[Red yeast-rice-induced muscular injuries: Analysis of French pharmacovigilance database and literature review]. / Atteintes musculaires et levure de riz rouge : analyse des données de la base nationale de pharmacovigilance et revue de la littérature.

Red yeast rice (RYR) is a dietary supplement containing monacolins obtained by fermentation of Monascus purpureus strains. Because of its structural homology with lovastatin, monacolin K inhibits HMG-CoA reductase and shows hypocholesterolemic properties comparable to synthetic statins. We studied all cases of myopathy involving RYR reported in the French national pharmacovigilance database (6 cases) and in scientific literature (9 cases). Among these cases, 9 showed elevated creatine kinase, 3 rhabdomyolysis and 2 myalgia. Recent studies seem to show good efficacy of the RYR, however, our work reports the existence of related muscular disorders. In addition, dietary supplements currently available on the market may show considerable variability of formulation and/or the presence of contaminants. When clinicobiological disorders occur, physicians should consider the eventual use of an herbal treatment.

Is acetaminophen associated with a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database.

AIM: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe mostly drug-induced cutaneous reactions. Acetaminophen is an over-the-counter drug used worldwide to treat pain and reduce fever. In 2013, the US Food and Drug Administration informed the public that acetaminophen was associated with a rare risk of SJS/TEN. The aim of the present retrospective study was to analyse reports of acetaminophen as a possible suspect in the development of SJS/TEN from the French Pharmacovigilance Database (FPDB). METHODS: Cases of TEN/SJS with acetaminophen as a suspect drug registered in the FPDB, collected from January 2002 to December 2013, were analysed by an expert group. The algorithm of drug causality for epidermal necrolysis (ALDEN) was used as a reference tool for SJS/TEN to assess the causality of each suspect drug. RESULTS: After exclusion of 16 nonvalidated cases, 112 cases (47 TEN, 51 SJS, 14 SJS/TEN overlaps) involving 574 suspected drugs (5⋅1/case) were analysed. In 80 cases, the acetaminophen ALDEN score was inferior or equal to that of other drugs, associated with a higher suspicion for causality. In 32 cases, acetaminophen had the highest score but matched with a 'very unlikely' or 'unlikely' causality in 12 cases. For the 20 remaining cases with a 'possible' or ' probable' causality, a protopathic or a confounding bias was likely in 14 cases. CONCLUSIONS: After analysis of the French pharmacovigilance data using the ALDEN algorithm, we found no obvious SJS/TEN risk related to the use of acetaminophen in this large national series.

Safety profile of etifoxine: A French pharmacovigilance survey.

Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine-related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs. Etifoxine-related ICSRs were extracted from the French Pharmacovigilance database from 1 January 2000 to 30 April 2012 and data from the marketing authorization holder up to 31 December 2011 were also obtained. Of the 350 cases retained for analysis, 123 (35%) were considered serious. Dermatological or acute hypersensitivity reactions were the most frequent ADRs (59%) mainly isolated cutaneous eruptions. However, there were 24 cases of severe toxidermia (DRESS in 5, erythema multiforme in 10 and Stevens-Johnson syndrome in 5) with etifoxine as the most suspected drug in 11 patients, and seven cases of vasculitis or serum sickness-like reaction. Liver disorders were reported in 34 patients of whom 25 developed acute hepatitis with a cytolytic biological pattern in 16. Other unexpected ADRs included 16 reversible cases of metrorrhagia with positive rechallenge in 5, and three cases of biopsy-proven microscopic colitis of which one recurred after etifoxine re-administration. Although etifoxine has been marketed for more than 30 years, this survey identified a number of unexpected and sometimes serious ADRs, in particularly severe toxidermia and acute cytolytic hepatitis. A recent update of the French etifoxine summary of the product characteristics (SPC) was based on these findings.

Bullous pemphigoid induced by vildagliptin: a report of three cases.

To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86-year-old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79-year-old man presented with bullous pemphigoid after 37-month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77-year-old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.

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.

Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey.

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence.

[Drugs and heat wave: SIRIUS, a multicentric case-control study in patients older than 65 years during 2007 summer in France]. / Médicaments et chaleur: étude SIRIUS cas-témoins multicentrique chez les sujets de plus de 65 ans durant l'été 2007 en France.

OBJECTIVE: To evaluate in real conditions the role of drugs in heat-related adverse effects. METHODS: We performed a multicentric case-control study in 3 university hospitals in France, including 36 cases (patients older than 65 years hospitalized with hyperthermia or dehydration between 1st July and 31st August 2007) and 51 controls. We compared drugs and changes in drug dosage according to the values of renal function. RESULTS: At inclusion, clearance creatinine was available for only 12 patients (mean = 31.6 ml/min), and three-fold higher in controls (p < 0.001). Cases took more drugs than controls (4.3 vs. 3.9; p < 0.001), particularly neuroleptic drugs (3.6% vs. 0.5%; p = 0.007). CONCLUSION: Despite its small size, our study shows that patients suffering from dehydration in summer are those with more severe renal impairment, taking more drugs (particularly neuroleptics). This pilot work could allow to improve methodology of further studies on drugs during heat waves.

Zoledronic Acid and renal toxicity: data from French adverse effect reporting database.

BACKGROUND: Zoledronic acid-associated renal impairment leading to renal failure has been recently reported in a cohort of US patients. However, the presence of such toxicity in other populations has not yet been determined. OBJECTIVE: To analyze French cases of zoledronic acid-associated nephrotoxicity. METHODS: We evaluated available cases with acute deterioration of renal function associated with zoledronic acid therapy drawn from the French Adverse Event Reporting System database until July 1, 2004. RESULTS: We identified 4 men and 3 women between the ages of 52 and 70 years, with multiple myeloma or different types of metastatic cancer, who had experienced renal impairment during zoledronic acid therapy. Four patients developed de novo acute renal failure, while the other 3 patients experienced acute deterioration of preexisting chronic renal failure. Renal failure occurred after various durations of zoledronic acid therapy (1-120 days). Three patients completely recovered and one partially recovered their previous renal function after discontinuation of zoledronic acid, but renal impairment was associated with a fatal outcome in 2 cases; the outcome of the other case was unknown. Our data confirm the previously reported risk factors for zoledronic acid-associated nephrotoxicity such as advanced cancer, multiple myeloma, preexisting renal failure, diabetes, hypertension, and concomitant use of nephrotoxic drugs. CONCLUSIONS: These cases emphasize the need for regular monitoring of renal function during zoledronic acid treatment, with particular attention to patients with preexisting impaired renal function.