Uppsala Monitoring Centre Research Articles

Adverse Drug Reactions in a Complementary Medicine Hospital: A Prospective, Intensified Surveillance Study

Background. Anthroposophic medicine is one of the widely used approaches of complementary and alternative medicine. However, few prospective studies have generated safety data on its use. Objectives. We aimed to assess adverse drug reactions (ADRs) caused by anthroposophical medicines (AMEDs) in the anthroposophical Community Hospital Havelhoehe, GERMANY. Study Design and Methods. Between May and November 2007, patients of six medical wards were prospectively assessed for ADRs. Suspected ADRs occurring during hospitalization were documented and classified in terms of organ manifestation (WHO SOC-code), causality (according to the Uppsala Monitoring Centre WHO criteria), and severity. Only those ADRs with a severity of grade 2 and higher according to the CTCAE classification system are described here. Results. Of the 3,813 patients hospitalized, 174 patients (4.6%) experienced 211 ADRs (CTCAE grade 2/3 n = 191, 90.5%, CTCAE grade 4/5 n = 20, 9.5%) of which 57 ADRs (27.0%) were serious. The median age of patients with ADRs (62.1% females) was 72.0 (IQR: 61.0; 80.0). Six patients (0.2%) experienced six ADRs (2.8% of ADRs) caused by eight suspected AMEDs, all of which were mild reactions (grade 2). Conclusion. Our data show that ADRs caused by AMEDs occur rarely and are limited to mild symptoms.

Differences in spontaneously reported hypersensitivity and serious adverse events for intravenous iron preparations: comparison of Europe and North America

Spontaneously-reported rates of adverse events (AEs) of intravenous (i.v.) iron products have not been compared since 2007. AEs in Europe (Eur) and North America (NA) have never been compared. New products have been marketed and many changes in prescribing habits have occurred since then, and the effect on AEs reporting is unclear. It was hypothesized that changing practices for i.v. iron products has caused changes in the rates of serious AEs and large differences exist between Eur and NA. Rates of AEs for three i.v. iron preparations (iron sucrose [IS], ferric gluconate [FG] and high and low MW iron dextran [HMWID, LMWID]) were compared by product and continent from January 1, 2003 to June 30, 2009 for selected countries in Eur and NA, using the Uppsala Monitoring Center's database. Rates of total, anaphylaxis and other serious allergic AEs were calculated as number of AEs divided by i.v. iron sales standardized to 100 mg dose equivalents (DEq) of iron. Quarterly sales (millions of 100 mg DEq of iron) increased from the first quarter 2003 to the end of the second quarter of 2009 by 1% for FG, 16% for IS and 2% for ID. Total AEs for NA plus Eur were similar for FG and IS, but total AEs were 6- to 7-fold higher for ID. Rates of anaphylaxis were 6- to 11-fold higher in Eur plus NA combined for ID than for IS or FG. In NA, there were substantially higher reports for total, anaphylaxis and other serious allergic AEs with FG compared to IS, whereas the reverse was the case in Eur. Odds ratios (OR) showed higher risks of anaphylaxis with FG in NA vs. Eur (OR = 4.40, P < 0.0001) and lower risks with IS (OR = 0.24, P < 0.0001). Odds of anaphylaxis with LMWID in Eur vs. FG and IS were 42.08 and 16.92 (both P < 0.0001), respectively. In NA, odds of anaphylaxis with ID vs. FG and IS were 2.36 and 17.73 (both P < 0.0001), respectively. Differences between NA and Eur may be related to varied treatment practices. ID had the highest rates of all types of AEs, and IS and FG had a continued trend for lowest rates of AEs.

