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Background: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. Objectives: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. Methods: A cross‐sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. Results: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. Conclusion: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies acting on the calcitonin gene‐related peptide or its receptor (CGRP‐mabs) are novel drugs for resistant migraine prophylaxis. As CGRP‐mabs cause inhibition of vasodilatation, their use is reserved to patients with no recent history of cardiovascular diseases. We report a case of myocardial infarction associated with erenumab. Case: A 57‐year‐old woman with a familial history of coronaropathy was first treated with erenumab 70 mg for 6 months and then increased to 140 mg. Almost 5 months after, the patient presented chest pain, increased troponin, and abnormal electrocardiogram. A myocardial infarction without coronarography abnormality was diagnosed through MRI. Conclusion: Further evidence is needed to assess the risk of myocardial infarction in patients treated with a CGRP‐mab. In patients over 40 years of age, the risk of coronary or cardiovascular events should be assessed using risk tables or algorithms to take into account cardiovascular risk factors. This may be complemented by appropriate examinations to measure the burden of coronary atherosclerosis, if necessary. [ABSTRACT FROM AUTHOR]

Owing to a broad spectrum and low cost antimicrobial, cotrimoxazole is largely prescribed. However, its use is associated with various adverse drug reactions (ADRs) that warrant to ensure rational prescribing. This study aimed to describe spontaneous reports of cotrimoxazole ADRs and to evaluate the quality of prescription in patients who had ADRs. Suspected cotrimoxazole‐induced ADRs cases reported to the Bordeaux regional pharmacovigilance center (France) during a 5‐year period were described. Seriousness was assessed according to international criteria. Quality of prescription was assessed by compliance with the Summary of Product Characteristics (SPC) and relevance of cotrimoxazole indication. Then, an ADR was considered as preventable if the cotrimoxazole indication was not relevant, or potentially preventable if indication was relevant but the prescription was not compliant with the SPC. A total of 96 cases were analyzed: median age was 60.5 years (range: 4–94); 59.4% of patients were male. ADRs were mostly cutaneous disorders (n = 46) and hematological disorders (n = 25). A total of 60 serious ADRs occurred in 55 patients. Prescribers complied with all SPC recommendations in 21.9% of cases. Indication of cotrimoxazole was relevant or highly relevant in 41 cases. In 58% of cases, the occurrence of a cotrimoxazole‐induced ADR would have been preventable or potentially preventable. In a context of increasing interest for this antibiotic to treat infections due to resistant bacteria, physicians should be more aware of the potential consequences of inappropriate prescribing cotrimoxazole and reserve its use when there is no alternative and under suitable monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Analgesics are among the most widely used drugs worldwide. This study describes the population treated with narcotic analgesics, their therapeutic indications and how the data have evolved over a decade. Methods: A cross-sectional, national, multicentre survey study was conducted that included surveys taken every year from 2007 to 2019 in a national sample of 1500 randomly selected dispensing pharmacies. Results: The mean age of patients, mostly women (around 60%), remained stable over the study period (63.2 ± 17.1 years in 2007, 68.2 ± 17.2 years in 2019). The proportion of patients treated for more than 3 months increased from 2007 to 2019. Most prescriptions involved morphine, oxycodone and fentanyl (98.5% of all prescriptions in 2019). Morphine prescriptions dropped dramatically from 49.6% (2007) to 32.3% (2019) of the total narcotic analgesics. Fentanyl prescriptions varied from 40.1% in 2007 to 32.2% in 2019. Prescriptions of oxycodone, regardless of the indication, increased steadily from 2007, from 8.3 to 34% in 2019, becoming the most prescribed narcotic analgesic for the first time since the beginning of the survey. Conclusions: This study demonstrates how narcotic opioids are prescribed, thanks to the active participation of health professionals, and confirms the striking increase in the prescription of oxycodone. [ABSTRACT FROM AUTHOR]

Aims: Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10‐year period through its prevalence. Methods: A cross‐sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed. Results: The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly. Conclusion: The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics. [ABSTRACT FROM AUTHOR]

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high‐risk myelodysplastic syndrome or low‐blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure. Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2‐sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re‐challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). Conclusion: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Introduction: Qualitative approaches based on drug causality assessment estimate the causal link between a drug and the occurrence of an adverse event from individual case safety reports. Quantitative approaches based on disproportionality analyses were developed subsequently to allow automated statistical signal detection from pharmacovigilance databases. This study assessed the potential value of causality assessment for automated safety signal detection. Methods: All drug–serious adverse event pairs with a positive rechallenge and a semiology suggestive of drug causality were identified in the French pharmacovigilance database (BNPV) from 2011 to 2017. The results were compared with those obtained from automated disproportionality analyses of the BNPV/World Health Organization (WHO) VigiBase®, complemented by the list of signals validated by the WHO-UMC (Uppsala Monitoring Centre). Summary of Product Characteristics (SmPCs), Martindale®, Meyler's® and MedLINE® were used as other sources of information for the purpose of comparison. Results: Of the 155 pairs of interest, 115 (74.2%) were also identified by another source of information. Since the individual case reporting in the BNPV, 23 (14.8%) of the adverse events (AEs) have been added to the SmPC, seven of which were not identified by disproportionality. Finally, 40 pairs were not identified by any other source of information, 13 of which were considered as potential new safety signals after analysis of case reports by pharmacovigilance experts. The signals identified by causality assessment involved antineoplastic and immunomodulatory drugs especially, in comparison with signals identified by WHO-UMC or by disproportionality within the BNPV. Conclusion: The approach therefore appears useful as an additional tool for safety signal detection, especially for antineoplastic and immunomodulating agents. [ABSTRACT FROM AUTHOR]

Background: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly.Objective: This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life.Patients and Methods: An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups.Results: There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Median age was 64 years (Inter Quartile Range = 56-71) and 15% of patients were aged ≥75; 57% were male. Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only.Conclusions: ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore, be treated with these targeted therapies. [ABSTRACT FROM AUTHOR]

