Pharmacovigilance for evaluating adverse drug reactions: value, organization, and methods.
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Adverse Drug Reaction Reporting Systems↗
Biomedical subjects
Maryse Lapeyre-Mestre
Publications and source records attributed to Maryse Lapeyre-Mestre.
Influence of HCV or HBV coinfection on adverse drug reactions to antiretroviral drugs in HIV patients.
OBJECTIVE: To compare the profile of adverse drug reactions (ADRs) to antiretroviral (ARV) drugs in patients coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV) versus non-coinfected patients with human immunodeficiency virus (HIV) infection. METHODS: We used the French Pharmacovigilance Database from 2000 to 2002. Selected patients were classified into four groups: HIV+HCV, HIV+HBV, HIV+HBV+HCV and HIV patients. We compared patients' characteristics and profiles of ADRs to ARV drugs between the four groups. RESULTS: We identified 1,068 HIV, 172 HIV+HCV, 72 HIV+HBV and 26 HIV+HBV+HCV patients with 2,398, 446, 183 and 70 ADRs related to ARV drugs, respectively. The "seriousness" of these ADRs was similar in HIV and coinfected patients but death related to the ADRs was more frequent in HIV+HCV (9.4%) than in HIV (3.6%) patients (p<0.001). "Liver and bile system disorders" were more frequently reported in HIV+HCV and HIV+HBV patients than in HIV patients (17.3% and 20.8%, respectively, versus 8.9%, p<0.001). In HIV+HBV patients, the occurrence of these ADRs was independently associated in a logistic regression model to male gender [odds ratio (OR): 9.28, 95% confidence interval (CI): 2.74-31.36], exposure to zalcitabine (OR: 17.82, 95% CI: 1.49-212.95) or efavirenz (OR: 5, 95% CI: 1.44-17.33). "Red blood cell disorders" were also more frequent in HIV+HCV (7.4%) than in HIV (4.4%) patients (p<0.01). CONCLUSION: Hepatic or haematological (mainly anaemia) ADRs to ARV drugs are more frequent in coinfected patients than in HIV patients. This study underlines the importance of hepatitis B or C in the occurrence of ADRs in HIV patients on ARV drugs.
Adult↗
Using a capture-recapture method to assess the frequency of adverse drug reactions in a French university hospital.
AIMS: There is evidence that different methods used to identify and quantify adverse drug reactions (ADR) in hospitals are not exhaustive (spontaneous reporting or computerized medical databases). The combination of these different sources of data could improve knowledge about ADR frequency in hospitals. The aim of this study was to estimate the incidence of serious ADRs handled in medical wards of a French university hospital using data from the Programme de Medicalization des Systemes d'Information (PMSI) and spontaneous reports recorded in the French Pharmacovigilance Database. METHODS: The study period was the first semester of 2001. RESULTS: From PMSI, all hospitalization summaries including an ICD-10th code related to a potential ADR were selected. From the French Pharmacovigilance Database, all serious ADRs which occurred during the study period and were reported by physicians working in the University Hospital were collected. After identification of common cases, the capture-recapture method was applied in order to estimate the real number of ADRs occurring during the first semester of 2001. From PMSI, we identified 274 different hospital stays related to an ADR. Out of 241 reports selected from the French Pharmacovigilance Database, we retained 151 ADRs for analysis. Fifty-two ADRs were common in the two databases, giving an estimated number of serious ADRs of 796 [95% confidence interval (CI) 638, 954], corresponding to 2.9% of inpatients (95% CI 2.3, 3.5). CONCLUSIONS: This study shows the lack of exhaustiveness of ADR reporting whatever the sources of data and underlines the interest of merging data from different databases to identify fully the real impact of ADR in hospitals.
Adolescent↗
Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems.
Several non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non-case methodology was applied, 'cases' being reports of liver damage and 'non-cases' or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non-cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug-related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.
Adverse Drug Reaction Reporting Systems↗
HMG CoA reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring systems.
