Patient involvement in pharmacovigilance: determinants and evolution of reporting from 2011 to 2020 in France.

INTRODUCTION: Because patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012. OBJECTIVES: To describe evolution and analyze determinants of patient reporting activity in France in order to assess patient involvement in pharmacovigilance. METHOD: Using the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare the characteristics of adverse drug reaction (ADR) reports from patients and healthcare professionals (HCP) between 2011 and 2020. The relationship between regional patient ADR report activity and regional care provision and socio-professional characteristics was analyzed using the principal component analysis. RESULTS: A significant and higher increase in ADR reports over time from patients (r = 0.89, p < 0.001) compared to HCP (r = 0.27, p = 0.002) has been observed. Patient ADR report activities compared to HCP concerned more women (80% vs. 55%, p < 0.001), younger age classes (p < 0.001), reporting through web portal (83% vs. 17%, p < 0.001), and less serious events (26% vs. 63%, p < 0.001). In the principal component analysis, regional patient reporting activity was related to socio-professional categories, age classes, and densities of hospital beds and physicians. CONCLUSION: Our results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance.

Clinical and biological assessment of lamotrigine and levetiracetam plasma assays at the Rennes University Hospital.

INTRODUCTION: Requests for lamotrigine and levetiracetam plasma assays have increased significantly since their development in the biological and forensic toxicology laboratory at the University Hospital of Rennes in 2015. The purpose of this study was to evaluate the follow-up of French National Authority for Health (HAS) guidelines for antiepileptic drug assays and the impact of assay results on medical management. METHODS: Two hundred and forty-two assay results of these two antiepileptics for 169 patients hospitalized in different care wards between 2015 and 2018 were retrospectively analyzed. RESULTS: The mean age of the study population was 50.3±25.4 years. Of the 207 assays prescribed for epilepsy, 177 (85.5%) were in line with the 2007 HAS guidelines, namely: 76/177 (42.9%) for therapeutic adjustment in the event of seizure recurrence or aggravation; 45/177 (25.4%) for specific clinical situations; 23/177 (13%) for proven or suspected poor compliance; 23/177 (13%) for suspected overdose; 8/177 (4.5%) following initiation of treatment; and 2/177 (1.1%) for drug interaction management. Thirty of the 207 assays (14.5%) were thus inappropriate. No significant differences were found regarding the hospitalization frequency after a visit to the emergency room (P=0.9) between patients with lamotrigine and/or levetiracetam plasma assays in therapeutic ranges versus those with concentrations outside the therapeutic ranges. Dosage changes were more frequent in patients with assays in therapeutic ranges compared to patients with plasma assays outside the therapeutic ranges (P=0.0015), suggesting a treatment reassessment primarily based on clinical criteria. CONCLUSION: The analysis of requests for antiepileptic drug assays at the University Hospital of Rennes revealed that clinicians were well aware of the HAS guidelines. In addition, the assay results were mainly consistent with clinical intuition, suggesting a real added value for patient management. However, the consequences in terms of changes in medical care seem limited. This assessment illustrates the importance of strengthening the dialogue between pharmacists, biologists and clinicians.

[Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. / Les hyponatrémies sous ISRS/IRSNA : étude épidémiologique descriptive et comparative des taux d'incidence de cas notifiés à partir des données de la Banque nationale de pharmacovigilance et de l'Assurance maladie.

INTRODUCTION: Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are frequently prescribed. These antidepressants can potentially induce serious hyponatremia through the SIADH syndrome. That seems to concern all molecules of these classes but the individual risk of each molecule is not well known. The aims of the study were to compare the incidence rate of each molecule in order to identify the existence of molecules more at risk of inducing hyponatremia and to characterize a profile of patients at risk for hyponatremia during a treatment with a SSRI or a SNRI. METHOD: The cases of hyponatremia under SSRI/SNRI were extracted from the French pharmacovigilance database (BPNV). The exposition to the different SSRIs/SNRIs in the French population was estimated from the French National Health Insurance database (SNIIRAM) using a sampled database (Echantillon Généralistes des Bénéficiaires). The study ran from 01/01/2011 to 31/12/2013. The primary study endpoint was the incidence rate of notifications of the hyponatremia cases in patients treated by SSRI/SNRI and recorded into the BNPV database, related to the average annual number of corresponding treatments initiated during the same period. RESULTS: The number of cases of hyponatremia included in the study was 169 for 3 749 800 adult patients initiating treatment. The incidence rate of cases was 1.64 for 100 000 persons per year (PY). The standardized incidence rates between the different molecules showed no difference except for duloxetine (2.79/100 000 PY p > 0.03). Identified risk factors were age, with a large increase of incidence rate from 75 years old (incidence 12.5 higher) and female gender. CONCLUSIONS: Comparison of the incidence rates from spontaneous reports indicates a greater risk of hyponatremia for duloxetine for 2011-2013. This result needs to be confirmed by other studies. The advanced age and female sex are risk factors, irrespective of the molecule.

Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies.

OBJECTIVE: We aimed to explore whether the prevalence of manic switch was underestimated in randomized controlled trials (RCTs) compared to observational studies (OSs). METHOD: Meta-analyses and simple and systematic reviews were identified by two reviewers in a blinded, standardized manner. All relevant references were extracted to include RCTs and OSs that provided data about manic switch prevalence after antidepressant treatment for a major depressive episode. The primary outcome was manic switch prevalence in the different arms of each study. A meta-regression was conducted to quantify the impact of certain variables on manic switch prevalence. RESULTS: A total of 57 papers (35 RCTs and 22 OSs) were included in the main analysis. RCTs underestimated the rate of manic switch [0.53 (0.32-0.87)]. Overestimated prevalence was related to imipraminics [1.85 (1.22-2.79)]; to serotonin-norepinephrine reuptake inhibitors [1.74 (1.06-2.86)]; and to other classes of drugs [1.58 (1.08-2.31)], compared to placebo treatment. The prevalence of manic switch was lower among adults than among children [0.2 (0.07-0.59)]; and higher [20.58 (8.41-50.31)] in case of bipolar disorder. CONCLUSION: Our results highlight an underestimation of the rates of manic switch under antidepressants in RCTs compared to the rates observed in observational studies.

Cutaneous melanoma in patients treated with tumour necrosis factor inhibitors: a retrospective series of 15 patients.

BACKGROUND: Several case reports suggested that tumour necrosis factor-α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour. OBJECTIVE: Our objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow-up. METHODS: We performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti-TNF therapy. RESULTS: Fifteen cases were included. First, 10 patients (mean age: 55.6 years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7 months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti-TNF therapy (mean duration of treatment: 10.8 months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy. CONCLUSION: Our case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.

Moxifloxacin-rifampicin combination for the treatment of non-staphylococcal Gram-positive orthopedic implant-related infections.

OBJECTIVE: We aimed to describe the effectiveness and safety of the moxifloxacin-rifampicin combination in non-staphylococcal Gram-positive orthopedic implant-related infections. METHODS: Patients treated with the moxifloxacin-rifampicin combination for an implant-related infection from November 2014 to November 2016 were retrospectively identified from the database of the referral centers for bone and joint infections in Western France. RESULTS: Twenty-three cases of infection due to Streptococcus spp. (n=12), Cutibacteriumacnes (n=6), and Enterococcus faecalis (n=5) were included. Ten patients with hip prosthesis were included. Infection was polymicrobial in 11 cases. According to the MIC, moxifloxacin was 1.5 to 11.7 times as active as levofloxacin against non-staphylococcal Gram-positive bacteria. We reported an 81.8% success rate, and no severe adverse effect. CONCLUSION: The moxifloxacin-rifampicin combination is a valuable alternative for the treatment of non-staphylococcal Gram-positive implant-related infections because of the good activity of moxifloxacin against these bacteria and the potential activity on the biofilm.

[Aspirin: Indications and use during pregnancy]. / Aspirine : indications et utilisation durant la grossesse.

Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.

[Disulone and hepatosiderosis]. / Disulone et hépatosidérose.

