Efficacy and safety of topiramate in binge eating disorder: a systematic review and meta-analysis.

BACKGROUND: To assess the efficacy and safety of topiramate in treating binge eating disorder (BED), using a systematic review and meta-analysis of the available randomized clinical trials (RCTs). METHODS: The RCTs assessing topiramate vs placebo with or without adjunctive psychotherapy in BED were reviewed using a systematic search in the PubMed, Web of Science, PsycINFO, Cochrane Database of Systematic Review, and ClinicalTrials.gov search Websites, from inception to November 2019. Main outcomes were the changes in binge frequency, quality of life, and weight, respectively. Effect estimates were pooled using random-effect models and presented as risk ratios (RRs) or mean differences (MDs) and their 95% confidence interval (95% CI). Data extraction was performed by two independent reviewers. RESULTS: Three studies were eligible for inclusion, involving 528 BED patients. Topiramate was found to be significantly more efficacious than placebo in reducing: (a) the number of binge episodes per week (MD = -1.31; 95% CI = -2.58 to -0.03; I2 = 94%); (b) the number of binge days per week (MD = -0.98; 95% CI = -1.80 to -0.16; I2 = 94%); and (c) weight (MD = -4.91 kg; 95% CI = -6.42 to -3.41; I2 = 10%). However, participants in the topiramate groups withdrew significantly more frequently for safety reasons, relative to placebo participants (RR = 1.90; 95% CI = 1.13-3.18, I2 = 0%). CONCLUSIONS: Preliminary findings support a possible efficacy of topiramate for the treatment of BED, even if safety concerns could limit the practical use of this treatment in BED subjects.

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

OBJECTIVE: Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. METHODS: Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. RESULTS: One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). CONCLUSION: The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses.

[Evaluation of the website of the Nord-Pas-de-Calais regional pharmacovigilance center]. / Évaluation du site internet du centre régional de pharmacovigilance du Nord-Pas-de-Calais.

We posted the Nord-Pas-de-Calais regional pharmacovigilance center website and distributed a survey to its potential users between August 2014 and October 2014 (135 general practitioners, 45 pharmacists, 14 patients). Satisfaction was 7.3±1.6 out of 10 points for the visual aspect, 7.8±1.5 out of 10 points for navigation and 7.6±1.4 out of 10 points for content. The website was declared useful by 98% respondents, particularly for the reporting of adverse drugs reactions (89%).

Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy.

Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations.

[Drug Shortage May Have Serious Outcome: the French Exemple of Phenytoine]. / Des ruptures de stock aux conséquences parfois graves : l'exemple de la phénytoïne, à propos de 7 cas.

In 2012, in France, phenytoin sodium was used as a substitute for phenytoin base during a shortage at the dose of 100 mg for 100 mg, according to the French Health Agency recommendations. However, this substitution was problematic because the two specialties were not bioequivalent. We report here the case of a 29-year old woman who presented with severe epilepsy. The substitution of phenytoin base by phenytoin sodium induced an increase of seizure frequency leading to several hospitalizations and sick leave. Phenytoin base was finally available again in 2013 which allowed a reduction of seizure frequency. Six similar cases, including one death, were reported to the French pharmacovigilance system. Drug shortages are increasingly common and can have serious consequences. Reporting the difficulties that drug shortage causes to health authorities is important in order to improve their management and to better support patients.

[Temporary recommendation for use on off-label baclofen: viewpoint of Prescribers of the CAMTEA system]. / La « recommandation temporaire d'utilisation ¼ sur le baclofène : point de vue des prescripteurs du dispositif CAMTEA.

The use of high dose baclofen for alcohol-dependence emerged in France from 2008 based on empirical findings, and is still off-label. However, due to the rapid increase in this prescribing practice, the French health authorities have decided to frame it using an extraordinary regulatory measure named "temporary recommendation for use" (TRU). Baclofen prescribers from CAMTEA, a regional team-based off-label system for supervising baclofen prescribing, which was developed much prior to the TRU, discuss herein the pros and cons of this measure and the applicability of its different aspects in the daily clinical practice.

Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database.

OBJECTIVES: The aim of this research was to describe the cases of TNF-α antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-α antagonists and occurrence of alopecia. METHODS: All spontaneous reports of TNF-α antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-α antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-α antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. RESULTS: Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-α antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-α antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-α antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. CONCLUSION: The present study confirms a strong link between TNF-α antagonist exposure (class effect) and the occurrence of alopecia.

Severe tinnitus induced by off-label baclofen.

