Systemic Adverse Drug Reactions Research Articles

Selected National Pharmacovigilance Websites

Pharmacovigilance involves the detection, assessment, understanding, and prevention of adverse drug reactions (ADRs), nationally and internationally. Effective communication, which relies increasingly on the Internet, is a crucial aspect of pharmacovigilance activities. The aim of this study was to perform an exploratory survey of national pharmacovigilance websites and compare their contents. Of 99 international pharmacovigilance organizations known to us (listed in the Side Effects of Drugs Annual 30), 45 included website addresses and 35 provided some or all of the information in English. We reviewed 10 of these 35 websites in order to identify their contents. The 10 sites that we selected contained the most extensive information on pharmacovigilance of those that we were able to access. Reviewing these sites, we identified 32 items of information that we used to assess the scope of each website systematically, using a scoring system based on the presence or absence of those items. All the websites gave clear descriptions of national pharmacovigilance requirements and the reporting systems for ADRs, and all included devices. Beyond this, there was great variability in content from site to site. Few websites allowed access to raw pharmacovigilance data, such as individual case reports. Online drug safety communication from the selected national websites we examined is highly variable from site to site, although a wider study is needed to confirm this. Agreement on the key components of pharmacovigilance websites would facilitate the development of a standardized format to improve online communication.

Efficacy on Climacteric Symptoms of a New Estradiol Transdermal Patch with Active Matrix in Comparison with a Reference Reservoir Patch

Two randomized prospective multicentre parallel group studies were performed (one in Germany and the other in Italy) in symptomatic postmenopausal women. The goal was to assess the efficacy on climacteric symptoms and the safety of a new estradiol (CAS 50-28-2) transdermal patch with solid active matrix (SAM) in comparison to a conventional liquid reservoir (LR) type estradiol transdermal patch. Both patches released 50 micrograms/day estradiol. One group of patients received the SAM patch and the other the LR patch in 4-week cycles, with a twice-weekly application of the patches for 3 weeks, followed by one week without patches. Progestin opposition was achieved with medroxyprogesterone acetate 5 mg/day orally in the last 11 days of patch application in the German study and with 10 mg/day in the last 12 days of patch application in the Italian study. Both studies were divided into two Parts: Part 1 with three 4-week cycles for a total of 12 weeks and Part 2 for other ten 4-weeks cycles in which the patches could be applied also continuously. The total duration of the study was therefore 52 weeks. Germany study. 133 patients resulted randomized to the SAM group and 129 to the LR group. Both estradiol patches quickly relieved climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the Kupperman Index. At the end of Part 1, in the SAM group 91% and in the LR group 96% of patients reported relief from climacteric symptoms. At the end of Part 2 the percentages were 98% and 95%, respectively. The two patches were therapeutically equivalent with a power greater than 99.7%. Both patches were systemically fairly well tolerated. Only 4.5% of patients in the SAM group and 3.9% in the LR group discontinued prematurely for possible adverse reactions related to estradiol. There was no significant difference between the two patches with regard to systemic tolerability. Conversely, with regard to local skin reactions, the SAM patch was significantly (p < 0.01) better tolerated than the LR patch. The adhesion to the skin of the SAM patches was better than that of the LR patches. RESULTS. Italian study. 139 patients resulted randomized to the SAM patch and 128 to the LR patch. Also in this study both types of patches relieved the climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the visual analogue scale (VAS) recordings of severity of hot flushes and of sweats. At the end of Part 1 both patches relieved 95% of patients from climacteric symptoms. At the end of Part 2, i.e. after 52 weeks, 100% of patients were relieved from climacteric symptoms. Of these, 72% in the SAM group and 78% in the LR group reported complete disappearance of symptoms. Also in the Italian study, therefore, the two patches were found therapeutically equivalent. Both patches stopped or even reversed bone mineral loss in L2-L4 and had some favorable effects on lipid metabolism. Both patches were systemically equally fairly well tolerated with premature discontinuations for systemic adverse drug reactions in only 5.0% of patients in the SAM group and 3.9% in the LR group. Conversely, as in the German study, the SAM patches were significantly better tolerated by the skin (p < 0.0001). The two types of estradiol transdermal patches were equivalent in providing an effective and rapid relief from climacteric symptoms. Systemically both patches were fairly well tolerated. The SAM patches were significantly better tolerated by the skin. The better local tolerability combined with better adhesion and cosmetic properties render the SAM patches very patient friendly and improve the compliance in the long term estrogen replacement therapy required to reduce osteoporosis and cardiovascular risks.

