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Background: The WHO Foundation Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre [UMC]) has received many individual case safety reports (ICSRs) associating HMG-CoA reductase inhibitor drug (statin) use with the occurrence of muscle damage, including rhabdomyolysis, and also peripheral neuropathy. A new signal has now appeared of disproportionally high reporting of upper motor neurone lesions.Aim and Scope: The aim of this paper is to present the upper motor neurone lesion cases, with other evidence, as a signal of a relationship between statins and an amyotrophic lateral sclerosis (ALS)-like syndrome. The paper also presents some arguments for considering that a spectrum of severe neuromuscular damage may be associated with statin use, albeit rarely. The paper does not do more than raise the signal for further work and analysis of what must be regarded as a potentially very serious and perhaps avoidable or reversible adverse reaction, though it also suggests action to be taken if an ALS-like syndrome should occur in a patient using statins.Methods: The 43 reports accounting for the disproportional reports in Vigibase (the database of the WHO Programme for International Drug Monitoring) are summarised and analysed for the diagnosis of an ALS-like syndrome. The issues of data quality and potential reporting bias are considered.Results: 'Upper motor neurone lesion' is a rare adverse event reported in relationship to drugs in Vigibase (a database containing nearly 4 million ICSRs). Of the total of 172 ICSRs on this reported term, 43 were related to statins, of which 40 were considered further: all but one case was reported as ALS. In 34/40 reports a statin was the sole reported suspected drug. The diagnostic criteria were variable, and seven of the statin cases also had features of peripheral neuropathy. Of a total of 5534 ICSRs of peripheral neuropathy related to any drug in Vigibase, 547 were on statins. The disproportional reporting of statins and upper motor neurone lesion persisted after age stratification, and such disproportionality was not seen for statins and Parkinson's disease, Alzheimer's disease, extrapyramidal disorders, or multiple sclerosis-like syndromes.Discussion: Because the cases were sometimes atypical we propose the use of the term 'ALS-like syndrome' and speculate whether this is part of a spectrum of rare neuromuscular damage. The diagnosis of ALS is often problematic, and the insidiousness and chronicity of the disease make causality with a drug difficult to assess. The disproportionally high reporting makes this an important signal nevertheless, since ALS is serious clinically and statins are so widely used. Wide use of the statins also makes a chance finding more probable, but is unlikely to cause disproportional reporting when there are no obvious biases identified.Conclusion: We emphasise the rarity of this possible association, and also the need for further study to establish whether a causal relationship exists. We do advocate that trial discontinuation of a statin should be considered in patients with serious neuromuscular disease such as the ALS-like syndrome, given the poor prognosis and a possibility that progression of the disease may be halted or even reversed. [ABSTRACT FROM AUTHOR]

The expanded use of multiple antiretroviral drugs during pregnancy has led to a reduction in the occurrence of perinatal transmission of HIV to <2%, but has led to concerns regarding both short-term toxicity and the long-term impact on the woman and her child. Enhanced toxicity of nevirapine has been noted among women with CD4+ lymphocyte counts >250 cells/μL at treatment initiation and among pregnant women on long-term didanosine and stavudine. These drugs should be avoided in such situations if alternatives are available. Efavirenz has been associated with birth defects in monkeys, and several cases of neural tube defects have been reported in humans after first trimester exposure, so treatment with this drug should be avoided during the first trimester. Protease inhibitors have been associated with an increased risk of maternal glucose intolerance, pre-eclampsia and preterm birth in some, but not all, studies. Pregnancies exposed to antiretroviral therapy should be registered with the Antiretroviral Pregnancy Registry as early in pregnancy as possible in order to provide data on the risk of birth defects after exposure.The pharmacokinetics of nucleoside and non-nucleoside reverse transcriptase inhibitors are not significantly changed in pregnancy, so standard dosing may be used. However, concentrations of several protease inhibitors are lower in pregnancy, so ritonavir-boosting or increased doses are required. Of great theoretical concern is the impact of resistance mutations that develop following single-dose nevirapine therapy on the response to later therapy among women and their infected infants. The use of dual nucleoside therapy for 3–7 days after single-dose nevirapine in the mother reduces but does not eliminate the risk of nevirapine resistance; alternative regimens for prevention of resistance are under study, as are the subsequent responses of the mother and her infant to therapy. Short courses of prophylactic zidovudine and nevirapine have been well tolerated in neonates. Concern has been raised, however, that these exposures may lead to persistent mitochondrial dysfunction or later cancers, underscoring the need for long-term surveillance of antiretroviral-exposed, HIV-uninfected infants. [ABSTRACT FROM AUTHOR]

Focuses on an article written about Lapdap, a combination drug for the treatment of falciparum malaria, published in the June 12, 2005 issue of "Sunday Times--Britain" newspaper. Concerns raised by the World Health Organization regarding the safety of taking Lapdap; Efforts made to delay or prevent the development of drug resistance.

Focuses on the side effects of rofecoxib. Pharmacovigilance and drug safety concerns; Signals of increased risk of cardiovascular disorders with the use of rofecoxib.

