Are lipid-lowering drugs associated with a risk of cataract? A pharmacovigilance study.

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.

Infectious risk of biological drugs vs. traditional systemic treatments in moderate-to-severe psoriasis: a cohort analysis in the French insurance database.

The aim of this study was to compare the infectious risk between a group of psoriasis patients treated by biological drugs (BD) and a group treated by traditional systemic treatments (TST). We built a retrospective observational cohort study from the French health insurance database in the Midi-Pyrénées area (2.9 million inhabitants, southwest of France) using data from 01/01/2010 to 12/31/2013. We compared the infectious risk between 'exposed' patients treated with BD (adalimumab, etanercept, infliximab, or ustekinumab) and 'unexposed' patients treated by TST (phototherapy, acitretin, methotrexate, or cyclosporine). We realized a survival analysis on the first infectious event, defined as an anti-infective drug delivery or a hospital diagnosis of infection. We selected 101 'exposed' and 788 'unexposed' patients. In our multivariate Cox model, 'exposure' did not seem to decrease the time frame of the first infectious event compared with 'nonexposure' (HR = 0.94, P = 0.62). Among all treatment, the safest seemed to be ustekinumab while the least safe was etanercept. We found factors statistically associated with the risk of infection: gender (female vs. male), economic deprivation, chronic hepatitis B or C, history of cancer, at least one infectious event, and the number of different drugs during the 6-month period before the study. We did not find any difference of infective risk between the BD and the TST. This result enhances the recent PSONET registries conclusions.

[Women's knowledge of folic acid]. / Connaissance des femmes en âge de procréer sur l'acide folique : des progrès à faire !

Many trials have shown that folic acid supplementation before and during pregnancy reduces the risk of neural tube defects in general population. We investigated the knowledge of folic acid in women of child-bearing age. Women of child-bearing age were interviewed by 20 pharmacists living in Haute-Garonne between January and February 2014. One hundred ninety-six women were included in the present study. Out of them, 36% of women never heard of folic acid and 82% were not aware of its benefits. Knowledge was higher in older women, women in a couple and women with higher educational level (P<10-2). This study underlines that women are not enough aware of benefits of folic acid during pregnancy. Moreover, previous studies have shown that French women have low use of folic acid during peri-conceptional period. Information of general population will be required for a better prevention of folic acid-preventable NTDs.

[Factors Associated with Direct Oral Anticoagulants versus Vitamin K Antagonists in Patients with Non-valvular Atrial Fibrillation]. / Facteurs associés à la prescription d'anticoagulants oraux directs versus anti-vitamines K dans la fibrillation atriale non valvulaire.

OBJECTIVE: Describing the factors associated with direct oral anticoagulants (DOA) prescription in patients with atrial fibrillation (AF). METHOD: This study was performed in Toulouse on a cohort of patients received in rhythmology consultation, treated with vitamin K antagonists (VKA) or DOA for AF. A multivariate model was performed using logistic regression to describe the factors associated with DOA prescription and secondly, those associated with discontinuation of the anticoagulant. RESULTS: Among the 140 patients included, 96 (66%) were treated with VKA and 48 (34%) with DOA. Recent AF diagnosis (OR 7.52, 95% CI [2.41;23.29], p = 0.001), previous exposure to VKA (OR 17.11, 95% CI [4.48;60.91], p<0.001), and no current exposure to anti-platelet agents (APA) (OR 7.69, 95% CI [1.22; 50.00], p = 0.030) were associated to DOA prescription. Discontinuation of the anticoagulant (n=24) was associated to DOA intake (OR 2.71, 95% CI [1.21; 6.08], p = 0.016). DISCUSSION: DOA are less prescribed than VKA in patients treated with APA. DOA switch to VKA was not systematic in patients diagnosed for a long time. However, international normalized ratio (INR) values were stable in most of patients treated with VKA at the switching to DOA. A more powerful study would confirm the factors associated with DOA prescription.

Adverse drug reactions to self-medication: a study in a pharmacovigilance database.