Aims: In 2017, concerns regarding adverse events (AEs) associated with the Mirena levonorgestrel intrauterine device were largely echoed in the media in France. This resulted in a tremendous reporting of AEs to pharmacovigilance centres. The aim of this study was to describe the reporting of AEs regarding Mirena in France and to study the impact of media coverage on this reporting. Methods: All cases reports involving Mirena recorded in the French national pharmacovigilance database from marketing (21 July 1995) until 04 August 2017 were extracted. To allow studying the influence of mediatisation, reports were described separately for the periods preceding and following the observed media coverage peak (15 May 2017). Results: Overall, 3224 reports were considered, 510 (15.8%) recorded before the media coverage peak, and 2714 (84.2%) after. Before the peak, 76.5% of reports originated from health professionals; median time‐to‐report was of 5.5 months (interquartile range: 1.7–18.6), and median number of AEs per report was 1 (range: 1–17). After the peak, 98.6% originated from patients; median time‐to‐report was 21 months (interquartile range: 8.1–45.5), and median number of AEs per report was 6 (range: 1–37). After the peak, most reports mentioned anxio‐depressive disorders (38.8 vs 10.6% before) or sexual disorders (47.3 vs 6.9%). Other emphasised AEs were weight increase (42.3 vs 10.2%) and pain (gastrointestinal, 19.1 vs 3.5%; musculoskeletal, 22.2 vs 4.5%). Conclusion: This study highlighted the importance of mediatisation impact on spontaneous reporting with changes concerning amounts of reports, type of reporter, and type of reported AEs. For Mirena, this led to generate signals regarding anxio‐depressive and sexual disorders. [ABSTRACT FROM AUTHOR]

The article presents case of 64-year-old man treated with Continuous Positive Airway Pressure for obstructive sleep apnoea syndrome for six years and a case of 68-year-old man, with a history of myocardial infarction six months before, complained of dyspnoea, significant fatigue, and frequent awakenings during night. It discusses the need for clinicians to be aware of side effect of ticagrelor and search for central apnoeas in patients complaining from dyspnoea and fatigue during treatment.

Following a severe case of rhabdomyolysis in our University Hospital after a co‐administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long‐term treatment by fusidic acid. All cases of rhabdomyolysis during a co‐administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase®. In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co‐administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase®, 182 cases were retrieved; mean age was 68 years, median duration of co‐administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co‐administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient. [ABSTRACT FROM AUTHOR]

Objective: To assess the characteristics of life-threatening adverse drug reactions in patients admitted to medical intensive care unit and to define those that could facilitate early identification.Design: A prospective 6-month observational study.Patients: Of the 436 admissions to the teaching hospital medical intensive care unit, all patients aged over 15 years and who had received documented drug treatment were included (n = 405).Measurements: Characteristics of patients [age, gender, underlying diseases, organ failure(s), drugs taken, Severity Acute Physiologic Score II, length of stay, outcome at discharge] were prospectively collected using a standardised questionnaire. A panel of experts assessed putative serious adverse drug reaction(s) for each drug taken and each organ failure at admission by using a standardised causality assessment method. Characteristics of patients with and without serious adverse drug reactions at admission were compared using univariate and then stepwise descending multivariate logistic regression.Results: Of the 405 patients included, 111 (27.4%) presented an adverse drug reaction leading to organ failure. In 48% of cases adverse drug reactions were preventable, 23% were undiagnosed and 19% contributed to death. Age over 75 years [odds ratio (OR) 2.25; 95% confidence interval (CI) 1.15-4.38; p = 0.02], having more than three drugs (OR 6.90; 95% CI 1.44-33.00; p = 0.02) and a diagnosis of haematological malignancy (OR 6.19; 95% CI 2.07-18.53; p = 0.001) were independently associated with serious adverse drug reactions.Conclusions: Preventable life-threatening adverse drug reactions were frequently involved in organ failure at admission to medical intensive care; many of them had not been identified. [ABSTRACT FROM AUTHOR]

Background: The French pharmacovigilance system is based on a network of 31 regional centres located in teaching hospitals and coordinated by the French Medicines Agency ("Agence Française de Sécurité Sanitaire des Produits de Santé" [Afssaps]). Since 1984, they have shared a common database of adverse drug reactions (ADRs) that are spontaneously reported by healthcare professionals. The objective of this study is to describe the characteristics of the reports and the reporting trends in the French pharmacovigilance spontaneous reporting database from 1986 to 2001.Methods: All the reports from January 1986 to December 2001 were included. Drugs and ADRs were translated to anatomical therapeutic chemical (ATC) codes and MedDRA classifications, respectively.Results: The total number of reports was 197 580 over the 16-year period, with linearly increase over time. The median (interquartile range [IQR]) age of the patients was 53 (34-70) and the male/female ratio was 0.82. The median (IQR) time between the date of occurrence of the ADR and the date of report was 73 days (34-166). The reporter was a specialist in 74% of the reports and a general practitioner in 17%. The annual rate of reporting according to medical demography strongly increased for the specialists, especially since 1994. At least one ADR was considered as serious in 44.8% of the reports. The ADRs were most frequently related to nervous system drugs (23%), followed by cardiovascular drugs (19%) and systemic anti-infectives (17%). The latter class had the fastest progression mostly due to antiretroviral therapy since 1996. According to the Medical Dictionary for Regulatory Activities (MedDRA) coding, the system organ most often reported was skin and subcutaneous tissue disorders (29%), followed by nervous system disorders (19%), gastrointestinal disorders (12%), blood and lymphatic system disorders (12%), vascular disorders (12%) and general disorders and administration site conditions (12%).Discussion: All spontaneous reporting systems are affected by under-reporting. One of their goals is to generate early signals, which might be more affected by reporting bias than by under-reporting. Some improvements should be made in the design of the French database, but data collected since 1986 constitute an essential tool for the routine work of the 31 pharmacovigilance centres.Conclusion: This first description of the data of the French pharmacovigilance database involving all drugs and ADRs shows an increasing tendency to reporting over time, especially in specialists and for systemic anti-infective drugs. The database that uses hierarchical international classifications for drugs and adverse reactions may be used for further studies and could be the basis for an automatic signal generation system. [ABSTRACT FROM AUTHOR]

Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty-five cases of parachute use were identified and most ( n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4-methylenedioxymethamphetamine ( MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were to determine the patterns of analgesic adverse drug reactions (ADRs) and to assess their preventability and contributing factors. Methods: This is a retrospective, descriptive study conducted on ADRs of analgesics and other drugs indicated as analgesics, spontaneously reported to the Bordeaux pharmacovigilance center from January 2011 to June 2012. Results: The 141 cases selected for the analysis included 16 cases of medication errors (11.3 %) and 15 addiction cases (10.6 %). In total, 214 ADRs were registered, for which 173 analgesic medicines were suspected. The most frequent ADRs reported were nervous system disorders (26.6 %), psychiatric disorders (15.0 %), and skin and subcutaneous tissue disorders (12.1 %). Tramadol alone or in combination (17.3 %), followed by morphine (15 %), fentanyl (9.8 %), and paracetamol (8.7 %) were the most frequently involved analgesics. More than half of the cases (54.6 %) were serious and led to hospitalization or prolonged hospitalization. Preventability was determined for 134 cases (95 %): 51.5 % were considered as preventable, 26.1 % not preventable, and 22.4 % not assessable. The main contributing factors for the preventable cases included negligence of recommendations for analgesic use and failure to consider patients' risk factors when prescribing. Conclusions: A significant number of analgesic ADRs could be prevented, and being aware of their contributing factors promotes efficient analgesia with minimum risks to the patients. [ABSTRACT FROM AUTHOR]

To assess the incidence of hospital admissions related to adverse drug reactions ( ADRs) in France and the frequency of preventable ADRs in France, a prospective study was conducted among a representative randomly selected sample of medical wards in public hospitals between December 2006 and June 2007; all patients admitted during a 2-week period were included. An ADR-related hospitalization case was defined as a hospital admission because of an ADR, and an independent committee reviewed and validated all potential cases. Preventability was assessed using the French ADR preventability scale. Data were extrapolated to the population of France. Among 2692 admissions, 97 were related to an ADR (incidence 3.6%, 95% confidence interval, CI [2.8-4.4]). Patients admitted for an ADR were significantly older than those admitted for other reasons ( P < 0.001). A third (32.0%) of ADR-related hospitalizations were 'preventable', 16.5% 'potentially preventable'. Drug interactions accounted for 29.9% of ADR-related hospitalizations. The most frequent causes of ADR-related hospitalizations were vascular disorders (20.6%), mainly bleeding complications, central nervous system disorders (11.3%), gastrointestinal disorders, and general disorders (9.3%). Antithrombotic and antineoplastic agents were the most frequently involved (12.6% each), followed by diuretics and analgesics (9.0% each). Vitamin-K-antagonists ( VKAs) were the most common drugs associated with admission. The estimated annual number of ADR-related hospitalizations in France was 143 915 (95% CI [112 063-175 766]). ADRs were a significant cause of hospital admission in 2006-2007, in particular those due to VKAs. As new oral anticoagulants ( NOACs) have been marketed, more attention needs to be paid to ensure a safe use of antithrombotic agents. [ABSTRACT FROM AUTHOR]

The article assesses the risk of myopathy associated with dipeptidyl peptidase 4 (DPP-4) inhibitors in combination with statins. Topics mentioned include the analysis of data from pharmacovigilance spontaneous reporting databases and the results of the study based French Base Nationale de Pharmacovigilance and the VigiBase, the World Health Organization global individual case safety reports database, which confirmed a potential muscular toxicity of the inhibitor.

Objective: The objective of this study was to evaluate the performance of Standardised MedDRA® Queries (SMQs) in adverse drug reaction (ADR) identification.Methods: ADR cases included in the last complete year of the French Pharmacovigilance database for research were used to test four SMQs (narrow and broad): agranulocytosis, demyelination, osteonecrosis and psychosis. Reference cases were identified by free-text search and validated by two authors. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of narrow and broad searches of each SMQ were calculated and reported as proportions with 95% exact confidence interval (CI).Results: Among 20,830 cases reported in 2009, 337 validated cases of agranulocytosis, 17 of demyelination, 52 of osteonecrosis and 230 of psychosis were included in the reference sets. Estimations of SMQ narrow search performance were as follows: Se 62.9% (95% CI 57.5-68.1) and PPV 46.8% (95% CI 42.1-51.5) for agranulocytosis; Se 88.2% (95% CI 63.6-98.5) and PPV 34.1% (95% CI 20.5-49.9) for demyelination; Se 94.2% (95% CI 84.1-98.8) and PPV 74.2% (95% CI 62.0-84.2) for osteonecrosis; and Se 75.1% (95% CI 69.0-80.6) and PPV 87.8% (95% CI 82.3-92.0) for psychosis. Results obtained using the broad search were similar except for PPV concerning osteonecrosis (52.7% [95% CI 42.1-63.1]) and psychosis (61.4% [95% CI 55.7-66.8]). For all selected SMQs, Sp and NPV were greater than 98% for both narrow and broad searches.Conclusion: Heterogeneous performance of SMQs for case retrieval was found and seems to be related to the characteristics of the condition of interest. It could therefore be expected that for other SMQs, performance may be affected in the same manner. [ABSTRACT FROM AUTHOR]