Pharmacovigilance in the Middle East

Background: The importance of countries to support their own national pharmacovigilance cannot be understated: citizens may have unique ethnicities, traditions, and diets influencing reaction to medication; alternate brands of therapy may be imported or manufactured and differ in ingredients or production processes; ADRs and toxicities associated with traditional and herbal remedies also need to be monitored. The objective of this study is to inventory national pharmacovigilance systems in place in the Middle East region. Methods: The Uppsala Monitoring Center Assessment of Country Pharmacovigilance Situation (February 2008) was adapted and translated into Arabic. Survey domains pertain to general program overview; information technology support; suspected ADR reporting and subsequent data use; pharmacovigilance activity and advocacy. A comprehensive search was conducted to determine the existence of a governing body responsible for medication safety in 13 Arabic speaking Middle Eastern countries. Surveys were emailed to the head of the identified centres, with follow-up messages and telephone calls subsequently made as necessary. Results: Data for 10 countries was obtained: representatives from two countries did not respond (Lebanon, Syria). Six described formal national pharmacovigilance programs (Egypt, Iraq, Jordan, Oman, Saudi Arabia, and the UAE), while five (Bahrain, Kuwait, Palestine, Qatar, Yemen) reported no active program or designated center. All active programs were recently formed (&lt; 5 years). The majority (83%) are government funded and two (33%) receive suspected ADR reports and offer drug information services. Most (83%) welcomed reports from a wide variety of health professionals, as well as from the public. Sixty-seven percent facilitated submission to the centre by email, but none directly through a web-based platform. All used the information for drug regulatory purposes but only 2 (33%) reported dissemination of safety information to the public. Conclusion: This is the first comprehensive review of the status of pharmacovigilance in the Middle East. While a number of countries participate in suspected ADR reporting activities, an estimated population of 30–50 million is without formal domestic programs. Technology must be exploited to ease spontaneous reporting and subsequent data management. Existing mechanisms for regional collaboration should be advanced so experience from model programs can be shared.

Canada's own "Dr. Safety"

A Lifetime in Safety. Ed Napke. Uppsala Monitoring Centre; 2011. This compilation of previously published articles by Dr. Ed Napke, founder of the Canadian Adverse Drug Reaction (ADR) Reporting Program, is largely a chronicle of how the program, now called the Canada Vigilance Program, was

Global Trigger Tool: Proficient Adverse Drug Reaction Autodetection Method in Critical Care Patient Units.

ABSTRACTBackgroundEmergency department (ED) being the most crucial part of hospital, where adverse drug reactions (ADRs) often go undetected. Trigger tools are proficient ADR detection methods, which have only been applied for retrospective surveillance. We did a prospective analysis to further refine the trigger tool application in healthcare settings.ObjectiveTo estimate the prevalence of ADRs and prospectively evaluate the importance of using trigger tools for their detection.Materials and methodsA prospective study was conducted in the ED for the presence of triggers in patient records to monitor and report ADRs by applying the Institute for Healthcare Improvement (IHI) trigger tool methodology.ResultsFour hundred sixty-three medical records were analyzed randomly using 51 trigger tools, where triggers were found in 181 (39.09%) and ADRs in 62 (13.39%) patients. The prevalence of ADR was 13.39%. According to the World Health Organization (WHO)-Uppsala Monitoring Centre (UMC) causality scale, 47 (75.8%) were classified as probable and 15 (24.2%) as possible, wherein 39 (62.9%) were predictable and 8 (12.9%) were definitely preventable. Most common triggers were abrupt medication stoppage (34.98%), antiemetic use (25.91%), and time in ED >6 hours (17.49%). The positive predictive values (PPVs) of triggers such as international normalized ratio (INR) > 4 (p = 0.0384), vitamin K administration (p = 0.002), steroid use (p = 0.0001), abrupt medication stoppage (p = 0.0077), transfusion of blood or blood products (p = 0.004), and rash (p = 0.0042) showed statistically significant results, which make the event detection process more structured when these triggers are positive. Presence of five or more triggers has statistically significant chances of developing an ADR (p < 0.05).ConclusionTrigger tool could be a viable method to identify ADRs when compared to the traditional ADR identification methods, but there is insufficient data on IHI tool and its use to identify ADRs in the general outpatient setting. Healthcare providers may benefit from better trigger tools to help them detect ADRs.How to cite this articlePandya AD, Patel K, Rana D, Gupta SD, Malhotra SD, Patel P. Global Trigger Tool: Proficient Adverse Drug Reaction Autodetection Method in Critical Care Patient Units. Indian J Crit Care Med 2020;24(3):172–178.

