 73,507 involved ARBs, including 2119 diarrhea. The reporting risk of diarrhea was higher with ARBs than with ACEIs (ROR = 2.06 (1.55-2.17)). Diarrhea with ARBs mainly occurred in females with a mean age of 65 years. After exclusion of olmesartan (to minimize a notoriety bias), two ARBs were significantly associated with diarrhea: eprosartan (ROR = 1.93 (1.32-2.72) and telmisartan (ROR = 1.41 (1.23-1.62) but not the six others. The present study found first that diarrhea is more frequently reported with ARBs than with ACEIs and second that the risk of diarrhea differs according to the different ARBs. Diarrhea with ARBs is not a class effect.

Summary Anticholinergic drugs (also called antimuscarinics or atropinics) increase the risk of falls, cognitive impairment and/or mortality in older patients. These drugs belong to the lists of potentially inappropriate medications in the elderly. The aim of this review was to present and discuss the different tools available to measure the atropinic risk in drug exposure of older patients. Several scales, developed from biological and/or clinical criteria, allow to classify anticholinergic drugs according to their atropinic potency and to assign to them an atropinic burden. Total atropinic burden of patient drug exposure can be calculated as the sum of atropinic score of each drug. Other tools include drug daily doses to better estimate the atropinic risk. These different methods are a precious help to decrease atropinic exposure in the elderly. Nevertheless, they have to be considered as upgradable and it is necessary to adapt them regularly according to the introduction of new drugs in clinical practice.

A fifth vaccine against Covid-19, NVX-CoV2373 Nuvavoxid® (Novavax), a protein-based adjuvanted vaccine, was recently marketed in Europe. The main clinical trial before marketing concluded to a 'vaccine efficacy' of 89.7% without talking about other validated efficacy parameters. We further analysed the data of this clinical trial using the different validated methods of risk expression: absolute risks (AR), AR reduction (ARR) and number needed to treat (NNT). ARR and NNT values were 1.22% and 82, respectively, for an RR value of 0.10. Description of these parameters allowed defining some interesting characteristics of NVX-CoV2373 efficacy according to age, race, variant and coexisting illness. Finally, we ask that the results of clinical trials be systematically presented, using not only RR but also including AR, ARR and NNT.

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea.

Aim: To compare different β-adrenoceptor antagonists for the risk of reporting nightmare. Methods: The study involved two approaches: first, we investigated in VigiBase®, the World Health Organization Individual Case Safety Report (ICSR) database, the disproportionality between exposure to each β-adrenoceptor antagonists and reports of nightmares between 1967 and 2019. Second, in a pharmacoepidemiological–pharmacodynamic analysis, we assessed whether use of β-adrenoceptor antagonists with moderate and high lipid solubility or strong 5-HT1A affinity were associated with an increased risk of reporting nightmares. We conducted multivariate logistic regression to estimate reporting odds ratios (RORs) of nightmares compared to all other adverse drug reactions. Results: Of the 126,964 reports recorded with β-adrenoceptor antagonists, 1138 (0.9%) were nightmares. The highest risk of reporting a nightmare was found with exposure of pindolol (adjusted ROR 2.82, 95%CI, 2.19–3.61), metoprolol (1.89, 1.66–2.16), and alprenolol (1.77, 1.06–2.97). Compared to use of low lipid solubility β-adrenoceptor antagonists, use of moderate or high lipid solubility β-adrenoceptor antagonists were significantly more associated with nightmare reports (aROR moderate vs. low 1.72, 95%CI 1.47–2.00 and aROR high vs. low 1.84, 95%CI 1.53–2.22). Use of moderate or high 5-HT1A affinity of β-adrenoceptor antagonists was associated with an increased ROR of nightmares compared with low 5-HT1A affinity of β-adrenoceptor antagonists (aROR moderate vs. low 1.22, 95%CI 1.04–1.43 and aROR high vs. low 2.46, 95%CI 1.93–3.13). Conclusion: In our large pharmacovigilance study, nightmares are more frequently reported for pindolol and metoprolol, and among β-adrenoceptor antagonists with high lipid solubility and high 5-HT1A receptor affinity.