Background: In the context of the European reassessment of the benefit-risk balance of hormonal contraceptives, French data about thromboembolic events were requested.Objective: The aim of this study was to determine the number of patients exposed to hormonal contraception or cyproterone acetate among hospitalized females diagnosed with a thromboembolic event in 2012, to retrospectively analyze specific risk factors of venous and arterial thromboembolism and to assess the magnitude of the under-reporting of such events to the national pharmacovigilance system.Methods: This cross-sectional study included 15- to 49-year-old women with pulmonary embolism, venous cerebral thrombosis, ischemic stroke, or myocardial infarction, hospitalized in 2012, and identified within the computerized hospital databases of 30 French teaching hospitals.Results: Among the 2,966 cases identified, 803 (27.1 %) patients had been exposed to a hormonal contraceptive (747) or to cyproterone acetate (56). Among these, there were 452 venous thromboembolic events (VTEs) and 351 arterial thromboembolic events (ATEs). Age ≥40 years and personal thrombophilia diagnosed after the event were the main VTE risk factors, while current smoking and age ≥40 years were the main ATE risk factors. The mean number of associated risk factors was significantly lower for VTE than for ATE (1.1 vs 2.3). The proportion of cases with no risk factors was higher for third- and fourth-generation than for first- and second-generation combined oral contraceptives. Overall, the under-reporting rate was 92.5 % (95 % CI 70.0-97.3).Conclusion: This study highlighted the need to strengthen the knowledge of patients and health professionals about thromboembolic risk factors at the first prescription and renewal of hormonal contraceptives. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. Methods Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. Results Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). Conclusions Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co-prescription bias could be eliminated using an automated method. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: An updated probabilistic causality assessment method and the Liverpool algorithm presented as an improved version of the Naranjo algorithm, one of the most used and accepted causality assessment methods, have recently been proposed. Objective: In order to test the validity of the probabilistic method in routine pharmacovigilance, results provided by the Naranjo and Liverpool algorithms, as well as the updated probabilistic method, were each compared with a consensual expert judgement taken as reference. Methods: A sample of 59 drug-event pairs randomly sampled from spontaneous reports to the French pharmacovigilance system was assessed by expert judgement until reaching consensus and by members of a pharmacovigilance unit using the updated probabilistic method, the Naranjo and Liverpool algorithms. Probabilities given by the probabilistic method, and categories obtained by both the Naranjo and the Liverpool algorithms were compared as well as their sensitivity, specificity, positive and negative predictive values. Results: The median probability for drug causation given by the consensual expert judgement was 0.70 (inter-quartile range, IQR 0.54-0.84) versus 0.77 (IQR 0.54-0.91) for the probabilistic method. For the Naranjo algorithm, the 'possible' causality category was predominant (61 %), followed by 'probable' (35 %), 'doubtful', and 'almost certain' categories (2 % each). Category distribution obtained with the Liverpool algorithm was similar to that obtained by the Naranjo algorithm with a majority of 'possible' (61 %) and 'probable' (30 %) followed by 'definite' (7 %) and 'unlikely' (2 %). For the probabilistic method, sensitivity, specificity, positive and negative predictive values were 0.96, 0.56, 0.92 and 0.71, respectively. For the Naranjo algorithm, depending on whether the 'possible' category was considered in favour or in disfavour of drug causation, sensitivity was, respectively, 1 or 0.42, specificity 0.11 or 0.89, negative predictive value 1 or 0.22 and positive predictive value 0.86 or 0.95; results were identical for the Liverpool algorithm. Conclusion: The logistic probabilistic method gave results closer to the consensual expert judgment than either the Naranjo or Liverpool algorithms whose performance were strongly dependent on the meaning given to the 'possible' category. Owing to its good sensitivity and positive predictive value and by providing results as continuous probabilities, the probabilistic method seems worthy to use for a trustable assessment of adverse drug reactions in routine practice. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions. Methods: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0). Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions. Results: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion reaction (p<0.001). Among the seven deaths related to an infusion reaction, five patients were treated for head and neck cancer. Infusion reactions were more likely to be severe when they occurred during the first administration(OR¼7.4095%CI [2.21–24.71]), adjusted for age, sex, region of France, quarter of the year, indication, year of occurrence, and premedication. Conclusion: Our study found that reports of infusion reactions more often concerned patients treated for head and neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion, especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E–mediated mechanism, reliable tests for their detection need to be readily available. [ABSTRACT FROM AUTHOR]

Background: Automated disproportionality analysis of spontaneous reporting is increasingly used routinely. It can theoretically be influenced by a competition bias for signal detection owing to the presence of reports related to well-established drug-event associations.Objective: The aim of the study was to explore the effects of competition bias on safety signals generated from a large spontaneous reporting research database.Methods: Using the case/non-case approach in the French spontaneous reporting research database, which includes data of reporting in France from January 1986 to December 2001, the effects of the competition bias were explored by generating safety signals associated with six events of interest (gastric and oesophageal haemorrhages, central nervous system haemorrhage and cerebrovascular accidents, ischaemic coronary disorders, migraine headaches, muscle pains, and hepatic enzymes and function abnormalities) before and after removing from the database reports relating to drugs known to be strongly associated with these events, whether they constituted cases or non-cases. As this study was performed on a closed database (last data entered 31 December 2001), potential signals unmasked by removal were considered as real signals if no or only incomplete knowledge about the association was available from the literature before 1 January 2002.Results: For gastric and oesophageal haemorrhages, after removing reports involving antithrombotic agents or NSAIDs, three potential signals were unmasked (prednisone, rivastigmine and isotretinoin). For central nervous system haemorrhage and cerebrovascular accidents, after removing reports involving antithrombotic agents, three potential signals were unmasked (ethinylestradiol, interferon-α-2B and methylprednisolone). For ischaemic coronary disorders, after removing reports involving anthracyclines, bleomycine, anti-HIV drugs or triptans, one potential signal was unmasked (ondansetron). For migraine headaches, after removing reports involving nitrates, calcium channel blockers, opioid analgesics or intravenous immunoglobulins, six potential signals were unmasked (ammonium chloride, leflunomide, milnacipran, montelukast, proguanil and pyridostigmine). For muscle pains, after removing reports involving statins or fibrates, seven potential signals were unmasked (hydroxychloroquine, lactulose, levodopa in combination with dopadecarboxylase inhibitor, nevirapine, nomegestrol, ritonavir and stavudine). Finally, for hepatic enzymes and function abnormalities, after removing reports involving NSAIDs, anilides, antituberculosis drugs, antiepileptics, ketoconazole, tacrine, or amineptine, two potential signals were unmasked (caffeine, metformin). Of all these unmasked potential signals, ten appeared non/incompletely documented as at 1 January 2002 and were considered as real signals, with three of these later being confirmed by the literature and finally considered as true positives (isotretinoin, methylprednisolone and milnacipran).Conclusion: This study confirms that a competition bias can occur when performing safety signal generation in spontaneous reporting databases. The minimization of this bias could lead to previously masked signals being revealed. [ABSTRACT FROM AUTHOR]