Although self-medication is widely developed, there are few detailed data about its adverse drug reactions (ADRs). This study investigated the main characteristics of ADRs with self-medication recorded in the Midi-Pyrénées PharmacoVigilance between 2008 and 2014. Self-medication included first OTC drugs and second formerly prescribed drugs later used without medical advice (reuse of previously prescribed drugs). Among the 12 365 notifications recorded, 160 (1.3%) were related to SM with 186 drugs. Around three-forth of the ADRs were 'serious'. Mean age was 48.8 years with 56.3% females. The most frequent ADRs were gastrointestinal and neuropsychiatric and main drug classes involved NSAIDs, analgesics, and benzodiazepines. Phytotherapy-homeopathy accounted for 9.1% of drugs.

Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to antagonize the effects of antihypertensive drugs, and these associations can lead to an increase in arterial blood pressure. However, the impact of NSAIDs on hypertension treatment management in large-scale populations remains poorly evaluated. We examined whether the introduction of NSAID into the treatment regimen would induce an intensification of hypertension treatment (defined as the introduction of a new antihypertensive drug). METHODS: We conducted a cohort study involving 5,710 hypertensive subjects included in the French health insurance system database who had been treated and stabilized with their antihypertensive therapy and not exposed to any NSAID between 1 April 2005 and 1 April 2006. The maximum follow-up duration was 4 years. RESULTS: Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95 % confidence interval (CI) 1.05-1.71] for NSAIDs in general, 1.79 (95 % CI 1.15-2.78) for diclofenac and 2.02 (95 % CI:1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACEIs; HR 4.09, 95 % CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95 % CI 1.80-7.31), but not with other antihypertensive drugs. CONCLUSIONS: Exposure to NSAIDs leads to an intensification of hypertension treatment, especially in patients treated with ACEIs or ARBs. Renin-angiotensin system blockers should be avoided whenever NSAIDs are prescribed.

The importance of drug-drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France.

PURPOSE: To quantify the importance of drug-drug interactions (DDIs) in the occurrence of adverse drug reactions (ADRs) reported with serotoninergic reuptake inhibitors in a pharmacovigilance database. METHODS: All spontaneous reports of ADRs registered in 2008 by the Midi-Pyrénées PharmacoVigilance Centre that contained mention of one of the serotoninergic reuptake inhibitor (SRI) antidepressants marketed in France were reviewed. DDIs were identified according to the French National Drug Formulary (Vidal) and the interaction supplement of the French independent drug bulletin La Revue Prescrire. ADRs explained by DDIs were characterised. RESULTS: Among the 2,101 spontaneous reports recorded, 177 involved at least one SRI antidepressant. Among the 156 ADRs with at least one theoretical DDI, 41% (95% confidence interval 34-49%) could be explained by a DDI. The most frequent antidepressant involved in DDIs was escitalopram, followed by fluoxetine and citalopram. Among the 65 ADRs related to DDIs, 37 (52.9%) were "serious", mainly bleedings, confusion and falls, hyponatremia and serotoninergic syndromes. The most frequent drug interactions occurred with psychotropics (antipsychotics, benzodiazepines, among others), followed by antithrombotic agents (antagonists of vitamin K, antiplatelets), diuretics and angiotensin II antagonists. The group with ADRs related to DDIs was older than the group with ADRs not related to DDIs. ADRs were threefold more "serious" in the case of DDIs. CONCLUSION: Around 40% of ADRs reported with SRIs were related to DDIs. Most of these occurred after association with psychotropics, antithrombotics, or diuretics, especially in the elderly.

Life-threatening drug-associated hyperkalemia: a retrospective study from laboratory signals.

