REview of potentially inappropriate MEDIcation pr[e]scribing in Seniors (REMEDI[e]S): French implicit and explicit criteria.

PURPOSE: To establish a consensus on both explicit and implicit criteria in order to identify potentially inappropriate prescribing (PIP) in French older people aged 75 years and over or 65 years and over with multimorbidity. METHODS: Fifteen experts in geriatrics, general practice, pharmacy, and clinical pharmacology were involved in a two-round Delphi survey to assess preliminary explicit and implicit criteria based on an extensive literature review and up-to-date evidence data. Experts were asked to rate their level of agreement using a 5-level Likert scale for inclusion of criteria and also for rationale and therapeutic alternatives. A consensus was considered as reached if at least 75% of the experts rated criteria as "strongly agreed" or "agreed." RESULTS: The new tool included a seven-step algorithm (implicit criteria) encompassing the three main domains that define PIP (i.e. overprescribing, underprescribing, and misprescribing) and 104 explicit criteria. Explicit criteria were divided into 6 tables related to inappropriate drug duplications (n = 7 criteria), omissions of medications and/or medication associations (n = 16), medications with an unfavourable benefit/risk ratio and/or a questionable efficacy (n = 39), medications with an unsuitable dose (n = 4) or duration (n = 6), drug-disease (n = 13), and drug-drug interactions (n = 19). CONCLUSION: The REMEDI[e]S tool (REview of potentially inappropriate MEDIcation pr[e]scribing in Seniors) is an original mixed tool, adapted to French medical practices, aimed at preventing PIP both at the individual level in clinical practice and the population level in large-scale studies. Therefore, its use could contribute to an improvement in healthcare professionals' prescribing practices and safer care in older adults.

Ischaemic colitis associated with intravitreal administration of aflibercept: A first case report.

In patients with age-related macular degeneration (AMD), the intravitreal injection of antivascular endothelial growth factor (anti-VEGF) agents reduces disease progression and choroidal neovascularization. We report on a first case of ischaemic colitis associated with intravitreal injection of the anti-VEGF agent aflibercept in an 80-year-old female patient. Conservative treatment resulted in a favourable clinical outcome. The anti-VEGF agent was discontinued, and the symptoms did not recur. Although the intravitreal injection of anti-VEGF agents has not previously been linked to the occurrence of ischaemic colitis, consideration of aflibercept's pharmacological properties and the chronological relationship between the administration of this anti-VEGF agent and the occurrence of this systemic adverse event are strongly suggestive of a causal relationship in the present case. Although systemic complications have been rarely associated with intravitreal injections of anti-VEGF agents, physicians should be aware that novel adverse events can still occur in AMD patients treated with anti-VEGF agents.

The drugs that mostly frequently induce acute kidney injury: a case - noncase study of a pharmacovigilance database.

AIMS: Acute kidney injury (AKI) is associated with a high hospitalization rate, accelerated long-term decline in kidney function and a high mortality rate. Adverse drug reactions (ADRs) constitute one of the most important modifiable factors in the context of AKI. Most studies of drug-induced AKI have focused on a sole drug class. The objective of the present study was to establish a comprehensive overview of drug-induced AKI on the basis of spontaneously reported ADRs in the French national pharmacovigilance database (FPVD). METHODS: We performed a case-noncase study of drug-induced AKI. Cases corresponded to the reports of AKI recorded in the FPVD between 1 January 2015 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs (excluding AKI) recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and the 95% confidence interval. RESULTS: Of the 38 782 ADRs recorded in the FPVD during the study period, 3.2% were classified as cases of AKI. A total of 1254 patients experienced AKI (males: 55%; mean age ± standard deviation: 68.7 ± 15.0 years). Overall, 15.2% of the patients required renal replacement therapy. Two or more concomitantly administered drugs were involved in 66% of the cases of AKI. The most frequently implicated drug classes were antibacterial agents for systemic use (29.5%), diuretics (18.5%), agents acting on the renin-angiotensin system (16.3%), antineoplastic agents (10.2%) and anti-inflammatory agents (5.4%). Gentamicin, eplerenone, spironolactone, candesartan, cisplatin and acyclovir had the highest RORs (>10). CONCLUSION: A comprehensive study of a national pharmacovigilance database enabled us to identify the drug classes that most frequently induced AKI. Even though most of the identified drugs were already known to induce AKI, the present work should raise physicians' awareness of the compounds responsible for triggering this potentially life-threatening condition.

