François Montastruc

Cancer Risk of Anti-TNF-α at Recommended Doses in Adult Rheumatoid Arthritis: A Meta-Analysis with Intention to Treat and per Protocol Analyses

Background The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown. Methodology/Principal Findings Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59–1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82–1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71–2.66] and 1.90 [0.98–3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97–2.64] and 1.22 [0.72–2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs. Conclusions/Significance This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.

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 als 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.

Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems.

Abstract Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4–9.7)], France (ROR, 2.4 [95% CI, 1.5–3.7]), and Italy (ROR, 5.1 [95% CI, 1.7–14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase.

Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase(®), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase(®) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase(®). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase(®) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics.

Risk of thrombosis in patients with primary immune thrombocytopenia and antiphospholipid antibodies: A systematic review and meta-analysis.

Antiphospholipid antibodies (aPL) are common in ITP, but their role for the occurrence of ITP-related thrombosis is controversial. We performed a systematic review and a meta-analysis to investigate the risk of thrombosis associated with lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2GP-I antibodies in primary ITP. The literature search was run on Medline, Cochrane and ISI Web of Science from January 1st 1980 to December 31st 2014. Unpublished studies were searched in meeting abstracts. The main analysis assessed the risk of all thromboses (arterial or venous) associated with the presence of LA, aCL or anti-β2GP-I antibodies. Random-effect models were used to calculate odds ratios (OR) and their 95% confidence intervals (CI). Searches in electronic databases retrieved 776 citations. Twelve additional studies from unpublished literature were added. Eventually, 10 cohort studies totalizing 1574 patients were included in the analysis. The pooled OR for the risk of all thromboses associated with LA was 6.11, 95% CI [3.40-10.99]; it was 2.14, 95% CI [1.11-4.12] with aCL. The ORs were similar when stratifying on the type of thrombosis (arterial vs. venous). Only two studies assessed the risk of thrombosis associated with anti-β2GP-I antibody positivity; consequently, no pooled OR was computed for these antibodies. This meta-analysis highly suggests that LA positivity, and to a less extent aCL antibodies, are associated with an enhanced risk of thrombosis in primary ITP patients. Further prospective studies are needed to identify the factors associated with the risk of thrombosis among LA patients before assessing prevention strategies.

Effets indésirables « graves » du tramadol : bilan 2010-2011 de pharmacovigilance en France

OBJECTIVE Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency. METHODS All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed. RESULTS During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled » SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis. CONCLUSION This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia.

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

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.

Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics

AIMS The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase®). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF. RESULTS A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase® for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively. CONCLUSION We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs.

Psychomotor developmental effects of prenatal exposure to psychotropic drugs: a study in EFEMERIS database.

Little is known about neurodevelopment of children exposed to psychotropic drugs during pregnancy. The purpose of this study was to evaluate the effects of prenatal exposure to psychotropic drugs on psychomotor development in children. This observational study used the EFEMERIS database. The database records the drugs prescribed and delivered during pregnancy and the resulting outcomes. Neurodevelopment at nine and 24 months of children born to women exposed to psychotropic drugs (anxiolytics, antidepressants, neuroleptics and anti‐epileptics) during the second and/or third trimesters of pregnancy was compared to children who were not exposed to these drugs. Psychomotor development of 493 children (1.5%) exposed to psychotropic drugs during pregnancy was compared to 32 303 unexposed children. Exposure to psychotropic drugs during pregnancy was associated with an increased risk of abnormal motor development at 9 months (OR = 1.3 [1.1–2.2]) and abnormal motor and mental development at 24 months (OR = 4.8 [2.1–11.0] and OR = 2.3 [1.05–4.9]). Increased risk was observed in children born to women exposed to anti‐epileptic drugs, neuroleptics or antidepressants during pregnancy. This study found a higher rate of deviation from the normal developmental milestones in children born to women exposed to psychotropic drugs during pregnancy and more particularly antidepressants, neuroleptics and anti‐epileptics.

Atropinic burden of prescription forms in France: a study in community pharmacies in 2013

Dear Editor, Atropinic drugs can lead to serious adverse drug reactions (ADRs) [1, 2]. Their use is associated to increased mortality, mainly in elderly [3]. Lists of atropinics were built, allowing investigation of different populations. Most of the studies were performed in elderly people, but few data relate to general population. The present work evaluates atropinic burden (AB) in community pharmacy. The study was performed in a community pharmacy in Midi-Pyrénées region (southwestern France) between 28 January and 6 April 2013. All first prescription forms (PFs) were analyzed using Anticholinergic Drug Scale (ADS) [1] which classifies drugs according to three levels [0 (no atropinic activity) to 3 (major atropinic activity)]. AB was defined as the sum of each value for the drugs of the investigated PF. Data were analyzed with 9.3 SAS version using Z, ANOVA F, and Pearson tests. (mainly oxomemazine, hydroxyzine, amitriptyline). The mean number of atropinics by PF was 1.3±0.6 (range 1–5), with 147 (16.4 %) including at least one drug from level 3. The mean AB was 3.5±2.1 for psychiatrists and 1.8±1.2 for GP showing a significant association (p<0.0001) between AB and specialty. There was no association with age, gender, place of practitioner work or the number of drugs. ADS was chosen since it is applicable in clinical practice and a good predictor of peripheral atropinic ADRs. Duráns [2] list was not used since it was not published at the time of the study. After exclusion of level 1 (i.e. drugs with only in vitro binding properties on muscarinic receptor) [1], the values were 304 (9.6 %) atropinics and 367 (13.0 %) PFs. Thus, the main result of our study is that, in general population , around one PF out of ten included at least one atropinic drug with clinically significant properties. From a methodological point of view, one could discuss the size and the representativeness of the sample. The number of PF included is significant, and data (not shown) indicate that the community pharmacy was representative. Self-medication was not investigated which could have led to underestimations. This work confirms the interest of community pharmacies to perform pharmacoepidemiological studies. In conclusion, the present work found a high level of prescription of atropinic drugs in general population (around one