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Summary Introduction Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates. Materials and methods Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol). Results We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR = 1.83; 95% CI = [1.53; 2.2]) but not with other fibrates: bezafibrate (ROR = 0.44; 95% CI = [0.2; 0.99]), ciprofibrate (ROR = 1.15; 95% CI = [0.76; 1.73]) and gemfibrozil (ROR = 0.91; 95% CI = [0.45; 1.84]). Conclusion With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates.Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol).We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR=1.83; 95% CI=[1.53; 2.2]) but not with other fibrates: bézafibrate (ROR=0.44; 95% CI=[0.2; 0.99]), ciprofibrate (ROR=1.15; 95% CI=[0.76; 1.73]) and gemfibrozil (ROR=0.91; 95% CI=[0.45; 1.84]).With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

Depressive disorders and use of antidepressants are associated with adverse effects on sexual function. In pharmacoepidemiological studies, sexual disorders are reported by more than 50 % of patients taking serotonin reuptake inhibitors (SRIs). The aim of this study was to determine the reporting rate of sexual disorders in association with SRIs, and to investigate the association between reported cases and the use of SRIs. All cases of adverse drug reactions (ADRs) involving sexual disorders, spontaneously reported to the French Pharmacovigilance Database from 1 January 1985 to December 2009, were reviewed. Cases of sexual disorders in SRI users were described. We calculated the rate of reported sexual disorders as a percentage of the total ADRs reported for each drug. The association between reported cases and the use of SRIs was assessed using reporting odds ratios (ROR) with 95 % confidence intervals (CIs). A total of 11,863 ADRs in association with SRIs were collected, of which 98 (0.83 %) were spontaneous reports of sexual disorders. Subjects were, on average, 45.0 ± 10.6 years of age and mainly male. Sexual disorders were associated with the use of SRI antidepressants (ROR 4.47; 95 % CI 3.61–5.53), milnacipran (ROR 11.72; 95 % CI 5.79–23.72), fluvoxamine (ROR 6.91; 95 % CI 3.79–12.58), paroxetine (ROR 5.54; 95 % CI 3.92–7.83), venlafaxine (ROR 3.50; 95 % CI 1.93–6.36), fluoxetine (ROR 3.46; 95 % CI 2.26–5.29), citalopram (ROR 2.69; 95 % CI 1.28–5.67) and sertraline (ROR 2.49; 95 % CI 1.03–6.01). It is likely that there are instances of underreporting, particularly for ADRs that are embarrassing to talk about spontaneously. Despite the likely underreporting of this well-described adverse effect, this case/non-case study performed in a large national pharmacovigilance database confirms the existence of the risk of sexual disorders associated with SRIs, and is an example of the lack of sensitivity of spontaneous notification to measure ADRs. Minimization of antidepressant-induced sexual dysfunction could be an important factor to avoid unsuccessful treatment. Physicians should advise their patients on the possible sexual adverse effects.

Aims The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs. Methods Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared. Results Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 ± 21 vs. 69.4 ± 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 ± 0.9 mmol l−1 in the DXP group compared with 2.5 ± 1 mmol l−1 in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8). Conclusions Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP.

Hyperprolactinaemia is a common endocrinological disorder that can be caused by a variety of physiological and pathological conditions, although in a large proportion of cases hyperprolactinaemia is drug-induced. Serotonin reuptake inhibitors (SRIs) are reportedly associated with hyperprolactinaemia; however, the number of published cases in the literature is limited.The aim of the study was to investigate the association between exposure to SRIs and the risk of reporting of hyperprolactinaemia in a spontaneous reporting database.All cases of adverse drug reactions (ADRs) involving hyperprolactinaemia spontaneously reported to the French Pharmacovigilance Database from 1985 to December 2009 were reviewed. Cases of hyperprolactinaemia in SRI users were described. In a case/non-case analysis, the association between reported cases of hyperprolactinaemia and the use of SRIs was assessed by calculating reporting odds ratios (ROR) with their 95% confidence intervals (CIs).A total of 11 863 reports with SRIs were collected, of which 187 reported hyperprolactinaemia ADRs. Subjects were 39.7 ± 13.5 years of age on average and mainly female (71%). We observed an increased risk of reporting of hyperprolactinaemia with the use of SRIs as antidepressants (overall ROR 3.3; 95% CI 2.8, 3.8), particularly with fluvoxamine (ROR 4.5; 95% CI 2.8, 7.2), citalopram (ROR 3.9; 95% CI 2.6, 5.8), fluoxetine (ROR 3.6; 95% CI 2.8, 4.7) and paroxetine (ROR 3.1; 95% CI 2.3, 4.2). Duloxetine, milnacipran and sertraline were not associated with an increased risk of reporting of hyperprolactinaemia.Treatment with SRIs is associated with an increased risk of reported hyperprolactinaemia. When investigating the aetiology of diagnosed hyperprolactinaemia, physicians should systematically enquire about treatment with SRIs. The risk of hyperprolactinaemia should be mentioned in the labelling of all SRI compounds.