Severe neonatal hypercalcemia related to maternal exposure to nutritional supplement containing Spirulina

Spirulina platensis (Norst.) Geitler is a microalgae widely harvested in Asia, Africa and South America and used for centuries in these countries as a natural medicine and a nutritional complement. Indeed, this cyanobacterium could exert antioxidant, anti-inflammatory, anti-infective, hypolipidemic and anticancer properties [1–3]. It could also represent a nutritional supplement in developing countries, as it contains important quantities of proteins, minerals, B complex and liposoluble vitamins, particularly vitamin D [1]. In developed countries, nutritional supplements containing S. platensis are increasingly used and sold over the counter. They represent a “natural”, “ethnic” and “obviously safe”medication. Pregnant women are particularly exposed to these supplements. We here report a case of severe neonatal hypercalcemia related to an excessive maternal exposure to S. platensis. In April, 2010, a neonate was hospitalised the first day of his live in our university hospital for generalised seizures. His parents had no medical antecedent, there was no consanguinity, pregnancy was normal and the neonate was eutrophic with no malformation. Serum calcium was increased to 3.10 mmol/L (normal 10 ng/ml) and calcitriol (1,25dihydroxycholecalciferol) was greatly increased (260 pg/ml, normal 18–60 pg/ml). In the mother’s serum, 25hydroxycholecalciferol was normal (28 ng/ml) but calcitriol was increased (125 pg/ml, i.e. twice normal). Questioning revealed exposure to vitamin D supplementation at the beginning of pregnancy, and then daily exposure to S. platensis from the fourth month of pregnancy. S. platensisrelated maternal intoxication with 25-hydroxycholecalciferol hydroxylated to calcitriol by the placental 1α-hydroxylase is suspected to be responsible for foetal hypercalcemia. Causality assessment was scored “likely” according to the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) criteria [4]. The safety of nutritional supplements containing S. platensis is poorly evaluated. The supplements seem to contain low levels of algal toxins, particularly microcystins (hepatotoxins), but S. platensis decreases in vitro hepatocyte viability [5]. Anatoxins (neurotoxins) have been detected in some S. platensis preparations [6]. No human S. platensis-induced hepatitis or neurological disease has been reported to our knowledge. Sparse S. platensis-related G. Moulis (*) :A. Batz :G. Durrieu : J.-L. Montastruc Service de Pharmacologie Clinique, Faculte de Medecine, Centre Midi-Pyrenees de Pharmacovigilance, de Pharmacoepidemiologie et d’Informations sur le Medicament, Unite INSERM U 1027, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse, 37 Allees Jules-Guesde, 31000 Toulouse, France e-mail: gmoulis@hotmail.com

P1-14 Identifying adverse events of vaccines using a Bayesian method of medically guided information sharing

IntroductionThe detection of adverse events following immunisation (AEFI) fundamentally depends on how these events are classified. Standard methods impose a choice between either grouping similar events together to gain power...