Aims Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death-related drugs recorded in a large pharmacovigilance database during the last 10 years. Methods A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. Results Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. Conclusion Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries.

Several papers have reported that tramadol can induce hypoglycemia. However, in some reports, confounding factors can be found, like coadministration of hypoglycemic drugs. We used the WHO pharmacovigilance database (VigiBase® ) to investigate whether tramadol alone could be associated with hyponatremia. All 2010-2019 ICSRs (Individual Case Safety Reports) with the PT term "hyponatremia" and tramadol were included. Two disproportionality analyses were performed: 1/after inclusion of all reports, 2/after exclusion of concomitant hypoglycemic drugs. Results are expressed as Reporting Odds Ratios (ROR; 95% CI). Among 10 038 436 ICSRs, 97 639 were included. In comparison with codeine, a significant association was found between tramadol use and reports of hypoglycemia before [ROR = 1.54 (1.43-1.66)] or after [ROR = 1.43 (1.31-1.56)] exclusion of hypoglycemic drugs. Tramadol use is associated with a higher risk of hypoglycemia reports than codeine, the other step 2 analgesic, in the presence as well as in the absence of other hypoglycemic drugs. We concluded that hypoglycemia is an adverse drug reaction of tramadol, which can be observed in diabetic as well as in non-diabetic patients.

Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off-label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug-related deaths registered in World Health Organization pharmacovigilance database, during the past decade.Fatal outcomes registered between 2010 and 2019 in children (18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval.Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days-23 months. Reports mostly came from the Americas and Europe and involved, besides anti-infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate…) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged23 months, in the Americas and Africa.Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti-infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age.

What is known and objective There is limited data on the specific risks of anaphylaxis induced by beta-lactam drugs. The aim of this study was to compare the risks of reporting beta-lactam-induced anaphylaxis using the national pharmacovigilance database of Vietnam (NPDV). Methods The multivariate generalised linear regression model was applied for signal generation and comparison of beta-lactams. Results Between 2010 and 2016, there were 2,921 reports of anaphylaxis (19.93%) from 14,655 spontaneous reports of beta-lactam use in the NDPV. Anaphylaxis signal generation was also found for the subgroup J01D (cephalosporins and carbapenems) (ROR = 1.27 [1.16-1.39]) and beta-lactamase-sensitive penicillins (ROR = 1.74 [1.27-2.35]). In the third generation cephalosporin subgroup, different risks were identified for the following combinations of beta-lactams: 1) cefotaxime with cefoperazone+sulbactam; 2) cefixime/cefpodoxime/cefdinir with cefoperazone+sulbactam or ceftizoxime/cefoperazone/ceftazidime/ceftriaxone/cefotaxime. For the second generation cephalosporin subgroup, different risks were found for cefotiam compared to cefmetazole, cefaclor, cefamandole and cefuroxime. What is new and conclusion These findings identified and highlighted the different anaphylactic risks caused by various beta-lactams in the main subgroups.