OBJECTIVE: The γ-aminobutyric acid type B (GABA-B) receptor agonist baclofen is approved for spasticity up to the dose of 80 mg/d. Recently, off-label use of high-dose baclofen (HDB), up to 400 mg/d, has been increasing for treating alcohol use disorders (AUDs), although the efficacy and safety profiles of HDB are relatively unknown. We report 2 cases of tinnitus in patients treated with HDB for AUD. CASE SUMMARIES: The first case concerns a 60-year-old man who reported tinnitus when he reached a 180 mg/d dose of baclofen after 3 months of treatment. Tinnitus persisted until the dose was reduced to 90 mg/d. The second case concerns a 45-year-old woman who presented with tinnitus when she reached a 210 mg/d dose of baclofen after 4 months of treatment. Tinnitus persisted until the dose was reduced to 60 mg/d. DISCUSSION: Using the Naranjo scale, imputability to baclofen was considered probable in both cases. GABA-B receptors have been reported to be implicated in both the etiology and the treatment of tinnitus. There may be an individual susceptibility to develop tinnitus under baclofen therapy because of some GABA-B genetic polymorphisms that remain to be determined. CONCLUSION: HDB may be responsible for the occurrence of severe tinnitus, possibly in a dose-dependent manner. This appears to be coherent with the previously known involvement of GABA-B receptors in the pathophysiology of tinnitus.

Baclofen-induced manic symptoms: case report and systematic review.

BACKGROUND: The gamma-aminobutyric acid type B receptor agonist baclofen is approved for spasticity and is used off-label for diverse types of addictive disorders, notably alcohol dependence. Baclofen may induce numerous neuropsychiatric adverse drug reactions, including behavioral disinhibition. However, this precise adverse drug reaction has never been assessed using either a validated causality algorithm or a scale for manic symptoms. METHODS: We report a case of a 49-year-old male patient who exhibited de novo mania during treatment with baclofen for alcohol dependence. Symptoms were evaluated using the Young Mania Rating Scale, and the causality of baclofen was determined using the Naranjo algorithm. This case was also compared with other cases of baclofen-induced mania through a systematic literature review. RESULTS: Mr. X, taking 180 mg/d of baclofen, presented with mania and scored 24 of 44 on the Young Mania Rating Scale, and the imputability of baclofen was "probable" using the Naranjo algorithm (8 of 13). In addition, 4 other cases of baclofen-induced mania were reported in the literature; 3 cases had a bipolar I disorder history. Baclofen-induced manic symptoms occurred mostly during the dose-escalation phase. CONCLUSION: Baclofen-induced manic symptoms may appear in patients with or without bipolar disorder. Particular attention is required during the dose-increase phase and in patients with a history of mood disorders.

[Mesalazine-related interstitial lung disease: an under-diagnosed effect?]. / Pneumopathie interstitielle diffuse sous mésalazine: un effet indésirable sous diagnostiqué?

We report the case of a woman treated with adalimumab and mesalazine for a Crohn's disease who presented 9 years after the beginning of the treatments an interstitial lung disease (ILD) discovered by chance during a routine medical examination. Several hypotheses were evocated: progression of the Crohn's disease with a pulmonary involvement then the role of adalimumab was finally suspected. Adalimumab treatment was stopped, but several months later, the pulmonary disease persisted. Six months after the initial medical consult, mesalazine treatment was suspected and stopped. The ILD improved and finally completely resolved with no recurrence after one year. Interstitial lung disease is a rare side effect of mesalazine probably underdiagnosed by physicians especially in patients treated with TNF alpha inhibitors.

[Weight gain during treatment with thalidomide: a case report]. / Prise de poids lors d'un traitement par thalidomide: à propos d'un cas.

We report a case of weight gain induced by thalidomide in a 39-year-old female patient with Behçet's disease treated for an indication of severe, bipolar, aphthous stomatitis.

[Ecchymosis during montelukast therapy: about one case]. / Ecchymoses associées à la prise de montélukast: à propos d'un cas.

A young girl aged 13-years-old treated with montelukast, fluticasone/salmeterol, desloratadine, fluticasone furoate and salbutamol has presented numerous spontaneous bruises after that treatment with montelukast was substituted by the generic form. Stopping montelukast allow a significant improvement in bruises.

Fluctuating anaemia in treated HIV patients: could be a PICA?

HIV infected patients are frequently exposed to anaemia, due to antiretroviral agents and/or prophylactic treatment of opportunistic infections. Anemia due to PICA, unusually evoked in our western countries, could be a more frequent situation than imagined. We report two cases of fluctuating anemia with no HIV or iatrogenic origin, observed in two HIV infected women, 47 years old and 33 years old respectively, coming from Africa and treated with antiretroviral agents. The anemia was explained by a culturally sanctioned practice of kaolin ingestion, in the broader context of PICA and resolved after the withdrawal of kaolin ingestion. PICA, and in particular kaolin ingestion, must be investigated when HIV infected patients came from Africa and presented significative unexplained anemia.