Background: Automated disproportionality analysis of spontaneous reporting is increasingly used routinely. It can theoretically be influenced by a competition bias for signal detection owing to the presence of reports related to well-established drug-event associations. Objective: The aim of the study was to explore the effects of competition bias on safety signals generated from a large spontaneous reporting research database. Methods: Using the case/non-case approach in the French spontaneous reporting research database, which includes data of reporting in France from January 1986 to December 2001, the effects of the competition bias were explored by generating safety signals associated with six events of interest (gastric and oesophageal haemorrhages, central nervous system haemorrhage and cerebrovascular accidents, ischaemic coronary disorders, migraine headaches, muscle pains, and hepatic enzymes and function abnormalities) before and after removing from the database reports relating to drugs known to be strongly associated with these events, whether they constituted cases or non-cases. As this study was performed on a closed database (last data entered 31 December 2001), potential signals unmasked by removal were considered as real signals if no or only incomplete knowledge about the association was available from the literature before 1 January 2002. Results: For gastric and oesophageal haemorrhages, after removing reports involving antithrombotic agents or NSAIDs, three potential signals were unmasked (prednisone, rivastigmine and isotretinoin). For central nervous system haemorrhage and cerebrovascular accidents, after removing reports involving antithrombotic agents, three potential signals were unmasked (ethinylestradiol, interferon-a-2B and methylprednisolone). For ischaemic coronary disorders, after removing reports involving anthracyclines, bleomycine, anti-HIV drugs or triptans, one potential signal was unmasked (ondansetron). For migraine headaches, after removing reports involving nitrates, calcium channel blockers, opioid analgesics or intravenous immunoglobulins, six potential signals were unmasked (ammonium chloride, leflunomide, milnacipran, montelukast, proguanil and pyridostigmine). For muscle pains, after removing reports involving statins or fibrates, seven potential signals were unmasked (hydroxychloroquine, lactulose, levodopa in combination with dopadecarboxylase inhibitor, nevirapine, nomegestrol, ritonavir and stavudine). Finally, for hepatic enzymes and function abnormalities, after removing reports involving NSAIDs, anilides, antituberculosis drugs, antiepileptics, ketoconazole, tacrine, or amineptine, two potential signals were unmasked (caffeine, metformm). Of all these unmasked potential signals, ten appeared non/incompletely documented as at 1 January 2002 and were considered as real signals, with three of these later being confirmed by the literature and finally considered as true positives (isotretinoin, methylprednisolone and milnacipran). Conclusion: This study confirms that a competition bias can occur when performing safety signal generation in spontaneous reporting databases. The minimization of this bias could lead to previously masked signals being revealed. [ABSTRACT FROM AUTHOR]

Background: Improving the detection of drug safety signals has led several pharmacovigilance regulatory agencies to incorporate automated quantitative methods into their spontaneous reporting management systems. The three largest worldwide pharmacovigilance databases are routinely screened by the lower bound of the 95% confidence interval of proportional reporting ratio (PRR₀₂.₅), the 2.5% quantile of the Information Component (IC₀₂.₅) or the 5% quantile of the Gamma Poisson Shrinker (GPS₀₅). More recently, Bayesian and non-Bayesian False Discovery Rate (FDR)-based methods were proposed that address the arbitrariness of thresholds and allow for a built-in estimate of the FDR. These methods were also shown through simulation studies to be interesting alternatives to the currently used methods.Objective: The objective of this work was twofold. Based on an extensive retrospective study, we compared PRR₀₂.₅, GPS₀₅ and IC₀₂.₅ with two FDR-based methods derived from the Fisher's exact test and the GPS model (GPS(pH0) [posterior probability of the null hypothesis H₀ calculated from the Gamma Poisson Shrinker model]). Secondly, restricting the analysis to GPS(pH0), we aimed to evaluate the added value of using automated signal detection tools compared with 'traditional' methods, i.e. non-automated surveillance operated by pharmacovigilance experts.Methods: The analysis was performed sequentially, i.e. every month, and retrospectively on the whole French pharmacovigilance database over the period 1 January 1996-1 July 2002. Evaluation was based on a list of 243 reference signals (RSs) corresponding to investigations launched by the French Pharmacovigilance Technical Committee (PhVTC) during the same period. The comparison of detection methods was made on the basis of the number of RSs detected as well as the time to detection.Results: Results comparing the five automated quantitative methods were in favour of GPS(pH0) in terms of both number of detections of true signals and time to detection. Additionally, based on an FDR threshold of 5%, GPS(pH0) detected 87% of the RSs associated with more than three reports, anticipating the date of investigation by the PhVTC by 15.8 months on average.Conclusions: Our results show that as soon as there is reasonable support for the data, automated signal detection tools are powerful tools to explore large spontaneous reporting system databases and detect relevant signals quickly compared with traditional pharmacovigilance methods. [ABSTRACT FROM AUTHOR]

Purpose: In France, early detection of adverse effects does not currently involve any automatic signal detection method. The present objective was to assess the feasibility and measure the potential benefit of the incorporation of an automatic signal detection tool (GPS) in the French pharmacovigilance system. Methods: GPS was first applied to the data collected from 1 January 2000 to 31 December 2008 and then to the data collected from 1 January 2000 to 31 March 2009. A total of 1,414 original signals were detected. They were shared out for further expertise among 32 centres, i.e. the 31 Regional Pharmacovigilance Centres and the French medicine agency (AFSSAPS) pharmacovigilance department. Results: The participating centres ( n = 28) analysed 1,292 signals in May 2009. Overall, 277 signals whether known or unknown were thus considered worth following up. Half of the other 893 categorised signals were 'well-known' (35.7%) and non-interpretable/non-pertinent signals (36.6%); 4% were not categorised because of a lack of time. Analysis of the signals was time-consuming, but the working time estimated by the participants was highly variable (median time: 6 h; minimum: 2 h maximum: 26 h). Conclusions: The results of this study are in favour of the integration of an automated signal detection tool to complement the current pharmacovigilance activities. The Anatomic Therapeutic Chemical for drug classification poses difficulties in many situations; the international proprietary name might be more efficient. The variability observed in the time needed for analysis suggests that a standardised methodology should be employed. Overall, the findings of this prospective study will contribute to refining the signal management procedure to be implemented in the future. [ABSTRACT FROM AUTHOR]

Purpose: Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. Methods: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. Results: Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. Conclusions: Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment. [ABSTRACT FROM AUTHOR]

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems.Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents.Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma.Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p < 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn's disease were more prevalent in published cases than in pharmacovigilance reports (p < 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001).Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required. [ABSTRACT FROM AUTHOR]