Background Since donepezil and memantine are currently used for treating Alzheimer’s disease, it is interesting to analyse, reassess and compare their safety profile in order to promote a better use. Methods All spontaneous reports of suspected serious adverse drug reactions with donepezil alone and with memantine alone recorded in the French Pharmacovigilance Database during 6 years were retrospectively analysed. Results The most frequent adverse drug reactions with donepezil alone and memantine alone were respectively: bradycardia (10% versus 7%), weakness (5% versus 6%) and convulsions (4% versus 3%). Conclusion The most adverse drug events with donepezil and with memantine are associated with elderly people, even if they do not receive any other treatment. Donepezil and memantine have an acceptable safety profile but physicians should take special care when they prescribe any drug known to cause bradycardia or to reduce the epileptogenic threshold.

Objective After the diagnosis of transsexualism, hormone therapy is an established stage of gender identity disorder treatment for inducing secondary sex characteristic development of the target gender while reducing that of the birth sex. The aim of this study was to review existing data about the risk of hormone therapy in transsexual people. Methods A PubMed search was done to identify relevant data about adverse drug reactions (ADRs) and mortality associated to hormones exposure. Furthermore, case reports of hormonal therapy-induced ADRs were identified in the French Pharmacovigilance DataBase (FPDB). Results Review of currently available data showed an increase of thromboembolic effects and hyperprolactinemia with oestrogens. Both oestrogens and testosterone derivatives could induce hepatic effects. Currently, there is no significant association between hormone exposure and cancer or mortality in transsexual people. Five ADRs were found in FPDB, and two of them were related to misuse (voluntary overdose and prescription error). Conclusion Potential for under-reporting and under-identification in the FPDB of hormonal therapy-induced ADRs in transsexual people should be underlined. Technical improvement of the FPDB could facilitate further identification of reports concerning the risk associated with hormonal therapy in transsexual subjects.

The prescription of antidepressants in the elderly has changed since the marketing of new antidepressants such as selective serotonin reuptake inhibitors (SSRIs). We analysed the adverse effects associated with antidepressants in subjects aged > or =75 years reported to the pharmacovigilance centres in France. Among the 2381 cases recorded between 1985 and 2001, the distribution of adverse effects may reflect sales figures: 1040 for SSRIs (44%), 586 for tricyclic and related antidepressants (25%), 46 for monoamine oxidase inhibitors (2%) and 654 for other antidepressants (27%). Adverse effect patterns differed according to antidepressant class. For SSRIs, hyponatraemia was predominant (30%), followed by psychiatric (13%) and nervous system (10%) effects. For tricyclic antidepressants, psychiatric effects (confusion, agitation) [21%] were the most frequent followed by cardiovascular effects (15%). However, the consequences of adverse effects such as hyponatraemia are far from negligible in the elderly.

The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs.Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared.Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 ± 21 vs. 69.4 ± 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 ± 0.9 mmol l(-1) in the DXP group compared with 2.5 ± 1 mmol l(-1) in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8).Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP.

Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Repeat renal biopsies and serial serum creatinine measurements were done in 36 adults who were treated for steroid-dependent or -resistant idiopathic nephrotic syndrome with 5.54 ± 0.81 mg/kg/day of cyclosporin A (CsA). Pre-CsA renal biopsy (RB1) had been carried out 11.6 ± 12.2 months prior to CsA treatment. It showed minimal glomerular changes (MCD) in 22, and 1 to 16 glomeruli with lesions of focal segmental glomerulosclerosis (FSGS) per biopsy in 14. Pretreatment serum creatinine levels were (μmol/liter) 97.6 ± 39.4 and were higher in FSGS (117.1 ± 48.3) than in MCD (85.2 ± 26.9; P

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(pH0)) in the French pharmacovigilance system.GPS(pH0) 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.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).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.

BackgroundTerm and preterm neonates are at higher risk for serious adverse drug reactions than older children and adults. To date, no study has investigated spontaneous reports of adverse drug reactions (ADRs) following direct drug exposure of neonates.MethodsThis is a retrospective study of all spontaneous reports of ADRs registered in the French Pharmacovigilance Database from 1986 to 2012. All reports concerning individuals from birth to ≤30 days, 1 month or 4 weeks were retrieved. ADRs classified as related to ‘pregnancy’ or ‘breastfeeding’ were discarded. Reports were described with regards to characteristics of the infant, the reported ADR(s) (registered according to the Medical Dictionary for Regulatory Activities [MedDRA]) and the reported suspected medicine(s) (registered according to the Anatomical Therapeutic Chemical [ATC] Classification) Causality assessment was performed using the French Causality assessment method.ResultsA total of 1688 unique reports were analysed. More than half of these reports included at least on serious ADR (n=995; 59%). Median age at ADR occurrence was 9 days and a slight predominance of male neonates was observed (male/female ratio of 1.3). Fourteen percent of neonates presented a medical history of preterm birth, infection or genetic and/or congenital abnormality. Overall, 3127 ADRs were described in these reports. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%), blood and lymphatic system disorders (12%), gastrointestinal disorders (8%), investigations (8%) and nervous system disorders (8%). In the majority of ADRs reported (n=2279, 73%), infants fully recovered without sequelae but 4% of neonates deceased as a consequence of the reported ADR. Approximately 1/3 of the reported ADRs fell under 10 categories of ADRs the MedDRA classification and 1 out of 5 ADRs was coded as drug maladministration, medication error, overdose or drug maladministration without clinical consequences. A total of 2238 medicinal products out of the 2797 reported were described as suspect or interacting. Therapeutics classes must commonly incriminated were antiinfectives for systemic use and nervous system drugs. Active substances most frequently related to serious adverse reactions were zidovudine, ibuprofen and nevirapine. A total of 4103 drug-ADR pairs were described in the database; the global intrinsic causality score was ‘doubtful/unlikely’ for 35% of them and the extrinsic causality score was ‘never described before’ for only 6% of these pairs. Among the 10 most frequently encountered drug-ADR pairs, 2 active substances were mainly implicated: zidovudine and phytomedione (Vitamin K).ConclusionsWe have provided a unique overview of ADR notifications after direct drug exposure in the neonates. Reporting of ADRs in neonates is scarce. The majority of ADRs are classified as serious and a subsequent proportion is associated to drug administration errors. The number of commonly incriminated drugs is limited and causality assessment is particularly challenging. There is still a need to increase awareness and education of health professionals on neonatal drug safety and to promote detailed ADR reporting in this paediatric population.

The prescription of antidepressants in the elderly has changed since the marketing of new antidepressants such as selective serotonin reuptake inhibitors (SSRIs). We analysed the adverse effects associated with antidepressants in subjects agedor =75 years reported to the pharmacovigilance centres in France. Among the 2381 cases recorded between 1985 and 2001, the distribution of adverse effects may reflect sales figures: 1040 for SSRIs (44%), 586 for tricyclic and related antidepressants (25%), 46 for monoamine oxidase inhibitors (2%) and 654 for other antidepressants (27%). Adverse effect patterns differed according to antidepressant class. For SSRIs, hyponatraemia was predominant (30%), followed by psychiatric (13%) and nervous system (10%) effects. For tricyclic antidepressants, psychiatric effects (confusion, agitation) [21%] were the most frequent followed by cardiovascular effects (15%). However, the consequences of adverse effects such as hyponatraemia are far from negligible in the elderly.