OBJECTIVE: HMG CoA Reductase inhibitors, more commonly called statins, are used in the pharmacological management of hyperlipidaemia. At present, the use of these drugs is increasing worldwide. They have been linked to certain adverse drug reactions, including impotence. The aim of the present study is to explore the basis of the association between statin use and impotence using data from spontaneous reports. METHOD: We analysed the cases of impotence associated with statins that were collected by the Spanish and French pharmacovigilance systems. We used cases of impotence as a numerator and consumption data as a denominator to estimate the cumulative reported incidence of impotence. RESULTS: Thirty-eight cases of impotence associated with statins have been identified in the database of the Spanish pharmacovigilance system; overall, there was a temporal sequence of events in all cases and the adverse reaction disappeared after drug withdrawal in 93% of the cases. Sixteen patients had also been treated with other drugs. In France, 37 cases were collected. In 85% of these cases recovery from the adverse reaction was observed after drug withdrawal; there was a positive rechallenge in five cases, and 15 patients were receiving other drugs at the same time. No significant differences among reported incidences with different statins were found. CONCLUSION: Considering the widespread use of this drug class and the under-reporting of this particular reaction it could affect a large number of patients. The reaction seems to be reversible in most of the cases after drug withdrawal. Doctors should be aware of this potential adverse reaction when prescribing statins to their patients.
Adult↗
Heat-related morbidity in patients with orthostatic hypotension and primary autonomic failure.
We investigated the effects of high-external-temperature exposure on neurogenic orthostatic hypotension (OH). Thirty-one patients with autonomic failure (AF) and pharmacologically treated OH related to probable multiple-system atrophy (n=7), Parkinson's disease (n=10), pure autonomic failure (n=7), and diffuse Lewy body disease (n=7) and 26 parkinsonians without AF were included. Prevalence and severity of clinical events were studied during the August 2003 heat wave and the 2004 summer. The prevalence of OH-related events was significantly higher in 2003 [45.1 vs. 11.5%; P=0.0052; OR=6.31 (1.35--33.53)] and 2004 [42.3 vs. 12.0%; P=0.014; OR=5.40 (1.28--22.68)] in AF than in controls. The mean severity score for clinical events was significantly higher in AF than in controls during 2003 heat wave (1.2+/-1.4 vs. 0.2+/-0.5) but similar in summer 2004 (0.7+/-1.0 vs. 0.1+/-0.3). Severe events (unusual home care, assistance, or hospitalization) were only observed in AF patients. A nonstatistically significant higher prevalence of clinical events was observed in AF patients prescribed fludrocortisone (66.7%) by comparison to heptaminol (42.9%), midodrine (45.5%), or midodrine plus fludrocortisone (28.6%). This study shows that AF patients have a poor clinical outcome when exposed to high temperatures and that heat exposure is a risk factor for OH worsening.
Aged↗
Drug related falls: a study in the French Pharmacovigilance database.
OBJECTIVE: To investigate the risk of falls associated with drugs among the French population using data reported to the French spontaneous reporting system and recorded in the French Pharmacovigilance database. METHODS: All cases including a fall were searched in the French Pharmacovigilance database between 1995 and 1999. Drugs involved and characteristics of patients were investigated. In a second step, we estimated the risk associated with psychotropic and cardiovascular drugs in a case/non case comparison, where cases were reports including a fall and non cases all other reports. This risk was estimated by calculation of crude and age and gender adjusted reporting odds ratios (ROR). RESULTS: During this period, 328 reports including a fall were reported (0.4% of the database). Patients were female in 70%. Mean age was 76 +/- 18 years. Comparisons between cases and non cases showed that cases were more likely to be women (OR: 1.9; 95% confidence interval (CI) [1.5-2.4]) and older. After adjustment on age and gender, falls remained significantly associated with exposure to benzodiazepines (4.7 [3.7-5.9]), imipraminic antidepressants (3.6 [2.5-5.1]), serotonin reuptake inhibitor (SRI) antidepressants (2.2 [1.5-3.1]) or nitrates (1.9 [1.2-2.8]). CONCLUSION: This study confirms that taking psychotropic drugs strongly increases the risk of falls. The role of cardiovascular drugs (except nitrates) remains not significant when confounding factors are taken into account. According to the very high prevalence of psychotropic drug use in the French elderly, further study are needed to investigate the relative effect of some drugs on falls, like for example SRIs or short acting benzodiazepines.
Accidental Falls↗
[New methods for studying drug associated risk: experience of the Toulouse Regional Pharmacovigilance Center].
