The history of pharmacovigilance.

This article reviews the main historical events before the 21st century and explained their consequences in the current pharmacovigilance legislation.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

OBJECTIVE: Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. METHODS: In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. RESULTS: The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64-0.88) and a QT cutoff of 550 ms. CONCLUSION: The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Pharmacovigilance monitoring of a cohort of pregnant women vaccinated against influenza A(H1N1) variant virus in the Nord-Pas de Calais region of northern France.

OBJECTIVE: During the 2009-2010 influenza A variant virus (A(H1N1)v) pandemic in France, a national pharmacovigilance program was set up to monitor vaccinated, pregnant women, especially the reactogenicity of the vaccine and its impact on the outcome of pregnancy and on the newborn. Here, we present the results for the cohort of pregnant women constituted in the Nord-Pas de Calais region of northern France. STUDY DESIGN: Vaccinated pregnant women were included in the study by the region's vaccination centers between November 2009 and April 2010. RESULTS: Eight hundred and six pregnant women were included and 781 were followed up until delivery. The risk of adverse events after vaccination and the maternal, fetal and neonatal medical conditions in our cohort did not appear different from the risk observed in the general population. CONCLUSIONS: Our results suggest that A(H1N1)v vaccination of pregnant women did not have an adverse impact on the pregnancies' course and outcome.

Torsade de pointes induced by ioxaglate intracoronary injection in patients with pre-existent drug-induced QT prolongation: case reports and review of literature.

We report two cases of torsade de pointes directly related to intracoronary contrast media injection in patients without previous history of neither arrhythmia nor syncope but chronically treated with a drug prolonging ventricular repolarization. We discussed the effects of the contrast medium used on repolarization and concluded that three suggestions may be highlighted from the case reports presented and from the literature: (i) a QT prolongation should be systematically searched before coronary angiography; (ii) it seems important to correct QT prolongation when it results from a reversible cause (such as drug-induced) before nonurgent coronary angiography; and (iii) if there is no reversible cause explaining QT prolongation, contrast media should be used cautiously in such patient and nonionic iso-osmolar contrast media should be preferred.

Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia.

BACKGROUND AND PURPOSE: Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t-PA) during the acute phase of cerebral ischaemia. EXPERIMENTAL APPROACH: The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t-PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg.kg(-1)), monoclonal anti-neutrophil antibody (mAbRP3; 12 h, 0.3 mg.kg(-1)) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion. KEY RESULTS: Depletion of circulating neutrophils significantly reduced t-PA-induced ICH (vinblastine, 4.6 +/- 1.0; mAbRP3, 5.2 +/- 1.0 vs. saline, 10.8 +/- 2.7 haemorrhages; P < 0.05). This depletion was associated with a decrease in cerebral infiltration by neutrophils and a decrease of endothelium-dependent, vascular dysfunction in isolated MCA, induced by the ischaemia/reperfusion and t-PA treatment. Brain infarct volume was significantly decreased after vinblastine treatment (159 +/- 13 mm(3) vs. 243 +/- 16 mm(3) with saline; P < 0.01) but not after depletion with mAbRP3 (221 +/- 22 mm(3)). CONCLUSIONS AND IMPLICATIONS: Our results showed that pharmacological depletion of PMNs prevented t-PA-induced ICH, in parallel with a decrease in cerebral infiltration by PMNs and a decreased endothelial dysfunction in cerebral blood vessels.

[Severe muscle disorders associated with statins: analysis of cases notified in France up to the end of February 2002 and data concerning the risk profile of cerivastatin]. / Atteintes musculaires sévères sous statines: bilan des cas notifies en France jusqu'a fin février 2002 et données concernant les risques liés a la cérivastatine.

BACKGROUND AND METHODS: After the withdrawal of cerivastatin from the market, a survey was performed concerning severe muscular disorders associated with statin treatments that were notified to the French national and pharmaceutical industry pharmacovigilance systems up to February 2002. RESULTS: Among the 238 cases analysed, 69 were related to cerivastatin, 86 to simvastatin, 49 to pravastatin, 23 to atorvastatin and 9 to fluvastatin. The reporting rate was six- to ten-times higher for cerivastatin than for other statins. A major risk factor for rhabdomyolysis with cerivastatin was its association with gemfibrozil. CONCLUSION: Postmarketing surveillance appears to be a major tool for early detection of safety problems with a new drug.

[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.

[Drug-induced heart failure (excluding that caused by anthracyclines)]. / Insuffisances cardiaques d'origine médicamenteuse (en dehors des anthracyclines).

The principal drugs implicated in or disclosing cardiac insufficiency are drawn from a review of the literature and observations by the French national pharmacovigilance database, from 1984 to April 2003. Several pharmacological classes are identified: in addition to antimitotic drugs, such as anthracyclines, many drugs are implicated in cardiac insufficiency, e.g. immunomodulators, anti-inflammatory drugs (including coxibs), antiarrhythmic drugs, anaesthetic drugs, antipsychotic drugs, and antidiabetic drugs (including glitazones). It is usual to classify these drugs according to three categories: (i) drugs likely to cause cardiac insufficiency de novo (such as cyclophosphamide, paclitaxel, mitoxantrone, interferons, interleukin-2 etc.); (ii) drugs likely to worsen preexisting cardiac insufficiency (such as antiarrhythmics, beta-blockers, calcium antagonists, nonsteroidal and steroidal anti-inflammatory drugs, sympathomimetic drugs etc.); and (iii) drugs only occasionally causing cardiac insufficiency. This review shows that this classification is, in fact, artificial. If cardiac toxicity is a constant concern when using antimitotic drugs or some immunomodulator drugs, it is advisable to exercise caution in the use of many other drugs when treating patients with cardiac insufficiency, even if the clinical situation is well controlled. In particular, drug-drug interactions and patient medical history must be taken into account.

Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999.

OBJECTIVES: Adverse drug interactions increase morbidity and mortality. To prevent these, situations leading to adverse prescriptions must be clarified. This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the North of France over a 3-month period. METHODS: All prescriptions administered between 1 January 1999 and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet. The regional French healthcare database was compiled to further classify contraindications. RESULTS: There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients per 3,990,167 general population). There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%). Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, beta-blockers and analgesics (opioids and floctafenine). In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents. CONCLUSIONS: Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contraindications with potentially harmful drug interactions is 27 in 10,000 prescriptions. This would extrapolate to nearly 200,000 contraindications on same-prescription sheets in France in the first quarter of 1999.

Involvement of thrombolysis in recombinant tissue plasminogen activator-induced cerebral hemorrhages and effect on infarct volume and postischemic endothelial function.

BACKGROUND AND PURPOSE: In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. METHODS: Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR. RESULTS: No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8+/-2.3 petechiae versus 3.0+/-1.0 petechiae in rtPA group; P<0.001). This increased severity was associated with a significant increase of both infarct volume (182+/-10 versus 144+/-15 mm3 in rtPA group; P<0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9+/-0.5% versus 13+/-1% in rtPA group; P<0.05). CONCLUSIONS: Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.

Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999.

OBJECTIVES: Adverse drug interactions increase morbidity and mortality. To prevent these, situations leading to adverse prescriptions must be clarified. This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the north of France over a 3-month period. METHODS: All prescriptions administered between 1 January and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet. The regional French healthcare database was compiled to further classify contra-indications. RESULTS: There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients/3,990,167 general population). There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%). Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, betablockers and analgesics (opioids and floctafenine). In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents. CONCLUSIONS: Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contra-indications with potentially harmful drug interaction was 27 in 10,000 prescriptions. This would extrapolate to nearly 200,000 contra-indications on the same-prescription sheets in France in the first quarter of 1999.

[Adverse effects of statins]. / Effets indésirables des statines.

The safety of the hydroxymethyl glutaryl-coenzyme A reductase inhibitors (statins) has been called into question following the recent withdrawal from the market of one of the class, cerivastatin. The withdrawal of cerivastatin highlighted concerns regarding the safety of the entire class. According to data from several large clinical trials, the statins (except cerivastatin) are well tolerated. The most important and clinically relevant adverse effect reported with statins is myopathy. Myopathy is a clinical diagnosis of elevated creatine phosphokinase and/or myalgia along with fatigue. However, the severe from (i.e. statin-associated rhabdomyolysis) is an uncommon syndrome and occurs at a rate of approximately 1/100,000 patients/years. Statin-associated myopathy is related to statin doses, and often to drug/drug interactions. Other clinically relevant adverse effects associated with statin therapy include liver transminases elevation, which is relatively mild and often self-limiting There is no evidence from clinical trials of a significant alteration of ophthalmological function with statins. The issue of statin-induced cancer remains inconclusive. Overall, the statins seem to exhibit a favourable risk/benefit ratio, and this undoubtedly justifies life-long clinical use of statins for cardiovascular prevention.

Comparative effects of clarithromycin on action potential and ionic currents from rabbit isolated atrial and ventricular myocytes.

Prolongation of QT interval by several antibacterial drugs is an unwanted side effect that may be associated with development of ventricular arrhythmias. The macrolide antibacterial agent clarithromycin has been shown to cause QT prolongation. To determine the electrophysiologic basis for this arrhythmogenic potential, we investigated clarithromycin effects on (i). action potentials recorded from rabbit Purkinje fibers and atrial and ventricular myocardium using conventional microelectrodes and (ii). potassium and calcium currents recorded from rabbit atrial and ventricular isolated myocytes using whole-cell patch clamp recordings. We found that (i). clarithromycin (3-100 microM) exerted concentration-dependent lengthening effects on action potential duration in all tissues, with higher efficacy and reverse frequency-dependence in Purkinje fibers. However, clarithromycin did not cause development of early afterdepolarizations, and the parameters other than action potential duration were almost unaffected; (ii). clarithromycin (10-100 microM) reduced the delayed rectifier current. Significant blockade (approximately 30%) was found at the concentration of 30 microM. At 100 microM, it decreased significantly the maximum peak of the calcium current amplitude but failed to alter the transient outward and inwardly rectifier currents. It was concluded that these effects might be an explanation for the QT prolongation observed in some patients treated with clarithromycin.

The cost of adverse drug reactions.

In addition to their impact on human health, adverse drug reactions (ADRs) also have significant impact on healthcare costs. These costs are essentially hospital costs, in particular arising from an increase in length of stay caused by an ADR. Although it has been estimated that the occurrence of an ADR during hospitalisation or leading to hospitalisation is responsible for a cost of approximately EURO2800, several studies have also pointed out that the structure of ADR cost is heterogeneous, a factor which must be taken into account when developing preventive strategies. ADR cost evaluation remains difficult from a methodological point of view given that most studies have only evaluated the direct cost. Because of the substantial annual estimated cost of ADRs in industrialised countries, it is necessary to implement preventive programmes, with different strategies consisting of: educational programmes; identifying risk groups; implementing good drug practice; and clinical and laboratory monitoring for ADRs. Promoting pharmacoeconomic studies and co-operation between clinicians, medical pharmacologists and pharmacists remains the key factor for preventing ADRs and decreasing their costs.

Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes.

Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.