Drug-induced yawning: a review of the French pharmacovigilance database.

OBJECTIVE: To review the reports with 'yawning' as an adverse drug reaction (ADR) reported into the French Pharmacovigilance Database. METHODS: All the observations with 'yawning' reported in the French Pharmacovigilance Database until December 2004 were reviewed. We recorded drug(s) involved, characteristics of patients (age, sex and underlying disease) and of ADR (seriousness, delay in occurrence, evolution, imputability). RESULTS: Twenty-eight reports were recorded between 1985 and December 2004. The sex ratio of the patients included in these reports was 1.5 and the mean age was 46.2 (2-78) years. Thirty-eight drugs were involved, mainly serotoninergic agents (serotonin reuptake inhibitors [12]), dopaminergic agents (levodopa [3], dopamine agonists [3], monoamine oxidase B inhibitor [1]), opioids (morphine [1], methadone [1], buprenorphine [1], dextromethorphan [1]), benzodiazepines (4) and sodium channel inhibitors (lidocaine [2], flecainide [1]). Four ADRs were rated 'serious' (leading to hospitalisation). Patient outcome was usually favourable after drug withdrawal. CONCLUSION: Despite its necessary methodological drawbacks (mainly under-reporting), this study reveals that several drugs may induce yawning in humans. Our work also indicates that stimulation of central dopamine or serotonin receptors elicits yawning in humans. This study underlines the role of several drugs in yawning and shows that this ADR is not systematically listed in the summary product characteristic even when it can be explained by the pharmacodynamic properties of the drugs.     

Medication-related falls in the elderly: causative factors and preventive strategies

People are living to older age. Falls constitute a leading cause of injuries, hospitalization and deaths among the elderly. Older people fall more often for a variety of reasons: alterations in physiology and physical functioning, and the use (and misuse) of medications needed to manage their multiple conditions. Pharmacological factors that place the elderly at greater risk of drug-related side effects include changes in body composition, serum albumin, total body water, and hepatic and renal functioning. Drug use is one of the most modifiable risk factors for falls and falls-related injuries. Fall-risk increasing drugs (FRIDs) include drugs for cardiovascular diseases (such as digoxin, type 1a anti-arrhythmics and diuretics), benzodiazepines, antidepressants, antiepileptics, antipsychotics, antiparkinsonian drugs, opioids and urological spasmolytics. Psychotropic and benzodiazepine drug use is most consistently associated with falls. Despite the promise of a more favourable side-effect profile, evidence shows that atypical antipsychotic medications and selective serotonin reuptake inhibitor antidepressants do not reduce the risk of falls and hip fractures. Despite multiple efforts with regards to managing medication-associated falls, there is no clear evidence for an effective intervention. Stopping or lowering the dose of psychotropic drugs and benzodiazepines does work, but ensuring a patient remains off these drugs is a challenge. Computer-assisted alerts coupled with electronic prescribing tools are a promising approach to lowering the risk of falls as the use of information technologies expands within healthcare.     

Non-puerperal lactation associated with antidepressant drug use

Aims The aim of the present study was to estimate the relative risk of non-puerperal lactation in patients using antidepressants in general, and specifically for serotonergic (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) and non-serotonergic antidepressants.
Methods All suspected adverse drug reactions in women and reported from January 1986 until August 1996 to the Netherlands Pharmacovigilance Foundation, a spontaneous adverse drug reaction reporting programme, were analysed. Adverse drug reaction (ADR) reporting odds ratios, defined as the ratio of the exposure odds among reported cases of non-puerperal lactation to the exposure odds of reported other ADRs, were calculated adjusted for age and year of reporting.
Results Thirty-eight cases of non-puerperal lactation were reported, of which 15 were associated with the use of antidepressant drugs. In general, antidepressants were associated with a higher risk of non-puerperal lactation in comparison with other drugs (ADR reporting odds ratio 8.3 [ 95%CI: 4.3–16.1]). Serotonergic antidepressants (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) were associated with a higher risk (OR 12.7 [95%CI: 6.4–25.4]), whereas other antidepressants were not (OR 1.6 [95%CI: 0.2–11.6]), compared with all other drugs.
Conclusions Our results indicate that serotonergic antidepressants are associated with an approximately eight times higher risk of non-puerperal lactation compared with other antidepressants. This effect is probably mediated by an indirect inhibition effect of serotonin on the dopaminergic transmission. This finding is in line with the occurrence of other antidopaminergic effects, such as extrapyramidal symptoms, in patients using serotonergic antidepressants.     

