Adverse Effects of Treatment with Valproic Acid during the Neonatal Period.

INTRODUCTION: Valproic acid (VPA) is rarely used in neonatal period. In children under 2 years old, serious adverse effects are appear to be more frequent. AIM: The aim of our study is to report the adverse effects observed in a population of full-term newborns treated with VPA. METHOD: Full-term newborns, hospitalized at the Toulouse CHU, who presented with neonatal seizures and who received long-term treatment with VPA between 2004 and 2014 were included. RESULTS: For 5 of the 123 newborns treated with VPA, treatment had to be discontinued due to adverse effects. Three patients presented with disturbances in consciousness within 48 hours of treatment initiation, one case with a moderate overdose and two with hyperammoniemia (157 and 327 µmol/L) without any drug overdose or underlying liver or metabolic disease (VPA-induced hyperammonemic encephalopathy). Two patients presented with secondary hematological alterations. No patient presented with liver toxicity or exacerbation of an underlying metabolic disease. CONCLUSION: While the serious adverse effects of VPA noted were all reversible with the discontinuation of the treatment, the occurrence of encephalopathies with hyperammoniemia is a serious complication that is potentially lethal and calls for close clinical monitoring of newborns treated with valproate. We provide precautions for the implementation and follow-up of VPA in newborns.

Peripheral arterial occlusive disease during ponatinib therapy after failure of imatinib: a case report.

WHAT IS KNOWN AND OBJECTIVE: Peripheral vascular adverse events have been reported with ponatinib treatment in chronic myeloid leukaemia (CML) after failure of dasatinib or nilotinib. We here report peripheral arterial occlusive disease (PAOD) in a patient who had previously received only imatinib as tyrosine kinase inhibitor. CASE DESCRIPTION: The patient was a 70-year-old man with no history of cardiovascular disease. He developed arterial hypertension 5 months after the initiation of ponatinib and PAOD 41 months later. WHAT IS NEW AND CONCLUSION: Peripheral arterial occlusive disease can occur several years after the initiation of ponatinib in patients who had previously received only imatinib. Long-term surveillance is required for preventing the complications of ponatinib-associated PAOD.

Severe adverse effects of bromocriptine in lactation inhibition: a pharmacovigilance survey.

OBJECTIVE: To assess the nature and conditions of the occurrence of adverse drug reactions (ADRs) of bromocriptine, which is used to inhibit lactation. DESIGN: Observational study. SETTING: Cases from the French pharmacovigilance database and the marketing authorisation holders. SAMPLE: Serious ADRs reported between 1994 and 2010 in association with bromocriptine used for lactation inhibition in France. METHODS: Each case was checked to confirm the bromocriptine indication, the seriousness of the ADR, the modalities of bromocriptine use, and to identify possible associated predisposing factors. MAIN OUTCOME MEASURES: Number and description of serious ADRs, with a particular focus on misuse and associated predisposing factors. RESULTS: Among 105 serious ADRs, including two fatal cases, the most frequent were cardiovascular (70.5%), neurological (14.3%), and psychiatric (8.6%) disorders. Cardiovascular disorders primarily consisted of ischaemic manifestations (n = 47): acute ischaemic stroke (n = 18, one death), myocardial infarction (n = 11, one death), and reversible postpartum cerebral angiopathy (n = 10). Misuse was identified in 52 cases (70.3%) of cardiovascular disorders, and mostly consisted of bromocriptine continuation despite the occurrence of first symptoms suggesting an ADR or the absence of a progressive titration of bromocriptine. About half of these women had cardiovascular predisposing factors, mainly tobacco smoking, overweight or obesity, or a history of hypertension or pre-eclampsia. CONCLUSIONS: This survey, together with published data, provides further evidence that serious ADRs still occur after bromocriptine use in lactation inhibition, and that most of these ADRs could have been avoided. The use of bromocriptine should therefore be limited to cases where no other options are available to inhibit lactation.

Ischaemic stroke after exposure to aflibercept: interaction with vitamin K antagonist and/or direct pharmacodynamic effect?

WHAT IS KNOWN AND OBJECTIVE: Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of vascular endothelium, and their inhibition led to the development of a number of drugs used for malignancies or exudative neo-vascular age-related macular degeneration (AMD). CASE SUMMARY: We report a case of ischemic stroke in an 87-year-old woman having received intravitreal aflibercept, a new anti-VEGF for AMD. She had been treated with ranibizumab since 2007. In 2013, ranibizumab was replaced with aflibercept, followed by a decrease in the International Normalized Ratio, complicated by a stroke a few days later. The rechallenge was positive. WHAT IS NEW AND CONCLUSION: A potential time-dependent interaction between aflibercept and VKA antagonist and/or a direct effect of aflibercept may have contributed to the occurrence of the ischaemic stroke. Currently available data suggest some pharmacokinetic and pharmacodynamic effects of aflibercept by explaining its pro-thrombotic profile.