This review examines the methods used to study adverse drug reactions (ADRs) and to quantify drug risk in pharmacovigilance. Beside analysis of spontaneous reports (the basic and universal alert method in pharmacovigilance), epidemiological methods can also be used. Classical methods are based on intensive recording, case-control or cohort studies, and clinical trials. Other more recent methods have been applied to pharmacovigilance. Using recent personal data, the authors present and discuss these new methods. Case/non-case studies quantify drug risk based on a pharmacovigilance database, and are used as signals in pharmacovigilance. Analysis of laboratory data can also be used to evaluate biological ADRs such as elevated liver enzyme and creatine phosphokinase levels. Cross-linkage studies can be used to minimize the consequences of under-notification in pharmacovigilance. Finally, ADR perception analysis is a useful method to evaluate the perceived social and medical importance of drug risks in different populations (public, pharmacists, general practitioners, medical specialists).
Adverse Drug Reaction Reporting Systems↗
[Cardiac effects of cytokines produced after rituximab infusion].
Rituximab (Mabthera) is used in the treatment of refractory low-grade non-Hodgkin's lymphoma or in case of relapse after chemotherapy. Among the different adverse reactions with this drug, the most common is a constellation of symptoms (fever, rigors and chills) that occur more frequently during administration of the first dose of drug. These symptoms could be related to a cytokine-release syndrome. We report the case of a 46 year-old patient, presenting a familial cardiomyopathy, deceased a few minutes after having developed this syndrome, at the time of the 2nd infusion of rituximab. Several hypothesis have been suggested to explain this sudden death: a cardiac failure following deterioration of the systolic function, potentially related to the negative inotropic effects of TNFalpha, and/or an impairment of the diastolic function following the volemic overload. The impact of the reflex "administration of monoclonal antibody/cytokine-release syndrome" was only little investigated under physiologic or pathologic conditions. In spite of a risk of adverse reactions apparently moderated compared to the other drugs used in this context, this case report underlines the need for a special attention when using rituximab among patients with cardiac risk factors (reassessment of the benefit-risk ratio, specific monitoring, pre medication). More generally, it underlines the need for a systematic and continuous identification and reporting of adverse drug reactions to the French network of regional pharmacovigilance centres.
Antibodies, Monoclonal↗
Drug counselling in pregnancy: an opinion survey of French community pharmacists.
PURPOSE: The aim of the present study was to determine whether community pharmacists recommend appropriate medications and give valid information to pregnant women. METHODS: A total of 163 community pharmacists randomly selected in the Midi-Pyrénées area were interviewed by means of an open questionnaire. Ten scenarios were proposed concerning back pain, headache, coughs and sore-throats, fever, constipation, nausea, dyspepsia, 'venous insufficiency', allergic rhinitis and insomnia. RESULTS: Out of the total, 130 pharmacists accepted to answer. Out of them 94.5% reported advising homeopathy, especially for coughs and allergy. They often advised medication for pain, fever, nose and oropharynx disorders, 'venous insufficiency', dyspepsia or constipation. By contrast, they referred the women to the general practitioner for nausea and vomiting or back pain. Advice without drug dispensation was given for gastrointestinal disorders or 'venous insufficiency'. Phytotherapy only concerned 0.5-2% of the answers except for anxiety and sleep disturbances (59%), 'venous disorders'(17%) and sore-throat (9%). Pharmacists' answers were sometimes inappropriate involving (1) pharmacologically illogical advice, (2) drugs for which neither clinical nor experimental data are available and (3) drugs potentially harmful in pregnancy. CONCLUSIONS: The present study shows that French community pharmacists do not always give appropriate advice to pregnant women. As primary health care providers, pharmacists have to improve counselling regarding drug use in pregnancy.
Community Pharmacy Services↗
Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials.
Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications.
Adult↗
Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy.
STUDY OBJECTIVE: To investigate the adverse drug reactions (ADRs) from peginterferon alfa-2b plus ribavirin in patients infected with the hepatitis C virus (HCV). DESIGN: Prospective, observational, pharmacovigilance study. SETTING: Gastroenterology department of a French university hospital. PATIENTS: A cohort of consecutive outpatients who were treated with peginterferon alfa-2b plus ribavirin for viral hepatitis. INTERVENTION: During the 1-year period of HCV therapy visits, a medical staff member trained in pharmacovigilance interviewed the patients about all ADRs and their use of other drugs. The ADRs assessed as serious were confirmed from regular review of the medical records. MEASUREMENTS AND MAIN RESULTS: A total of 87 patients were treated for HCV. Among these, peginterferon alfa-2b plus ribavirin therapy was started in 51 patients; one patient was lost to follow-up after 1 month. The ADRs were assessed as serious in 10 patients (20%): suicide (one patient), hospitalization (three patients), and definitive discontinuation of peginterferon alfa-2b plus ribavirin (six patients). The ADRs contributed to or were the main reason for withdrawing HCV drugs in 8 patients (16%). Dosage reductions of ribavirin and/or peginterferon alfa-2b were required in 10 patients (20%) and seemed less frequent than that needed in clinical trials. Compared with results of clinical trials, a similar frequency of hair loss, higher frequency of injection-site reactions, lower frequency of depression or insomnia, and higher frequency of endocrine ADRs or blurred vision were detected. CONCLUSION: Results suggest some differences in the frequencies of ADRs compared with data from clinical trials. A longer period of monitoring is warranted to improve knowledge about ADRs of pegylated interferon. A medical staff member trained in pharmacovigilance is useful to collect quantitative and qualitative data about ADRs.