Suspected Adverse Drug Reactions Reported For Children Worldwide

As a first step towards implementing routine screening of safety issues specifically related to children at the Uppsala Monitoring Centre, this study was performed to explore reporting patterns of adverse reactions in children. The first aim of this study was to characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. The second aim was to highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. This was an exploratory study of internationally compiled individual case safety reports (ICSRs). Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010. The reports in VigiBase originate from 97 countries and the likelihood that a medicine caused the adverse effect may vary from case to case. Suspected duplicate and vaccine reports were excluded from the analysis, as were reports with age not specified. The Medical Dictionary for Regulatory Activities (MedDRA®) and the WHO Anatomical Therapeutic Chemical (ATC) classification were used to group adverse reactions and drugs. In the general review, reports from 1968 to 5 February 2010 were divided into child (aged 0-17 years) and adult (≥ 18 years) age groups. To highlight increases in reporting rates of specific adverse reactions during recent years, reports from 2005 to February 2010 were compared with reports from 1995 to 1999. The ten adverse reactions with the greatest difference in the proportion of reports between the two time periods were reviewed. In the latter analysis, the reports were subdivided into age groups: neonates ≤ 27 days; infants 28 days-23 months; children 2-11 years; and adolescents 12-17 years. A total of 3,472,183 reports were included in the study, of which 7.7% (268,145) were reports for children (0-17 years). Fifty-three percent of the child reports were for males, whilst 39% of reports in the adult group were for males. The proportion of reports involving children among Asian reports was 14% and was 15% among reports from Africa and Latin America, including the Caribbean. Among reports from North America, Oceania and Europe, 7% of the reports involved children. For the ATC drug classification groups, the largest difference in percentage units between the child and adult groups was seen for the anti-infective (33 vs 15%), respiratory (11 vs 5%) and dermatological (12 vs 7%) drug groups. Skin reactions were most commonly reported for the children; these were recorded in 35% of all reports for children and 23% of all reports for adults. Medication error-related terms in the younger age groups were reported with an increased frequency during recent years. This was particularly noticeable for the infants aged 28 days-23 months, recorded with accidental overdose and drug toxicity. Reactions reported in suspected connection to medicines used for attention-deficit hyperactivity disorders (ADHD) completely dominated the 2- to 11-year age group and were also common for the adolescents. This study presents variations in the reporting pattern in different age groups in VigiBase which, in some cases, could be due to susceptibilities to specific drug-related problems in certain age groups. Other likely explanations might be common drug usage and childhood diseases in these age groups. Reports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.

The Uppsala Monitoring Centre (UMC) has successfully applied a pilot algorithm to its database to show clusters that help identify antimicrobial resistance.

The Uppsala Monitoring Centre (UMC) has successfully applied a pilot algorithm to its database to show clusters that help identify antimicrobial resistance.

Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

BackgroundIn spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT) are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR) database (Vigibase™) over the past 40 years.MethodsThe WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC) provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs) of anti-malarials was analyzed according to those clusters.ResultsFrom 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries) submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious.ConclusionsThis paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of development, the presence of well functioning national pharmacovigilance systems is vital to ensure safe and responsible scale up of ACT deployment. Bringing together the competencies of national pharmacovigilance centres and various types of organizations in the NGO, academic and private sectors with global coordination to create short- and long-term solutions may help address the lag between rapidly growing ACT use and poor ADR reporting.

The Uppsala Monitoring Centre (UMC) announced that it has now entered 6 million ADR reports into Vigibase.

The Uppsala Monitoring Centre (UMC) announced that it has now entered 6 million ADR reports into Vigibase.

Tetany: Possible adverse effect of bevacizumab

Bevacizumab a recombinant humanized monoclonal antibody was approved in 2004 by US FDA for metastatic colorectal cancer. It is reported to cause potentially serious toxicities including severe hypertension, proteinuria, and congestive heart failure. To correlate adverse event tetany with the use of bevacizumab. World Health Organization's Uppsala Monitoring Centre, Sweden, for reporting of adverse drug reactions from all over the world, identified 7 cases with tetany-related symptoms to bevacizumab from four different countries. These 7 patients reported to UMC database developed adverse events described as musculoskeletal stiffness (1), muscle spasm (1), muscle cramps (1), lock jaw or jaw stiffness (4), and hypertonia (1), with hypocalcaemia. After detailed study of the possible mechanism of actions of bevacizumab and factors causing tetany, it is proposed that there is a possibility of tetany by bevacizumab, which may occur by interfering with calcium metabolism. Resorption of bone through osteoclasts by affecting VEGF may interfere with calcium metabolism. Another possibility of tetany may be due to associated hypomagnesaemia, hypokalemia, or hyponatremia. Tetany should be considered as a one of the signs. Patient on bevacizumab should carefully watch for tetany-related symptoms and calcium and magnesium levels for their safety.

