[Exception drugs status: specific characteristics and the role in the proper use of drugs]. / Les médicaments d'exception: spécificité et rôle dans le cadre du bon usage des médicaments.

BACKGROUND: In 1994, the French health care system established a special status for certain costly drugs reimbursed for ambulatory use: exception drugs. Drugs with this status are reimbursed only when prescribed for specified indications. The purpose of this study was to identify the specific characteristics of drugs with the exception status, and to understand the role of this status in proper use of drugs. METHODS: Drugs included in the study were analyzed using three types of data: administrative, clinical and economic. RESULTS: For most of the drugs, prescription was restrictive. For five of them, the sickness fund accepted reimbursements for fewer indications than mentioned in the marketing authorisation. For the majority, reimbursement was 100%. The exception drugs were indicated for the treatment of 15 diseases. Eighty percent of expenditures for exception drugs concerned ten drugs. CONCLUSION: The characteristics considered in the study did not enable a specific description of the inherent features of exception drugs. This special status was established for the purpose of economic efficiency. Currently, its role in ensuring proper use of drugs is questionable.

When patients report diseases that prescribers seem unaware of: discordance between patient and physician reporting of risk-related previous history in NSAID users from the CADEUS study.

Prescribers are often unaware of possibly dangerous previous medical histories (PMHs) of their patients. Data from a study of nonsteroidal anti-inflammatory drug (NSAID) users served to identify factors associated with this lack of awareness. In this study, we analyzed the factors that may have led prescribers to report the absence of some PMHs that the patients reported as being present. Of 26,618 patients prescribed an NSAID, 469 (1.7%) reported a PMH of unstable angina, 648 (2.4%) reported heart failure, 2,244 (8.4%) reported gastric or duodenal ulcer, 489 (1.8%) reported upper gastrointestinal tract bleeding (UGIB), 5,343 (20.0%) reported gastroesophageal reflux disease (GERD), and 7,832 (29.4%) reported dyspepsia. Between 64 (GERD) and 92% (UGIB) of these patient-reported PMHs were absent in the corresponding prescribers' reports. This discordance was associated with the following factors: patients of younger age, female patients, less frequent patient-prescriber contact, prescription of NSAID by a specialist, no recent specialist consultation, hospitalization or surgery related to the PMH, and no dispensation of proton-pump inhibitors (PPIs) for digestive disorder-related PMHs. The study showed that a substantial proportion of prescribers seemed unaware of the presence of risk-related PMHs that the patient reported when asked.

Impact of antidepressants on the risk of suicide in patients with depression in real-life conditions: a decision analysis model.

BACKGROUND: The impact of antidepressant drug treatment (ADT) on the risk of suicide is uncertain. The aim of this study was to determine in a real-life setting whether ADT is associated with an increased or a reduced risk of suicide compared to absence of ADT (no-ADT) in patients with depression. METHOD: A decision analysis method was used to estimate the number of suicides prevented or induced by ADT in children and adolescents (10-19 years old), adults (20-64 years old) and the elderly (65 years) diagnosed with major depression. The impact of gender and parasuicide history on the findings was explored within each age group. Sensitivity analyses were used to assess the robustness of the models. RESULTS: Prescribing ADT to all patients diagnosed with depression would prevent more than one out of three suicide deaths compared to the no-ADT strategy, irrespective of age, gender or parasuicide history. Sensitivity analyses showed that persistence in taking ADT would be the main characteristic influencing the effectiveness of ADT on suicide risk. CONCLUSIONS: Public health decisions that contribute directly or indirectly to reducing the number of patients with depression who are effectively administered ADT may paradoxically induce a rise in the number of suicides.

Patterns of risperidone prescription: a utilization study in south-west France.