Medication exposure and spontaneous abortion: a case-control study using a French medical database.

PURPOSE OF INVESTIGATION: Few studies have been conducted to investigate drug effects on spontaneous abortion risk. The objective of the present study was to evaluate the potential association between first trimester drug exposure and spontaneous abortion occurrence. MATERIALS AND METHODS: The authors performed a nested case-control study using data from TERAPPEL, a French medical database. Cases were the women who had a spontaneous abortion (before the 22nd week of amenorrhea) and controls were women who gave birth to a child. Analyzed variables were: maternal age, obstetric history, tobacco, and alcohol and drug consumption during the first trimester of pregnancy. For comparison of drug exposures between cases and controls, the authors calculated odds ratios (ORs) by means of multivariate logistic regressions adjusted on age and on other drug exposures. RESULTS: The study included 838 cases and 4,508 controls that were identified in the database. In adjusted analyses, cases were more exposed than controls to "non-selective monoamine reuptake inhibitors" [OR=2.2 (CI 95% 1.5-3.3)], "antiprotozoals" [OR = 1.6 (CI 95% 1.1 - 2.5)] and "centrally acting antiobesity products" [OR = 3.4 (CI 95% 1.9 - 6.2)]. Conversely, controls were more exposed than cases to H1 antihistamines [OR = 0.6 (CI 95% 0.4 - 0.9)]. CONCLUSION: This exploratory study highlights some potential associations between first trimester drug exposure and risk of spontaneous abortion. Further studies have to be carried out to investigate these findings.

Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database.

OBJECTIVE: To compare pregnancy outcome between women exposed and unexposed to oseltamivir during pregnancy. DESIGN: A comparative observational cohort study of women exposed to oseltamivir during pregnancy. SETTING: A French prescription database (EFEMERIS) that includes data for pregnant women was used. EFEMERIS records prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes in Haute-Garonne, South West France. POPULATION: Women who delivered from 1 July 2004 to 31 December 2010. METHODS: The study compared exposed and unexposed pregnant women. Two women unexposed to oseltamivir were individually matched, by maternal age, month, and year of delivery, with one women exposed to oseltamivir. Multivariable conditional logistic regression and multivariable Cox proportional hazards regression were used to evaluate associations between each outcome and exposure to oseltamivir during pregnancy. MAIN OUTCOME MEASURES: Pregnancy loss for any cause, preterm delivery, low birthweight, neonatal pathology, and congenital malformation. RESULTS: A cohort of 337 (0.58% of women included in EFEMERIS) women exposed to oseltamivir were compared with 674 unexposed women. The risk for pregnancy loss (HR 1.52; 95% CI 0.80-2.91), for preterm birth (adjusted OR 0.64; 95% CI 0.31-1.27), and for neonatal pathology (adjusted OR 0.62; 95% CI 0.23-1.54) did not differ between exposed and unexposed groups. When exposure during organogenesis was considered, one case of congenital anomaly (2.0%) among 49 exposed women and one case (1.0%) among 99 unexposed women were observed (crude OR 2.00; 95% CI 0.13-32.00). CONCLUSIONS: There was no significant association between adverse pregnancy outcomes and exposure to oseltamivir during pregnancy.

Adverse drug reactions in an emergency medical dispatching centre.

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

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital.

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

Healthcare cost impact of biological drugs compared with traditional systemic treatments in psoriasis: a cohort analysis in the French insurance database.

BACKGROUND: Biological drugs have dramatically improved the management of moderate to severe psoriasis. Little is known about their economic impact in daily clinical practice. OBJECTIVE: The aim of this study was to estimate the costs of biological drugs, in term of health resources consumption, and to compare it with costs induced by traditional systemic treatments. METHODS: This cohort study was built from the French health insurance database in the Midi Pyrénées area (2.8 million inhabitants, South West of France). We compared health care costs between 'exposed' patients treated with biological drugs (adalimumab, etanercept, infliximab or ustekinumab) and 'unexposed' patients defined as patients who received traditional systemic treatments (phototherapy, acitretin, methotrexate or cyclosporin) during a 6-month period. RESULTS: A total of 1924 patients met the inclusion criteria. Sixty-nine patients were 'exposed', whereas 1855 patients were 'unexposed'. 'Exposed' patients had a mean total healthcare cost of 8107€ vs. 1678€ (P < 0.001) for 'unexposed' patients. They had higher costs concerning inpatient admission, medication and consultations including dermatology consultations, laboratory, non-medical care and transportation. Biological drug prescription was associated with an increase in the use of anti-infective drugs and with a reduction in the use of psychoactive drugs. CONCLUSION: The mean total health care expenditure in patients treated with biological drugs was five times higher as compared with patients treated with traditional systemic treatments. The limitation of the study is the short duration of follow-up comprising a loading dose period for some biological drugs. This may have contributed to an overestimation of drug-related costs.