[Benzodiazepine or non-benzodiazepine hypnotics withdrawal syndrome during hospitalization: A series of 22 cases]. / Syndrome de sevrage aux benzodiazépines ou apparentés au cours d'une hospitalisation, à propos de 22 cas.

Twenty-two cases related to benzodiazepine (BZD) withdrawal syndrome were identified and reported to Amiens's regional pharmacovigilance center between January 1st, 1995 and March 25th, 2014, all with a favourable outcome after reintroduction of a BZD. Despite being a very classical well-known side effect, physicians may underestimate this risk. Our series also confirms that the patient is misinformed about the consequences of an abrupt BZD discontinuation especially when the BZD has been consumed for many years. Interviewing patient and his family on the nature of the current medical treatments should be systematic and an early diagnostic step taken by physicians faced with a recent behavioral disorder. Moreover, this would prevent unnecessary, sometimes invasive, expensive investigations and a prolonged hospitalization.

[Vascular calcifications, the hidden side effects of vitamin K antagonists]. / Les calcifications vasculaires sous anti-vitamines K : un effet indésirable méconnu.

Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA.

Valvular heart disease associated with long-term treatment by methysergide: a case report.

This case report concerns a woman treated continuously since at least 10 years by methysergide for cluster headache. The echocardiographic and histological features of the severe valve fibrosis presented by this patient are very similar to those described with 5 HT(2B) receptors agonistic drugs.

Medication-overuse headache: A pharmacovigilance study in France.

BACKGROUND: Overusing medication for primary headaches or other medical conditions can lead to dependency and medication-overuse headache (MOH) as an adverse drug reaction (ADR). OBJECTIVES: To analyse reports of ADRs associated with MOH recorded in the French national pharmacovigilance database (FPVD). METHODS: This retrospective study selected all MOH cases reported in the FPVD from January 2000 to June 2023. A search of the High-Level Group Term "headache" was performed for drugs classified under ATC codes for the musculoskeletal and nervous systems. Specific keywords were searched in report narratives to further reduce their number. Voluntary intoxication reports were excluded. Only MOH cases according to the International Classification of Headache Disorders or with a medical diagnosis of MOH were considered. RESULTS: Among the 2674 reports associated with the HLGT "headache", for 649 ATC drug codes, only 234 reports correspond to MOH, primarily notified by physicians. The median age was 45 years (IQR: 32-56), with 74.4% females and approximately 61.0% having pre-existing primary headaches. In all, 53.4% of the reports were classified as serious. Among patients, 84.2% had an isolated "headache" as the ADR. One drug was suspected in 47.4% of cases, two drugs in 29.1%, and three or more in 23.5%. In total, 473 suspected drugs, corresponding to 104 active ingredients, were involved, including analgesics (63.0%), in particular, acetaminophen-containing drugs, opioids, triptans and ergots, and non-steroidal anti-inflammatory drugs (12.7%). Antiepileptics and psycholeptics were found in 6.6% and 6.1% of cases, respectively. Drug withdrawal was successful in 84.6% of drug-discontinuation cases. Warnings about MOH are mentioned in the summary of product characteristics (SmPCs) for triptans, ergots, and certain acetaminophen-containing drugs, but not other drug classes. CONCLUSIONS: Certain drug classes show a high reporting rate of MOH and caution should be exercised when prescribing these drugs. Notably, warnings about MOH must be mentioned in the SmPC of all concerned drug classes.

Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross-sectional study.