Upper gastrointestinal adverse drug reactions and cyclo-oxygenase-2 inhibitors (celecoxib and rofecoxib): a case/non-case study from the French Pharmacovigilance Database

Objective To evaluate the gastrointestinal safety of cyclo-oxygenase-2 inhibitors under their real conditions of use. Design Case/non-case study. Setting Adverse drug reactions (ADRs) in adults recorded in the French Pharmacovigilance Database between 25 May 2000 and 31 December 2002. Materials Cases were all reports of serious oeso-gastro-duodenal ADRs (oeso-gastro-duodenal ulcers, oesophagitis, gastritis, duodenitis). Five non-cases were randomly selected for one case from all other non oeso-gastro-duodenal reports in the database after matching them for age, gender and period of occurrence. Analysis Coxib exposure was compared among cases and non-cases, with adjustment for matching factors: French Regional Pharmacovigilance Centres that collected ADRs, reporter health professionals characteristics and exposures to non-selective non-steroidal anti-inflammatory, aspirin, anticoagulant, antiplatelet and gastroprotective drugs. Results Included in the study were 505 cases and 2,525 non-cases. A positive association was found between occurrence of oeso-gastro-duodenal ADRs and coxib (adjusted odds ratio 14.9 [95% CI 9.3–23.7]), diclofenac (9.2 [3.8–22.2]), ibuprofen (7.3 [3.2–16.6]) or oxicam (25.3 [11.9–53.6]) use. Conclusion Despite the compulsory limits of the case/non-case methodology, the present study shows that coxibs did induce serious gastrointestinal ADRs in real clinical practice. These results underline the need for pharmacoepidemiological studies under real conditions of use in order to verify (or not) the conclusions of clinical trials.     

Psychotropic drugs and falls: new evidence pertaining to serotonin reuptake inhibitors

Falls are a significant cause of fatal and nonfatal injuries in older persons. Risk factors include previous falls, several disease states, and certain drugs such as tricyclic antidepressants and antihypertensives. We conducted a MEDLINE search from January 1966-March 1999 to identify studies and review articles on the association of neuroleptics, benzodiazepines, and antidepressants with fall risk in older people. The focus was on the risk associated with serotonin reuptake inhibitors, biologic plausibility, and limitations of these studies. It was thought that the agents did not increase the risk of falls, although recent evidence suggests that this is not the case.     

Drug dependence associated with triptans and ergot derivatives: a case/non-case study

Introduction

The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database.

Methods

Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to “drug abuse,” “physical or mental drug dependence,” and “pharmacodependence,” whereas “non-cases” were defined as all the remaining SED reports. The method’s reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%.

Results

Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8–22.3] for sumatriptan to 21.5 for eletriptan [10.1–45.6], while in the ergot derivative group, it ranged from 12 [8–17.9] for ergotamine to 20.6 [8–53] for dihydroergotamine.

Conclusions

These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.     

老年精神障碍患者精神药物临床使用分析

目的:了解老年精神障碍患者精神药物临床使用情况。方法:收集肇庆市第三人民医院2008年1月1日-2008年12月31日出院,年龄60a或以上老年住院精神障碍患者的病历175份,采用限定日剂量(DDD)和药物利用指数(DUI)对精神药物的使用进行回顾性分析。结果:非典型抗精神病药利培酮的使用频率居首位,其次为奋乃静;抗抑郁药中舍曲林居首位,其次为帕罗西汀;在联合用药方面,抗精神病药与苯二氮艹卓类药物、抗抑郁药与苯二氮卓艹类药物和情感稳定剂、抗精神病药与抗抑郁药联用较多。在使用的33种精神药物中除舒必利、丙戊酸钠、阿普唑仑、三唑仑外,其余药物的DUI均≤1.0。结论:我院对老年精神障碍患者精神药物的使用基本合理。非典型抗精神病药、新型抗抑郁药的使用越来越多。     

Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database.
Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA).
Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline.
Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.     