Systemic Adverse Drug Reactions Secondary to Anti-VEGF Intravitreal Injection in Patients with Neovascular Age-Related Macular Degeneration

The wet form of age related macular degeneration (AMD), known also as exudative or neovascular, is characterized by the formation of a pathological choroidal neovascular membrane (CNV) responsible for most cases of severe blindness. Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein acting as a growth factor selective for endothelial cells; it regulates angiogenesis and enhances vascular permeability and plays a leading role in this disorder. The consistent association between CNV and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular AMD. The importance of VEGF for the development of AMD-related CNV has led to the development of a strategy able to block its pathologic effects. The rationale is that a blockade of VEGF actions could be effective in arresting choroidal angiogenesis and also reducing the vascular permeability, which is frequently the main cause of visual acuity deterioration. However, VEGF has also important functions in vascular physiology. The effects of anti-VEGF therapy may inhibit these functions. Herein we report the systemic adverse events secondary to intravitreal administration of these compounds i.e. the main cardiovascular effects (thrombosis, hemorrhage, hypertension, proteinuria), as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thrombophlebitis.

The lack of knowledge about the voluntary reporting system of adverse drug reactions as a major cause of underreporting: direct survey among health professionals

Underreporting suspected adverse drug reactions (ADRs) is one of the main problems that face the pharmacovigilance (PhV) systems based on yellow card schemes. To measure the knowledge level on the suspected ADR voluntary reporting system among physicians and pharmacists in Venezuela and to study its relationship with different variables. A population-based, anonymous, and self-administered questionnaire was addressed to health professionals along the national territory of Venezuela. An algorithm was developed to classify the knowledge level on the voluntary reporting system. Taken as a whole, the level of knowledge on the voluntary reporting system was "poor." Among the 515 participant physicians, 62.3% (95%CI = 58.0-66.5%) had a "poor" level of knowledge; PhV was associated with "control" of medicines use, and only 24.7% had ever reported a suspected ADR. "Medical specialty" was the only variable that showed a relationship with the knowledge level (p = 0.0041). Among the 78 participant pharmacists, 66.7% had a "poor" knowledge level (95%CI = 55.1-76.9%). The knowledge level on the voluntary reporting system among physicians and pharmacists in Venezuela is poor. These results strengthen the hypothesis that being unaware of the adverse effects of medicines and not knowing the existence of a PhV system is a major cause of underreporting. A careful study of the actual knowledge of PhV could be the basis to set up interventions specifically designed to overcome misleading concepts and to improve the reporting rate at a national level.

Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency

BackgroundSubcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy.MethodsWe evaluated the efficacy and safety of the SCIG Vivaglobin® (formerly known as Beriglobin® SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children < 14 years) using the Short Form 36 (SF-36) for patients ≥ 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children < 14 years of age. Treatment preferences were assessed in adults.ResultsThe mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p < 0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by ≥ 5 points were observed in 5 of 8 SF36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p ≤ 0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%).ConclusionThis study confirms that therapy with Vivaglobin® at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.

Nervous system adverse responses to topiramate in the treatment of neuropsychiatric disorders

Importance of the field: Nervous system adverse drug reactions (NS-ADRs), such as cognitive complaints and paresthesia, are among the most frequent and clinically important ADRs of topiramate. Studying ADR profiles across disorders is clinically relevant because treatment decision-making in neuropsychiatry is highly guided by ADR profiles.Areas covered in this review: We used medline searches (until July 2009) to review the NS-ADRs of topiramate across the most investigated topiramate indications: alcohol dependence, essential tremor, binge-eating disorder, bulimia nervosa, migraine and epilepsy. We compared NS-ADRs between these disorders but did not carry out meta-analysis.What the reader will gain: ADR profiles greatly differed between disorders. Drop-outs due to ADRs highly varied between disorders: from 2% in the bulimia nervosa group to 29% in the migraine group. Paresthesia was the most common NS-ADR for all disorders but frequencies also differed between disorders. Cognitive complaints were frequent and were reported in comparable proportions.Take home message: When prescribing topiramate in neuropsychiatry, physicians should be aware that NS-ADR profiles have been found to differ between disorders. Differences in drop-out rates due to ADRs and in frequencies of specific NS-ADRs across disorders must be taken into account when evaluating the potential harm of topiramate in clinical practice.