Lacosamide use during breastfeeding: A case report and a literature review.

Lacosamide, a voltage-gated sodium channel inhibitor, is an anti-seizure medication (ASM) from the age of 4. We report on the case of a woman treated with lacosamide for pharmacoresistant epilepsy who breastfed her infant for more than 6 months after birth. The infant's blood concentrations of lacosamide were 2.4 mg/L on Day 1 and less than 1 mg/L on Day 10 (reference values are 1-10 mg/L). No adverse drug reactions (ADRs) were reported for the infant. Eight cases of breastfeeding by mothers receiving lacosamide are described in the literature. These data confirm that a significant amount of lacosamide seems to pass into breast milk, with a relative infant dose (RID) above 20% in two cases but a low RID (1.8%) in another case. Nevertheless, blood tests, performed in two breastfed infants, revealed low concentrations of lacosamide. No ADRs were reported in eight of the breastfed infants; however, one infant, whose mother was also treated with levetiracetam, presented poor feeding and sleepiness at Day 15 of life. Given the well-known benefits of breastfeeding for both mothers and their infants, as well as the above reassuring data, breastfeeding of healthy full-term infants could be possible for mothers on lacosamide monotherapy. Nonetheless, relatives should be warned that data concerning the safety of lacosamide during breastfeeding are scarce and that long-term neurodevelopment outcomes in breastfed children are unknown. Clinical monitoring of breastfed infants for drowsiness, adequate weight gain, or cutaneous rash is recommended. Additionally, the infants' serum levels should be measured in case of an unexplained adverse reaction.

What place for intelligent automation and artificial intelligence to preserve and strengthen vigilance expertise in the face of increasing declarations?

In 2018, the "Ateliers de Giens" (Giens Workshops) devoted a workshop to artificial intelligence (AI) and led its experts to confirm the potential contribution and theoretical benefit of AI in clinical research, pharmacovigilance, and in improving the efficiency of care. The 2022 workshop is a continuation of this reflection on AI and intelligent automation (IA) by focusing on its contribution to pharmacovigilance and the applications and tasks could be optimized to preserve and strengthen medical and pharmacological expertise in pharmacovigilance. The evolution of pharmacovigilance work is characterized by many tasks with low added value, a growing volume of pharmacovigilance reporting of suspected side effects, and a scarcity of medical staff with expertise in clinical pharmacology and pharmacovigilance and human resources to support this growing need. Together, these parameters contribute to an embolization of the pharmacovigilance system at risk of missing its primary mission: to identify and characterize a risk or even a health alert on a drug. The participants of the workshop (representatives of the Regional Pharmacovigilance Centres (CRPV), the French National Agency for Safety of Medicinal Products (ANSM), patients, the pharmaceutical industry, or start-ups working in the development of AI in the field of medicine) shared their experiences, their pilot projects and their expectations on the expected potential, theoretical or proven, AI and IA. This work has made it possible to identify the needs and challenges that AI or IA represent, in the current or future modes of organization of pharmacovigilance activities. This approach led to the development of a SWOT matrix (strengths, weaknesses, opportunities, threats), a basis for reflection to identify critical points and consider four main recommendations: (1) preserve and develop business expertise in pharmacovigilance (including research and development in methods) with the integration of new technologies; (2) improve the quality of pharmacovigilance reports; (3) adapt technical and regulatory means; (4) implement a development strategy for AI and IA tools at the service of expertise.

Quantitative Prediction of Adverse Event Probability Due to Pharmacokinetic Interactions.

INTRODUCTION: Iatrogeny due to drug-drug interactions is insufficiently documented, due to the high number of possible combinations. OBJECTIVE: This study aimed to design a simple but general method to predict the variation of adverse events (AE) frequency due to a pharmacokinetic or pharmacodynamic interaction. METHODS: Three prediction models were designed using a logistic probability density function. Each prediction model was based on three components: the AE odds ratio of each drug in the combination, and the area under the curve ratio (Rauc) of the pharmacokinetic interaction, if any. Pharmacodynamic interaction was assumed to be additive on logit scale. Rauc was predicted using a well-validated mechanistic static model, freely available online. No combination study is required. The method was evaluated against a wide range of AEs (28 High Level Terms) and 211 drug combinations (involving 43 victim drugs and 55 perpetrators), by comparing the observed and predicted frequencies. The observed odds ratios were estimated with a disproportionality analysis from the FDA Adverse Event Reporting System, using an approach that minimizes biases. RESULTS: With the best model, the rate of prediction considered as correct (within 50-200% of the observed value) was 72%, and the bias was negligible (-5%). The AE odds ratio due to pharmacokinetic and pharmacodynamic interactions was equally well predicted. CONCLUSIONS: A simple workflow to implement the method in practice is proposed. This method may help to foresee and to anticipate the harmful consequences associated with drug-drug interactions, at virtually no experimental cost, when the odds ratio of an AE is known for each drug alone and the AUC ratio is known or predicted by a suitable model.