Benzodiazepines and injurious falls in community dwelling elders

BACKGROUND: Benzodiazepines are frequently used medications in the elderly, in whom they are associated with an increased risk of falling, with sometimes dire consequences. OBJECTIVE: To estimate the impact of benzodiazepine-associated injurious falls in a population of elderly persons. METHOD: A nested case-control study was conducted using data collected during 10 years of follow-up of the French PAQUID (Personnes Agées QUID) community-based cohort. The main outcome measure was the occurrence of an injurious fall, which was defined as a fall resulting in hospitalization, fracture, head trauma or death. Controls (3 : 1) were frequency-matched to cases. Benzodiazepine exposure was the use of benzodiazepines over the previous 2 weeks reported at the follow-up visit preceding the fall. RESULTS: Benzodiazepine use was significantly associated with the occurrence of injurious falls, with a significant interaction with age. The adjusted odds ratio for injurious falls in subjects exposed to benzodiazepines was 2.2 (95% CI 1.4, 3.4) in subjects aged > or = 80 years and 1.3 (95% CI 0.9, 1.9) in subjects aged <80 years. The population attributable risk for injurious falls in subjects exposed to benzodiazepines was 28.1% (95% CI 16.7, 43.2) for subjects aged > or =80 years. The incidence of injurious falls in subjects aged > or = 80 years exposed to benzodiazepines in the PAQUID cohort was 2.8/100 person-years. Over 9% of these falls were fatal. According to these results and to recent population estimates, benzodiazepine use could be held responsible for almost 20 000 injurious falls in subjects aged > or = 80 years every year in France, and for nearly 1800 deaths. CONCLUSION: Given the considerable morbidity and mortality associated with benzodiazepine use and the fact that existing good practice guidelines on benzodiazepines have not been effective in preventing their misuse (possibly because they have not been applied), new methods for limiting use of benzodiazepines in the elderly need to be found.     

Drug interactions with cholinesterase inhibitors: an analysis of the French pharmacovigilance database and a comparison of two national drug formularies (Vidal, British National Formulary).

BACKGROUND: Cholinesterase inhibitors (ChEIs) could be involved in several drug-drug interactions (DDIs) because of their complex pharmacodynamic and/or pharmacokinetic properties. AIM: To identify spontaneous reports in the French Pharmacovigilance Database containing DDIs with the three ChEIs marketed in France (donepezil, galantamine or rivastigmine) and to compare the informativity of two national drug references, the French national formulary (Vidal) and the British National Formulary (BNF), for their ability to identify ChEI-related DDIs. METHODS: Spontaneous reports submitted to the French Pharmacovigilance Database concerning donepezil, galantamine or rivastigmine were reviewed by two clinical pharmacologists from Toulouse Regional Pharmacovigilance Centre. Spontaneous reports containing DDIs were identified according to Vidal, BNF or their own judgement (and with use of the interaction supplement of the French independent drug information bulletin La Revue Prescrire). Then, the potential of DDIs to result in adverse drug reactions (ADRs) was evaluated. Finally, the presentations of the different ChEIs in the two references (Vidal, BNF) were compared for their DDI informativity. RESULTS: A total of 1058 spontaneous reports were identified that involved ChEIs in the French Pharmacovigilance Database up to 31 March 2006; of these 376 (35.5%) contained at least one DDI according to experts' judgement. In total, 118 DDIs (31.4%) were the cause of ADRs. Most of the DDIs were due to pharmacodynamic interactions (247 cases, 65.7%). The most frequently encountered drugs involved in DDIs were bradycardic (205 cases, 54.5%) and anticholinergic (118 cases, 31.4%) drugs. DDIs were found in 309 spontaneous reports (29.2%) according to Vidal and in 127 (12.0%) according to BNF. In total, 88 'serious' ADRs were related to DDIs (including seven deaths, mainly due to cardiovascular ADRs). The most frequently observed ADRs due to DDIs were cardiovascular (67 cases, mainly bradycardia, atrioventricular block and arterial hypotension) and neurological (33 cases, mainly mental confusion). Comparison of the different presentations of summary of product characteristics (SPC) showed that Vidal was more informative than BNF for all the ChEIs, and that galantamine had the most complete data in the two references. CONCLUSION: DDIs were present in more than one-third of spontaneous reports including ChEIs registered in the French Pharmacovigilance Database. Approximately, one-third of these DDIs were the cause of ADRs. The informativity of European drug dictionaries differs substantially and Vidal was found to be more informative than BNF for all the ChEIs.     