Analysis of patients' narratives posted on social media websites on benfluorex's (Mediator® ) withdrawal in France.

WHAT IS KNOWN AND OBJECTIVE: Websites and discussion lists on health issues are among the most popular resources on the Web. Use experience reported on social media websites may provide useful information on drugs and their adverse reactions (ADRs). Clear communication on the benefit/harm balance of drugs is important to inform proper use of drugs. Some data have shown that communication (advisories or warnings) is difficult. This study aimed to explore the Internet as a source of data on patients' perception of risk associated with benfluorex and the impact of wider media coverage. METHODS: Three French websites were selected: Doctissimo, Atoute.org considered the best-known and visited website in France for health questions and Vivelesrondes (Long live the Tubbies) for overweight people. Three periods were chosen: (1) before November 2009 (i.e. before benfluorex withdrawal), (2) between November 2009 and November 2010 (when the risk of valvulopathy with benfluorex appeared in social media) and (3) after November 2010. RESULTS AND DISCUSSION: Two hundred twenty initial postings were analysed. These lead to 660 secondary postings which were analysed separately. In period 1, 114 initial postings were analysed, mostly concerning efficacy of the drug (72%). In period 2, 42 initial postings were analysed involving mainly ADRs or warnings (73%). In period 3, 64 initial postings were analysed; most frequent expressing anger directed at the healthcare system (58%) and anxiety about cardiovascular ADRs (30%). Online consumer postings showed that there were drastic changes in consumers' perceptions following media coverage. WHAT IS NEW AND CONCLUSION: This study suggests that analysis of website data can inform on drug ADRs. Social media are important for communicating information on drug ADRs and for assessing consumer behaviour and their risk perception.

[Generic substitution in primary care in 2011: differences according to pharmacological classes?]. / Différences de taux de substitution des médicaments génériques en Midi-Pyrénées en fonction des classes pharmaco-thérapeutiques.

BACKGROUND: Generic substitution has been permitted for several years in France and is promoted in order to reduce health expenditures. However, reluctance concerning use of generic drugs exists for different reasons: suspicions about their efficacy and/or safety, differences in content (excipients) and discussions about bioequivalency. The aim of our study was to determine whether or not the substitution ratio differs according to pharmacological classes used in primary care. METHODS: We conducted a descriptive study in the French Health Insurance Database using reimbursement data on drugs prescribed and delivered in the Midi-Pyrénées administrative district between March 2010 and March 2011. We selected different pharmacological classes largely used in primary care. For each class, a substitution ratio was calculated (DDD of generics delivered/DDD of brand name plus generics). A Chi(2) test was used in order to detect a difference between these substitution ratios. RESULTS: The global substitution ratio was 72.32%. Values varied from 28.36% for thyroid hormones to 90.39% for antibiotics, with significant statistical difference (P<0.001). The substitution ratio was less than 50% for thyroid hormones (28.36%) and antiepileptics (45.28%). Higher substitution ratios were observed for protein pump inhibitors (88.81%), statins (87.81%), antidepressors (87.37%) and diuretics (86.1%). CONCLUSION: This study highlights major differences in terms of the generic substitution ratio between different pharmacological classes. This difference can be explained in part by published guidelines. Further studies are needed to ascertain the precise point of view of patients, general practitioners and pharmacists concerning this issue.

Statin-induced lupus: a case/non-case study in a nationwide pharmacovigilance database.

Statin use has been advocated to prevent atheromatous complications in lupus patients and may be widely prescribed for these patients in future. Statin-induced lupus has also been described, though the risk is not confirmed. The goal of this study was to detect a safety signal regarding statin-induced lupus. We conducted a case/non-case study in the French PharmacoVigilance Database from January 2000 until December 2010. Cases were drug-induced lupus reports. Non-cases were all reports of other adverse drug reactions (ADRs). Exposure to statins at the time of ADR was screened in each report. Among 235,147 ADR reports, 232 were drug-induced lupus. Exposure to statins was present in 17 (7.3%) cases and in 10,601 (4.7%) non-cases. Reporting odds ratio (ROR) for statin exposure associated with lupus erythematosus was 1.67 (95% confidence interval 1.02-2.74). The ROR was > 1 for each statin but fluvastatin. This pharmacoepidemiological study suggests a link between statin exposure and lupus induction. The benefit-to-risk ratio of statin therapy in lupus patients should be evaluated through randomized controlled trials.