Hearing loss can have a negative impact on communication, with significant vocational, educational, and social consequences. Drugs are one of the causes of hearing loss in children. The objective of our study was to describe drug-induced hearing loss in the pediatric population. Reports of hearing loss from 1985 to December 2019 in the pediatric population (< 18 years) were extracted from the French PharmacoVigilance Database (FPVD). We performed a retrospective and descriptive analysis of adverse drug reaction (ADR) reports. A total of 70 ADR reports were identified among the 51,216 reports registered in the FPVD, 37 involving adolescents (12–17 years, 52.9%), 28 children (2–11 years, 40.0%), and 5 infants (28 days–23 months, 7.1%). Overall, 40 reports (57.1%) involved girls. A total of 56 reports (80.0%) were “serious.” The most frequent hearing disorders were deafness (n = 31, 44.3%) and hypoacusis (n = 22, 31.4%). Suspected drugs (ATC 5th level) were amikacin (n = 11, 15.7%), cisplatin (n = 11, 15.7%), doxorubicin (n = 4, 5.7%), vincristine (n = 4, 5.7%), clarithromycin (n = 4, 5.7%), ceftriaxone (n = 3, 4.3%), isotretinoin (n = 3, 4.3%), and vancomycin (n = 3, 4.3%). This study shows that about three out of four cases of drug-induced hearing loss in the pediatric population were “serious”. It also underlines the under-reporting of these ADRs and the importance of strengthening hearing monitoring in children during and long after drug exposure.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Paradoxical adverse drug reactions (ADRs) are defined as being opposing reactions to the pharmacological effect of drugs in relation to its pharmacodynamic properties. Their diagnosis is difficult as they are relatively rare with atypical clinical presentation (with the possibility of being confused with drug ineffectiveness or the worsening of the underlying disease). This kind of ADR may be particularly subject to under-notification. The aim of the present study is to describe paradoxical ADRs using the French PharmacoVigilance DataBase (FPVDB). We analysed all reports recorded in the FPVDB with drugs defined as “suspect” and which included the term “paradoxical reaction” (PR) (according to MedDRA classification) from 01/01/1984 to 12/31/2018. The drugs were classified according to the Chemical Therapeutic Anatomical Classification (ATC). We found 57 reports of PR, with half of them recorded between 2015 and 2018. The median age of patients was 46 years, mainly male (54%). The most frequently involved drugs were immunomodulating agents (n = 28, 49%) and psychotropics (n = 28, 49%). The leading paradoxical ADRs were psychiatric (anxiety, sleep and behavioural disorders) and skin-related. In 19 cases (33%), PR was related to benzodiazepines mainly occurring in patients in extreme ages (five cases in children and patients > 70, respectively, 53%). For psychotropic-induced PR (n = 28), known contributory factors (alcohol consumption, underlying psychiatric diseases) were found in 18 cases (64%). Paradoxical reactions with immunomodulating agents were mainly related to skin ADRs (n = 25). For psychotropics, paradoxical ADRs occurred rapidly after a mean delay of 1 day, predominantly following high doses. We also identified several “unexpected” paradoxical reactions, such as cognitive degradation with donepezil, or a return to impulsive smoking addiction with varenicline. This study highlights that pharmacovigilance databases like the French database make it possible to investigate the main characteristics of paradoxical reactions to drugs. This ADR was mainly found in the FPVDB with psychotropic drugs and immunomodulating agents. Moreover, pharmacovigilance databases enable the identification of some signs of “unexpected paradoxical reactions”. In order to identify this type of ADR more effectively, work on awareness and harmonization is required to register these reports. The addition of the term “paradoxical reaction to the drug” to the list of other symptoms would facilitate their identification and analysis.

Fluoroquinolones are widely used to treat bacterial infections. Many in vitro and in vivo studies have established a chemical relationship between fluoroquinolones’ particular chemical structure and photosensitivity. The aim of this study was to establish a relationship between the chemical structure of fluoroquinolones and the risk of photosensitivity adverse effects from real-world data. All the Individual Case Safety Reports (ICSRs) related to fluoroquinolones and registered in the World Health Organization global database (VigiBase®) up to December 31, 2017 were collected. A disproportionality analysis was performed in order to quantify the photosensitivity risk for each fluoroquinolone by calculating their reporting odds ratio (ROR). Up to December 31, 2017, 282,805 ICSRs related to fluoroquinolones were selected, of which 1647 were photosensitivity adverse event cases. Sparfloxacin had the highest adjusted ROR of 161.10 (95% confidence interval [CI] 133.66–194.02) followed by grepafloxacin (40.30 [26.30–59.60]) closely followed by lomefloxacin (32.61 [28.61–37.07]), then enoxacin (11.04 [8.33–14.32]) and fleroxacin (8.22 [5.06–12.56]). This study confirms the high reporting rate of photosensitivity adverse effects for sparfloxacin from real-world data. Moreover, our data suggest more photosensitivity adverse effects reporting for fluoroquinolones with a halogen at their 8th position.

