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Aim: The present study investigated the risk of bleeding when antidepressants are added to antithrombotics., Methods: Using data registered in VigiBase ® , the WHO pharmacovigilance database, between 01/01/2000 and 31/12/2022, we compared the risk of reporting "serious" bleeding (Reporting Odds Ratio, ROR) with antidepressants + antithrombotics versus antithrombotics alone., Results: Increased values of ROR were found for the association Serotonin Reuptake Inhibitors (SRIs) + Direct Oral Anticoagulants (DOACs) versus DOACs alone (ROR=1.49(1.17-1.89)). Similar results were found for Factor Xa inhibitors or Thrombin inhibitors. This association was also found for other antithrombotics: Vitamin K Antagonists (ROR=1.37(1.12-1.68)), Platelet Aggregation Inhibitors PAIs (ROR=1.38(1.21-1.57)) and Heparins (2.04(1.59-2.62)) but not with other antidepressants (Non-Selective Monoamine Reuptake Inhibitors, NSMRIs)., Conclusion: The present study suggests an increased risk of "serious" bleeding when SRIs (but not NSMRIs) are associated with antithrombotics (all antithrombotics and not only DOACs)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH., Methods: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs., Results: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x - 2.55, R 2 = 0.68, Pearson coefficient correlation = 0.82)., Conclusion: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Introduction: Paradoxical adverse drug reactions (ADRs) are defined as being opposing reactions to the pharmacological effect of drugs in relation to its pharmacodynamic properties. Their diagnosis is difficult as they are relatively rare with atypical clinical presentation (with the possibility of being confused with drug ineffectiveness or the worsening of the underlying disease). This kind of ADR may be particularly subject to under-notification. The aim of the present study is to describe paradoxical ADRs using the French PharmacoVigilance DataBase (FPVDB)., Method: We analysed all reports recorded in the FPVDB with drugs defined as "suspect" and which included the term "paradoxical reaction" (PR) (according to MedDRA classification) from 01/01/1984 to 12/31/2018. The drugs were classified according to the Chemical Therapeutic Anatomical Classification (ATC)., Results: We found 57 reports of PR, with half of them recorded between 2015 and 2018. The median age of patients was 46 years, mainly male (54%). The most frequently involved drugs were immunomodulating agents (n = 28, 49%) and psychotropics (n = 28, 49%). The leading paradoxical ADRs were psychiatric (anxiety, sleep and behavioural disorders) and skin-related. In 19 cases (33%), PR was related to benzodiazepines mainly occurring in patients in extreme ages (five cases in children and patients > 70, respectively, 53%). For psychotropic-induced PR (n = 28), known contributory factors (alcohol consumption, underlying psychiatric diseases) were found in 18 cases (64%). Paradoxical reactions with immunomodulating agents were mainly related to skin ADRs (n = 25). For psychotropics, paradoxical ADRs occurred rapidly after a mean delay of 1 day, predominantly following high doses. We also identified several "unexpected" paradoxical reactions, such as cognitive degradation with donepezil, or a return to impulsive smoking addiction with varenicline., Conclusion: This study highlights that pharmacovigilance databases like the French database make it possible to investigate the main characteristics of paradoxical reactions to drugs. This ADR was mainly found in the FPVDB with psychotropic drugs and immunomodulating agents. Moreover, pharmacovigilance databases enable the identification of some signs of "unexpected paradoxical reactions". In order to identify this type of ADR more effectively, work on awareness and harmonization is required to register these reports. The addition of the term "paradoxical reaction to the drug" to the list of other symptoms would facilitate their identification and analysis.

Introduction: Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia., Purpose: The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases., Methods: Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded., Results: A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis., Conclusion: Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