Extent of pharmacovigilance among resident doctors in Edo and Lagos states of Nigeria

Systematic attention to adverse drug reactions (ADRs) started with the thalidomide disaster in the early 60s of the 20(th) century. In 1968 ten countries supported a spontaneous reporting system for ADR and collaborated with the WHO pilot research project for international drug monitoring. This survey was conducted to determine the level of awareness of resident doctors about ADRs reporting, the extent of their involvement in pharmacovigilance activities and to build a useful data base that will improve the quality of health care in Nigeria. This cross-sectional observational survey was conducted in University of Benin Teaching Hospital (UBTH) and Irrua Specialist Teaching Hospital (ISTH), Lagos University Teaching Hospital (LUTH) and Lagos State University Teaching Hospital (LASUTH) in Edo and Lagos states, Nigeria, respectively. STUDY DESIGN / METHODS: A cross-sectional observational survey was used in this study. Total population under survey being 971 residents with the sample size of 350 statistically determined. The survey conducted revealed that 78.1% (258) of the respondents had inadequate knowledge about pharmacovigilance with 71.2% (235) unaware of the yellow forms for ADR reporting distributed by the National Agency for Food and Drug Administration and Control (NAFDAC). The respondents (92.4%) have observed ADRs in the course of their training and practice, yet only 25.5% of cases were reported. The reported cases (7.3%) were to the National Agency for Food and Drug Administration and Control. The study showed a statistically significant difference between the institution of respondents, knowledge and experience about pharmacovigilance (p < 0.05). There is marked under-reporting of cases and a low level of awareness about pharmacovigilance among resident doctors in Edo and Lagos states. This may be what obtains in other states in Nigeria.

Consumers' reports of suspected adverse drug reactions volunteered to a consumer magazine