Adult↗
Neurotological complications after radiosurgery versus conservative management in acoustic neuromas: a systematic review-based study.
OBJECTIVE: Treatment modalities for acoustic neuroma (AN) include surgery, observation and gamma-knife surgery. The aim of this study was to compare neurotological complications resulting from two treatment alternatives to microsurgery: radiosurgery and observation. MATERIAL AND METHODS: We conducted a systematic review of the literature dealing with radiosurgery for AN and compared the rate of neurotological complications in this population with that in a cohort of patients managed conservatively. RESULTS: We found that neurotological complications, namely facial hypoesthesia (p = 0.002), hearing loss (p < 0.05) and hydrocephalus (p = 0.02), were more frequently encountered after radiosurgery than with conservative management. In contrast, we found that the risk of growth of AN is significantly higher with conservative management and that the rate of stability of the tumor did not differ significantly between the two treatments. CONCLUSION: We prefer a conservative management regimen for patients who cannot be operated on for their AN. However, there are some difficulties inherent in this conservative management policy, namely non-compliance and difficulties in establishing the evolution of the tumor.
Facial Neuralgia↗
Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients.
AIMS: Low molecular weight heparins (LMWHs) are widely used as curative or preventive treatments of thromboembolic diseases. The aim of our study was to: investigate the pattern of prescription of LMWHs in different departments of French teaching hospitals; andestimate the incidence of adverse drug reactions (ADRs) induced by LMWHs and associated risk factors for the occurrence of bleeding events. METHODS: This prospective study was performed in two teaching hospitals in Toulouse (south-western France) in March 1999 in different medical wards. All patients receiving a prescription for a LMWH were included in the survey. All data were prospectively recorded in each ward. RESULTS: A total of 334 patients were included. Sex ratio (male/female) was 1.25 and mean age was 72.5 +/- 16.3 years (extremes:18-101). 450 prescriptions for LMWHs were collected (1.34 prescription per patient) and involved mainly enoxaparin (61%), which was more frequently used than tinzaparin in patients over 75 years old (71.7 vs 28.3%; p < 0.0001). Ninety-nine patients received a LMWH for curative treatment (corresponding to 127 prescriptions of which 99 were for enoxaparin and 28 were for tinzaparin [p < 0.0001]). Indications included therapy for deep venous thrombosis, pulmonary embolism, acute coronary syndrome, unstable angina pectoris, non-Q-wave myocardial infarction. Serious renal insufficiency was significantly more frequent in patients from the geriatrics department (p < 0.00001). Enoxaparin was prescribed more frequently in patients with serious or moderate renal insufficiency than tinzaparin (72 vs 61%, p < 0.05). The incidence of LMWHs-induced ADRs was 10.5% occurring in 22 cases during preventive treatment of deep venous thrombosis and in 13 cases during curative therapy. ADRs were classified as 'serious' in 11 cases (31.4%). Reported ADRs were bleeding events (n = 15), thrombocytosis (n = 13), thrombopenia (n = 4) and hepatic cytolysis (n = 1). The mean delay for the occurrence of bleeding effects was 8.0 +/- 9.1 days (range 1-40). Multivariate analysis of the influence of several criteria on the occurrence of haemorrhagic effects showed that the decrease of creatinine clearance (10 ml/min) was associated with an increased haemorrhagic risk (relative risk [RR] = 1.34, 95% CI 1.12-1.65; p < 0.05). Moreover, the risk of adverse bleeding effects increased for patients with a creatinine clearance <20 ml/min (RR = 2.8; 95% CI 1.00-7.8). CONCLUSION: Our data firstly show a different pattern of LMWHs prescription in different clinical wards. Secondly, the risk of bleeding ADRs in patients treated by LMWHs increases significantly with renal function impairment for the two LMWH preparations studied. More pharmacoepidemiological studies are necessary in patients with several risk factors, particularly in elderly people who often have renal impairment, in order to determine the optimal pattern use of each LMWH.