Pharmacovigilance: scope for a dermatologist.

Pharmacovigilance is defined as the science of detection, assessment, and prevention of adverse drug reactions in humans. Under-reporting of drug reactions is the major problem and has various reasons. The WHO has initiated the program of reporting all adverse drug reactions now co-ordinated by the Uppsala Monitoring Centre in Uppsala, Sweden, with oversight by an international board. This article presents in brief the relevance, functioning, importance, and the procedure of reporting adverse drug reactions. Dermatologists have the greatest opportunity in reporting various reactions that can happen as they come across majority of these drug reactions, prescribed by all sectors of the health system.

New vaccine reports from FDA to the Uppsala Monitoring Centre

UMC worked with the FDA and SRA – the contractor that operates the VAERS program for CDC (Centers for Disease Control and Prevention) and FDA – over a number of months to validate the format of the reports. After this was completed, we were sent a CD containing vaccine reports covering the period 1990 to July 2010. At the time of the writing, 245,454 reports (reports up to 2007) have been uploaded into VigiBase, and are available for searching via VigiSearch. This figure includes around 140,000 reports that are completely new in VigiBase, and older ones that have been updated from Intdis to the E2B format.

Pharmacovigilance Data Mining With Methods Based on False Discovery Rates: A Comparative Simulation Study

The early detection of adverse reactions caused by drugs that are already on the market is the prime concern of pharmacovigilance efforts; the methods in use for postmarketing surveillance are aimed at detecting signals pointing to potential safety concerns, on the basis of reports from health-care providers and from information available in various databases. Signal detection methods based on the estimation of false discovery rate (FDR) have recently been proposed. They address the limitation of arbitrary detection thresholds of the automatic methods in current use, including those last updated by the US Food and Drug Administration and the World Health Organization's Uppsala Monitoring Centre. We used two simulation procedures to compare the false-positive performances for three current methods: the reporting odds ratio (ROR), the information component (IC), the gamma Poisson shrinkage (GPS), and also for two FDR-based methods derived from the GPS model and Fisher's test. Large differences in FDR rates were associated with the signal-detection methods currently in use. These differences ranged from 0.01 to 12% in an analysis that was restricted to signals with at least three reports. The numbers of signals generated were also highly variable. Among fixed-size lists of signals, the FDR was lowered when the FDR-based approaches were used. Overall, the outcomes in both simulation studies suggest that improvement in effectiveness can be expected from use of the FDR-based GPS method.

Alopecia in Association with Lamotrigine Use

The WHO Programme for International Drug Monitoring, maintained by the Uppsala Monitoring Centre (UMC), has more than 90 member countries contributing individual case safety reports (ICSRs) from their existing national pharmacovigilance systems; these reports are stored in the WHO global ICSR database, VigiBase. A continuous increase of ICSRs of alopecia in suspected connection to lamotrigine use has been observed in VigiBase; however, only limited information has been published on this topic. To examine in greater detail the association between lamotrigine and alopecia by outlining the characteristics of the accumulated reports in VigiBase. An analysis of all reports in VigiBase, up to 1 April 2009, where lamotrigine was suspected of having caused alopecia. Lamotrigine was suspected of being involved in the development of alopecia in 337 patients, reported from 19 countries. The age of the patients ranged between 5 months and 84 years (mean 36 years), with a predominance (58%) of patients <40 years of age. 272 patients were female. In 291 reports, lamotrigine was the only drug suspected by the reporter, and in 112 reports, lamotrigine was the sole reported drug. Commonly co-reported drugs were other antiepileptic drugs. For 217 patients, alopecia was reported as the single event. In 11 patients, the reaction abated on cessation of lamotrigine. One patient was reported to have had a recurrence of alopecia on re-administration of lamotrigine. The UMC continues to receive reports of alopecia associated with the use of lamotrigine. Although alopecia may not be regarded as serious from a regulatory perspective, this adverse reaction has the potential to affect compliance, resulting in decreased efficacy of the treatment regimen and detrimental effects on patient health outcomes.