Purpose: With increasing age, adults are often exposed to anticholinergic drugs and are prone to potential adverse drug reaction, among which cognitive impairment. If the short-term cognitive effects of anticholinergic drugs are well established, their long-term cognitive effects have less been studied., Objective: To provide a systematic review of longitudinal studies which assessed the effect of anticholinergic exposure on cognition in individuals over 50 years., Materials: We searched the MEDLINE database for studies with a minimal 6-month follow-up, assessing anticholinergic exposure through a biological measure or a clinical list and reporting at least one cognitive outcome. We used the modified Newcastle-Ottawa scale and additional criteria regarding the anticholinergic exposure to assess studies' methodological quality. Given the heterogeneity of the studies, we performed a systematic review., Results: Among the 1574 references retrieved, 25 studies were included. Anticholinergic medications were mostly defined through the Anticholinergic Cognitive Burden Scale (n = 14/25). Six studies evaluated baseline drug collection, 14 used longitudinal aggregated measure, and 5 multiple drug exposure measures over time. Seventeen studies assessed anticholinergic burden. Cognitive function was assessed by mild cognitive impairment/dementia incidence (n = 15) or neuropsychological tests (n = 14). Most studies were of poor quality and retrieved discordant results. However, studies with good quality (n = 4) suggested a relationship between anticholinergic drug exposure and/or burden and cognitive function., Conclusion: Our review suggests a deleterious effect of anticholinergic exposure on mid/long-term cognitive function but should be confirmed in studies with improved methodology. Meanwhile, prescription of anticholinergic drugs should remain cautious.

Introduction: Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase ® , the World Health Organization Global Individual Case Safety Report (ICSR) database., Methods: In VigiBase ® , we performed a case/non-case study using data registered from 1981 (spironolactone's marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting "Breast malignant tumors" compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals., Results: During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52-0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44-0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals., Conclusion: This study did not find evidence for breast cancer associated with spironolactone.

Background: Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure., Objectives: To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018., Methods: Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors., Results: During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46)., Conclusion: This study did not find evidence for Parkinsonism associated with tamoxifen.

Aim: The aim of our study was to study the pattern of prescription of direct-acting oral anticoagulants (DOACs) according to the French recommendations., Methods: We performed a cross-sectional study using anonymous data of patients covered by the French National Health Insurance information system (SNIIRAM) from 1 January 2010 to 31 December 2013 in the area of Midi-Pyrénées (southwest of France)., Results: Of the 355,608 patients identified, 325,216 (91.5%) were included, of whom 22,142 received at least one DOAC. About 39.1% (8,652 patients) had DOAC in an orthopedic indication, 46.5% (10,303 patients) in a cardiac indication, and 16.1% (3568 patients) in an indeterminate indication. Overall, guidelines were largely followed as for renal function monitoring, prescribing in orthopedic indications, in cardiac indications in patients aged 80 years and older, and in the case of concomitant use of verapamil. However, inappropriate prescriptions were observed for cardiac indications, and for dosage adjustments in orthopedic indications, with respect to both the age of patients (75 years and older) and those taking verapamil or amiodarone concomitantly. Guidelines were more followed in women and patients aged 80 or more., Conclusions: Among patients receiving DOACs, 58% were exposed to a prescription falling outside the guidelines. This study on DOAC prescription patterns revealed insufficiencies in the compliance with the French guidelines in certain indications.

Purpose: The purpose of this study was to measure the rate of substitution failure to generic antiepileptic drugs (AEDs) compared to two other pharmacotherapeutic classes (neuroleptics, beta-blockers)., Methods: We conducted a cohort study involving beneficiaries of the French health insurance system from January 2009 to November 2012. Substitution failure to generic drugs was estimated by the rate of switchback (i.e. from generic drug back to its branded drug). We selected the patients who had a dispensation of a branded AED for 60 days or more during the 90 days preceding the generic substitution. Cox proportional hazard regression was used to model time to switchback for antiepileptics vs. other therapeutic classes in the 90 days after generic substitution, adjusting for age, gender and polytherapy., Results: The cohort included 6727 patients of whom 1947 were exposed to AEDs, 2398 to neuroleptics and 2382 to beta-blockers. The switchback rate was 62% for AEDs. AED users were more likely to switch back as compared to beta-blocker (crude hazard ratio 1.87; 95% CI 1.68-2.07 for patients under 75) or neuroleptic users. The same observation was made in patients above 75 years (crude hazard ratio 1.36; 95% CI 1.16-1.60)., Conclusions: Compared to beta-blocker users, AED users were more likely to switch back to the branded drug, whereas this difference was not observed with neuroleptics. These results could reflect a poor acceptance of switching AEDs to generic compounds in France.

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.

