Laboratory Monitoring of Patients Treated with Antihypertensive Drugs and Newly Exposed to Non Steroidal Anti-Inflammatory Drugs: A Cohort Study

BACKGROUND: Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs. METHODS: We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing. RESULTS: General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3-86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5-11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists. CONCLUSION: Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions

Drugs associated with restless legs syndrome: A case/noncase study in the French pharmacovigilance database

BACKGROUND: Several case reports have suggested that drugs could induce restless legs syndrome. However, no systematic review of this adverse drug reaction (ADR) in a pharmacovigilance database has been published. OBJECTIVE: To assess the frequency of restless legs syndrome in the French Pharmacovigilance Database. METHODS: We selected all ADR reports from January 1, 1984 to December 31, 2009 coded as restless legs syndrome. Restless legs syndrome diagnosis was validated from case descriptions. Using a case/noncase approach, reporting odds ratio and 95% confidence interval were calculated for ''suspected'' drugs with 2 or more observations. RESULTS: Twenty-six ADR reports were found. Four cases were excluded because of alternative diagnosis. Fourteen cases were women (64%). Median age was 57. Most frequently suspected drugs were antidepressants (reporting odds ratio, 15.9 [6.4-39.7]; amitriptyline, escitalopram, mianserine, mirtazapine, duloxetine), neuroleptics (17.8 [6.1-51.7]; thioridazine, loxapine, risperidone, aripiprazole) or tramadol (18.2 [6.3-52.8]). CONCLUSIONS: Restless legs syndrome is a very rare ADR that was more frequently reported in association with antidepressants, neuroleptics, or tramadol.Fil: Perez Lloret, Santiago. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rey, María Verónica. Centre National de la Recherche Scientifique; FranciaFil: Bondon Guitton, Emmanuelle. Inserm; FranciaFil: Rascol, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Montastruc, And Jean-Louis. Inserm; Franci

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with parkinson disease

BACKGROUND: Impulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies. OBJECTIVE: To assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke). METHODS: Outpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders-short version. Full medical history and Unified Parkinson's Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system. RESULTS: Two hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6-6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7-65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1-12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01). CONCLUSIONS: Impulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Inserm; FranciaFil: Rey, María Verónica. Inserm; FranciaFil: Fabre, Nelly. No especifíca;Fil: Ory, Fabienne. No especifíca;Fil: Spampinato, Umberto. No especifíca;Fil: Brefel Courbon, Christine. No especifíca;Fil: Montastruc, Jean Louis. No especifíca;Fil: Rascol, Olivier. Inserm; Franci

Authors' Reply to Coste et al.: "Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?"

"Authors'Reply to Coste et al"International audienc

Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

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

Pharmacoepidemiology and its input to pharmacovigilance

International audienceThe aim of this article is to discuss the contribution of pharmacoepidemiology to pharmacovigilance in the context of drug safety monitoring. Because this contribution requires a comparison of the approaches and a presentation of their respective merits, we have tried to show that this comparison did not necessarily mean opposing these methods, which would not serve any useful purpose. We wanted to underline the fact that the notion of contribution of one to the other implied a complementarity that we propose to demonstrate. Pharmacovigilance is essentially based on the study of spontaneous reports and the clinical and pharmaceutical analysis of the implication of given drugs in adverse drug reactions. It yields performances that are unequalled to this day when safety warning signs relate to rare adverse events or to drugs that are rarely used, or when the drug-related event has specificities that are not found for other aetiologies. Pharmacoepidemiology for its part, through its population-related studies and the possible use of a comparison group, enables a quantification of risks that is impossible to carry out using spontaneous reporting alone. It also enables the highlighting and quantification of safety signals for events that are frequent and multifactorial, where the role of a drug in individual cases can be difficult to detect, and therefore difficult to identify from spontaneous reporting. All in all, this is the major contribution of pharmacoepidemiology to pharmacovigilance, where it can be said that it complements pharmacovigilance in drug safety monitoring but in no way could replace it

L’apport de la pharmaco-épidémiologie à la pharmacovigilance

International audienceThe aim of this article is to discuss the contribution of pharmacoepidemiology to pharmacovigilance in the context of drug safety monitoring. Because this contribution requires a comparison of the approaches and a presentation of their respective merits, we have tried to show that this comparison did not necessarily mean opposing these methods, which would not serve any useful purpose. We wanted to underline the fact that the notion of contribution of one to the other implied a complementarity that we propose to demonstrate. Pharmacovigilance is essentially based on the study of spontaneous reports and the clinical and pharmaceutical analysis of the implication of given drugs in adverse drug reactions. It yields performances that are unequalled to this day when safety warning signs relate to rare adverse events or to drugs that are rarely used, or when the drug-related event has specificities that are not found for other aetiologies. Pharmacoepidemiology for its part, through its population-related studies and the possible use of a comparison group, enables a quantification of risks that is impossible to carry out using spontaneous reporting alone. It also enables the highlighting and quantification of safety signals for events that are frequent and multifactorial, where the role of a drug in individual cases can be difficult to detect, and therefore difficult to identify from spontaneous reporting. All in all, this is the major contribution of pharmacoepidemiology to pharmacovigilance, where it can be said that it complements pharmacovigilance in drug safety monitoring but in no way could replace it.L’objectif de cet article est de présenter l’apport de la pharmaco-épidémiologie à la pharmacovigilance. Nous avons choisi de présenter cet apport dans le contexte de l’activité de surveillance de la sécurité du médicament. Si l’étude de l’apport de la pharmaco-épidémiologie à la pharmacovigilance nécessite une comparaison des méthodes et une présentation de leurs mérites respectifs, nous nous sommes efforcés de démontrer que comparaison n’était pas opposition, et qu’il y avait plus à perdre qu’à gagner à placer ces deux approches en compétition. Enfin, nous avons souhaité souligner que la notion d’apport de l’une à l’autre impliquait une complémentarité que nous nous sommes efforcés de présenter. La pharmacovigilance repose essentiellement sur l’étude de la notification spontanée et l’analyse clinique et pharmacologique de la responsabilité du médicament dans la survenue de cas individuels d’événements indésirables. Elle offre, par cet exercice, des performances à ce jour inégalées quand la détection des signaux de sécurité concerne des événements rares ou des médicaments d’utilisation rare, ou lorsque l’événement d’origine médicamenteuse présente des spécificités non retrouvées avec d’autres étiologies. La pharmaco-épidémiologie, par son approche populationnelle et l’utilisation possible d’un groupe de comparaison, permet la quantification des risques impossible à effectuer à partir des données de notification spontanée. Elle autorise aussi la mise en évidence et la quantification de signaux de sécurité pour des événements fréquents, multifactoriels, où le rôle du médicament dans la survenue de cas individuels peut être difficile à percevoir et donc, à être identifié par la notification spontanée. C’est là l’apport majeur de la pharmaco-épidémiologie à la pharmacovigilance, dont on peut dire pour conclure qu’elle complète la pharmacovigilance dans la surveillance de la sécurité du médicament, mais ne pourrait en aucun cas s’y substituer