[Management of medication errors in general medical practice: Study in a pluriprofessionnal health care center]. / Gestion des erreurs médicamenteuses en médecine générale : étude en maison de santé pluridisciplinaire.

BACKGROUND: Medication errors are the most frequent medical care adverse events in France. Their management process used in hospital remains poorly applied in primary ambulatory care. OBJECTIVES: The main objective of our study was to assess medication error management in general ambulatory practice. The secondary objectives were the characterization of the errors and the analysis of their root causes in order to implement corrective measures. METHODS: The study was performed in a pluriprofessionnal health care house, applying the stages and tools validated by the French high health authority, that we previously adapted to ambulatory medical cares. RESULTS: During the 3 months study 4712 medical consultations were performed and we collected 64 medication errors. Most of affected patients were at the extreme ages of life (9,4 % before 9 years and 64 % after 70 years). Medication errors occurred at home in 39,1 % of cases, at pluriprofessionnal health care house (25,0 %) or at drugstore (17,2 %). They led to serious clinical consequences (classified as major, critical or catastrophic) in 17,2 % of cases. Drug induced adverse effects occurred in 5 patients, 3 of them needing hospitalization (1 patient recovered, 1 displayed sequelae and 1 died). In more than half of cases, the errors occurred at prescribing stage. The most frequent type of errors was the use of a wrong drug, different from that indicated for the patient (37,5 %) and poor treatment adherence (18,75 %). The systemic reported causes were a care process dysfunction (in coordination or procedure), the health care action context (patient home, not planned act, professional overwork), human factors such as patient and professional condition. The professional team adherence to the study was excellent. CONCLUSION: Our study demonstrates, for the first time in France, that medication errors management in ambulatory general medical care can be implemented in a pluriprofessionnal health care house with two conditions: the presence of a trained team coordinator, and the use of validated adapted and simple processes and tools. This study also shows that medications errors in general practice are specific of the care process organization. We identified vulnerable points, as transferring and communication between home and care facilities or conversely, medical coordination and involvement of the patient himself in his care.

[The congress of the French Society of Pharmacology and Therapeutics celebrate in Nancy, 20 April 2016, 40 years of French Regional Pharmacovigilance Centres!]. / Le congrès de la Société française de pharmacologie et de thérapeutique célèbre à Nancy, le 20 avril 2016, les 40ans des centres régionaux français de pharmacovigilance !

In 1976, the Regional Pharmacovigilance Centres were created in France to collect and analyze adverse drug reactions. Even if they have, to date, managed and transmitted more than 583,000 adverse drug reactions to the French and international health authorities, the missions of these university hospital structures supervised by clinical pharmacologists are not limited to this activity. They also provide a consulting and diagnostic aid for drug diseases. Their other main mission is information about drugs and their proper use for health professionals and patients on any matter relating to medicines. These queries are used to adjust and focus the training of health professionals in prevention of drug risks and improvement of drug use. Beside signal detection and identification of alerts, the 31 Regional Pharmacovigilance Centres collaborate with the French Drug Agency (Agence nationale de sécurité du medicament et des produits de santé [ANSM]) by achieving expertise on drugs and participation in various working groups and committees. Finally, Regional Pharmacovigilance Centres participate in scientific advancement through research and publication activities.

[Pristinamycin/Vitamin k antagonists drug interaction: a French pharmacovigilance database study]. / Interaction pristinamycine/antivitamine K: analyse de la base française de pharmacovigilance.

OBJECTIVE: To analyse pristinamycin/vitamin K antagonists (VKA) drug interaction by using data recorded in the French pharmacovigilance database (FPVB). METHODS: All cases with an increase effect of a VKA and an association with pristinamycin recorded in the FPVB between 1985 and 2013 were included. Data concerning patients, VKA treatments and side effects were recorded for a descriptive analysis. RESULTS: During this period, 31 reports with a VKA overdose after an association with pristinamycin were included. Fluindione is the most often involved VKA (77% of cases). In 20 cases (65.4%), VKA overdose caused bleeding and 24 cases (77.4%) were serious. CONCLUSION: Although mechanism is unknown, pristinamycine/AVK drug interaction is a reality that needs to be reported in the summary of product characteristics of these drugs and better known by practitioners to act in patients' interest.

Cetuximab infusion reactions: French pharmacovigilance database analysis.