Purpose: After reports of malaise in infants immediately after the oral administration of two brands of vitamin D solutions, a 'Dear Doctor letter' (DDL) containing recommendations for the administration of vitamin D was sent to all French paediatricians and pharmacies and a large number of French general practitioners (GPs) with a predominantly paediatric practice. The DDL and a press release were published on the French Medicines Agency website and distributed via a mailing list. The objective of this study was to assess the effectiveness of such a DDL and to collect the opinions of healthcare professionals on the best way to provide them with information. Methods: A questionnaire was sent to a national random sample of 145 paediatricians, 680 GPs and 230 pharmacists. Results: Only 49% of responding paediatricians, 48% of GPs and 67% of pharmacists were aware of the warning. Among the participating healthcare professionals aware of the warning and who prescribed/dispensed these vitamins, 50% of paediatricians and 68% of GPs stated that they had changed their prescribing behaviour, and 68% of pharmacists stated that they had modified their advice when dispensing. According to the responding healthcare professionals, postal letters remained the best way to issue safety warnings. Some of the respondents suggested that the DDL be more distinctive in terms of being a DDL and that the information be more widely disseminated to other stakeholders involved in the healthcare system. Conclusions: This survey of a national random sample of healthcare professionals revealed that many of the respondents paid little attention to the DDL and were therefore unlikely to change their practices. A potential supplementary method for disseminating recommendations for medicine administration could be to apply stickers on medicine boxes, as this approach has the additional advantage of directly informing the concerned population, i.e. the parents. [ABSTRACT FROM AUTHOR]

Background: Different methods have been proposed for assessing a possible causal link between a drug treatment and an adverse event in individual patients. They approximately belong to three main categories: expert judgement, operational algorithms and probabilistic approaches.Objective: To compare, in a set of actual drug adverse event reports, three different methods for assessing drug causality, each belonging to one of the three main categories: expert judgement, the algorithm used by the French pharmacovigilance centres since 1985, and a novel method based on the logistic function.Methods: Fifty drug-event pairs were randomly sampled from the database of the Bordeaux pharmacovigilance centre, France. To serve as the gold standard, the probability for drug causation, from 0 to 1, was first determined for each drug-event pair by a panel of senior experts until consensus was reached. Causality was then assessed by members of the Bordeaux pharmacovigilance centre by using the French algorithm and the logistic method. Results expressed as a probability with the logistic method and as a score from 0 to 4 with the French algorithm were then compared with consensual expert judgement, as were the sensitivity, specificity and positive and negative predictive values.Results: Probabilities ranged from 0.08 to 0.99 (median 0.58; mean 0.60) for experts versus 0.18-0.88 (median 0.73; mean 0.67) for the logistic method. Consensual expert judgement was not discriminant (p = 0.50) in ten cases. For the algorithm, only three of five causality scores were found, doubtful scores being clearly predominant (74%) followed by possible (16%) and probable (10%) scores. Sensitivity and specificity were 0.96 and 0.42, respectively, for the logistic method versus 0.42 and 0.92 for the algorithm. Positive and negative predictive values were 0.78 and 0.83, respectively, for the logistic method versus 0.92 and 0.42 for the algorithm.Conclusions: Agreement between the three approaches was poor, and only satisfactory for drug events judged as drug-induced by consensual expert judgement. The logistic method showed high sensitivity at the expense of poor specificity. Conversely, the algorithm had poor sensitivity but good specificity. The comparatively good sensitivity and positive predictive values of the logistic method suggest that it may be more useful in the routine or automated assessment of case reports of suspected but still unknown adverse drug reactions. With a substantial rate of false positives relative to true negatives (low specificity), the logistic method does not replace, but can be complemented by, critical clinical assessment of individual cases in evaluating drug-related risk. [ABSTRACT FROM AUTHOR]

Purpose To study whether reports related to known drug-event associations could hinder the detection of new signals by increasing the detection thresholds when using disporportionality analyses in spontaneous reporting (SR) databases. Methods The French SR database (2005-2006 data) was used to test this hypothesis for the following events: bleeding, headache, hepatitis, myalgia, myocardial infarction, stroke, and toxic epidermal necrolysis (TEN). For each of these, using the Proportional Reporting Ratio (PRR) and the Reporting Odds Ratio (ROR), the number of cases needed to trigger a signal out of 50, 100, and 200 reports for a hypothetical newly introduced drug were computed before and after removing from the database reports involving drugs known to be associated with the event. Results For bleeding and stroke, removing potentially competitive data resulted in a decrease of the number of cases needed to trigger a signal for a newly introduced drug for both PRR and ROR (e.g., from 9 to 4, and 5 to 3 cases out of 50 reports for bleeding and stroke, respectively using the PRR). They were not or only slightly modified for the other studied events. Conclusions Removing reports related to known drug-event associations could increase the sensitivity of signal detection in SR databases. This should be considered when using SR databases for signal detection as it could result in earlier identification of new drug-event associations. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Some pharmaceutical tablets have an appearance that resembles that of ecstasy (a logo and often a name referring to it, a given shape and/or a colour). These are sometimes sold in the street as ‘ecstasy’. In order to assess the knowledge of this phenomenon, surveys were conducted among designer drug users (DDUsers), pharmacists and pharmaceutical firms. Three surveys were conducted: the first one was conducted among DDUsers by means of an anonymous questionnaire; the second one consisted of a 1-month postal survey within a network of 155 community pharmacies in the Aquitaine region, Southwestern France and the third one consisted of a postal questionnaire sent to 71 pharmaceutical firms. Nineteen users, 77 pharmacists and 25 pharmaceutical firms participated in the surveys. All DDUsers knew the existence of what they call ecstasy ‘swindles’, but less than one quarter of the pharmacists and one third of pharmaceutical firms were aware of the potential recreational and involuntary misuse of medicines. The phenomenon of ‘swindle’ in the illicit market is not new. However, the sale of medicines because of their appearance or logo seems to be quite rare. In order to limit this diversion, prevention should be reinforced. In addition, recommendations on the appearance of medicine tablets should be set up by regulatory agencies in charge of medicine approval. [ABSTRACT FROM AUTHOR]