Use of psychotropic drugs in 0 to 5 years old children in Aquitaine (France): prevalence and associated factors

PURPOSE: To describe the use of psychotropic drugs in children aged 0-5 years, in the Aquitaine region of South-west France and identify associated socio-demographic, familial and medical factors. METHODS: Data used in this study come from the regional drug claims database of the National Health Insurance System of Aquitaine and from postal self-questionnaires sent to parents and prescribing physicians. RESULTS: In Aquitaine, psychotropic drugs were redeemed at least once in 2002 for 3.2% of young children. Hydroxyzine, niaprazide or diazepam were claimed at least once by 2.7% of children registered in the database. Prescribers were mostly general practitioners (76.7%) and pediatricians (20.1%). Psychotropic claims were more frequent in children having the highest number of medical consultations in 2002 (more than 7: odds ratio (OR) = 1.5 [95% confidence interval (CI): 1.3-1.7]) or of drug deliveries (7-15 deliveries: OR = 1.8 [95%CI: 1.6-2.1]; more than 15 deliveries: OR = 3.2 [95%CI: 2.7-3.9]). Psychotropic claim frequency increased with age. No association of psychotropic use with parental psychotropic use, socio-professional category and familial situation was found. CONCLUSIONS: Psychotropic delivery prevalence in Aquitaine in young children was below 5% in 2002. It notably concerned drugs of which the use is not devoid of toxicity because of anticholinergic properties.     

Sudden unexpected death in infants under 3 months of age and vaccination status- -a case-control study

AIMS: To determine whether DTPP+Hib vaccination (diphtheria, tetanus, pertussis, poliomyelitis +/- haemophilus) increased the risk of sudden unexpected death (SUD) in children under 3 months of age. METHODS: We conducted a multicentre case-control study in the 28 French 'SIDS Centers'. Case selection was based on death labelled sudden infant death syndrome (SIDS) of an infant aged between 30 and 90 days. Three living controls were selected, matched for sex, gestational age and born immediately after the victim in the same maternity unit. RESULTS: We identified 114 cases of SUD aged between 30 and 90 days and 341 live controls matched for age and sex and born in the same maternity unit as the case. DTPP+/-Hib immunization did not increase the risk of SUD (OR 1.08) (95% CI 0.49, 2.36) in children under 3 months of age when adjusted for sleeping position, illness in the week before death, maternal tobacco consumption, birth weight, type of mattress, breastfeeding and sex. However, low birth-weight (6.53 [2.29, 18.9]), multiple birth (5.1 [1.76, 15.13]), no breastfeeding (1.77 [1.1, 2.85]), prone sleeping position (9.8 [5, 8, 18, 9]), soft mattress (3.26 [1.69, 6.29]), recent illness (3.44 [1.84, 6.41]) and parental smoking (1.74 [1.2, 2.96]) were confirmed as risk factors in early SIDS. CONCLUSIONS: DTPP+/-Hib immunization is not a risk factor for early SUD. In this population, we found the same risk factors as described for SIDS.     

Non-sedating antihistamine drugs and cardiac arrhythmias -- biased risk estimates from spontaneous reporting systems?

AIMS: This study used spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of non-sedating antihistamine drugs and compared the risk estimate before and after the regulatory action to recall the over-the-counter status of some of these drugs. METHODS: All suspected adverse drug reactions (ADRs) reported until July 1999 to the Netherlands Pharmacovigilance Foundation Lareb were used to calculate the ADR reporting odds ratio, defined as the ratio of exposure odds among reported arrhythmia cases, to the exposure odds of other ADRs (non-cases), adjusted for gender, age, reporter, year of reporting and comedication, stratified for the periods before and after the governmental decision in the Netherlands. RESULTS: Seven-hundred and thirty-seven cases of arrhythmia were reported, out of which there were 43 instances where the patients were using non-sedating antihistamines. In general non-sedating antihistamines are associated with cardiac arrhythmia to a higher extent in comparison with other drugs (ADR reporting odds ratio 2.05 [95% CI: 1.45, 2.89]). The association between arrhythmias and non-sedating antihistamine drugs calculated before 1998 was not significantly higher than 1 (OR 1.37 [95% CI: 0.85, 2.23]), whereas the risk estimate calculated after the governmental decision did significantly differ from 1 (OR 4.19 [95% CI: 2.49, 7.05]). CONCLUSIONS: Our data suggest that non-sedating antihistamines might have an increased risk for inducing arrhythmias. Our findings, however, strongly suggest that the increased risk identified can at least partly be explained by reporting bias as a result of publications about and mass media attention for antihistamine induced arrhythmias.     