BACKGROUND: Disulone (dapsone + iron oxalate) is a sulfone used in the treatment of numerous skin diseases. We report two cases of hepatosiderosis secondary to long-term administration of Disulone. PATIENTS AND METHODS: Case n degrees 1. A 51-year-old man was treated with Disulone for a neutrophilic skin disease. After 17 years of treatment, elevated serum ferritin and free iron with hemolysis were found. Liver biopsy confirmed hepatosiderosis. A diagnosis of genetic hemochromatosis was ruled out by the absence of C282Y mutation of the HFE gene. Case n degrees 2. A 52-year-old man receiving Disulone for dermatitis herpetiformis for 25 years presented elevated serum ferritin and free iron with hemolysis. Hepatic iron overload was confirmed by liver biopsy. The absence of C282Y mutation (HFE gene) ruled out a diagnosis of genetic hemochromatosis. DISCUSSION: In our two cases, hepatosiderosis was noted after long-term administration of Disulone. This complication has been reported only rarely. In murine models, a relationship was found between prolonged administration of dapsone and hepatic iron overload as revealed by hemolysis. Although it is difficult to extrapolate this relationship to humans with any certainty, our patients had also chronic hemolysis and iron overload secondary to administration of Disulone. Moreover in France, dapsone is marketed in combination with iron oxalate, with the attendant risk of iron overload. These cases raise the question of the need for serum ferritin analysis during Disulone therapy.

[Myoclonic encephalopathy associated with proton pump inhibitors]. / Encéphalopathie myoclonique: rôle des inhibiteurs de la pompe à protons.

Two men (66 and 73 Years) with a cardiovascular history were hospitalized for rapid onset encephalopathy associated with myoclonia and an extrapyramidal syndrome. On the basis of the French Pharmacovigilance system, this symptomatology has been attributed to the coadministration of a proton pump inhibitor, lansoprazole (15mg/day) with levodopa. Lansoprazole withdrawal led to a normalisation of the situation.

[Adverse effects and drugs for Alzheimer's disease]. / Effets indésirables et médicaments de la maladie d'Alzheimer.

Molecules currently available or in late phases of development for the treatment of Alzheimer's disease have modest and apparently equivalent efficacies. Thus, the choice will depend on the safety profile of these drugs and on the patient characteristics. The aim of this review is to undertake an inventory of adverse effects and interactions reported in the literature for anticholinesterasics (the only ones approved by authorities). As most of the molecules described in this article are still in early phases of development, data reported here mainly issued from clinical trials carried out on specific populations. Most of these reported adverse effects have not been attributed according to the rules of pharmacovigilance. Nevertheless, we believe that the data presented in this review will be of great interest to clinicians and pharmacovigilance specialists as the compounds concerned become available on the market.

[Drug distribution systems in hospitals]. / Le circuit du médicament à l'hôpital.

Any drug generally made and marketed by drug companies must respect the quality standards conferred by New Drug Approval regarding both safety and efficacy. Once prescribed by a doctor, inside a hospital, the drug, or more precisely the decision of its prescription will follow a complex circuit, involving numerous intermediates (human and technical) leading to drug dispensation and follow-up. Regulatory guidelines and rules harmonise and standardise this drug pathway in hospitals. Any weakness in this distribution system will be the source of nosocomial drug iatrogeny. The present review aims at describing the different steps and stages from the prescription to an individual patient to drug administration and follow-up. The evaluation of this system will be mentioned in the perspective of optimisation. The computerised system is essential allowing tracking of a drug, and providing help for decision-making (by confrontation with data bases) and a research tool (i.e, pharmacoepidemiology). Different experiences of assessment of the performance of such a drug distribution system inside hospitals will be presented, trying to check the quality reference: the right drug, the right patient, the right moment, in good conditions. The challenge is to optimise and secure all steps of the process. This goal needs assessment and quality control of the different phases, opening the discussion between hospital policy and regulatory and technical considerations.

[Acting out and psychoactive substances: alcohol, drugs, illicit substances]. / Passage à l'acte et substances psychoactives: alcool, médicaments, drogues.