International audience

In adults, statins safety profile is well known. However, literature data on their adverse drug reactions (ADRs) remain scarce in children in real-life setting. In order to better characterize ADRs related to 'real-life' use of statins in children, we reviewed statin-related ADRs recorded in the World Health Organization (WHO) global database of individual case safety reports (ICSRs), VigiBase. Methods. Individual case safety reports (ICSRs) in children (2-11 years) and adolescents (12-17 years) associated with statins from January 1, 1987, to July 18, 2017, were extracted from VigiBase. Characteristics of ICSRs, type of ADRs according to MedDRA classification (SOC and PT), and ICSR seriousness were described using SAS 9.4. A total of 311 ICSRs were identified for 8 statins with 712 ADRs. Musculoskeletal disorders (n = 85, 27.3%) were the first registered ADRs followed by general disorders (n = 67, 21.5%; mainly asthenia and pain). More than 1 out of 5 ADRs were 'injury, poisoning and procedural complications' (n = 67), mainly accidental or intentional exposures (n = 44, 14.1%), overdoses (n = 14, 4.5%), or off-label use (n = 11, 3.5%). Overall, 133 (42.8%) reports were 'serious', including 11 deaths. Deaths mainly involved adolescents with intentional overdose and completed suicide with other associated drugs in 75% of reports. Our study identified rare but serious safety issues (rhabdomyolysis, myalgia, and hepatocellular injury). These ADRs can impact quality of life or lead to life-threatening complications in children. Our results should be supplemented with other data sources. Spontaneous statin ADR reports in children to pharmacovigilance networks must be promoted.

Background Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin. Methods A disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism. Results Among 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine. Conclusions This study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.

Summary Introduction In France since 2011, report of adverse drug reactions (ADRs) has been extended to patients (and patients’ associations) who can declare directly ADRs to their regional pharmacovigilance centre. In pharmacovigilance, informativeness of ADRs reports is important to improve signal's detection. The present study was performed to compare the quality of patients’, physicians and community pharmacists’ reports. Methods We performed a retrospective study investigating the quality of patients’, physicians and community pharmacies’ ADRs reported to Toulouse University PharmacoVigilance Centre (TUPVC) from January 2014 to June 2017. We used mandatory and non-mandatory criteria, as defined by European Medicines Agency. Reports’ quality was defined as “satisfactory” when more than 90% of items were completed. We also compared reports’ quality according to ADRs seriousness and the used reporting tools (email or the mobile app VigiBip®). Results The number of reports to TUPVC increased between 2014 and 2016 (+51%) for patients and remained stable for pharmacists and physicians. According to the mandatory criteria, quality of the investigated reports was “satisfactory” (more than 90% of the items filled) whatever the reporter and without significant differences between reporters. For the non-mandatory criteria, clinical description of ADRs and ADRs’ outcome were only filled over 90%. Significant differences were observed between the different reporters: community pharmacists informed better clinical description, ADR outcome and concomitant drugs versus both patients and physicians. Physicians informed better medical history and biological data whereas patients informed medical history and other aetiologies better than pharmacists and clinical description of ADRs better than physicians. Conclusion The present study failed to show differences between pharmacies’, physicians’ and patients’ ADRs reports, for the mandatory criteria. However, significant differences were found for non-mandatory criteria with drug data more filled by pharmacists and medical ones more by physicians and patients.

At the request of French Regulatory Authorities, a new formulation of Levothyrox® was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90–1.11. Bioequivalence was concluded. In a previous publication, we questioned the ability of an ABE trial to guarantee the switchability within patients of the new and old levothyroxine formulations. It was suggested that the two formulations should be compared using the conceptual framework of individual bioequivalence. The present paper is a response to those claiming that, despite the fact that ABE analysis does not formally address the switchability of the two formulations, future patients will nevertheless be fully protected. The basis for this claim is that the ABE study was established in a large trial and analyzed using a stringent a priori acceptance interval of equivalence. These claims are questionable, because the use of a very large number of subjects nullifies the implicit precautionary intention of the European guideline when, for a Narrow Therapeutic Index drug, it recommends shortening the a priori acceptance interval from 0.80–1.25 to 0.90–1.11.

Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database. In VigiBase®, we performed a case/non-case study using data registered from 1981 (spironolactone’s marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting “Breast malignant tumors” compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals. During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52–0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44–0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals. This study did not find evidence for breast cancer associated with spironolactone.