Background: Since its introduction in France, ketoprofen for topical use has been associated with a large number of cutaneous adverse effect reports. Therefore, the French Medicine Agency progressively introduced warnings and contraindications to its use. Despite this, serious adverse drug reactions (ADRs) still occur. Objective: To describe clinical patterns and estimate costs of spontaneously reported cutaneous ADRs of topical ketoprofen. Methods: All cases of cutaneous ADRs of topical ketoprofen reported to the Bordeaux regional pharmacovigilance center between January 1989 and December 2006 were included. Clinical patterns, in respect of adherence to recommendations, causality, seriousness, and direct costs incurred by the ADRs, were assessed. Results: A total of 136 cases were reported (median age: 42 years, 55.9% women). Proper use of topical ketoprofen regarding indications, warnings, and contraindications was not respected by one-third of the patients. Almost all cases occurred during sunny months. Symptoms consisted predominantly of bullous eruptions (29.4%) or contact dermatitis (27.2%). Generalized lesions were observed in 37.5% of patients. Causality was considered at least possible for most of the cases (92.6%). These ADRs induced hospital admission in 15 cases (11.0%). The total estimated cost was h42 962 ($US66 559), corresponding to h316 per case. This mean cost was nine times higher for serious ADRs. Conclusion: Topical ketoprofen is used to treat benign symptoms but can be associated with serious and costly cutaneous ADRs. Furthermore, the number of cases and the calculated costs may have been greatly under-estimated in the present study. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors are used in Alzheimer's disease, mostly in elderly persons with co-morbidities and receiving co-medications that could increase the risk of serious adverse reactions.Objective: To identify factors associated with serious adverse drug reactions (ADRs) in patients treated with cholinesterase inhibitors.Methods: All ADRs associated with donepezil, rivastigmine or galantamine were identified in the French pharmacovigilance database, from the launching of these drugs to January 2007. Serious ADRs (SADRs) were those that led to death, hospitalization or prolongation of hospitalization, or that were life threatening. A multiple logistic regression analysis was used to identify factors associated with seriousness in the reported adverse reactions.Results: We identified 773 reports of ADRs related to cholinesterase inhibitor use, among which 438 (57%) concerned SADRs. The median age of patients was 80 years (interquartile range: 75-84 years); 65.1% were women. The most represented ADRs were those responsible for CNS disorders (17.0%), gastrointestinal disorders (16.2%) and cardiac rhythm disorders (11.2%). Factors associated with an increased risk of SADRs were: age (odds ratio [OR] 1.92; 95% CI 1.22, 3.02 for subjects aged 85 years and over), use of atypical antipsychotics (OR 2.15; 95% CI 1.04, 4.46), use of conventional antipsychotics (OR 2.06, 95% CI 1.10, 3.85), use of antihypertensive drugs (OR 2.11; 95% CI 1.47, 3.02) and use of drugs targeting the alimentary tract and metabolism (OR 1.62; 95% CI 1.06, 2.46). The use of benzodiazepines (long-acting or others), antidepressants (tricyclic or others) or antiarrhythmic drugs was not associated with the reporting of SADRs.Conclusions: An increased risk of SADRs related to cholinesterase inhibitors was associated with the use of antipsychotics (with no difference between conventional and atypical antipsychotics), drugs targeting the alimentary tract/metabolism and antihypertensive drugs. It was not associated with the use of other psychotropic drugs, other non-psychotropic CNS drugs or with the use of antiarrhythmic agents. The association with drugs targeting the alimentary tract and metabolism could result from a protopathic bias or reflect the particular sensitivity to serious nausea and vomiting in patients already treated for gastrointestinal disorders. These results confirm that attention needs to be paid to patients receiving both cholinesterase inhibitors and antipsychotics. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors are used in Alzheimer's disease, mostly in elderly persons with co-morbidities and receiving co-medications that could increase the risk of serious adverse reactions. Objective: To identify factors associated with serious adverse drug reactions (ADRs) in patients treated with cholinesterase inhibitors. Methods: All ADRs associated with donepezil, rivastigmine or galantamine were identified in the French pharmacovigilance database, from the launching of these drugs to January 2007. Serious ADRs (SADRs) were those that led to death, hospitalization or prolongation of hospitalization, or that were life threatening. A multiple logistic regression analysis was used to identify factors associated with seriousness in the reported adverse reactions. Results: We identified 773 reports of ADRs related to cholinesterase inhibitor use, among which 438 (57%) concerned SADRs. The median age of patients was 80 years (interquartile range: 75-84 years); 65.1% were women. The most represented ADRs were those responsible for CNS disorders (17.0%), gastrointestinal disorders (16.2%) and cardiac rhythm disorders (11.2%). Factors associated with an increased risk of SADRs were: age (odds ratio [OR] 1.92; 95% CI 1.22, 3.02 for subjects aged 85 years and over), use of atypical antipsychotics (OR 2.15; 95% CI 1.04, 4.46), use of conventional antipsychotics (OR 2.06, 95%CI 1.10, 3.85), use of antihypertensive drugs (OR 2.11; 95%CI 1.47, 3.02) and use of drugs targeting the alimentary tract and metabolism (OR 1.62; 95% CI 1.06, 2.46). The use of benzodiazepines (long-acting or others), antidepressants (tricyclic or others) or antiarrhythmic drugs was not associated with the reporting of SADRs. Conclusions: An increased risk of SADRs related to cholinesterase inhibitors was associated with the use of antipsychotics (with no difference between conventional and atypical antipsychotics), drugs targeting the alimentary tract/metabolism and antihypertensive drugs. It was not associated with the use of other psychotropic drugs, other non-psychotropic CNS drugs or with the use of antiarrhythmic agents. The association with drugs targeting the alimentary tract and metabolism could result from a protopathic bias or reflect the particular sensitivity to serious nausea and vomiting in patients already treated for gastrointestinal disorders. These results confirm that attention needs to be paid to patients receiving both cholinesterase inhibitors and antipsychotics. [ABSTRACT FROM AUTHOR]