Context: Adverse drug reactions (ADRs) are responsible for 5 % of hospital admissions, but hospital re-admission induced by ADRs remains poorly documented., Objective: The aim of this study was to estimate the rate of hospital re-admission and the factors associated with re-admission in the patients over the age of 65 years. Secondary, we described the characteristics of cases of ADRs leading to re-admission for drugs other than chemotherapy agents., Methods: Data were extracted from hospital discharge summaries provided by the Department of Medical Information of Toulouse University Hospital. All patients over the age of 65 years admitted to the hospital in 2010 for an ADR, identified from ICD-10 codes, were selected. All subsequent admissions of members of this cohort within 1 year of discharge following the index admission were reviewed retrospectively. The risk factors associated with hospital re-admission for ADRs were analyzed. Medical records were used for descriptive analysis of re-admission due to drugs other than chemotherapy agents., Results: We found that 553 of the 1000 patients admitted for ADRs in 2010 were re-admitted to hospital within 1 year. Among them, 87 cases were re-admitted for ADRs (estimated rate of 87/1000 re-admission for an ADR within 1 year). A comparison of the patients re-admitted for ADRs (n = 87) with those of patients re-admitted for other causes (n = 410) suggested that only cancer increased the risk of re-admission for ADRs (OR = 7.69 [4.59-12.88] 95 % CI). ADRs due to the same drug combination were the suspected cause of repeat admission in half the cases (other than chemotherapy). Hospital re-admission was considered avoidable in four cases (22 %)., Conclusion: This study shows an estimated rate of re-admission for an ADR around 87/1000 within 1 year, and the same drug combination were the suspected cause of repeat admission in half the cases. At least, 11 % of cases were avoidable.

Aim: Atropinic drugs in patients with Alzheimer disease (AD) can decrease the effects of anticholinesterase drugs and/or induce adverse drug reactions (ADRs). Several atropinic risk scales defining an atropinic burden of drugs were proposed but were little used in AD patients., Methods: All ADRs' notifications of AD patients registered in the Midi-Pyrénées PharmacoVigilance Database between 1999 and 2013 were analyzed using Anticholinergic Drug Scale (ADS) and Anticholinergic Duran's list. The primary objective was to quantify atropinic burden in AD patients and the secondary one to investigate associated factors., Results: Among the 475 notifications, at least one atropinic drug was found in 282 notifications (59.4%) according to ADS and 214 (45.1%) according to Duran. Mean number of atropinics per notifications was 0.9 ± 0.9 (ADS) and 0.7 ± 0.9 (Duran). Mean atropinic burden per notifications was 1.2 ± 1.5 (ADS) and 0.9 ± 1.3 (Duran). Atropinic burden ≥ 3 was found in 87 notifications (18.2%) according to ADS and 50 (10.5%) according to Duran. There was no association between atropinic burden and age of patients. The number of drugs is associated to a high atropinic burden., Conclusion: The present work found an association between an atropinic drug and an anticholinesterase agent in around 1 out of 2 AD patients and a clinically significant atropinic burden (≥ 3) in around 1 to 2 AD patients out of 10. The benefit harm balance of atropinic drugs must be discussed before each prescription in AD patients.

Purpose: The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Médicalisation des Systèmes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre., Methods: The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs., Results: During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4 %) and central (11.3 %) ADRs in PMSI database versus cutaneous (22.4 %) and general (17.5 %) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1 %) in PMSI database versus anti-infectives (38.2 %) in FPVDB. The estimated number of ADRs was 717 [95 % confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6 % (95 % CI 0.4, 0.8)., Conclusions: Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.

Purpose: Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs., Methods: The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated., Results: Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a 'certain' causality score (I4) and 13 (7.5 %) a 'likely' score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded., Conclusion: This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.

