Marine Auffret

Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation

High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p<0.001), from 0.9% for AWAC=0 to 9.4% for AWAC >35. There was also a significant gradual risk for EMS associated with DDB (<0.001). Multivariate analysis demonstrated a significant interaction between DDB and AWAC on EMS risk (p=0.047). Each 20mg/d increase in DDB was associated with an OR of EMS in AWAC >35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol.

Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study.

In France, the off-label use of high-dose baclofen (HDB) for alcohol dependence is spreading. HDB induces frequent neuropsychiatric adverse events (AEs). Borderline personality disorder (BPD) is a major axis-two psychiatric disorder that exposes to frequent comorbid alcohol dependence and increased risky behaviors. We investigated the drinking and safety outcomes of patients with BPD treated with HDB for comorbid alcohol dependence. In a prospective cohort of 204 patients with alcohol dependence treated by HDB, 23 patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for BPD. We paired two control participants without a psychiatric history with each BPD patient according to age and sex. We compared the average lengths of follow-up, average doses of baclofen received, rates of heavy drinking days, rates of serious AEs, and rates of AEs resulting in baclofen withdrawal. Between BPD patients (n=23) and controls (n=46), there were no significant differences in mean age (45.3±11.2 vs. 45.2±11.2 years), sex ratio (43.5% women), mean duration of follow-up (8.0±4.0 vs. 7.7±4.2 months; P=0.77), and average daily dose of baclofen (102.2±42.7 vs. 94.6±9.7 mg/day; P=0.44). However, the mean rate of heavy drinking days (74.3±25.3 vs. 41.7±33.3%; P<10E−4), the rate of serious AEs (65.2 vs. 6.5%; P<10E−4), and the rate of treatment discontinuation after AEs (52.2 vs. 8.6%; P<10E−4) were significantly higher in BPD. The benefit/risk balance of HDB appears to be unfavorable in comorbid BPD patients compared with nonpsychiatric patients.

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.

Proactive Regional Pharmacovigilance System Versus National Spontaneous Reporting for Collecting Safety Data on Concerning Off-Label Prescribing Practices: An Example with Baclofen and Alcohol Dependence in France

IntroductionOff-label prescribing (OLP) may raise serious safety concerns that traditional spontaneous reporting of adverse drug reactions (ADRs) may not identify in a timely manner. In France, the ‘Multidisciplinary Consultation Service for Off-Label Prescribing in Addiction Medicine’ (CAMTEA) is a proactive regional system established to identify ADRs associated with the OLP of baclofen for alcohol dependence.ObjectiveThe aim was to demonstrate, using the French pharmacovigilance database (FPVD), that CAMTEA allowed for the reporting of a substantial amount of ADRs, comparable in nature to those provided via spontaneous reporting.MethodThe 2012–2013 FPVD notifications associated with baclofen OLP were extracted. The ten most frequent types of ADRs among ‘serious’ and ‘non-serious’ reports were listed. The frequency of each type of ADR was compared between CAMTEA and spontaneous reporting, and the magnitudes of the differences were assessed using standardized differences.ResultsA total of 428 baclofen reports (1043 ADRs) were identified, among which 221 (51.64%) originated from CAMTEA. The ten most frequent ADRs in ‘serious’ reports were (1) confusion (17.3%), (2) seizures (11.5%), (3) drowsiness/sedation (11.5%), (4) agitation (10.9%), (5) coma (9.6%), (6) hallucinations (7.7%), (7) falls (7.1%), (8) behavioral disorders (5.8%), (9) withdrawal syndrome (5.1%), and (10) space–time disorientation (5.1%). A standardized difference of <0.2 was identified for six out of the ten most frequent ‘serious’ ADRs, and eight of the ten ‘non-serious’ ADRs.ConclusionA proactive regional pharmacovigilance system could collect a substantial amount of safety data on a specific OLP practice. The profile of the ADRs collected was similar to that seen in the nationwide spontaneous reporting system.

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

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence.