PURPOSE: Life-threatening hyperkalemia may be induced by drugs and preventable in at-risk patients. This study was designed to describe cases of 'serious' drug-associated hyperkalemia. METHODS: Adult subjects with a serum potassium concentration above 6.5 mmol/L detected at admission or during hospital stay in nephrology, cardiology, geriatric, emergency or intensive care units were identified by biology laboratories of hospitals and clinics located in Midi-Pyrenees (southwest France). Patients dialyzed for end-stage kidney disease were excluded. Data were collected from medical files. Hyperkalemia was defined as drug-associated if at least one drug known to increase serum potassium concentration was taken when hyperkalemia occurred (among drugs taken in outpatient care for hyperkalemia detected at admission and among drugs taken in outpatient care and continued at hospital and drugs introduced from admission for hyperkalemia detected during hospital stay). RESULTS: Of 168 hyperkalemia cases, 102 (60.7%) were classified as drug-associated. They concerned elderly patients (mean age: 76.1 years) often having arterial hypertension and/or cardiac diseases (88.2%). Risk factors, mainly acute kidney failure, were observed in almost all cases (98.0%). Drugs predominantly involved were angiotensin-converting enzyme inhibitors (47.1%), spironolactone (41.2%), angiotensin II receptor antagonists (23.5%) and potassium supplements (23.5%). In 10% of cases, death could be attributed to hyperkalemia. CONCLUSIONS: Laboratory databases allowed an exhaustive identification of hyperkalemia cases. The frequency of drug-related hyperkalemia and their characteristics suggest that treatment with drugs known to increase serum potassium concentration can be inappropriate, especially regarding associations or indications, and is highly risky for predisposed patients.

[Post-marketing safety profile of avocado-soybean unsaponifiables]. / Profil d'effets indésirables des insaponifiables d'avocat et de soja.

AIM: To determine the post-marketing safety profile of avocado-soybean unsaponifiables since their commercialization in France until 2008. METHODS: We used data provided by French spontaneous reporting system via the network of National Pharmacovigilance centres. We analysed all suspected adverse drug reactions (ADRs) concerning avocado-soybean unsaponifiables (ASU) reported between 1978 and 2008 and notified in the French Pharmacovigilance Database. RESULTS: We kept 117 ADRs concerning 117 patients (mean age 65.5 years, 72% female). ADRs (35.9%) were "serious" (resulted in hospitalisation or prolonged it). No death was reported. In most of cases, causality of ASU was "possible" and others drugs were also suspected. The most frequently reported ADRs were cutaneous (32.5% of all ADRs, with eczemas or urticaria), hepatic (16.2%, mostly hepatocellular injuries) and gastrointestinal (12%, with 9 cases of colitis and/or diarrhea) ADRs. In these cases, dechallenge of ASU allowed rapid regression of symptoms. Others significant ADRs were coagulation and platelet (6.8%), neurological (6%) and metabolic or nutritional (4.3%) disorders. DISCUSSION-CONCLUSION: This Pharmacovigilance analysis of ASU notified since their commercialisation in France highlights the diversity of ADRs with several class-organ involved. Cutaneous, hepatic and gastro-intestinal disorders were the most frequently reported ADRs. Since ASU is largely prescribed in France, incidence of their ADRs seems to be "very rare" (although we did not take into account the part of under-notification). These safety data should be discussed in the light of the poor expected clinical benefit of ASU in rheumatology (low "Service Medical Rendu") or in stomatology (insufficient "Service Medical Rendu").

Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France.

AIMS: The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS: A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS: Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS: Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely.

[Drug prescription and pharmacovigilance in spa therapy: a comparative study at a 20-year interval (1987 versus 2007)]. / Prescription médicamenteuse et pharmacovigilance en pratique thermale: étude comparative à 20 ans d'intervalle (1987 versus 2007).