Hyponatraemia as an Adverse Drug Reaction of Antipsychotic Drugs

Hyponatraemia due to antipsychotic use is a potentially serious problem; however, it is not known whether it is an adverse drug reaction (ADR) to antipsychotic use or is due to the underlying psychiatric disease. To estimate the strength of the association between antipsychotics and hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH), using information reported to the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (UMC). The WHO global individual case safety report database system (VigiBase) maintained by the UMC. Case-control study, with cases being reports of hyponatraemia/SIADH, and controls being reports of other ADRs. Each case was sampled with ten controls sequencing in time from the date the corresponding case was entered into the database. The potential contribution of the chemical structures and receptor affinity (dopaminergic and/or serotonergic) of the antipsychotics was studied, as was the influence of concomitant use of other medications known to cause hyponatraemia. The strength of the association between antipsychotic use and hyponatraemia in comparison with other drugs was expressed as reporting odds ratio (ROR), a measure of disproportionality, with corresponding 95% CIs, adjusted for age, sex and concomitant medication associated with hyponatraemia. In addition, stratification by the presence or absence of concomitant medication was performed. Up to August 2008, 3 881 518 suspected ADRs were reported and filed in VigiBase, with 912 reports on hyponatraemia related to antipsychotics. The adjusted ROR for the association between antipsychotic use and hyponatraemia was 1.58 (95% CI 1.46, 1.70). The adjusted RORs did not vary for the different chemical structures or dopamine D(2) and serotonin 5-HT(2A) receptor affinity profiles. The ROR was 3.00 (95% CI 2.65, 3.39) for the association between hyponatraemia and antipsychotic use in the absence of concomitant medication associated with hyponatraemia, and 1.16 (95% CI 1.06, 1.28) in the presence of concomitant medication associated with hyponatraemia. Antipsychotic use may be associated with reporting of hyponatraemia. Moreover, the concomitant use of medication associated with hyponatraemia potentially leads to under-reporting of antipsychotic-associated hyponatraemia. We advise testing patients whose psychiatric and/or physical condition deteriorates while on antipsychotics for hyponatraemia.

Pharmacovigilance: A Worldwide Master Key for Drug Safety Monitoring

Pharmacovigilance is like a sunshade to describe the processes for monitoring and evaluating ADRs and it is a key component of effective drug regulation systems, clinical practice and public health programmes. The number of Adverse Drug Reactions (ADRs) reported resulted in an increase in the volume of data handled, and to understand the pharmacovigilance, a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. The current global network of pharmacovigilance centers, coordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider litigious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries. Recently, pharmacovigilance has been confined, mainly to detect adverse drug events that were previously either unknown or poorly understood. Pharmacovigilance is an important and integral part of clinical research and these days it is growing in many countries. Today many pharmacovigilance centers are working for drug safety monitoring in this global pitch, however, at the turn of the millennium pharmacovigilance faces major challenges in aspect of better safety and monitoring of drugs. In this review we will discuss about drug safety, worldwide pharmacovigilance centers and their role, benefits and challenges of pharmacovigilance and its future consideration in healthcare sectors.