OBJECTIVE: To describe the patterns of prescriptions associated with risperidone in naturalistic clinical practice. METHOD: We analysed 500 prescription forms randomly selected from the social security insurance database in Aquitaine (south-west France). RESULTS: The prevalence of co-prescription was 42.5% for antidepressants, 46.4% for benzodiazepines, 26.6% for other neuroleptics, 21.8% for mood stabilizers and 19% for anticholinergic drugs. The high prevalence of co-prescribed antidepressants (59.3% Selective Serotonin Reuptake Inhibitors) may be explained by the frequent comorbidity of mood disorders in schizophrenia, and by the fact that risperidone was prescribed in naturalistic conditions in disorders other than schizophrenia. CONCLUSION: The high level of concomitant drug prescription in patients treated with risperidone illustrates the gap between clinical trials and utilization in naturalistic settings. The association antidepressant-risperidone has been insufficiently studied for efficacy or safety, and has to be explored further from both a pharmacological and clinical point of view.

Antidepressants: psychiatrists' opinions and clinical practice.

OBJECTIVE: To describe and compare psychiatrists' opinion on antidepressant drugs and their prescriptions to depressed patients. METHOD: Between January and September 1999 a representative sample of French psychiatrists was asked their opinion of the 15 most prescribed antidepressants, and then to describe the treatments of the current depressive episode of four depressive patients each, their changes and the reason thereof. RESULTS: A total of 232 psychiatrists and 935 patients participated. The best ranked antidepressants were clomipramine, paroxetine and amitriptyline for efficacy, tianeptine, paroxetine and citalopram for tolerability. In patients, the most often prescribed were paroxetine, fluoxetine and venlafaxine. Those least often stopped for intolerance were tianeptine (2.9%), citalopram (5.2%), venlafaxine (3.3%) and amitriptyline (5.7%) for lack of efficacy. There was no difference in stopping rates for inefficacy of tricyclics and serotonin-selective agents. CONCLUSION: The best predictors for the prescribed antidepressants were the psychiatrists' overall rankings and opinions of the tolerability of the drug.

Benzodiazepine use in patients hospitalized in a department of internal medicine: frequency and clinical correlates.

PURPOSE: Misuse and overuse of benzodiazepines (BZD) are common. Several studies have shown that benzodiazepines are frequently used in hospitalized patients, but fewer studies have been conducted to investigate whether BZD use increases during the hospital stay or whether patients have already taken BZD before admission. OBJECTIVE: To assess the prevalence of benzodiazepine use in hospitalized patients and to determine characteristics associated with this use. METHODS: Prospective study over a 4-month period based on all admissions to a department of internal medicine. The main outcome was the prevalence of benzodiazepine use at admission, during hospital stay and at discharge. RESULTS: Of 444 patients admitted, 147 (33%) used at least one benzodiazepine which was in 75% of the cases, short-elimination half-life BZD used as hypnotic. Of 105 (23.6%) patients using BZD at admission, 23 (5.2%) stopped BZD during hospital stay or when leaving hospital. The in-hospital prevalence of BZD use was 30% (133 patients). In 28 (6.3%) patients without BZD at baseline, BZD was introduced during the hospital stay then stopped at discharge in 18 (4%) patients. The prevalence of BZD use at discharge was 23.9% (106 patients). In multivariate analyses, BZD use was significantly associated with number of drugs taken during hospitalization (OR: 1.13; 95% CI: 1.03-1.24), and current neuropsychiatric diseases (OR: 2.12; 95% CI: 0.86-5.23), but not with gender, age or length of stay. CONCLUSION: Prevalence of BZD use appeared to be fairly high among hospitalized patients. There were very few new BZD users during hospital stay, most of whom were stopped at discharge. Most treatments were started before hospital, and continued during and after hospital stay without clear reevaluation.

Adverse drug reactions in a department of systemic diseases-oriented internal medicine: prevalence, incidence, direct costs and avoidability.