OBJECTIVES: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions. METHODS: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0). Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions. RESULTS: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion reaction (p < 0.001). Among the seven deaths related to an infusion reaction, five patients were treated for head and neck cancer. Infusion reactions were more likely to be severe when they occurred during the first administration (OR = 7.40 95% CI [2.21-24.71]), adjusted for age, sex, region of France, quarter of the year, indication, year of occurrence, and premedication. CONCLUSION: Our study found that reports of infusion reactions more often concerned patients treated for head and neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion, especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E-mediated mechanism, reliable tests for their detection need to be readily available.

[Tramadol-induced hypoglycemia. 2 cases]. / Hypoglycémie lors d'un traitement par tramadol. A propos de deux cas.

INTRODUCTION: Tramadol has been approved in France since 1994 for the treatment of moderate to severe pain. The most commonly reported adverse effects involve the central nervous system and gastrointestinal tract. To our knowledge, hypoglycemia has not previously been reported. CASE: We report 2 cases of hypoglycemia related to tramadol, one in a nondiabetic 88-year-old woman, and the other in a diabetic 8-year-old girl. Hypoglycemia resolved after tramadol discontinuation. DISCUSSION: The French Pharmacovigilance (Adverse Drug Reports) database includes several cases of hypoglycemia in patients receiving tramadol. Reports from the literature of dextropropoxyphene-induced hypoglycemia and a pharmacological study of tramadol in rats suggest that the micro opioid receptor is the principal target involved in this hypoglycemic mechanism.

[Validation of a measurement scale: example of a French Adverse Drug Reactions Preventability Scale]. / Validation d'une échelle de mesure: exemple de l'échelle française d'évitabilité des effets indésirables médicamenteux.

Adverse drug reactions (ADRs) have been recognised as an important cause of hospital admission. Most of these drug-related admissions were expected ADRs and, thus, partly preventable. However, as far as we know, the assessment of the preventability of ADRs was addressed in only two studies performed in France. In contrast, several other studies have been performed, mainly in the USA, and using different methods of assessing preventability. None of these methods were clearly evaluated with regard to reproducibility, validity or relevance. The purpose of this study was to initiate the validation of a French preventability scale. Here, we propose the first two phases of validation: the content validity and reliability of the scale. A working group of pharmacovigilance experts has been specifically established for this purpose. The content validity was assessed by collecting items representative of preventability. The choice and the formulation of items and a proposal of a score (global and for each item) were adopted after the consensus of the experts. A definitive version of the ADR preventability scale was used for the assessment of reliability. During the second phase, experts independently tested the new scale from observations of ADRs (49 central nervous system haemorrhages with antivitamine K). The concordance of the experts' judgements was calculated using two statistical methods (Kappa statistic and correlation coefficient). The content validity phase was performed during several workshops where experts discussed the choice and formulation of the best items. We decided to construct a scale with a small number of items, allowing a rapid evaluation of the preventability of ADRs. On the basis of a global score, four categories of preventability of ADRs ("preventable", "potentially preventable", "unclassable", "not preventable" ADRs) were proposed. The agreement of experts regarding the global score was low, with a poor correlation coefficient value (coefficient interclass = 0.491). Classification of ADRs in the four categories by the experts showed discrepancies (Kappa = 0.1136). The preventability assessment using this scale was feasible, although poor concordance between the judges has raised some questions. Several experts found use of this scale difficult in terms of a clear understanding of the items, and found that two of them were redundant. We have oversimplified some items and revision of their formulation will be necessary. Moreover, most of ADR notifications were poorly documented, resulting in a frequent choice of an "unevaluable" item. This represented an important bias in the calculation of the global score. This experience suggests the need for further studies to improve this French ADR preventability scale and validate it in differing circumstances, in order to provide a useful tool to enhance the rational use of drugs.

Acute liver enzyme elevations in HIV-1-infected patients.

BACKGROUND: Acute liver enzyme elevations (ALEE) have been associated with a first-line highly active antiretroviral therapy (HAART) and/or viral hepatitis coinfections in HIV-infected patients. By comparison, the frequency and the risk factors of ALEE in untreated patients and in patients treated with several antiretroviral regimens need to be assessed. PURPOSE: To describe the long-term frequency and the characteristics of ALEE in antiretroviral treated and untreated patients and to define risk factors for ALEE in a retrospective cohort of HIV-1-infected patients. METHOD: An HIV-infected cohort was retrospectively examined. ALEE was defined as levels of alanine amino transferase and/or alkaline phosphatase rising to at least 2.5 times above baseline values. Hazard ratios (HR) for ALEE were estimated using an extension of the Cox proportional model taking into account recurrent events. RESULTS: Out of 239 assessable patients, 12 (5%) were coinfected with hepatitis B virus (HBV) and 34 (14.2%) with hepatitis C virus (HCV). The incidence rate of ALEE was 9.9/100 patients-year and the cumulative incidence was 20.9%. HCV genotype 3 tended to give a higher risk of ALEE. Independent factors for developing ALEE in multivariate logistic regression were HBV (HR = 4.0) and HCV (HR = 3.4) coinfections, antiretroviral therapy (HR = 2.6), CDC stage C (HR = 2.5), and high alkaline phosphatase baseline values (HR = 1.7). CONCLUSION: The occurrence of ALEE is influenced more by the past medical history and the clinical background of the patients than by antiretroviral therapy. These patient-linked variables must be taken into account to avoid unwarranted treatment withdrawal.