PURPOSE: To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimer's disease (AD) or other dementia in France. METHODS: A cross-sectional multicentre study was conducted by the French network of the 31 regional pharmacovigilance centres on a given day. The subjects were selected by random draw to be a representative sample of French patients with dementia: consultations of dementia clinics, nursing-homes, acute and long care geriatric units, rehabilitation care geriatric units. The staff of each medical structure together with that of the pharmacovigilance centre defined a day for including the patients. Socio-demographic data, history, ADR and drugs given were registered. RESULTS: There were 1332 subjects included, 51.1% living at home, 48.8% in institutions, aged 82.0 ± 8.0 years (46-108); 61.3% suffered from AD. Mean number of drugs was 6.3 ± 3.1. Anti-dementia drugs were given to 66.4% subjects. ADR prevalence was 5.0% (95% CI: 3.9-6.2) without a significant difference between at home and institutionalized patients. ADR consisted of gastro-intestinal (23.2%), central nervous system (17.4%) and psychiatric disorders (8.7%). Of the ADR, 31.9% were serious, and 47.8% preventable. The drugs most often involved were anti-dementia (28.9%), cardio-vascular (28.9%) and psychotropic drugs (26.4%, anxiolytics, hypnotics, antidepressants, neuroleptics). CONCLUSION: This national scale study showed that iatrogenesis in patients with AD and related dementia can at times be serious and preventable. Therefore, special attention is required when prescribing psychotropic and anti-dementia drugs, as they are frequently used and induce half of the ADR in this population.

Use of the Capture-Recapture Method to Estimate the Frequency of Community- and Hospital-Acquired Drug-Induced Acute Kidney Injuries in French Databases.

Drug-induced acute kidney injury (AKI) can occur both in primary care (i.e., community-acquired AKI (CA-AKI)) and in hospital settings (i.e., hospital-acquired AKI (HA-AKI)). The reported prevalence of these events varies markedly from one study to another, mainly due to differences in the study design. To estimate the frequency of drug-induced AKIs (both CA-AKIs and HA-AKIs) observed in a French university hospital, we applied the capture-recapture method to 1) the French national pharmacovigilance database (FPVD) and 2) a cohort of hospitalized patients with drug-induced AKIs (documented by analyzing the French national hospital discharge database and the patients' electronic medical records). Drug-induced AKIs were determined according to the Naranjo algorithm and then categorized as CA-AKIs or HA-AKIs. A total number of 1,557 episodes of AKI were record during the study period, of them, the estimated total number of drug-induced AKIs was 593 [95% confidence interval (CI): 485-702], and the estimated prevalence was 38.1% [95%CI: 35.67-40.50]. The prevalences of HA-AKIs and CA-AKIs were similar (39.4% [36.24-42.54] and 37.4% [33.67-41.21], respectively). Only 6.1% of the drug-induced AKIs were recorded in the FPVD, and the proportions of recorded HA-AKIs and CA-AKI differed markedly (3.0% vs. 10.5%, respectively). One of the most frequently involved drug classes were antibiotics in the HA-AKI subgroup (13.0%) and antineoplastics in the CA-AKI subgroup (8.3%). Application of the capture-recapture method to two incomplete data sources can improve the ability to identify and quantify adverse drug reactions like AKIs. The frequency of drug-induced AKI is relatively high and is probably underestimated. The clinical management of an AKI might depend on where it originated.

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review.

Objectives: Cyproheptadine is a first-generation H1-antihistamine drug first that was distributed in the 1960s. While its orexigenic effect was observed early, cyproheptadine is not yet authorized for this indication in all countries today. There is an increasing medical interest and demand for the orexigenic effect of cyproheptadine, especially in children with poor appetite. As cyproheptadine might be evaluated in future clinical trials, we wanted to assess its safety profile. Methods: Using the French national pharmacovigilance database, we retrospectively analyzed all pediatric and adult reports of adverse effects of cyproheptadine recorded since its first distribution in France. Next, we performed a systematic review of the literature of cyproheptadine adverse effects. Results: Since 1985, 93 adverse effects were reported in the French pharmacovigilance database (adults 81.7%, children 18.3%); these were mainly neurological symptoms (n = 38, adults 71%, children 28.9%), and hepatic complications (n = 15, adults 86.7%, children 13.3%). In the literature, the most frequent adverse effect reported was drowsiness in adults or children, and five case reports noted liver complications in adults. We estimated the frequency of hepatic adverse effects at 0.27 to 1.4/1000, regardless of age. Conclusion: Cyproheptadine can be considered a safe drug. Mild neurological effects appear to be frequent, and hepatotoxicity is uncommon to rare. Randomized controlled trials are needed to evaluate the safety and efficacy of cyproheptadine before authorization for appetite stimulation, especially in young children as studies at this age are lacking. Possible hepatic complications should be monitored, as very rare cases of liver failure have been reported.