Adolescent↗
[Pharmacoepidemiology in clinical practice].
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Drug Therapy↗
Adverse drug reactions and off-label drug use in paediatric outpatients.
AIMS: To investigate the potential relationship between off-label drug use and increased risk of adverse drug reactions in paediatric outpatients. METHODS: A prospective pharmacovigilance survey of drug prescribing in office based paediatricians was carried out in Haute-Garonne County (south west of France). RESULTS: The study involved a sample of 1419 children under 16 years old. Forty-two percent of patients were exposed to at least one off-label prescription. The incidence of adverse drug reactions was 1.41% (95% CI 0.79, 2.11). Off-label drug use was significantly associated with adverse drug reactions (relative risk 3.44; 95% CI 1.26, 9.38), particularly when it was due to an indication different than that defined in the Summary Product Characteristics (relative risk 4.42; 95% CI 1.60, 12.25). CONCLUSIONS: Our data suggest an increasing risk of adverse drug reactions related to off-label drug use. This risk would be acceptable if further studies prove the potential benefit of such a drug use.
Adolescent↗
Gender differences in adverse drug reactions: analysis of spontaneous reports to a Regional Pharmacovigilance Centre in France.
The aim of this study was to investigate putative gender-related differences in adverse drug reactions (ADRs). Data were ADRs recorded in the database of the French Midi-Pyrénées Pharmacovigilance Centre in 1998. A total of 927 ADRs were spontaneously reported to the Centre in 1998, of which 53.1% were in females (difference vs. males not statistically significant). There was no statistically significant difference in the incidence of reported ADRs in males (3.6/10,000 inhabitants) vs. females (3.9/10,000 inhabitants) for the total population of the Midi-Pyrénées area. The number of reported ADRs was similar across different age groups (10-year age ranges). However, 'serious' ADRs were more frequently reported in males in the 0-9 and 60-69 age groups (and in females between 20 and 29 years old). There were significantly more neuropsychiatric (69 vs. 43, P = 0.05) and fewer cardiovascular (8 vs. 2, P = 0.05) ADRs reported in females than in males. ADRs were more frequently reported in females for some classes of drugs (such as genito-urinary, sex hormone, antineoplastic, antiparasitic and respiratory drugs). These results confirm that female gender is a risk factor for the development of ADRs.
Adolescent↗
Assessing the feasibility of using an adverse drug reaction preventability scale in clinical practice: a study in a French emergency department.
OBJECTIVE: To assess the preventability of adverse drug reactions (ADRs) leading to hospital admissions and to investigate the feasibility of the use of a standardised preventability scale in clinical practice. DESIGN: The study was a prospective pharmacovigilance study. All patients more than 15 years old admitted to an emergency department during a period of 4 weeks were included. Characteristics of patients admitted for a suspected ADR (cases) were compared to those admitted for other reasons (controls). Preventability was assessed in two different ways: (i). by using a standardised preventability scale; and (ii). by the assessment of four reviewers without the scale. Results of the two methods were compared. PATIENTS: In total, 671 patients were admitted to an emergency department during the study period. RESULTS: Overall, 44 ADRs were identified involving 41 patients. The incidence of hospital admissions for ADRs was 6.1 per 100 admissions (95% CI 4.4-8.3). According to the French causality assessment method, 71% of ADRs were 'possible', 18% were 'plausible' and 11% were 'likely'. Using the standardised preventability scale, one-third of all ADRs were considered as being preventable (9% 'definitely' and 25% 'potentially' preventable). Reviewers found that 54.5% of ADRs were 'preventable'. Discrepancies between the two methods concerned mainly cases defined as not preventable by the scale. In general, reviewers overestimated the preventability of ADR compared with the scale. CONCLUSIONS: These results emphasise that ADRs leading to hospitalisation are frequent, with one-third of them likely to be preventable. Moreover, the risk of ADRs mainly involved a small number of drugs. Our experience suggests that there is a need for further studies to validate the French standardised scale of preventability assessment.
Adult↗