In some countries, reporting of adverse drug reactions (ADRs) by patients has been incorporated into spontaneous reporting systems, primarily to increase the number of reports and detect new ADR signals earlier [1]. To date only seven countries have allowed patients to report ADRs: Sweden (since 1978 via KILEN), USA (since 1993), Australia, Canada, Denmark and the Netherlands (since 2003) and the UK (since 2005) [1]. An analysis of ADR reports to the Danish Medicines Agency (DKMA) showed that patients are more likely to report ADRs from the nervous and psychiatric system than are health professionals, that patients' share of reports on serious ADRs was comparable to that of physicians, and that patients provided new and unknown information about ADRs [2]. The use of the internet as a source of information and discussion forum for health matters is rapidly increasing. Therefore we decided to investigate the information about possible ADRs provided by consumers who had easy reporting access via the internet. A consumer magazine provided the opportunity for their readers and others to report ADRs via an open access website. This letter examines whether these reports contributed with information about ADRs not previously described in the product information. Data were collected from a questionnaire on the website of a consumer magazine during a 2-month period in autumn 2008 (September–October). If patients had experienced ADRs from the use of medicines, they were requested to answer the following questions: To which medicine did you have an ADR? What were you being treated for? What sort of ADRs did you experience? Did you tell anyone about the ADRs you experienced either at the time or later? Did you report your ADRs either via http://www.borger.dk or to the Danish Medicines Agency? We analysed the reports with respect to therapeutic groups [Anatomical Therapeutic Chemical (ATC) system][3] and types of reported ADRs (system organ classes) [4]. The reported ADRs were checked against the official summary of product information (SPC). ADRs not mentioned in the SPC were classified as unlabelled. Table 1 displays the number of reported ADRs distributed on therapeutic groups and the number of unlabelled ADRs (ATC level 1). Only 11 of the reports (3%) had been reported to the DKMA. In 42% of reports, patients had shared the information about ADRs with a healthcare professional, a family member or a relative. Forty percent of all ADRs were reported for medicines belonging to ATC group N (nervous system). In total, 15% of reported ADRs (n= 188) were not mentioned in the official product information. Of these ADRs, the highest share, 34%, was reported for medicines belonging to ATC group N (nervous system disorders). The majority of reported ADRs were of the types ‘nervous system disorders’ and ‘gastrointestinal disorders’. Table 1 Reports and ADRs of suspected medicines (ATC level 1) by therapeutic group Open access to other patients' reports as well as the simple structure of the questionnaire may have motivated many patients to report ADRs. Such a data collection method could be used as a rapid data collection instrument in the event of suspected serious or rare ADRs not previously documented. The large number of ADRs reported for psychotropic medicines (ATC group N) could reflect that people with central nervous system problems are more likely to report these symptoms than other people. Although the types of reported ADRs and suspected medicines are in line with results from other countries [1, 2, 5], patients also reported information about previously unlabelled ADRs. This study has confirmed that patients report rather unspecific symptoms, e.g. indisposition, dizziness and insomnia, as they use lay terminology to describe symptoms differently from terminology used by healthcare professionals. Patients also reported several ADRs such as drowsiness, weight gain and sexual problems, which prescribers may not consider serious but are troublesome to patients and limit the full enjoyment of daily life [1] and which patients find worthy of reporting in a questionnaire. The content and quality of the reported data are inappropriate for causality analysis as the reports contained no information about age, sex, diagnosis and concomitant medicines. Hence, the collected ADR data may actually consist of ADRs that patients believe to be possibly drug-related reactions rather than confirmed ADRs, and the value of these data in drug surveillance is limited. Consumer ADR reports might act as whistleblowers of new and previously undetected ADRs, but if the quality of the reports is questionable they bring too much noise rather than valuable information to the pharmacovigilance systems. Further studies to explore the quality, validity and impact of consumer reports in the pharmacovigilance systems are needed and appropriate systems for patient reports of ADRs should be explored. The unlabelled ADRs should lead to further investigations and possible detection of new ADRs.

Gene Transcript Abundance Profiles Distinguish Kawasaki Disease from Adenovirus Infection

Acute Kawasaki disease (KD) is difficult to distinguish from other illnesses that involve acute rash or fever, in part because the etiologic agent(s) and pathophysiology remain poorly characterized. As a result, diagnosis and critical therapies may be delayed. We used DNA microarrays to identify possible diagnostic features of KD. We compared gene expression patterns in the blood of 23 children with acute KD and 18 age-matched febrile children with 3 illnesses that resemble KD. Genes associated with platelet and neutrophil activation were expressed at higher levels in patients with KD than in patients with acute adenovirus infections or systemic adverse drug reactions, but levels in patients with KD were not higher than those in patients with scarlet fever. Genes associated with B cell activation were also expressed at higher levels in patients with KD than in control subjects. A striking absence of interferon-stimulated gene expression in patients with KD was confirmed in an independent cohort of patients with KD. Using a set of 38 gene transcripts, we successfully predicted the diagnosis for 21 of 23 patients with KD and 7 of 8 patients with adenovirus infection. These findings provide insight into the molecular features that distinguish KD from other febrile illnesses and support the feasibility of developing novel diagnostic reagents for KD based on the host response.

A web-based quantitative signal detection system on adverse drug reaction in China

To establish a web-based quantitative signal detection system for adverse drug reactions (ADRs) based on spontaneous reporting to the Guangdong province drug-monitoring database in China. Using Microsoft Visual Basic and Active Server Pages programming languages and SQL Server 2000, a web-based system with three software modules was programmed to perform data preparation and association detection, and to generate reports. Information component (IC), the internationally recognized measure of disproportionality for quantitative signal detection, was integrated into the system, and its capacity for signal detection was tested with ADR reports collected from 1 January 2002 to 30 June 2007 in Guangdong. A total of 2,496 associations including known signals were mined from the test database. Signals (e.g., cefradine-induced hematuria) were found early by using the IC analysis. In addition, 291 drug-ADR associations were alerted for the first time in the second quarter of 2007. The system can be used for the detection of significant associations from the Guangdong drug-monitoring database and could be an extremely useful adjunct to the expert assessment of very large numbers of spontaneously reported ADRs for the first time in China.