The drugs that mostly frequently induce gynecomastia: A national case - noncase study.

AIMS: Drug-induced gynecomastia accounts for up to 25% of cases of gynecomastia. The objective of the present study was to provide a comprehensive overview of drug-induced gynecomastia on the basis of spontaneously reported adverse drug reactions (ADRs) in the French national pharmacovigilance database (FPVD). METHODS: We performed a case - noncase study of drug-induced gynecomastia. Cases corresponded to reports of gynecomastia recorded in the FPVD between 1 January 2008 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and its 95% confidence interval. RESULTS: Of the 255,354 ADRs recorded in the FPVD between 1 January 2008 and 31 December 2015, 327 (0.31%) of relevant cases of gynecomastia and 106,800 noncases were analyzed. The RORs were statistically significant for 54 active compounds mentioned 429 times in cases of gynecomastia. A single drug was involved in 59% of cases. The most frequently implicated drug classes were antiretrovirals (23.5%), diuretics (15.5%), proton pump inhibitors (11.9%), HMG-CoA reductase inhibitors (9.1%), neuroleptics and related drugs (6.5%), calcium channel blockers (6.3%), and 5-alpha reductase inhibitors (4%). CONCLUSIONS: A comprehensive analysis of a national pharmacovigilance database highlighted the main drug classes suspected of inducing gynecomastia. A physiopathological mechanism (a hormone imbalance with elevated estrogen levels) is known or suspected for most of the drugs involved in gynecomastia. However, we noticed a lack of harmonization in the summary of product characteristics for original vs. generic medicines.

Cefixime-Induced Oromandibular Dystonia in an Adult: A Case Report.

INTRODUCTION: Cefixime, a third-generation cephalosporin, is commonly used in different infections. Tolerance is pretty good even if some side effects can be frequent like digestive disorders. Other effects, not mentioned in the Summary of Product Characteristics, can occur. METHODS: We report a case of recurrent, acute oromandibular dystonia in a cefixime-treated adult. CASE-REPORT: After the third dose of cefixime, prescribed for a bronchial infection, a patient experienced a first episode of oromandibular dystonia. Then, after each ingestion, the same effects appeared. After the discontinuation of cefixime, there was no recurrence. The diagnosis of acute oromandibular dystonia has been confirmed by a neurologist. DISCUSSION: Some cases of dystonia have been published with other ß-lactams antibiotics and with cefixime but they concerned children. Different mechanisms are proposed to explain the occurrence of dystonia during a treatment with cefixime. They involved certain neurotransmitters like dopamine, acetylcholine or GABA. CONCLUSION: Even if dystonia is not a side effect mentioned in the SPC, the drug's potential causal role must always be considered in case of involuntary contraction of muscles in a patient treated with cefixime or any other ß-lactam antibiotics.

[Severe muscle disorders associated with statins: analysis of cases notified in France up to the end of February 2002 and data concerning the risk profile of cerivastatin]. / Atteintes musculaires sévères sous statines: bilan des cas notifies en France jusqu'a fin février 2002 et données concernant les risques liés a la cérivastatine.

BACKGROUND AND METHODS: After the withdrawal of cerivastatin from the market, a survey was performed concerning severe muscular disorders associated with statin treatments that were notified to the French national and pharmaceutical industry pharmacovigilance systems up to February 2002. RESULTS: Among the 238 cases analysed, 69 were related to cerivastatin, 86 to simvastatin, 49 to pravastatin, 23 to atorvastatin and 9 to fluvastatin. The reporting rate was six- to ten-times higher for cerivastatin than for other statins. A major risk factor for rhabdomyolysis with cerivastatin was its association with gemfibrozil. CONCLUSION: Postmarketing surveillance appears to be a major tool for early detection of safety problems with a new drug.

[Adverse effects of statins]. / Effets indésirables des statines.