Purpose Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. Methods Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. Results An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. Conclusions A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and new issues in drug safety arise. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pharmacovigilance spontaneous reporting systems are primarily devoted to early detection of the adverse reactions of marketed drugs. They maintain large spontaneous reporting databases (SRD) for which several automatic signalling methods have been developed. A common limitation of these methods lies in the fact that they do not provide an auto-evaluation of the generated signals so that thresholds of alerts are arbitrarily chosen. In this paper, we propose to revisit the Gamma Poisson Shrinkage (GPS) model and the Bayesian Confidence Propagation Neural Network (BCPNN) model in the Bayesian general decision framework. This results in a new signal ranking procedure based on the posterior probability of null hypothesis of interest and makes it possible to derive with a non-mixture modelling approach Bayesian estimators of the false discovery rate (FDR), false negative rate, sensitivity and specificity. An original data generation process that can be suited to the features of the SRD under scrutiny is proposed and applied to the French SRD to perform a large simulation study. Results indicate better performances according to the FDR for the proposed ranking procedure in comparison with the current ones for the GPS model. They also reveal identical performances according to the four operating characteristics for the proposed ranking procedure with the BCPNN and GPS models but better estimates when using the GPS model. Finally, the proposed procedure is applied to the French data. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose (i) To monitor the potential clinical neurotoxic symptoms in patients treated with leflunomide in daily practice and (ii) to describe the characteristics of patients presenting with this peripheral nervous system symptoms. Method All patients treated with leflunomide between May 2000 and April 2003 and followed in the rheumatology department of the University Hospital participated in the study. Data concerning treatment patterns with leflunomide, demographic and disease characteristics were obtained from clinical charts. Neuropathy was diagnosed with nerve conduction study (NCS). Cases of neuropathy were described and then compared to other patients using univariate analyses. Results One hundred and thirteen patients were included in the study. M/F sex ratio was 0.45. Mean age at start of treatment was 55.6 years (range = 27-81). During the study period, eight incident cases of peripheral neuropathy and two cases of worsening of preexisting neuropathy were reported (incidence: 9.8%). Compared with other patients, neuropathy cases were older (69 vs. 54 years, p = 0.0006), more often diabetic (30% vs. 2.9%, p = 0.009) and more often treated with potentially neurotoxic drugs (20% vs. 1.9%, p = 0.039). At least one risk factor (potentially neurotoxic drug or diabetes) was found in 50% of patients with neuropathy versus 4% of patients without neuropathy (56% PPV, 96% NPV). Conclusion Cases of toxic neuropathy have been observed during treatment of rheumatoid arthritis with leflunomide. Their occurrence seems to be associated with known risk factors. Careful monitoring of the patient's neurological status during leflunomide treatment is therefore mandatory. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To describe adverse events occurring after mass vaccination with conjugate and nonconjugate vaccines and to assess the incidence of serious adverse effects. Methods: A mass immunisation campaign against meningococcal C disease was conducted in two French administrative areas, Landes and Pyrénées atlantiques, for 2 months (from October to December 2002). Adverse events were reported by families and physicians by means of a specific reporting form returned to the pharmacovigilance centre 15 days after vaccination. Results: The target population was 260,630 individuals aged between 2 months and 24 years. About 179,000 children and young adults were vaccinated. A total of 92,711 report forms were received by the pharmacovigilance centre, and 12,695 subjects presented at least one adverse event. The most frequently involved systems/disorders were application site disorders (48.4%), whole-body general disorders (21.8%), central and peripheral nervous system disorders (14.6%), and gastrointestinal system disorders (4.7%). Most of these adverse events were transient and not serious. There were 13 serious adverse events: one each of syncope, fever, headache with fever, neuralgia, serum sickness, arthritis, purpura, facial paralysis, multiple sclerosis, lipoma, and meningism, and two cases of bronchospasm. No significant difference was found in rates of adverse event reports between both vaccines. The estimated incidence of serious adverse effect reports was 7 per 100,000. Conclusions: This campaign was the second immunisation campaign undertaken in France involving both physicians and families as reporters. Although unlabeled adverse effects were identified during this campaign, they were mostly nonserious and have been known to occur with other vaccines. [ABSTRACT FROM AUTHOR]

Background: Global introspection is, with operational algorithms and Bayes' theorem, one of the three main approaches used to assess the causal relationship between a drug treatment and the occurrence of an adverse event. Objective: To analyze and compare the judgments of five senior experts using global introspection about drug causation on a random set of putative adverse drug reactions. Methods: A random sample of 150 drug-effect pairs was constituted. For each pair, five senior experts had to independently assess the probability of drug causation from 0 to 1 by using a 100 mm visual analog scale (VAS). For analysis, those probabilities were secondarily split into seven levels of causality: excluded (0–0.05); unlikely (0.06–0.25); doubtful (0.26–0.45); unassessable/ unclassifiable (0.46–0.55); plausible (0.56–0.75); likely (0.75–0.95); and certain (0.95–1). Agreement among the five experts was assessed using kappa coefficients (κ). Results: The overall agreement between experts was poor (κ=0.20), although significantly different from chance, and varied according to the level of causality. It was lower for the unlikely, doubtful, unassessable/ unclassifiable, and plausible categories (κ=0.03, 0.03, -0.01, and 0.13, respectively) than for VAS extremes: excluded, likely, and certain (κ=0.40, 0.32, and 0.30, respectively). Conclusion: This study confirms that experts express marked disagreements when assessing drug causality independently. The agreement rate was lower for intermediate levels of causality, especially when strong evidence was lacking for confirming or ruling out drug causality. Therefore, in a decision-making context, a step-by-step consensual approach such as the Delphi method seems necessary to make the assessment of such cases more reliable. [ABSTRACT FROM AUTHOR]

Using a case-control study design, we studied the factors associated with HIV-related avascular necrosis (AN). During a 6-year period, 12 symptomatic AN cases were validated, and each case was individually matched with 3 control cases. A conditional logistic regression model showed that current alcohol consumption and a history of steroid use were the only factors associated with the occurrence of AN. [ABSTRACT FROM AUTHOR]

Clinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety. Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. Whatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under-representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned. These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data. [ABSTRACT FROM AUTHOR]

Few data are available on the clinical impact of drug–drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients' characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63–84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the "antithrombotic agents" subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Drug interactions between inhaled corticosteroids and enzymatic inhibitors" in the April 28, 2009 issue.

The article discusses research, conducted by Bateman and colleagues and published within the issue, which investigated statin use in early pregnancy. Topics explored include the use of high density propensity scoring in analyzing data, the identification of major congenital malformations linked to statin use, and the research limitations cited such as statin classification, time of use, and medication adherence.