Does spontaneous adverse drug reactions' reporting differ between different reporters? A study in Toulouse Pharmacovigilance Centre.

INTRODUCTION: In France since 2011, report of adverse drug reactions (ADRs) has been extended to patients (and patients' associations) who can declare directly ADRs to their regional pharmacovigilance centre. In pharmacovigilance, informativeness of ADRs reports is important to improve signal's detection. The present study was performed to compare the quality of patients', physicians and community pharmacists' reports. METHODS: We performed a retrospective study investigating the quality of patients', physicians and community pharmacies' ADRs reported to Toulouse University PharmacoVigilance Centre (TUPVC) from January 2014 to June 2017. We used mandatory and non-mandatory criteria, as defined by European Medicines Agency. Reports' quality was defined as "satisfactory" when more than 90% of items were completed. We also compared reports' quality according to ADRs seriousness and the used reporting tools (email or the mobile app VigiBip®). RESULTS: The number of reports to TUPVC increased between 2014 and 2016 (+51%) for patients and remained stable for pharmacists and physicians. According to the mandatory criteria, quality of the investigated reports was "satisfactory" (more than 90% of the items filled) whatever the reporter and without significant differences between reporters. For the non-mandatory criteria, clinical description of ADRs and ADRs' outcome were only filled over 90%. Significant differences were observed between the different reporters: community pharmacists informed better clinical description, ADR outcome and concomitant drugs versus both patients and physicians. Physicians informed better medical history and biological data whereas patients informed medical history and other aetiologies better than pharmacists and clinical description of ADRs better than physicians. CONCLUSION: The present study failed to show differences between pharmacies', physicians' and patients' ADRs reports, for the mandatory criteria. However, significant differences were found for non-mandatory criteria with drug data more filled by pharmacists and medical ones more by physicians and patients.

Off-label and unlicensed drug use in children population.

INTRODUCTION: Off-label (OL) and unlicensed (UL) drug use is widely developed in the pediatric population according to previous reviews published in the early 2010s. The present study is a narrative review of the literature of OL-UL drug use from 2013. METHODS: We performed a literature search of research articles assessing OL-UL drug use in children (<18 years-old) published in Medline® from January 2013 until May 2017. RESULTS: Twenty-seven studies were included. OL drug use was defined by inappropriate age, indication, dosage or way of administration according to the summary of product characteristics in >80% of studies. UL drug used was defined by the use of drugs not licensed in the country or modifications of licensed drugs in >70% of studies. Among in- and out-patients, the frequency of patients exposed to at least one OL-UL drug ranged from 36.3 to 97.0% and from 18.6 to 40.2%, respectively. Drug use was categorized as OL mostly due to inappropriate age, dosage or indication. OL-UL drug use was the most prevalent in newborns (mainly preterms) and pre-school children (aged 2-5years). Various drugs were involved, depending on patients' age. Polypharmacy and long hospital stays were risk factors for OL-UL drug use. Whether OL-UL drug use leads to a higher incidence of adverse drug reactions is a controversial finding. CONCLUSIONS: OL-UL drug use is frequent in children. A standardized definition of OL-UL drug use is needed to better assess its frequency, risk factors and impact.

[Serious adverse drug reactions with tramadol reported to the French pharmacovigilance database between 2011 and 2015]. / Effets indésirables « graves ¼ du tramadol : bilan 2011­2015 de pharmacovigilance en France.

BACKGROUND: Tramadol is an opioid and a serotonin reuptake inhibitor drug. It is approved for moderate to severe pain in adults. The aim of this study was to assess tramadol safety through a national pharmacovigilance study in France since dextropropoxyphen withdrawal in 2011. METHODS: We described all serious adverse drug reactions (SADRs) reported with tramadol in adults in the French National PharmacoVigilance Database from August 1st, 2011 to December 31st, 2015. RESULTS: We identified 1512 SADRs during the study period. The most frequently reported SADRs were neurological (29.4%, including troubles of consciousness [13.2%] and seizures [6.7%]), psychiatric (22.8%, including confusions [14.6%] and hallucinations [7.3%]) and gastrointestinal (17.0%, mostly nausea and vomiting [9.6%]). Unexpected SADRs were also reported: hyponatremia, cholestatic hepatitis, serotonin syndrome. CONCLUSIONS: This study demonstrates new unexpected hepatic and metabolic SADRs. Tramadol alone can induce serotonin syndrome in overdose situations.

Adverse drug reactions of botulinum neurotoxin type A in children with cerebral palsy: a pharmaco-epidemiological study in VigiBase.

AIM: The aim of this study was to assess the risk of adverse drug reactions (ADRs) with botulinum neurotoxin type A (BoNT-A) in children with cerebral palsy (CP) using the World Health Organization global individual case safety report (ICSR) database, VigiBase. METHOD: We extracted all children ICSRs for ADRs with BoNT-A used as anti-spastic drug in CP recorded between 1995 and 2015 in VigiBase. We also performed a case/non-case method (disproportionality analysis) to assess the link between exposure to BoNT-A and each ADR of interest in children and adults, calculating reporting odds ratios (RORs). RESULTS: In VigiBase, 162 ICSRs were registered. They involved mainly males (n=95, 59%) and mean (SD) age was 7 years 11 months (4y 4mo). The most frequent ADR was dysphagia (27 ICSRs, 17%) followed by asthenia and muscular weakness (25 ICSRs each, 16%). Nineteen ICSRs (12%) were lethal. There was a significant association between BoNT-A and death in children (ROR=11.1 95%, confidence interval [CI] 7.0-17.7) but not in adults. INTERPRETATION: In children with CP, most ADRs seem to be linked to a systemic spread of BoNT-A. Our study suggests a higher risk of ADRs with BoNT-A in children than in adults.

Ergot and non-ergot dopamine agonists and heart failure in patients with Parkinson's disease.

PURPOSE: Some studies have suggested a potential risk of heart failure in patients with Parkinson's disease receiving dopamine (DA) agonists. However, the results are conflicting. We used VigiBase®, the World Health Organization (WHO) Global Individual Case Safety Reports (ICSRs) database, to investigate a potential signal strengthening of heart failure with DA agonists in Parkinsonian patients older than 45 years. METHODS: A case/non-case (disproportionality) analysis was performed in Vigibase® using ICSRs registered between 1978 and May 2016. The signal of disproportionality was calculated using reporting odds ratios (ROR). In our study, 154 ICSRs of heart failure occurring in 154 Parkinsonian patients (mean age 69.6 years, 51 % women) treated with DA agonists were included. RESULTS AND CONCLUSION: There was a significant signal between occurrence of heart failure and exposure to pergolide or cabergoline in particular and ergot derivatives in general. In contrast, none signal was found for rotigotine, pramipexole, apomorphine, or ropinirole in particular and non-ergot derivatives in general. The present study underlines the importance to prescribe as DA agonists in Parkinsonian patients only non-ergot derivatives, excluding ergot drugs.

Can drugs induce or aggravate sleep apneas? A case-noncase study in VigiBase® , the WHO pharmacovigilance database.

The potential favorizing role of drugs in sleep apnea syndrome (SAS) is unknown. This study investigates drugs associated with SAS in a pharmacovigilance database. SAS recorded as adverse drug reactions (ADRs) in VigiBase® , the WHO pharmacovigilance database (more than 11 million reports), from 1978 to 2015 was selected. The risk of SAS reports was estimated using the case-noncase method, with cases being SAS and noncases all other recorded ADRs. During this 37-year period, 3325 ADRs including the word SAS were registered (0.05% of the database). Mean age was 51.2 ± 16.9 years with 52% men. ADRs were 'serious' in around 82% of cases. The case-noncase study found an association between SAS and exposition with sodium oxybate, rofecoxib, quetiapine, and clozapine for individual drugs and coxibs, antipsychotics, benzodiazepines, and opium alkaloids for drug classes. The potential role of other drugs is discussed. This study suggests that SAS can be associated with some drugs (mainly psychotropics) that are able to reveal or aggravate such a disease. Physicians should take into account the role of drugs in the etiological appraisal and management of SAS.

Atropinic (Anticholinergic) Burden in Parkinson's Disease.

Use of atropinic drugs remains controversial in Parkinson's disease (PD) because there is insufficient evidence about their efficacy and they can induce serious adverse drug reactions. Atropinic risk scales were developed to help to identify atropinic drugs in prescription forms and to evaluate their burden in clinical practice. In the present review, we discuss the few studies investigating atropinic burden in PD and present the results of our study indicating that atropinic drugs are still widely prescribed in PD (almost 3 of 5 prescriptions) with a clinically significant atropinic burden in around 1 of 6 PD patients. Drugs mainly responsible for high values of atropinic burden were those used for nonmotor symptoms. Clinically significant atropinic burdens were mainly induced by associations of several "low-risk" drugs. Physicians must be aware that in addition to classical atropinic antiparkinsonian drugs, many others (psychotropics) can contribute to increased atropinic burden in PD patients. © 2016 International Parkinson and Movement Disorder Society.

Exposure to atropinic drugs and frailty status.

BACKGROUND: Atropinic drugs can increase the risk of falls, cognitive impairment, and mortality in older patients; however, whether exposure to atropinic drugs is associated with frailty status remains unknown. Our aim was to assess the association between frailty status and exposure to atropinic drugs in a geriatric day hospital population. METHODS: We carried out a cross-sectional study that included all the patients consulting for the first time at the Geriatric Frailty Clinic for Assessment of Frailty and Prevention of Disability in Toulouse, France, from January 2013 to October 2013. Frailty was defined by 3 or more of Fried et al's criteria. Atropinic drugs were those with clinical antimuscarinic effect from the Anticholinergic Drug Scale (excluding drugs weighted 1 point and not listed by Durán et al) and from Laroche et al list (to include drugs marketed in France not present in the Anticholinergic Drug Scale). To explore a dose-effect relationship, we calculated the atropinic burden using the Anticholinergic Drug Scale weights. We performed logistic regression models adjusted for age, gender, comorbidities, being community dwelling or not, cognitive status, educational level, and polypharmacy (≥6 drugs). RESULTS: We included 437 patients (227 frail and 210 robust or prefrail). Exposure to at least one atropinic drug was associated with frailty (odds ratio 1.97, 95% confidence interval 1.10-3.53, P = .02). Due to a statistically significant interaction between age and atropinic burden, a dose-effect relationship for atropinic burden was explored in patients younger than 85 years, showing a significant association between atropinic burden score and frailty (P = .01). The Odds ratio for an atropinic burden greater than or equal to 3 versus 0 was 3.84, 95% confidence interval 1.43-10.34 (P < .01). CONCLUSIONS: In a geriatric day hospital, population frailty is associated with a high atropinic burden.