Some reports have raised concerns regarding a potential risk of cataracts associated with statins. However, clinical and observational studies evaluating the risk led to conflicting results. We assessed whether lipid-lowering drugs (LLD) use is associated with an increased risk of cataract using the WHO's Individual Case Safety Reports database, VigiBase® . We performed a disproportionality analysis with all reports between 1/1/1988 and 12/31/2018 to measure the reporting risk of 'cataract' in patients ≥45 years. Primary analysis compared LLD users to non-users. To mitigate some potential confounding bias, we performed several sensitivity analyses excluding reports (i) with an association of at least two LLD, (ii) with antidiabetic and glucocorticoids and (iii) with lovastatin. We also analyzed the data according to the different classes of age limiting the period of study to years 2002-2012. We identified 14 664 reports of cataract (3 049 in LLD users, 66% women, 66 ± 20 years). Statins (84%, atorvastatin, simvastatin, rosuvastatin and lovastatin) were mostly reported, followed by fibrates (5.7%), nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (ezetimibe, PCSK9 inhibitors, 15%). LLD users were associated with a greater risk of reports than non-users (ROR 2.47, 95% CI 2.37-2.57). This association was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others. Similar trends were observed in sensitivity analyses (except for fibrates and nicotinic acid after exclusion of reports with at least two LLD or in older patients ≥75 years). Using a large real-life database (>18.5 million reports), we found a signal of cataract for LLD as a whole and statins, bile sequestrants and herbal drugs in particular. The signal disappeared for fibrates and nicotinic acid in older patients. No definite conclusions can be made for ezetimibe or PCSK9 inhibitors (evolocumab and alirocumab). This suggests that a decrease in cholesterol could be important in the pathophysiology of cataract in patients exposed to the main LLD.

International audience; In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox ®. In March 2017, at the request of French authorities, a new formulation of Levothyrox ® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. On June 2008 and February 2009, Dear Doctor Letters (DDLs) were sent by the French Health Authorities (AFSSAPS) to remind practitioners of risks with NSAIDs after the fifth month of pregnancy. The aim of this study was to evaluate the impact of these letters on NSAID prescriptions during late pregnancy. EFEMERIS is a French database that registers drugs prescribed and reimbursed during pregnancy and outcomes between 2004 and 2015. We performed a descriptive study and a 'before-and-after' comparison of NSAID prescriptions between 3 June 2006 and 3 June 2008 ('before group'), and between 1 March 2010 and 1 March 2012 ('after group'). We carried out a Cochran Armitage trend test to check whether the rate of women exposed to NSAIDs varies linearly over time. We identified 948 (4.38%) pregnant women in the 'before group' and 678 (2.73%) in the 'after group' receiving at least one NSAID prescription in late pregnancy (P < 0.0001). Between 2006 and 2012, mainly prescriptions for morniflumate/niflumic acid (1.7% vs. 0.9%; P < 0.0001), ibuprofen (0.8% vs. 0.6%; P = 0.01) and ketoprofen (0.7% vs. 0.3%; P < 0.0001) fell significantly after DDLs. The Cochran Armitage trend test shows that the percentage of women exposed to NSAIDs in late pregnancy decreased significantly during the study period (P < 0.0001). This study highlighted a significant decrease in the percentage of women receiving NSAID prescriptions during late pregnancy after DDLs. This decrease is not linked to a specific women's profile or prescriber's medical discipline.

Several vaccines are being developed as part of the COVID‐19 pandemic. The results of clinical trials for these vaccines were published with efficacy values of more than 90%, using mainly relative risk (RR). In this paper, we decided to reanalyse the data using the different validated methods of risk expression. Using main publications, absolute risks (AR), AR reduction (ARR), number needed to treat (NNT) were calculated for five COVID‐19 vaccines (tozinameran Comirnaty®, Moderna, Vaxzevria®, Janssen, and Sputnik V vaccines). AR, ARR, NNT, and RR values varied according to COVID‐19 vaccines. The order of the different vaccines was not the same according to the chosen efficacy parameters. This is a further example of the need to express results of clinical trials, using not only RR, but also AR, ARR, and NNT in order to clearly present the clinical interest of drugs.