The safety of the hydroxymethyl glutaryl-coenzyme A reductase inhibitors (statins) has been called into question following the recent withdrawal from the market of one of the class, cerivastatin. The withdrawal of cerivastatin highlighted concerns regarding the safety of the entire class. According to data from several large clinical trials, the statins (except cerivastatin) are well tolerated. The most important and clinically relevant adverse effect reported with statins is myopathy. Myopathy is a clinical diagnosis of elevated creatine phosphokinase and/or myalgia along with fatigue. However, the severe from (i.e. statin-associated rhabdomyolysis) is an uncommon syndrome and occurs at a rate of approximately 1/100,000 patients/years. Statin-associated myopathy is related to statin doses, and often to drug/drug interactions. Other clinically relevant adverse effects associated with statin therapy include liver transminases elevation, which is relatively mild and often self-limiting There is no evidence from clinical trials of a significant alteration of ophthalmological function with statins. The issue of statin-induced cancer remains inconclusive. Overall, the statins seem to exhibit a favourable risk/benefit ratio, and this undoubtedly justifies life-long clinical use of statins for cardiovascular prevention.

Ulceration of the oral mucosa following direct contact with ferrous sulfate in elderly patients: a case report and a review of the French National Pharmacovigilance Database.

OBJECTIVE: To report a series of cases of ulceration of the oral mucosa linked to direct contact with ferrous sulfate in elderly patients. CASE SUMMARY: The first case report concerns the occurrence of widespread oral ulceration in an 87-year-old woman with Alzheimer's disease. The ulceration extended from the side of the tongue to the floor of the mouth. No clear explanation was found and various local treatments were ineffective. Once it was realized that the ferrous sulfate tablets (given as an iron supplement) were crushed prior to administration (due to the patient's deglutition disorder), withdrawal of this treatment led to rapid resolution of the ulceration. Nine other cases of oral ulcerations associated with ferrous sulfate were identified in the French National Pharmacovigilance Database. All but one of the patients were over 80 years of age and the youngest patient (a 54-year-old) had dysphagia associated with facial paralysis. DISCUSSION: Only two other reports of oral ulceration due to ferrous sulfate have been published to date. Mucosal toxicity of ferrous sulfate (which is probably related to oxidative stress) has previously been reported for the hypopharynx, the esophageal lumen, and (after inhalation of a tablet) the tracheobronchial tree. CONCLUSION: The mucosal toxicity of ferrous sulfate must be taken into account when deglutition disorders are present (as in elderly patients) and appropriate pharmaceutical formulations (such as syrups) should be administered to at-risk patients. The use of iron salts other than ferrous sulfate could be considered.

Thromboembolic events in women exposed to hormonal contraception or cyproterone acetate in 2012: a cross-sectional observational study in 30 French public hospitals.

BACKGROUND: In the context of the European reassessment of the benefit-risk balance of hormonal contraceptives, French data about thromboembolic events were requested. OBJECTIVE: The aim of this study was to determine the number of patients exposed to hormonal contraception or cyproterone acetate among hospitalized females diagnosed with a thromboembolic event in 2012, to retrospectively analyze specific risk factors of venous and arterial thromboembolism and to assess the magnitude of the under-reporting of such events to the national pharmacovigilance system. METHODS: This cross-sectional study included 15- to 49-year-old women with pulmonary embolism, venous cerebral thrombosis, ischemic stroke, or myocardial infarction, hospitalized in 2012, and identified within the computerized hospital databases of 30 French teaching hospitals. RESULTS: Among the 2,966 cases identified, 803 (27.1 %) patients had been exposed to a hormonal contraceptive (747) or to cyproterone acetate (56). Among these, there were 452 venous thromboembolic events (VTEs) and 351 arterial thromboembolic events (ATEs). Age ≥40 years and personal thrombophilia diagnosed after the event were the main VTE risk factors, while current smoking and age ≥40 years were the main ATE risk factors. The mean number of associated risk factors was significantly lower for VTE than for ATE (1.1 vs 2.3). The proportion of cases with no risk factors was higher for third- and fourth-generation than for first- and second-generation combined oral contraceptives. Overall, the under-reporting rate was 92.5 % (95 % CI 70.0-97.3). CONCLUSION: This study highlighted the need to strengthen the knowledge of patients and health professionals about thromboembolic risk factors at the first prescription and renewal of hormonal contraceptives.