Influence of fluoroquinolone consumption in inpatients and outpatients on ciprofloxacin-resistant Escherichia coli in a university hospital.

BACKGROUND: The increase in fluoroquinolone-resistant Escherichia coli has raised the issue of treatment failure in common infections. Few studies have investigated the possible relationship between outpatient fluoroquinolone consumption and resistance in hospital. OBJECTIVE: To investigate the relationship between inpatient and outpatient fluoroquinolone use and ciprofloxacin-resistant E. coli in a teaching hospital. METHODS: An ecological study was conducted in Toulouse University Hospital and its surrounding area, the Midi-Pyrénées region (south-western France), in 2004-07. Dynamic regression models were built to study how the hospital resistance rate was linearly related to current and past values of fluoroquinolone consumption. Resistance forecasts for 2008 were then calculated and compared with actual rates for the first 5 months of the year. RESULTS: Mean resistance rate was 13.7% and mean fluoroquinolone use was 89.9 defined daily doses (DDDs)/1000 inpatient days in hospital and 2.6 DDDs/1000 inhabitants/day in the region. Taking into account past values of fluoroquinolone consumption in hospital and in outpatients, only levofloxacin use in the community remained significantly associated with resistance in hospital, with a lag of 12 months. This model explained 50% of the resistance variability. CONCLUSIONS: This ecological analysis, conducted on a teaching hospital scale, suggests that ciprofloxacin resistance in E. coli in hospital is linked to consumption of fluoroquinolones within the hospital and its surrounding community. Among all fluoroquinolones, levofloxacin use was found to be the most important factor. Consumption in outpatients appears to be a relevant determinant to consider in designing interventions to reduce resistance in hospitals.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database.

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

Evolution of drug consumption in a sample of French workers since 1986: the 'Drugs and Work' study.

PURPOSE: France is known to have a relatively high prescription rate for medicines. Few studies have investigated drug use among a healthy worker population. The aim of this study was to describe the changing patterns of drug use in French workers since 1986 and to evaluate the impact of programs developed to reduce drug consumption. METHOD: A cross-sectional survey has been performed every 10 years since 1986 among workers from the Toulouse metropolitan area (Southwestern, France) using an anonymous questionnaire given to workers during their compulsory annual medical visit. Results of the 2006 survey (2213 workers) were compared to those obtained in 1986 and 1996. A multivariate analysis was performed to investigate factors associated to the modification of drug use with time. RESULTS: During the last ten years, prevalence of overall drug consumption decreased (40.7% in 2006 vs. 46.7% in 1996, p < 0.001) in contrast to the increase observed between 1986 and 1996. Since 1986, patterns of drug use have been modified with a decrease in anti-infectious (OR = 0.24) digestive (OR = 0.54), psychotropic (OR = 0.54), endocrine (OR = 0.57) and cardiotropic (OR = 0.68) drug use. In contrast, there was a significant increase in musculosqueletic (OR = 2.16) drug use. Whatever the period, overall drug consumption was related to age, gender or extraprofessional problems. CONCLUSIONS: This study illustrates the changing patterns of drug use in a population of workers during the last 20 years and underlines the importance of awareness raising campaigns on prescription patterns.

Drug exposure and perceived adverse drug events reported by liver-transplant patients.

INTRODUCTION: Posttransplant patient outcome and quality of life are affected by different factors, such as post-graft context, psychological state, and polymedication. Many surveys have been carried out to study immunosuppressant ADRs, and have mainly used a questionnaire completed by patients, but few have asked patients about their drug exposure. The aim of this study is to describe drug exposure and adverse drug events (ADEs) reported by liver-transplant patients (LTP). METHODS: This observational, retrospective study assessed questionnaires from LTPs concerning demographic data, drug exposure, and ADEs. RESULTS: 118 LTPs exposed to 5.9 (+/- 2.8) drugs with immunosuppressive regimens, consisting mainly of tacrolimus (79.3%), cyclosporine (18.1%), or sirolimus (2.6%), were also exposed to antihypertensive drugs (43.2%), protonpump inhibitors (30.5%), statins (28.8%), drugs acting on bile composition (26.3%), and diuretics (19.5%). 1,389 ADEs were reported: 30.1% neurological, 13.4% cutaneous, 12.4% hematological, 11.1% digestive, 10.1% osteomuscular, 6.6% cardiovascular, and 16.3% others. Significantly more ADEs were reported by patients exposed to cyclosporine than those receiving tacrolimus (p < 0.05). Patients with a transplant for < 18 months had more tremors and those with a transplant for > 79 months reported more hirsutism, gingival hypertrophia, and arterial hypertension. CONCLUSIONS: This study shows the value of patient-reporting via structured interviews for both drug exposure and ADEs, and the importance of this approach to complement total data collection.