International audience; The current COVID-19 pandemic is an exceptional health situation including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different candidates were proposed. In this short article, we present the French public pharmacovigilance activities during this health crisis. Although COVID-19 is a confounding factor per se, owing to its potential for multi-organ damage including the heart and kidney, the quality of the transmitted data in adverse drug reaction reports, the timeliness of feedback from clinicians, and the real-time pharmacological and medical analysis by the French network of the regional pharmacovigilance centers made it possible to swiftly identify relevant safety signals. The French National Agency of Medicine was thus able to validate the data and convey their findings very early. This decentralized organization based on medical and pharmacological evaluation of case reports has proven to be efficient and responsive in this unique and challenging healthcare emergency.

Summary Introduction Since 2015, Toulouse University PharmacoVigilance Center (TUPVC) set up a pharmacovigilance (PV) general practitioner (GP) network, called PharmacoMIP-MG. A clinical research assistant (CRA) moves to the office of GPs included in the PharmacoMIP-MG network (PMIP-GPs). There, he collects the adverse drug reaction (ADR) reports and drug-related questions. This additional support is not available to GPs not included in the PV network (NoPMIP-GPs) who have to ask drug questions spontaneously to the TUPVC. Objective The objective of this study was to compare the number and characteristics of drug questions between PMIP-GPs and NoPMIP-GPs. Methods All questions asked by GPs to the TUPVC from 01 Jan 2015 to 31 Dec 2017 were reviewed. Questions were classified into two groups: “general” and “related to a patient”. The “related to a patient” category was divided in three subgroups: “ADRs”, Drug-Drug Interactions and “Drug Management”. Drugs were classified according to anatomical therapeutic chemical (ATC) classification. For comparisons, Wilcoxon test, Chi2 test or Fisher test were used. Results During the study period, the CRA collected 293 questions from the 165 PMIP-GPs. TUPVC received 333 questions asked spontaneously by the 3400 NoPMIP-GPs. PMIP-GPs asked significantly 3 times more questions than NoPMIP-GPs. Most of the GP questions were classified in the “related to a patient” category (74.9%). When we compared the proportion of “related to a patient” to “general” questions, there was no statistically significant difference between PMIP-GPs and NoPMIP-GPs. PMIP-GPs asked more questions about “ADRs”, but less on “Drug Management” and or “Drug-Drug Interactions”. The drugs most frequently involved were amiodarone, rivaroxaban and levothyroxine. Conclusion This is the first study about GPs’ drug-related questions asked to a PV center. We found that an organization, such as a CRA-GP “face to face” visit, increased the number of drug questions. This kind of organization should be developed in order to improve independent drug information outreach.

Introduction Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. Objective The present study was undertaken to investigate the reality of this putative drug–drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. Methods Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. Results Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as ‘fatal outcomes’. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9–139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6–13.8). Conclusion Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.

Atropinic drugs are known to potentially induce physical and/or mental impairments in the elderly. The aim of this study was to investigate trends of atropinic exposure in patients ≥65 years in France between 2006 and 2015. A repeated cross-sectional study was performed quarterly from January 1, 2006 to December 31, 2015, in the 'Echantillon Generaliste des Beneficiaires (EGB)', a representative sample of the French population. Exposed patients were identified using the Anticholinergic Duran's list. Outcomes were rate of patients exposed to at least one atropinic drug (atropinic prevalence rate) and atropinic burden per patient (sum of atropinic burden scores). Interrupted time series were used to analyze the impact of market withdrawal of some drugs with atropinic properties during the period of the study. The number of patients ≥65 years registered in the EGB ranged from 75 611 in 2006 to 95 389 in 2015. Atropinic prevalence rate decreased significantly from 45.6% in 2006 to 33.2% in 2015 (-12.4%, slope significance P < 0.05). Subjects aged ≥85 years were the most exposed. Total atropinic burden decreased significantly between 2006 and 2015 (2.2 ± 1.7 in 2006; 2.0 ± 1.5 in 2015; slope significance P < 0.05), especially in patients ≥85 years. Market withdrawals for safety reasons of some atropinic drugs were significantly associated with a decrease in the atropinic prevalence rate (P < 0.05) and atropinic burden per patient (P < 0.05). In conclusion, atropinic drug exposure in the elderly significantly decreased in France between 2006 and 2015. This decrease can be partly explained by regulatory measures against some atropinic drugs.