OBJECTIVES: Spa therapy is often considered as a dedicated period for a global treatment of patients. However, the prescription behaviours of spa physicians remain largely unknown. METHODS: A postal questionnaire concerning drug prescriptions during spa therapy and occurrence of adverse reactions to spa therapy was sent to the 95 spa physicians of South West of France. RESULTS: Seventy physicians answered to the survey. During spa period, most of them (67%) could associate drug prescription in complement of spa therapy. Drugs most often prescribed were analgesic (80%), non steroidal anti-inflammatory (57%) and antiinfectious (37%) drugs. Fifty nine per cent of the spa physicians could suppress part of the usual drug treatment of the patients. Spa related drugs which were the most often suppressed were anti-arthrosic and veinotonic drugs. Spa physicians could also modify or suppress drugs unrelated to the purpose of spa therapy, mainly psychotropics (anxiolytics or hypnotics), statins, diuretics or hypoglycemics (in case of inefficacy or adverse drug reactions). Spa physicians modified more drug prescriptions related to spa therapy than those unrelated to the purpose of spa therapy. Most of the spa physicians (77%) did observe adverse reactions to spa treatments. For 53% of the physicians, these adverse reactions could be "serious". The 2007 results were compared to those obtained during a similar survey performed 20 years before (1987). CONCLUSION: Spa therapy is often associated with change in drug prescriptions, with mainly a decrease in the number of prescribed drugs. Adverse reactions to spa therapy are rare and mainly "unserious". However, their imputability remains difficult to establish, thus justifying the need of a specific vigilance in spa therapy ("SpaVigilance").

The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France.

INTRODUCTION: Because of design, objectives and number of included subjects, clinical studies are insufficient to assess the safety of new drugs. Sometimes, serious adverse drug reactions (ADRs) led to withdrawal of the drug from the market after their approval. The objective of our study was to determine the scientific evidences leading to drug withdrawal for pharmacovigilance reasons in France. METHODS: Data coming from French Health Products Safety Agency, literature and Toulouse Pharmacovigilance Center allowed to identify all drugs withdrawn from the French market for pharmacovigilance reasons from 1998 to 2004. We classified data according to their study design (Randomized Clinical Trial [RCT], case serie or case report, case-control study, cohort study, observational study, animal study), the organ/system affected and the type of ADR. RESULTS: A total of 21 drugs were withdrawn for safety reasons between 1998 and 2004 in France. The most frequent ADRs were hepatic (n = 7), cardiovascular (n = 4) or neurological (n = 3) ones. Eleven withdrawals were due to type-B ('unexpected') reactions (52%). For 19 out of 21 drugs, scientific evidence leading to drug withdrawal came from spontaneous case reports (or case series). Among these, case reports were the sole evidence in 12 cases. Withdrawals were based on evidence from case reports in combination with case-control or cohort study in four cases, in combination with observational study in two cases or in combination with animal study in two other cases. In only one case, a RCT supported the decision. CONCLUSIONS: This study underlines the importance of spontaneous case reports in detecting signals and supporting withdrawal of drug for pharmacovigilance reasons in France. Health authorities suffer from lack of comparative data resource. In this perspective, a pharmaco-epidemiological population-based database could represent a helpful tool to both generate and test safety hypotheses.

Clinical and economic analysis of spa therapy in Parkinson's disease.

The effectiveness of spa therapy in the management of patients with Parkinson's disease (PD) has never been evaluated. This is assessed in this pilot study. A prospective, randomized, cross-over, controlled study was conducted in 31 PD patients who underwent a 20-week spa period, including spa therapy for 3 weeks, and a 20-week non-spa period. Effectiveness was assessed using quality of life scales (PDQ-39 and SF-36), motor scale (UPDRS) and psychological questionnaire (GHQ-28), at baseline and at 4 (T4) and at 20 weeks (T20). Direct medical costs (radiological and laboratory tests, physician fees, drug therapy, and ancillary care) were recorded over each 20-week period. At T4, spa therapy improved significantly several dimensions of PDQ-39 and SF-36, part IV of the UPDRS, and GHQ-28. At T20, no difference in any parameter was found. The mean direct medical cost over 20 weeks (euro;1,328 +/- 167; pound 776 +/- 97 per patient) in the spa period was slightly but significantly reduced in comparison with that of the non-spa period (euro;1380 +/- 523; pound 807 +/- 306 per patient). This cost-effectiveness analysis suggests that spa therapy is more effective and less expensive than conventional treatment alone and could be beneficial in the management of PD.

Limitations of current Parkinson's disease therapy.

Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinson's disease in the early stages of the disease. However, once the "honeymoon" period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from "dopa-resistant" motor symptoms (speech impairment, abnormal posture, gait and balance problems), "dopa-resistant" nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety.