Vanessa Rousseau

Analysis of chats on French internet forums about drugs and pregnancy

Some pregnant women use the internet to search for medical information. However, online information is not controlled. The objectives were to describe French online chats about drugs and pregnancy and evaluate the quality and reliability of information shared by internet users.

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.

Tumor necrosis factor inhibitors added to nonbiological immunosuppressants vs. nonbiological immunosuppressants alone: a different signal of cancer risk according to the condition. A disproportionality analysis in a nationwide pharmacovigilance database

We aimed at detecting a signal of an increased risk of cancer in patients treated with TNF inhibitor (TNFi) and nonbiological immunosuppressant (NBIS), compared with NBIS alone for autoimmune diseases. Secondly, we aimed at comparing this risk between the different TNFis. We conducted a disproportionality analysis (case/noncase study) from the French National PharmacoVigilance Database. We selected all the reports of serious adverse drug reactions from 2000 to 2010 in patients treated with NBIS for labeled indications of TNFi. Cases were all the reports of cancer that occurred after a minimal 3‐month exposure to NBIS. Noncases were all the other reports. We searched for exposure to TNFi and calculated reporting odds ratios (RORs), stratified by condition and type of cancer and adjusted by age, gender, history of cancer, type of NBIS and year of reporting. Of the 1918 reports included in the study population, 217 were cases (135 solid and 82 blood cancers). A safety signal was found in rheumatoid arthritis (RA) (ROR: 5.43, 95% CI[3.52–8.38]) particularly for nonmelanoma skin cancer (NMSC) (20.17[2.49–163.36]), and in psoriasis/psoriatic arthritis (3.45[1.09–10.92]). No signal was found in inflammatory bowel diseases (IBD) and ankylosing spondylitis, whatever the type of cancer. There was no difference between TNFis. This study puts the argument of an increased risk of cancer (particularly NMSC) in patients with rheumatoid arthritis exposed to TNFi and NBIS compared with NBIS alone, but not in IBD and ankylosing spondylitis patients. No signal was detected for melanoma potentially related to the lack of power. The signal seems similar whatever the TNFi.

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

Atropinic (Anticholinergic) Burden in Parkinson's Disease

Use of atropinic drugs remains controversial in Parkinsons 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.

Drug–drug interactions with imatinib: An observational study

AbstractMany patients treated with imatinib, used in cancer treatment, are using several other drugs that could interact with imatinib. Our aim was to study all the drug–drug interactions (DDIs) observed in patients treated with imatinib.We performed 2 observational studies, between the 1st January 2012 and the 31st August 2015 in the Midi-Pyrénées area (South Western France), using the French health insurance reimbursement database and then the French Pharmacovigilance Database (FPVD).A total of 544 patients received at least 1 reimbursement for imatinib. Among them, 486 (89.3%) had at least 1 drug that could potentially interact with imatinib. Paracetamol was the most frequent drug involved (77.4%). Proton pump inhibitors, dexamethasone and levothyroxine, were found in >10% of patients. In the FPVD, among a total of 25 reports of ADRs with imatinib recorded in the Midi-Pyrénées area, 10 (40%) had potential DDIs with imatinib. Imatinib was most frequently prescribed by hospital physicians and drugs interacting with imatinib, by general practitioners.Our study showed that at least 40% of the patients treated with imatinib were at risk of DDIs and that all prescribers must be cautious with DDIs in patients treated with imatinib. During imatinib treatment, we particularly recommend to limit the dose of paracetamol at 1300 mg per day, to avoid the use of dexamethasone, and to double the dose of levothyroxine.

Statins and diabetes: is there any difference between the different statins?

We read with great interest the paper from Thakker et al 1 discussing the risk of developing diabetes during statin exposure. After a systematic literature review and network meta‐analysis of 29 randomized trials including 163,039 participants, the authors found a significant association for statins in general, atorvastatin or rosuvastatin in particular, but not with other statins. 1 Since these results were obtained from clinical trials, we decided to investigate this safety signal in real conditions of life, using reports of adverse drug reactions (ADRs) in a pharmacovigilance database. Using Vigibase®, the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database , which included until March 2017 over 14 million reports, we performed a disproportionality analysis for the signal of diabetes with statins using the case/noncase method. ICSRs were included until March 16, 2017, whatever the country of origin and only if age (≥18 y) and gender were known. Doses were not taken into account since they are not exhaustively recorded in Vigibase®. Cases were ICSRs with diabetes and noncases all other ICSRs reports registered during the same period in Vigibase®. Diabetes cases were defined as reports registered under the 2 HLT MedDRA terms “diabetes mellitus” or “hyperglycemic conditions” in the SOC (system organ class) “Metabolism and Nutrition Disorders.” Drug exposure to statins was identified using Anatomical Therapeutic and Clinical (ATC) code C10AA (HMG CoA reductase inhibitors defined as “suspected” or “concomitant”). Statins included were atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin (alias itavastatin), pravastatin, rosuvastatin, and simvastatin. Strength of the link between exposure to statins

Risk of diabetes with fibrates and statins: a pharmacoepidemiological study in VigiBase®

In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase®. We included all reports registered until the 31st December 2017 in VigiBase® to measure the risk of reporting ‘hyperglycemia or new onset of diabetes’ (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin–fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug–drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72–1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71–0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28–1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin–fibrate DDI.

Vomiting and constipation associated with tramadol and codeine: a comparative study in VigiBase®

The most frequent adverse drug reactions (ADRs) of codeine and tramadol, the two main step 2 opioid analgesics, include nausea, dizziness, sedation, vomiting, and constipation [1]. The relative importance of vomiting and constipation remains discussed [1–3]. We performed a comparative analysis of ADRs in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database [4]. We used the disproportionality method [5, 6] including reports (age ≥ 18 years and gender known) registered from 1969 to 7 October 2017 under the MedDRA preferred terms Bvomiting^ or Bconstipation^. Drug exposure was identified using the anatomical therapeutic and clinical codes N02AX and N02AA, with drugs defined as Bsuspected^ or Bconcomitant^ [7, 8]. Associations of codeine or tramadol with antispasmodics (N02AG), other drugs (caffeine, barbiturates...) as well as the use of codeine + tramadol simultaneously were not included in the study. A sensitivity analysis compared tramadol + paracetamol (N02AJ) versus codeine + paracetamol. Strength of the association was quantified by reporting odds ratios (ROR) with their 95% confidence interval. Among the 10,265,261 ICSRs, 224,788 were included, 74.8% with tramadol [19.2% with paracetamol] and 25.2% with codeine [66.6%with paracetamol].Mean age (56.3 years) and sex ratio (64.4%women) were similar. Vomiting and constipation were more frequently reported with tramadol than with codeine. The sensitivity analysis including the association with paracetamol found similar trends (Table 1). Although the two drugs are structurally related (tramadol is a synthetic codeine analog) [1], we described differences in reports of vomiting and constipation. There are very few published clinical data. For vomiting, a meta-analysis of 3453 postoperative patients [9] and a 4-week randomized trial [10] failed to find any difference. In contrast, Rodriguez found a higher rate of vomiting with tramadol in a double-blind trial with 177 painful cancer patients [11] and Zavareh a three times higher value on a visual analog score for vomiting with tramadol following cholecystectomy [12]. Mullican [10] and Duthie [13, 14] reported more constipation with codeine. The major strength of our work is its high power, due to the number of ICSRs. In order to minimize a putative indication bias, frequent in such studies [6, 15], we compared two drugs used in similar indications. The main limitation of the paper is underreporting, like in each pharmacovigilance study. However, underreporting does not modify results of case non-case studies, since ADRs underreporting is similar inside a same pharmacotherapeutic class, allowing direct comparisons [16]. For these dose-dependent ADRs, doses were not included since they are not systematically recorded in VigiBase®. The results could have two explanations. First, a difference in the pharmacodynamic characteristics of the two drugs [1]. Tramadol is, first, a mu agonist and, second, an inhibitor of serotonin reuptake whereas codeine only stimulates mu opioid receptors. Activation of bothmu and serotonin receptors in the chemoreceptor trigger zone by tramadol can explain the differences with codeine. Opioid-induced constipation is a multifactorial process explained by a decrease in both gastrointestinal motility and gastrointestinal secretions. The second and probably more relevant explanation could involve both a * Jean-Louis Montastruc jean-louis.montastruc@univ-tlse3.fr