In humans, some psychotropic agents (alcohol, drugs, illicit substances) have been suggested to play a role in the occurrence of major behavioural disorders, mainly due to the suppression of psychomotor inhibition. Behavioural disinhibition is a physiological mechanism which allows humans to behave appropriately according to a given environmental situation. The behavioural disinhibition induced by either therapeutic dosage or misuse involves the loss of restraint over certain types of social behaviour and may increase the risk of auto or hetero-aggression and acting out. The increased use of psychotropic agents in recent years and the occurrence of unwanted effects are worrying and must be detected and evaluated. The objective of the present study was to establish a causal relationship between psychoactive substance use and occurrence of major behavioural disorders, such as paradoxical rage reactions and suicidal behaviour, based on a literature analysis. It consisted of reviewing reports of drug-induced violent reactions in healthy volunteers and demonstrating, where possible, a cause-effect relationship. Patients with schizophrenia and psychopathic personalities were not included in our study since psychiatric comorbidity could influence behavioural responses. Psychotropic agents included drugs, licit and illicit substances already associated with violence in the past. Many reports used the "Go/No Go test" to evaluate the disinhibiting effect of psychotropic substances; this allows the "cognitive mapping" of drugs. The results suggest that only alcohol, antidepressants, benzodiazepines and cocaïne are related to aggressive behaviour. The best known precipitant of behavioural disinhibition is alcohol, which induces aggressive behaviour. However, there are large differences between individuals, and attentional mechanisms are now recognised as being important in mediating the effects of alcohol. Suicidal tendency as an adverse antidepressant reaction is rare, especially with atypical antidepressants. However, the risk of acting out exists and the responsibility of antidepressant agents in the genesis of suicidal tendencies is now established. The disinhibiting effects of benzodiazepines are well-known and proven by clinical trials. It's a "model" of acting out, and the causal relationship is undeniable. That cocaïne is related to violent behaviour is demonstrated by its pharmacological actions on CNS. The chronic use of cocaïne induces "a limbic dyscontrol syndrome" based on the altered activity of limbic structures. On the contrary, we could not demonstrate a causal relationship between aggression and either cannabis, ecstasy or phencyclidine. Cannabis abusers look particularly for euphoria and relaxing effects. Aggression as an adverse cannabis reaction is very rare and occurs in most cases in association with other drugs and in predisposed individuals. Ecstasy use may lead to long-term alterations of neuronal function in the human CNS and cause psychiatric disorders. However, there is insufficient information about long-term use of ecstasy to estimate its role in the occurrence of behavioural disorders. Clinical and forensic assumptions about phencyclidine and violence were not warranted. However, the substance-effect relationships can be criticized in the case of alcohol, antidepressants, benzodiazepines and cocaïne. In fact, individual, social and psychiatric factors exert an influence on behaviour that is superior to the pharmacological effect of psychotropic agents. The most important parameter in drug-induced behavioural disinhibition is dosage, but mode of administration is also important. In addition, polysubstance abuse is very common. Substances may be taken simultaneously and alcohol is frequently combined with drugs. The combinations of substances result in multiple interactions, and very little is known about the effects of these interactions on violence in humans. Co-occurrence of substance abuse and other mental disorders is also very frequent. Multiple substance abuse should be avoided, because potential interactions between two or more drugs are more likely to cause violent behaviour. In the future, a specific treatment of these deleterious phenomena will have to be considered in order to reduce drug-induced iatrogenic behavioural disorders.

[Mechanisms of chronic cough pathophysiology]. / Passage à la chronicité d'une toux: quels mécanismes?

INTRODUCTION: In some situations such as post-virus or post whooping cough, a non productive subacute cough may occur without apparent local inflammation, epithelium abnormalities or bronchoconstriction. This subacute or chronic cough represents a real syndrome (cough disease) due to the central nervous system (CNS) and its ortho and parasympathic outputs. At the CNS level, functional disturbancies and neosynaptogenesis can be described, with the intervention of the NMDA-type glutamatergic receptors. STATE OF ART: The neurons located in the expiratory area of the breathing center (Pre-Boetzinger complex of the lower brainstem) present exagerated responses to stimuli, due to the repetitive stimulation of the NMDA receptors; this phenomenon is similar to long-term-potentiation (LTP), the molecular basis of learning, memory and neosynaptogenesis. The cough reflex is thus amplified and rapidly chronic and would justify any pharmacological intervention at the NMDA-receptors level. PERSPECTIVES: More recently 5TH4 receptors have been implied in the control of respiration; an overexpression of these receptors in the Pre-Boetzinger area could contribute to an increase of the cough reflex. CONCLUSION: The present review aims at summarizing the main rationale target to pharmacologically block the chronic cough.