Peut-on associer les associations fixes médicamenteuses ?

The number of fixed associations to treat intraocular pressure has increased over the recent years, to improve patient's treatment adherence. They are generally considered as comparable to the same components administered separately with, in some cases, less side effects. It could thus be appealing to combine fixed associations to reduce these side effects and retain efficacy. However, almost all fixed associations contain timolol, a beta blocker, with a risk of an excessive beta blocking dose and related systemic adverse drug reactions. Several fixed-associations contain a prostaglandin analogue. Their combination would not have a superior efficacy to one fixed combination taken alone. Furthermore, an increased risk or incidence of adverse drug reactions would appear. Specific clinical studies are required before recommending their use in daily clinical practice.

Determinants of Under-Reporting of Adverse Drug Reactions

A voluntary reporting system of adverse drug reactions (ADRs) is fundamental to drug safety surveillance but under-reporting is its major limitation. This bibliographic review sought to assess the influence of personal and professional characteristics on ADR reporting and to identify knowledge and attitudes associated with ADR reporting. A systematic review was conducted using the MEDLINE and EMBASE databases. We included papers that were published in English, French and Spanish, and covered a study population made up of health professionals. In each case, the following data were extracted: study population; workplace; study type; sample size; type of questionnaire; type of scale for measuring knowledge; response rate; personal and professional factors; and knowledge and attitudes (based on Inman's 'seven deadly sins') associated with reporting. Based on a search of computerized databases, we identified a total of 657 papers in MEDLINE and 973 in EMBASE. In all, the review covered 45 papers that fulfilled the inclusion criteria. Medical specialty was the professional characteristic most closely associated with under-reporting in 76% of studies involving physicians. Other factors associated with under-reporting were ignorance (only severe ADRs need to be reported) in 95%; diffidence (fear of appearing ridiculous for reporting merely suspected ADRs) in 72%; lethargy (an amalgam of procrastination, lack of interest or time to find a report card, and other excuses) in 77%; indifference (the one case that an individual doctor might see could not contribute to medical knowledge) and insecurity (it is nearly impossible to determine whether or not a drug is responsible for a particular adverse reaction) in 67%; and complacency (only safe drugs are allowed on the market) in 47% of studies. While personal and professional factors display a weak influence, the knowledge and attitudes of health professionals appear to be strongly related with reporting in a high proportion of studies. This result may have important implications in terms of public health, if knowledge and attitudes are viewed as potentially modifiable factors.

Adverse drug reaction (ADR) notification drop box: an easy way to report ADRs

Adverse drug reaction (ADR) notification drop box: an easy way to report ADRs

Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events.

BackgroundSpontaneous reporting systems for adverse drug reactions (ADRs) are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients.MethodsSerious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions.ResultsTen cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients.ConclusionSerious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.

A Collaborative Program between Pharmacists and Nurses to Improve Spontaneous Adverse Drug Reaction Reporting System in Prapokklao Hospital, Thailand