Background: Lists of potentially inappropriate medications (PIM) in the elderly were developed in order to identify patients and/or drugs at risk of adverse drug reactions (ADRs) or inefficacy. However, the relationship between PIMs and ADRs remains discussed. We hypothesized that PIM use is associated with more ADRs than other prescriptions., Methods: All ADRs registered by the Midi-Pyrénées PharmacoVigilance Center between the 1st January and the 30th June 2012 in patients ≥75 years were included. Data on patients (age, gender, Charlson comorbidity index), drugs (number, ATC classification, Laroche PIM classification) and ADRs (type, seriousness, mechanisms) were analyzed., Results: Among the 923 ADRs recorded, 272 (29.5%) were in patients ≥75 years. Mean age was 83.5 ± 5.5 years. Most of them (59%) were females. Mean Charlson index was 5.6 ± 2.0 by ADR report. These 272 prescriptions involved 1,775 drugs [mean value, 6.5 (±3.4) drugs by ADR report] with 129 (7.3%) PIM. Main PIM classes were nervous (n = 98, 76.0%) and cardiovascular (17.8%) drugs, including 32 atropinics (23.4%). ADR-associated drugs were mainly antithrombotics, antibacterials, and analgesics for non-PIM drugs whereas PIM-associated ADRs were mainly observed with digoxine, psycholeptics, and psychoanaleptics. ADRs were mainly found with non-PIM drugs (89.3%). Associated factors were the number of drugs for PIMs and the number of PIMs for PIM-induced ADRs., Conclusion: Out of the ADR reports registered in the Midi-Pyrénées PharmacoVigilance Database for patients ≥75 years, 1 drug out of 12 is potentially inappropriate (mainly benzodiazepines, imipraminic antidepressants, and atropinic drugs). PIM use is not associated with more ADRs' reports than other prescriptions.

Purpose: The purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre., Methods: A prospective, observational, monocentric clinical study performed over a 2-year period (2011-2012) in a French prehospital emergency dispatching centre, the Service d'Aide Médicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (age≥18) who called for any cause were included. We created an electronic trigger 'iatrogenic event' implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1% of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment., Results: The SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95% (CI 95% 0.90-1.00%) of cases. ADRs were as serious (SADR) in 51.06% (CI 95% 48.45-53.67%) of cases. The major ADR observed was haemorrhage, (42.81% (CI 95% 40.62-45.00%), n=628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69% (CI 95% 41.45-45.93%), n=641), followed by insulin (17.98% (CI 95%:17.06-18.90%), n=264)., Conclusions: Emergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious.

Thalidomide and lenalidomide are structural analogs and immunomodulatory drugs. Lenalidomide appears to have a different safety profile than thalidomide and could be less toxic, and as far as we know, we did not found any study comparing their safety profile. The objective of our study was to review and compare serious adverse drug reactions (SADRs) of thalidomide and lenalidomide spontaneously reported to the French Pharmacovigilance database. We extracted all medically confirmed spontaneous reports of SADR for lenalidomide-based regimens and thalidomide-based regimens from the French Pharmacovigilance database. A "serious" adverse drug reaction (ADR) was defined as an ADR that is fatal or life threatening, which causes hospitalization or prolongation of hospitalization, or permanent or significant disability. The study period was between marketing of 2 drugs and January 15, 2012. A total of 392 SADRs related to thalidomide-based regimens were identified in 244 patients and 377 SADRs related to lenalidomide-based regimens in 220 patients. In spite of their structural analogy, this study highlights interesting differences between lenalidomide and thalidomide's safety profile: nervous system and vascular disorders are more frequent with thalidomide-based regimens while hematologic, skin, infectious disorders and secondary primary cancers are more frequent with lenalidomide-based regimens.

Purpose: Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not., Methods: We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010., Results: Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand-foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6 ± 15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib., Conclusion: Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors.

Objective: Few studies have investigated potentially inappropriate medication (PIM) use in patients with Alzheimer's disease (AD). The aim of our study was to assess the prevalence of PIM in community-dwelling patients diagnosed with mild-to-moderate AD and identify the clinical factors associated with PIM prescriptions., Methods: REAL.FR is a 4-year, prospective, multicenter French cohort of AD patients recruited in centers of expertise. We analyzed patient baseline data at entry into the study. PIMs were assessed using the Laroche list. A multivariate logistic regression was conducted to assess factors associated with PIMs., Results: A total of 684 AD patients were enrolled in the study [mean age 77.9 ± 6.8 years, 486 (71.0 %) females]. According to the Laroche list, 46.8 % [95 % confidence interval (CI) 43.0-50.5 %] of the patients had at least one PIM. "Cerebral vasodilators" were the most widely used class of PIM, accounting for 24.0 % (95 % CI 20.9-27.3 %) of all prescriptions, followed by atropinic drugs (17.0 %, 95 % CI 14.1-19.8 %) and long half-life benzodiazepines (8.5 %, 95 % CI 6.4-10.6 %). Atropinic drugs were associated with cholinesterase inhibitors in 16 % of patients. In the multivariate analysis, only two factors, namely, female gender [odds ratio (OR) 1.5, 95 % CI 1.1-2.2] and polypharmacy (≥5 drugs; OR 3.6, 95 % CI 2.6-4.5) were associated with prescriptions for PIMs., Conclusions: These results reveal that approximately one out of two community-dwelling patients with mild-to-moderate AD treated by AD specialists use PIMs. They also indicate that the characteristics of the disease and the pharmacodynamic/pharmacokinetic profile of the drugs prescribed are not sufficiently taken into account by physicians when prescribing for AD patients.