Safety profile of etifoxine: A French pharmacovigilance survey.

Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine‐related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs. Etifoxine‐related ICSRs were extracted from the French Pharmacovigilance database from 1 January 2000 to 30 April 2012 and data from the marketing authorization holder up to 31 December 2011 were also obtained. Of the 350 cases retained for analysis, 123 (35%) were considered serious. Dermatological or acute hypersensitivity reactions were the most frequent ADRs (59%) mainly isolated cutaneous eruptions. However, there were 24 cases of severe toxidermia (DRESS in 5, erythema multiforme in 10 and Stevens–Johnson syndrome in 5) with etifoxine as the most suspected drug in 11 patients, and seven cases of vasculitis or serum sickness‐like reaction. Liver disorders were reported in 34 patients of whom 25 developed acute hepatitis with a cytolytic biological pattern in 16. Other unexpected ADRs included 16 reversible cases of metrorrhagia with positive rechallenge in 5, and three cases of biopsy‐proven microscopic colitis of which one recurred after etifoxine re‐administration. Although etifoxine has been marketed for more than 30 years, this survey identified a number of unexpected and sometimes serious ADRs, in particularly severe toxidermia and acute cytolytic hepatitis. A recent update of the French etifoxine summary of the product characteristics (SPC) was based on these findings.

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.

Phone-based safety monitoring of the first year of baclofen treatment for alcohol use disorder: the BACLOPHONE cohort study protocol

ABSTRACT Background: In France, baclofen is frequently used off-label for alcohol use disorder (AUD). Baclofen has been associated with diverse adverse events (AEs), but the causality of these AEs has never been properly assessed. Methods/Design: BACLOPHONE is a prospective multicenter cohort study conducted in the Hauts-de-France and Normandie French regions. BACLOPHONE consists of the phone-based monitoring of 792 patients during their first year of baclofen treatment for AUD. Two initial phone interviews assess the medical history, current medications, and substance use as well as complete the alcohol use identification test (AUDIT) and severity of alcohol dependence questionnaire (SADQ). Daily alcohol use and baclofen doses are noted throughout the follow-up. For every reported AE, additional phone interviews determine the seriousness of the AE, the causality of baclofen using validated causality algorithms, and the final outcome. The main objective of the study is to determine the rate of patients who stop baclofen due to an AE during the first year of treatment. Discussion: BACLOPHONE will provide important safety data on baclofen as a complement to the forthcoming efficacy data of randomized clinical trials.

Cytolyse hépatique sous dabigatran étexilate chez un sujet âgé

1 Centre regional de Pharmacovigilance de Lille, CHRU Lille,Faculte de Medecine, Lille, France2 Service de court Sejour Geriatrique, Centre hospitalier deValenciennes, Valenciennes, France3 Service de Pharmacie, Centre hospitalier de Valenciennes,Valenciennes, France4 Centre regional de Pharmacovigilance de Nancy, HopitalCentral, Nancy, France5 http://www.centres-pharmacovigilance.net/Texte recu le 20 fevrier 2013 ; accepte le 21 juin 2013Cas notifie au Centre Regional de Pharmacovigilance de Lillele 4 decembre 2012, n° LL1201210Mots cles : dabigatran etexilate ; cytolyse hepatique ; effet indesirableKeywords: dabigatran etexilate; cytolysis; adverse effect

Unexpected platelets elevation in a patient with idiopathic thrombocytopenia treated with oseltamivir for influenza infection.

Oseltamivir is a neuraminidase inhibitor approved for the prevention and treatment of influenza. Few haematological side effects have been reported with oseltamivir. We report herein the case of an unexpected platelet increase in a 46‐year‐old woman with idiopathic thrombocytopenia (ITP) treated with oseltamivir for influenza. The mechanism may involve the neuraminidase inhibition which decrease platelet surface sialic acid content and reduce their removal by the reticuloendothelial system. Oseltamivir may be responsible for platelet increase especially in patients with ITP.