Objectives: 1) to evaluate the collaborative program between pharmacists and nurses in improving the spontaneous reporting system of adverse drug reaction (ADR) in Prapokklao hospital; 2) to explore the impact of the collaborative program on knowledge of nurses about ADRs, the capability of nurses to detect and report ADRs, and the level of job satisfaction on the new roles of nurses in the experimental group. Methods: This programmatic research employed several methods including experimental approach which categorized nurses into experimental and control groups, and then compared knowledge as well as performance of nurses in detecting and reporting ADRs between both groups, and before and after training program. Eight out of 52 nurses in the experimental group were trained with knowledge about ADRs, and how to detect and report ADRs in hospitalized patients. The rest of them (44 nurses) in the experimental group obtained knowledge from researchers and training nurses. Nurses in both experimental and control groups were assessed about knowledge regarding ADRs before and after the introduction of the collaborative program, performance of nurses in monitoring and reporting ADRs compared to pharmacists, and job satisfaction of nurses in the experimental group by using an adapted questionnaire. The samples were nurses who were responsible to patient's charts in both groups. The study period started from December 2004 to June 2005. Results: Eight nurses trained by the program had a higher score of knowledge than before training. Forty-four nurses who were in the experimental group also had higher scores of post-test at the third month of investigation, compared to the baseline. Differences in the pre and post-test scores between nurses in experimental and control groups were statistically significant at 0.05. Intensive ADR monitoring carried out by pharmacists indicated that experimental wards had 3,572 patients with 371 ADR problems, while control wards had 3,467 patients with 266 problems. Nurses in the experimental groups could correctly report 174 problems of ADRs (46.9%), while 29 problems (10.9%) were reported by their counterparts. The difference in the capability to reporting ADR was at the significance level of 0.05. Nanrajo algorithm showed the level of probability and, the difference in the proportion of ADR reported by the experimental group was fourfold to the control group. This collaborative program between pharmacists and nurses significantly improved performance and knowledge of nurse as well as spontaneous ADR reporting system in Prapokklao hospital.

Connubial systemic cutaneous adverse drug reaction

Connubial systemic cutaneous adverse drug reaction

Drug skin tests and systemic cutaneous adverse drug reactions: an update

Drug skin tests can be helpful in determining the cause of a cutaneous adverse drug reaction (CADR). Patch tests and prick tests can be performed with any commercialized form of a drug. Intradermal tests (IDTs) have a greater value, but their techniques have not been standardized. Moreover, IDTs can be done only if an injectable form of the drug is commercialized and are restricted to patients with nonsevere CADR. Prick tests and IDTs are used in investigating immediate hypersensitivity. Patch tests both with IDTs with delayed readings are helpful for maculopapular rash and generalized or localized eczema. Results obtained with drug skin tests in β-lactam sensitization have been extensively published, but fortunately, during the last few years the value of skin tests in CADR due to other drug classes (e.g., synergistins, platinium salts or radiocontrast medias) was also studied. The analysis of recent literature permits to propose which tests to choose for each clinical feature of CADR and to give the list of all drugs, having had patch tests with positive results but, emphasizes the lack of standardization in performing and reading IDTs. This standardization is absolutely necessary to determine the thresholds of specificity of the IDT. Except for IDTs, drug skin tests induce only rarely adverse reactions. False-positive results can occur and should be considered by testing new products. The negative predictive value of drug skin tests is a crucial point that will have to be studied in more detail in the near future.

Factors that Influence Under-Reporting of Suspected Adverse Drug Reactions among Community Pharmacists in a Spanish Region

The spontaneous reporting system is the most efficient warning system of adverse drug reactions (ADRs). Pharmacists can play an important role in the detection and reporting of ADRs. The factors that affect under-reporting among these professionals are unknown in Spain. To identify the factors that influence community pharmacists' ADR under-reporting in Navarra, a Northern Spanish region. A case-control study was conducted on a population of 802 community pharmacists working in Navarra. Cases were pharmacists who had reported at least two ADRs to the region's drug surveillance unit between 2003 and 2005 and who agreed to participate in the study (18/20; 90%). A random sample of 60 controls was selected from the 762 pharmacists who had not reported any ADR during the same period of time. Factors positively associated with ADR reporting were age, years of work experience as a pharmacist, participation in educational activities related to the detection and resolution of drug-related problems, the habit of detecting ADRs as part of pharmacists' duties, having the basic knowledge needed to report ADRs, and disagreement with the common belief among healthcare professionals that 'to report an ADR it is necessary to be sure that the reaction is related to the use of a particular drug'. The most frequently mentioned reasons for not reporting ADRs were the ADR is not serious, the ADR is already known, uncertainty concerning the causal relationship between the ADR and the drug, forgetting to report the ADR and a lack of time. Pharmacists' knowledge, beliefs, behaviour and motivation play an important role in ADR reporting. Under-reporting might be improved through activities focused on modifying such factors.