Objective: Our aim was to characterize Adverse Drug Reactions (ADRs) related to drug-drug interactions (DDIs) related to involvement of cytochrome P450 (CYP450) isoenzymes in a pharmacovigilance database., Methods: ADRs recorded by Midi-Pyrénées PharmacoVigilance center (France) between 1 January and 31 August 2008 were extracted from the French PharmacoVigilance Database (FPVD)., Results: Among the 1,205 reported ADRs, 16 (1.3 %), can be explained by involvement of CYP450 isoenzymes (including 4 "serious"). All interactions involved CYP inhibitors, mainly for CYP3A4/5., Conclusion: The percentage of ADRs reported in the pharmacovigilance database and related to CYP450-induced DDIs appears to be relatively low (~ 1-2 %).

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.

Aim: The aim of the present study was to investigate bleeding adverse drug reactions (ADRs) in patients exposed to serotonin reuptake inhibitors (SRI) plus antiplatelet agents using the French Pharmacovigilance Database (FPVDB) regarding the controversial data in the literature., Methods: The case/non-case method was used to measure the association between bleedings and exposure to SRIs plus antiplatelet agents versus antiplatelet drugs alone., Results: Over 3 years, a total of 1,977 spontaneous reports of ADRs were collected with antiplatelet drugs, and antiplatelet agents plus SRIs in patients aged over 50 years, of which 1,331 (67.3 %) concerned bleeding. Multivariate logistic regression analysis failed to show any significant association [adjusted ROR = 0.8 (0.5-1.2)]., Conclusion: The data did not demonstrate any significant association between bleeding ADRs and exposure to SRI + antiplatelet agents versus antiplatelets alone. Considering other conflicting results, this risk should be kept in mind by physicians when treating patients with several risk factors.

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.

Background: Underreporting of adverse drug reactions is common but has been rarely studied in Parkinson's disease (PD)., Objective: To compare the prevalence of adverse events (AEs) in relation to antiparkinsonian drugs in PD patients using two different data collection methods: patient's spontaneous reporting versus a predefined investigator-driven structured interview. Secondary objectives were to assess factors related to spontaneous reporting and to compare the rate of AE reporting in PD patients with that of a group of non-parkinsonian post-stroke patients., Study Design: Cross-sectional study., Patients: Ambulatory, cognitively intact PD or post-stroke outpatients., Interventions: None., Outcome Measures: Patients were first asked by means of an an open question to disclose any unpleasant effects in connection with their current medications that had occurred during the previous week. Afterwards, a predefined questionnaire listing the most common AEs known to be related to antiparkinsonian drugs was used to question the same patients in a systematic manner about the presence of any AE during the same week. Chronological and semiological criteria were used to classify the reported AEs as "unrelated" or "possibly/plausibly related" to the antiparkinsonian treatment., Results: A total of 203 PD and 52 post-stroke patients of comparable age and sex were recruited. Eighty-five PD and five post-stroke patients reported spontaneously at least one AE (42 vs. 10%, p < 0.01), while 203 PD and 47 post-stroke patients reported at least one AE following the structured questionnaire (100 vs. 90%, p < 0.001). In PD patients, there were a total of 112 spontaneously reported AEs as compared with 1,574 according to the structured questionnaire (7%). Spontaneous disclosure of AEs was associated with experiencing >2 AEs [OR = 1.2 (1.1-3.2)], logistic regression). Seventy-four percent of PD patients had ≥1 AE possibly/plausibly related to antiparkinsonian drugs., Conclusions: Results showed that only 7% of AEs were reported spontaneously by patients, thus underscoring the importance of systematically asking about AEs in PD patients.