Joint symptoms in patients on bupropion therapy.

OBJECTIVE: To describe joint symptoms related to bupropion therapy. METHODS: We retrospectively reviewed adverse events in bupropion-treated patients reported to the Bourgogne Drug Surveillance Center, France, between October 2001 and December 2002. Joint symptoms classified by the causality assessment as related to bupropion were identified and examined. RESULTS: Four cases were found. Three patients had semi-delayed hypersensitivity reactions resembling serum sickness, manifesting as urticaria and arthralgia with or without a fever. The remaining patient had an unusual presentation consisting in acute monoarthritis of the wrist that started a few days after bupropion initiation. CONCLUSION: Hypersensitivity reactions to bupropion are fairly common and include rare cases of serum sickness-like reaction. Urticaria and incapacitating arthralgia are at the forefront of the clinical picture and may require a brief period of inpatient care. Antihistamines are the treatment of choice. Other manifestations such as acute monoarthritis might occur, although this awaits confirmation as we identified a single case.

VFEND® (voriconazole)-associated hypoglycaemia without identified drug interaction.

To report the first case of severe hypoglycaemia episodes related to voriconazole, involving neither over dosage nor any identified interaction with hypoglycaemic drugs. A 51-year-old man developed faints without loss of consciousness, with sweating in the morning for 3-4 days and low blood glucose, about 1 month after initiating voriconazole therapy. Hypoglycaemia was diagnosed and the patient required permanent intravenous glucose solutions for 8 days after voriconazole was stopped, after which glycaemia remained normal. A hyperinsulinaemia peak was observed, which disappeared when glycaemia normalized. Hypoglycaemia is known as a less common adverse event resulting from high voriconazole concentration and hepatic dysfunction. The mechanism of hypoglycaemia may be linked to insulinemia as its serum values are similar to glycaemia. Voriconazole may induce hypoglycaemia in patients without over dosage nor drug interaction.

Association between concomitant use of several systemic NSAIDs and an excess risk of adverse drug reaction. A case/non-case study from the French Pharmacovigilance system database.

AIMS: To examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs. METHODS: The French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others. RESULTS: Use of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9-1.5) and 2.2 (95%CI: 1.3-3.8) for hepatic injury, 7.3 (95%CI: 4.9-10.9) and 10.7 (95%CI: 2.9-40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5-4.1) and 4.8 (95%CI: 2.6-8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2-3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7-6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not. CONCLUSION: This study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

Incidence of drug-induced hepatic injuries: a French population-based study.

The incidence of hepatic adverse drug reactions (ADRs) remains unknown in the general population. The goal of this population-based study was to assess the incidence and seriousness of hepatic ADRs. All new cases of symptomatic drug-induced hepatic injuries were collected by 139 trained physicians (general practitioners [GPs] and specialists) between November 1997 and November 2000 in an area containing 81,301 inhabitants who could not go elsewhere for medical care. Over 3 years, 34 cases of hepatic ADRs were collected, 82% of them in outpatients. Global crude annual incidence rate was 13.9 +/- 2.4 per 100,000 inhabitants; corresponding standardized annual global rate was 8.1 +/- 1.5. There was no difference between urban and rural areas. Standardized incidence female/male ratio was 0.86 (0.26-2.90) until 49 years of age and 2.62 (1.00-6.92) after this age. Diagnosis was carried out by GPs in half of the cases. The outcome was recovery for 32 patients and death for 2. The main drugs implicated were anti-infectious, psychotropic, hypolipidemic agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). Our results suggest that the number of hepatic ADRs in the French population would be 16 times greater than the number noted by spontaneous reporting to French regulatory authorities. In conclusion, the incidence and seriousness of drug-induced hepatitis are largely underestimated in the general population. These results may be useful for further evaluation of drug-induced hepatotoxicity.