Long-term management of chronic pain with transdermal buprenorphine: A multicenter, open-label, follow-up study in patients from three short-term clinical trials

Transdermal buprenorphine is available in Europe for the treatment of moderate to severe chronic pain. It has been evaluated at doses of 35, 52.5, and 70 microg/h for the management of moderate to severe chronic cancer and noncancer pain in 3 randomized, double-blind, placebo-controlled trials, each of limited duration (approximately 14 days each). Long-term data are essential to determining the performance of an analgesic in the management of chronic pain. The purpose of this follow-up study was to obtain data on the efficacy and tolerability of long-term treatment with transdermal buprenorphine in cancer and noncancer patients with chronic persistent pain of moderate to severe intensity. This was an open-label, uncontrolled, follow-up study in patients from the 3 previous clinical trials who elected to continue treatment with transdermal buprenorphine 35 microg/h and sublingual buprenorphine tablets (0.2 mg) as needed for breakthrough pain. The patch was to be changed every 72 hours throughout the patient's course of pain therapy. At visits every 2 weeks for the first 4 weeks and every 4 weeks for the remainder of study participation, patients evaluated their pain relief retrospectively on a 4-point verbal rating scale. They also rated the ease of patch handling using a 3-point verbal rating scale. Patterns of dose escalation and dose stability were monitored over time. Adherence to therapy was determined based on the number of patients who complied with the dosing schedule. Adverse events were documented by type, intensity, location (systemic or local), and relationship to study medication. Two hundred thirty-nine patients were included in this follow-up study (120 women, 119 men; 100% white; mean [SD] age, 58 [11.3] years; mean weight, 70.8 [14.7] kg). One hundred thirty-four had cancer-related pain and 105 had pain of noncancerous origin. The mean duration of participation was 7.5 months, and 37 (15.5%) patients participated for >12 months. Maximum study participation was 3.4 years in cancer patients and 5.7 years in noncancer patients. One hundred eighty-eight (78.7%) patients were considered adherent to therapy. The majority (65.9%) of patients managed their pain with the patchalone or took no more than 1 additional sublingual tablet daily for breakthrough pain. At least satisfactory pain relief was reported by 215 (90.0%) patients, and the buprenorphine patch was generally well tolerated. The most common systemic adverse drug reactions were nausea (9.2%), dizziness (4.6%), vomiting (4.2%), constipation (3.8%), and tiredness (2.9%), whereas the most common local adverse drug reactions were erythema (12.1%), pruritus (10.5%), and exanthema (8.8%). Transdermal buprenorphine was generally well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain in these patients who had previously received buprenorphine in 3 short-term clinical trials.

Adverse drug events: counting is not enough, action is needed

estimate — that 10.4% of patients attending general practice experience an ADE — almost 2 million people have an ADE annually. Moreover, their findings show that these ADEs are not trivial, with about 1 million being moderate or severe and 138 000 requiring hospitalisation, a finding consistent with previous estimates. 3 Many of these ADEs are preventable, although the exact proportion of preventable events can be debated. There have now been more than 30 Australian studies estimating the number of ADEs in different settings. 3 It is clear that counting is not enough — it is time for action, but what can be done? Every developed country is trying to cope with the problem of ADEs. Australia has many structures and initiatives in place to reduce the occurrence of ADEs, and preventing ADEs necessarily involves them all. 3 Regulatory agencies, the medicines industry, quality use of medicines organisations and information providers, safety and quality organisations, professional bodies, health professionals and consumers can all assist. Prevention of ADEs cannot occur without better knowledge. It is noteworthy that the Therapeutic Goods Administration has adopted the European Medicines Agency guideline on pharmacovigilance planning. Increased pharmacovigilance, including observational studies, will require a substantial increase in resources. In Canada, less than 10% of the budget for drug regulation is allocated to issues concerning marketed products, including safety. Yet, in 50% of new drugs, serious adverse drug reactions are detected after market approval. 4 We need systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is marketed. Regulators may have to consider restricting prescribing of new medications if they have limited safety information, particularly when equally efficacious therapy is available. New systems for detecting early signals of potential adverse drug reactions in expanded populations could complement the current reporting system for adverse drug reactions. An example is the Drug Safety Research Unit in the United Kingdom, which captures information on the first 10 000 patients using a newly marketed drug. 5 We need to capitalise on and expand the importance and significance of consumer reporting.