OBJECTIVE: Adverse drug reactions (ADRs) are a major cause of hospital admission and in-hospital morbidity. Departments of internal medicine are at the forefront of this problem. To increase the knowledge base, we did a study of the frequency, hazard function, avoidability, and cost of ADRs as a cause for admission in internal medicine, or when occurring after admission. METHODS: This prospective cohort study was based on all admissions to an internal medicine unit over a 4-month period. Patients were intensively followed in order to assess any ADR occurring during the hospital stay. Causality, direct costs, and preventability were assessed. RESULTS: Of 444 admissions (2569 patient-days), 156 ADRs occurred in 116 patients (26.1% of all admissions); 95 (21.4%) of these had ADRs at admission, which were the reason for admission in 32 (7.2%). Twenty-one patients (4.7%) presented with 26 ADRs during hospitalization. The in-hospital ADR incidence rate was 10.1 per 1000 patient-days. The cost of ADRs leading to hospitalization was estimated at Euro 11,357 per hospital bed per year. Eighty percent of ADRs could be considered preventable. CONCLUSION: ADRs in hospitalized patients are common and often preventable. Since most ADRs occurred before admission, prevention strategies should preferentially target primary health care providers.

Excess costs related to non-steroidal anti-inflammatory drug utilization in general practice.

Data concerning the reasons for consultation and the use of NSAIDs were collected in 4643 patients, seen by 126 GPs over 2 days' consultation. In all, 11.6 per cent took NSAIDs. They were older (49 vs. 46 years, p = 0.02), took more drugs (3 vs. 2.5, p < 0.01), and more had ADRs (8 vs 2 per cent) than non-users, even after correction for age, sex and number of drugs taken. Some 33 per cent of NSAID users also took adjuvant medication for the prevention of gastric injury (including with COX-2 inhibitors meloxicam, nimesulide). Estimated excess costs associated with NSAID use were high, related to excess consultations (GP or specialist, for ADRs, approx. 5-8 million Euros per year in France) and to use of preventive medication (100 million Euros per year at least).

[Cost of hospitalizations for adverse drug effects]. / Coût des hospitalisations pour effet indésirable médicamenteux.

The French network of Regional Pharmacovigilance Centres evaluated in 1997 the prevalence of adverse effects of drugs (AED). In 1998, and again with the support of the French Drug Agency, in collaboration with the company CEMKA for economic evaluations, the incidence of AED-related hospitalizations in the medical department of French public hospitals was studied. The evaluation was performed over 14 consecutive days in 62 hospital departments, which were selected randomly. The total number of 3137 patients were hospitalized for a mean duration of 9 days and they were using a mean number of six different drugs. Taking into account the number of about 4 million patients admitted per year in the hospitals represented, it was estimated that the total number of AED-related hospitalizations amounts to about 130,000 annually (CI95%: 100,916-156,620). Using established cost calculations for hospitalized days (AP-HP, results of 1996) the mean cost for an AED-related hospitalization was estimated to be about FF16,000.

Patterns of neuroleptic drug prescription: a national cross-sectional survey of a random sample of French psychiatrists.

AIMS: To describe the psychiatric indications of neuroleptics (especially the relative share of schizophrenic and other psychotic disorders) and the usage patterns of these drugs (dose, duration, coprescriptions). METHODS: A one-day national cross-sectional survey in a random sample of 723 French psychiatrists was carried out in 1996. Each psychiatrist was asked to complete a standardized questionnaire for the first three patients seen the day of the survey to whom at least one neuroleptic was prescribed (initiated or renewed). RESULTS: One thousand seven hundred and fifty-four questionnaires were returned. Three quarters of the patients (74%) were psychotic (664 with schizophrenia, and 636 other psychosis), 19. 3% were depressive and 6.7% had other psychiatric disorders. Phenothiazines were the most often prescribed (40.8%), followed by butyrophenones (22.5%), benzamides (15.8%), other neuroleptics (14. 8%) and thioxanthenes (6.1%). Among schizophrenic subjects, an average number of 1.54 (95% CI: 1.50-1.60) neuroleptics were prescribed per patient, compared with 1.4 (95% CI: 1.32-1.41) and 1. 2 (95% CI: 1.14-1.23) in other psychotic and depressive subjects, respectively. Regardless of the indication, non-neuroleptic psychotropic drugs were coprescribed in 75.4%, mainly benzodiazepines (75.7%). Adjuvant drugs used in prevention or treatment of side-effects were coprescribed in 46.7%, mostly anticholinergic antiparkinsonians (86.1%). CONCLUSIONS: Neuroleptics are mainly prescribed for psychotic disorders and especially schizophrenia. However, current recommendations are not always followed.

Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment.

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.

Adverse drug reactions: physicians' opinions versus a causality assessment method.

Since spontaneous reporting of adverse drug reactions depends on the physician's opinion of the relationship between the drug and the adverse event, we compared physicians' opinions with the scores obtained by the causality assessment method used in France. During a 2 month period, all physicians who reported adverse drug reactions (ADRs) to our pharmacovigilance centre expressed their opinions on the causal link by means of visual analogue scales. ADR reports were then assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians' opinions. The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Physicians used a wide range of assessments, with a preponderance of extreme scores, resulting in a U-shaped distribution, while the standardized method gave generally low scores. Scores given by physicians were very high (causality considered very likely or likely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement occurred in only 6% of cases. Adding complete agreement and minor discrepancies raised the percentage to 49%.

[Organization and results of drug vigilance in France]. / Organisation et résultats de la pharmacovigilance en France.

Pharmacovigilance represents all methods of detection, assessment, information and prevention of adverse drug reactions (ADRs). It mainly involves the post-marketing phase because of the low probability of detecting all possible adverse effects of a drug during pre-marketing development. The most widely used method for pharmacovigilance is spontaneous reporting which is an excellent signal generator but precludes satisfactory calculation of incidence rates. The French Pharmacovigilance System has been set up in 1973; reporting of ADRs has been made mandatory in 1984 for prescribers. This system consists in a network of 30 regional centres under supervision of a coordinating committee at the French Drug Agency. The number of ADR cases received, assessed and recorded by the regional centres is around 10,000 per year; a similar number of cases are reported to the Drug Agency by the pharmaceutical industry. Moreover, Regional Centres work as Drug Information Centres answering more than 23,000 inquiries per year.

[Computerized data processing in the Pharmacovigilance Center of Bordeaux-Aquitaine. Analysis of clientele of the Center]. / Gestion informatisée des données du Centre de Pharmacovigilance de Bordeaux-Aquitaine. Analyse de la clientèle du centre.

Practitioners inquiries addressed to our Drug Information Centre are computerized since 1986. Their analysis allows to pinpoint special problems and needs for practitioners information, and to detect new adverse drug reactions. Time series analysis of calls (according to the practitioners specialities or geographic stay) allows to evaluate the effectiveness of the services provided by the Bordeaux Drug Information Centre.

Computerized comparison of six adverse drug reaction assessment procedures.

Several standardized assessment procedures are currently used in the evaluation of adverse drug reactions (ADRs). Disagreement in rating ADRs can result from between-raters variability and between-methods differences in weighting the evidence. We eliminated between-raters variability by computer simulation of 1134 ADRs (including all the possible combinations of criteria currently used) and by automatic rating using different algorithms adapted from six published methods. Percentage agreement (Po) and weighted kappa test (kappa w) between pairs of methods are always better than with randomized scores, but the strength of agreement is only moderate (0.26 less than Po less than 0.59; 0.14 less than kappa w less than 0.51). The weightings of criteria are evaluated in terms of sensitivity, specificity, and predictive values. Criteria are neither sensitive (0.41 less than Se less than 0.70) nor specific (0.18 less than Sp less than 0.63) and have poor predictive values. Disagreements on weightings are considerable for three major criteria: timing of event, dechallenge, and alternative etiologic candidates. We discuss some ways of improving reliability of ADR diagnosis.

Standardized assessment of adverse drug reactions: the method used in France. Special workshop--clinical.

The method used in France since 1977 for assessing adverse drug reaction (ADRs) is based on a three-stage process: assessment of three chronological criteria (challenge, dechallenge, and rechallenge); assessment of clinical and biological findings; and a combination of chronological and symptomatological assessments to obtain a 3-degree global score (1: doubtful, 2: possible, 3: probable). Bibliographical data (previously reported or unreported ADR) are assessed quite separately; thus, the method has a good sensitivity for detecting new ADRs.