Guillain-Barré Syndrome Associated with COVID-19 Vaccines: A Perspective From Spontaneous Report Data.

BACKGROUND AND OBJECTIVE: The concern surrounding the association between Guillain-Barré syndrome (GBS) and vaccination has increased with the widespread use of COVID-19 vaccines. The aim of this study was to assess the potential association of GBS with mRNA-based or adenovirus-vectored COVID-19 vaccines. METHODS: Reports of GBS associated with mRNA-based or adenovirus-vectored COVID-19 vaccines were extracted from the WHO pharmacovigilance database, exposure data from the Our World in Data website, and the background rates of GBS from published data. For countries contributing to VigiBase and with available data on COVID-19 vaccine exposure, reporting rates were estimated and observed-to-expected (OE) analyses were performed. RESULTS: A total of 2499 cases were included: 1157 (46.3%) cases with adenovirus-vectored COVID-19 vaccines and 1342 (53.7%) with mRNA-based COVID-19 vaccines. The male-to-female sex ratio was 1.09 and the median (IQR) age was 57 (45-66) years. The reporting rates (95% CI) per 100,000 person-years within the 42-day window were 5.57 (5.13-6.03) for adenovirus-vectored COVID-19 vaccines and 1.39 (1.31-1.47) for mRNA-based COVID-19 vaccines, while the background incidence was 1.2-3.1 per 100,000 person-years. For mRNA-based COVID-19 vaccines, the OE ratio was <1 for both time windows in all European countries and slightly elevated for the 21-day window in the USA. For adenovirus-vectored COVID-19 vaccines, the OE ratio was consistently > 2.0 for all countries. Sensitivity analyses minimally altered these results. CONCLUSIONS: These findings suggest both the absence of safety concern for GBS with mRNA-based COVID-19 vaccines and an increased risk with adenovirus-vectored COVID-19 vaccines. Back to top.

Gabapentinoid-induced peripheral edema and acute heart failure: A translational study combining pharmacovigilance data and in vitro animal experiments.

INTRODUCTION: Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure in connection with a potentially dual mechanism, vascular and cardiac. OBJECTIVES & METHODS: All cases of peripheral edema or heart failure involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were included to describe their onset patterns (e.g., time to onset). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries and on the electrophysiological properties of rat ventricular cardiomyocytes. RESULTS: A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57-85, range 32-95). The median time to onset were 23 days (IQR 10-54) and 17 days (IQR 3-30) for non-cardiogenic edema and acute heart failure, respectively. Cardiogenic and non-cardiogenic peripheral edema occurred frequently after a dose escalation (27/45, 60%), and the course was rapidly favorable after discontinuation of gabapentinoid (median 7 days, IQR 5-13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Acute application of gabapentinoids had no significant effect on Cav1.2 currents of ventricular cardiomyocytes. CONCLUSION: Gabapentinoids can cause concentration-dependent peripheral edema of early onset. The primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Cav1.2 blockade under the experimental conditions tested.

A capture-recapture method for estimating the incidence of off-label prescriptions: the example of baclofen for alcohol use disorder in France.

The local/regional incidence of off-label prescriptions can be difficult to estimate. Capture-recapture models can be used to indirectly estimate population sizes. Here, we used a capture-recapture model to estimate the number of patients treated off-label with baclofen for alcohol use disorder in northern France in 2013. Three capture sources were used: (i) the active case file at the region's largest Addiction Unit, (ii) the regional pharmacovigilance centre, and (iii) a sample of community pharmacies. After between-source overlaps had been identified, we used a log-linear model to produced eight estimates. Two models displayed the best goodness-of-fit, with estimates [95% confidence interval] of 1123 [714-2162] and 2180 [1598-2870] subjects, respectively. These two values are in line with a previous estimate of 1624 patients, based on an analysis of the French national health insurance database in 2013. Capture-recapture methods can be usefully applied to estimate the prevalence of OLPs in a specific geographical area, when direct counting is not feasible or the estimate through claim database is not possible.