The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France

INTRODUCTION: Because of design, objectives and number of included subjects, clinical studies are insufficient to assess the safety of new drugs. Sometimes, serious adverse drug reactions (ADRs) led to withdrawal of the drug from the market after their approval. The objective of our study was to determine the scientific evidences leading to drug withdrawal for pharmacovigilance reasons in France. METHODS: Data coming from French Health Products Safety Agency, literature and Toulouse Pharmacovigilance Center allowed to identify all drugs withdrawn from the French market for pharmacovigilance reasons from 1998 to 2004. We classified data according to their study design (Randomized Clinical Trial [RCT], case serie or case report, case-control study, cohort study, observational study, animal study), the organ/system affected and the type of ADR. RESULTS: A total of 21 drugs were withdrawn for safety reasons between 1998 and 2004 in France. The most frequent ADRs were hepatic (n = 7), cardiovascular (n = 4) or neurological (n = 3) ones. Eleven withdrawals were due to type-B ('unexpected') reactions (52%). For 19 out of 21 drugs, scientific evidence leading to drug withdrawal came from spontaneous case reports (or case series). Among these, case reports were the sole evidence in 12 cases. Withdrawals were based on evidence from case reports in combination with case-control or cohort study in four cases, in combination with observational study in two cases or in combination with animal study in two other cases. In only one case, a RCT supported the decision. CONCLUSIONS: This study underlines the importance of spontaneous case reports in detecting signals and supporting withdrawal of drug for pharmacovigilance reasons in France. Health authorities suffer from lack of comparative data resource. In this perspective, a pharmaco-epidemiological population-based database could represent a helpful tool to both generate and test safety hypotheses.     

Was the thrombotic risk of rofecoxib predictible from the French Pharmacovigilance Database before 30 September 2004?

OBJECTIVES: Rofecoxib was withdrawn from the market on 30 September 2004 following the results of a randomized controlled trial. Following this sudden decision, several controversies occurred in the literature to determine whether this adverse drug reaction (ADR) could have been detected earlier. The aim of this study was to investigate whether this kind of signal could have been seen using the French Pharmacovigilance Database before this date of rofecoxib withdrawal. METHODS: Using cases registered in the French Pharmacovigilance Database from May 2000 to December 2006, we applied the case-noncase method to "serious" thrombotic ADRs reported with oral formulations of rofecoxib or celecoxib in patients older than 15 years. Cases were all notifications of thrombotic ADRs [World Health Organization Adverse Reaction Terminology (WHO-ART) codes 1300] occurred under coxib (rofecoxib, celecoxib) and noncases all other reports registered in the database (whatever the drug). We calculated a cumulative odds ratio (OR) from 20 May 2000 to 31 December 2006, with a special interest for the period before the 30 September 2004. RESULTS: Among the 50,087 "serious" ADRs registered in the database during this period, 1,127 were thrombotic ones. Rofecoxib exposure was significantly associated with high values of odds ratio (OR) [4.2 (95% CI 1.97-8.61)] for thrombotic ADRs as early as the end of 2001. The values of ADR reporting ORs remained high (3.0-3.5) until 2006. For celecoxib, a significant trend occurred only from September 2004. CONCLUSION: Despite the compulsory limits of the case/noncase methodology, this study found an association between rofecoxib exposure and the occurrence of "serious" thrombotic ADRs as early as the end of the first year of rofecoxib marketing in France. The association between celecoxib and the occurrence of such ADRs appears less clear. Our work also shows the potential use of careful analysis of pharmacovigilance databases (investigating, for example, cumulative values of risk) in the early identification of new ADRs.