Aim: Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD)., Methods: All reports of adverse drug reactions (ADR) recorded in the FPVD between 1 January 1985 and 31 July 2008 and including the terms aggressiveness or violence were selected. We compared proportion of exposure to different drugs between cases (reports with violence) and noncases (other reports in the database)., Results: Among 537 cases, 56 were included (48 men, mean age 46 years). Misuse was observed in ten cases (18%). In 25 cases (44.6%), a previous psychiatric history was documented. Main drugs involved were nervous system (63.6%) followed by respiratory (7.8%), alimentary tract and metabolism (7.8%), dermatological (5.2%) and anti-infective (5.2%) agents. Case/noncase analysis found an association with dopaminergic agonists (pergolide, pramipexole, bromocriptine, piribedil), benzodiazepines (alprazolam, bromazepam) and serotoninergic antidepressants (taken as a whole), but not antipsychotics or antiepileptics. Association was also found with varenicline, isotretinoin, interferon alpha-2b, rimonabant, benfluorex, topiramate and antiviral drugs (ribavirin, efavirenz)., Conclusion: Dopaminergic agonists, benzodiazepines and serotoninergic antidepressants are the main pharmacological classes able to induce aggressive behaviour. This study also emphasises the putative role of other drugs less known to be involved in such ADR.

Patients and Methods: In order to investigate the effects of exposure to buprenorphine compared with methadone during pregnancy, a prospective multicenter study was conducted in collaboration with maternity hospitals, maintenance therapy centers, and general practitioners involved in addiction care. Ninety pregnant women exposed to buprenorphine and 45 to metadone were selected for the study., Results: During pregnancy, some women were exposed to illicit agents: cannabis (42% in the buprenorphine group vs. 58% in the methadone-treated group), heroin (17% vs. 44%), or cocaine (3% vs. 11%). Pregnancies ended in 85 vs. 40 live births, one vs. two stillbirths, two vs. one spontaneous abortion, two vs. one voluntary termination, and one vs. one medical termination in the buprenorphine and the methadone groups, respectively. Newborns had a birth weight of 2,892 ± 506 g (buprenorphine) vs. 2,731 ± 634 g (methadone) and a body length of 47.6 ± 2.5 cm vs. 47.1 ± 3 cm. 18.8% vs. 10% of newborns were delivered before 37 weeks of amenorrhea. Neonatal withdrawal syndrome occurred more frequently in the methadone group (62.5% vs. 41.2, p = 0.03). After adjustment for heroin exposure in late pregnancy, rates of neonatal withdrawal were no longer different between the methadone and buprenorphine groups. Twenty-one babies (84%) in the methadone group and 20 (57%) in the buprenorphine group (p = 0.03) required opiate treatment., Conclusions: We did not observe more frequent malformations or cases of withdrawal syndrome in the buprenorphine group than in the methadone-treated group. Buprenorphine appears to be as safe as the currently approved substitute methadone considered to date as the reference treatment for pregnant opioid-dependent women.

Background: Because of the limited data concerning drug risks in pregnancy, health professionals are often deprived of relevant and sufficient information related to prescribing or dispensing during pregnancy. However, previous studies have emphasised the widespread French prescription of several drugs (sometimes "typically French") which have not been assessed in pregnant women., Objectives: The aim of the present study was to create the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies., Methods: This feasibility study concerns pregnant women who gave birth to a baby between 1 July 2004 to 30 June 2005 in Haute-Garonne and who are registered in the French Health Insurance Service. Data sources include (1) the French Health Insurance Database (drugs prescribed during pregnancy), (2) the Mother and Child Protection Centre Database (newborn health at birth and 9 months after) and (3) the Antenatal Diagnostic Centre Database (medical pregnancy interruptions)., Results: The database is composed of 10,174 "mother-outcome" pairs. The prevalence rate of congenital anomalies was 2.2%. Pregnant women were prescribed 11.3 +/- 8.2 different drugs. Among the 20 most frequently prescribed drugs, around half of them have not been evaluated in pregnant women., Conclusions: The first results of this study show that implementation of a French database on prescription of drugs and pregnancy outcomes is feasible. Compared with several databases available in other countries, EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the baby 9 months after birth. Recording these data would make it possible to assess the risk of malformations due to a greater number of drugs and would contribute to international drug evaluation studies.