Acquired factor VIII haemophilia following influenza vaccination

Autoimmune diseases should present or be worsened by vaccination due to the pharmacological properties of vaccines. We report a case of acquired haemophilia mediated by anti-factor VIII antibody following a vaccination against influenza. A 72-year-old woman suffered from spontaneous bruises of the wrists at the end of October, 2009. She had been exposed for 31 years (1977–2008) to prednisone for a pulmonary sarcoidosis. She was also being treated with L-thyroxine for Hashimoto’s thyroiditis, amlodipine for essential arterial hypertension and paroxetine for depression. The patient was vaccinated against seasonal influenza (MUTAGRIP) 8 days prior to the first haemorrhagic symptom. No local complication was noted during the intramuscular injection. This was the first time she had been vaccinated with a seasonal influenza vaccine. The results of the clinical examination were normal, except the haemorrhagic syndrome. Platelet count was 320,000/μL, activated cephalin time (equivalent to activated partial thromboplastin time) was 72 s (indicator: 28 s) and prothrombine time was 100%. The amount of factor VIII was 1%, and antibody directed against factor VIII was detected at 8 Bethesda units, without any von Willebrand factor deficiency. There was no clinical or biological evidence for any haematopoietic malignancy or systemic disease. Antinuclear antibodies were detected at the limit of significance (titre: 1/160), without any specificity (antiDNA nor anti-extractable nuclear antigens). Symptomatic treatment with activated prothrombin complex concentrates (FEIBA) was prescribed for 24 h. Due to the ineffectiveness of prednisone (1 week at 1 mg/kg/day), rituximab was introduced (375 mg/m/week, 4 infusions), which resulted in clinical and biological remission: 3 weeks after the last infusion of rituximab, factor VIII and its auto-antibody were 8% and 4 Bethesda units respectively; 4 months after the last infusion, these values were 48% and not detectable, respectively. According to World Health Organization–Uppsala Monitoring Centre criteria [1], the score of causality assessment was considered to be “possible”. Acquired haemophilia is a very rare disorder due to an anti-factor VIII antibody: its incidence is estimated to range from 0.2 to 1.9/million/year [2]. An underlying cause is present in approximately half of cases: solid tumours, haematopoietic malignancies, auto-immune diseases, pregnancy and post-partum, infections, drugs (penicillins, sulfa antibiotics, phenytoin, chloramphenicol, methyldopa, interferon-α, fludarabine, levodopa, clopidogrel) [3–5]. None of the drugs taken by our patient were known to induce acquired haemophilia. To the best of our knowledge, no post-vaccination-acquired haemophilia has G. Moulis :G. Pugnet Service de Medecine Interne, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse, Toulouse, France

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or Hyponatraemia Associated with Valproic Acid

The Netherlands Pharmacovigilance Centre Lareb received four cases of severe symptomatic hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) in association with valproic acid use, in which a causal relationship was suspected. This study describes these cases and gives support for this association from Vigibase, the adverse drug reaction (ADR) database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. Cases of hyponatraemia in valproic acid users are described. In a case/non-case analysis, the strength of the association between reported cases of hyponatraemia and the use of valproic acid in Vigibase was established by calculating a reporting odds ratio, adjusted for possible confounding by concomitant medication. Four females aged 57, 67, 71 and 88 years developed symptomatic hyponatraemia or SIADH after starting valproic acid. Despite concomitant medication or co-morbidity, a causal relationship was plausible. In Vigibase, valproic acid is disproportionally associated with hyponatraemia and SIADH (corrected reporting odds ratio 1.83 [95% CI 1.61, 2.08]). Based on the described cases and the reports from Vigibase, a causal relationship between valproic acid use and hyponatraemia or SIADH can be suspected. The mechanism by which valproic acid could cause hyponatraemia or SIADH has not been fully elucidated. Valproic acid use could lead to reduced sensitivity of hypothalamic osmoreceptors. It also might directly affect tubular cell function, thereby leading to SIADH. It might be expected that a combination of effects on the osmoreceptors and a lack of compensation of the salt-water unbalance by the nephrons causes SIADH in some patients using valproic acid. It could be a dose- or concentration-related adverse effect. In this report, severe symptomatic hyponatraemia and SIADH have been associated with the use of valproic acid. With this study, not only is the number of published cases doubled, but also the data from Vigibase strongly support the association. Since hyponatraemia and SIADH have a high morbidity, health professionals should be aware of this potential ADR.