The WHO World Alliance on Patient Safety is a new, all encompassing project to improve medical care. Individual patients are the focus and all countries are encouraged to develop systems in which medical error, therapeutic accidents and failures are minimised. The potential for adverse events is present at all levels of healthcare and in all disciplines. One working group in the Alliance is charged with promoting and developing a 'reporting and learning' culture for adverse events in all areas of medical care. Central to current thinking for this group is a no-fault approach and to report near misses. The aim is not to provide certainty over the individual events, but rather to draw attention to possible improvements in systems that may prevent future problems. Adverse events relating to drug therapy have been reported for decades to national pharmacovigilance authorities, but this is aimed at finding problems with the drugs themselves as early as possible. The Alliance approach in the area of drug safety, by contrast, has a greater focus on safety in the systems of drug provision (including prescription and dispensing) and other systematic issues relating to safe drug provision, such as fraudulent drugs. Thus, current pharmacovigilance can be seen as representing a part of the reporting and learning envisaged by the Alliance. The two approaches are also complementary, but there are practical and philosophical areas of overlap in which difficulties may occur, such as anonymised reporting in a no-fault system and consequent impossibility for follow-up. In pharmacovigilance follow-up for more information is regarded as essential. Whether pharmacovigilance broadens into the area of patient safety or the latter involves completely new systems to do its work will be a matter for each country to consider. One thing is certain, working together both systems will improve patient care, but without cooperation more bureaucracy will take valuable health professional time with a lesser result. [ABSTRACT FROM AUTHOR]

Introduction: A major task for the Uppsala Monitoring Centre (UMC) is to detect early signals of suspected adverse drug reactions (ADRs) in the WHO Database. The database currently contains over 2.8 million spontaneously reported ADR case reports continuously collected by National Pharmacovigilance Centres in countries participating in the WHO Programme for International Drug Monitoring. The database is scanned every quarter and drug-ADR combinations are filtered out using different selection criteria intended to catch potential international drug safety signals at an early stage. Summary case data are reviewed by experts on the UMC’s review panel and the signals are presented to the Programme members in the restricted circulation document entitled ‘SIGNAL’. Objective: The aim of the study was to investigate: (i) how the signals presented in ‘SIGNAL’ are used; (ii) if they reach the right target group; (iii) if they are of interest and relevance to the recipients; (iv) if they are timely and; (v) if they make any difference. We were also interested in knowing the view of member countries regarding the definition of what a signal is. Methods: A questionnaire was sent out to 71 countries participating in the WHO Programme. The recipients were asked to state what actions were taken for 26 different signal headings included in three issues of ‘SIGNAL’ sent out during 2001 and to rate how useful they considered these topics to be. Results: Responses were received from 45 countries (63%). The Centres’ average ratings of relevance, importance and usefulness on a scale 1–10 of the selected 26 signals were all above the expected average rating 5.5. The content of ‘SIGNAL’ in general was seen as always or often useful in 63.5% of the respondents. In 2001, 17 countries took actions on at least one signal. Actions were rarely taken without considering the signal from the UMC. All responding centres agreed on the WHO definition of a signal, but there were differences in the interpretation of what constitutes a signal. Conclusion: The ‘SIGNAL’ publication is timely, plays an important role and has a direct impact on drug safety issues handled by members of the WHO Programme for International Drug Monitoring. [ABSTRACT FROM AUTHOR]

Over the past few years, a number of drugs have been withdrawn for safety reasons, either by drug approval authorities, or by the manufacturer. A recent example is the withdrawal of cerivastatin in connection with rhabdomyolysis. Several other drugs have also been taken off the market as a security measure, not because the nature of the risk involved was unknown but because the risk had proved apparently uncontainable. It seems that the inclusion of a warning or contraindication in the Summary of Product Characteristics (SPC) or sending a ‘Dear Doctor’ letter is insufficient to ensure compliant prescription behaviour. There appears to be a discrepancy between the careful use of evidence underpinning the SPC content and formal warnings and changes to the SPC and the effect they have on the prescription and dispensing of the drugs involved. This results in undue loss or damage for both the manufacturer and the patient. There are no easy solutions to tackle this problem; the ineffectiveness of labelling and ‘Dear Doctor’ letters has ramifications for the whole regulatory/ industrial/educational complex. We discuss briefly four possible strategies for improving the current situation, with the emphasis on the place the prescriber has in this process. The first strategy is education-based. Clinicians need to know about the comparative merits of the effectiveness and risk of drugs, as well as how they work pharmacologically, toxicologically, and what interactions they have with each other. The second strategy involves improving the information available for clinicians. Frequently, physicians do not consult the SPC for verification, leaving aside whether they have taken notice of the contents of the official SPC in the first place. It is recommended that the accessibility of SPCs is enhanced for doctors and pharmacists, drawing attention specifically to any changes. There needs to be a single body of information that covers every drug. The third strategy involves communication. There is much to be done in this area both in terms of follow-up and understanding of health professional's behaviour and how to empower best practise. The final strategy involves professional freedom. It goes without saying that doctors who issue off-label prescriptions may need to justify their actions. Deviating from the SPC should always be a considered decision and health professionals need to be aware of the additional responsibilities associated with such a decision. The dispensing pharmacist can play an important role in the implementation of warnings and contraindications. [ABSTRACT FROM AUTHOR]

The WHO database contains over 2.5 million case reports, analysis of this data set is performed with the intention of signal detection. This paper presents an overview of the quantitative method used to highlight dependencies in this data set. The method Bayesian confidence propagation neural network (BCPNN) is used to highlight dependencies in the data set. The method uses Bayesian statistics implemented in a neural network architecture to analyse all reported drug adverse reaction combinations. This method is now in routine use for drug adverse reaction signal detection. Also this approach has been extended to highlight drug group effects and look for higher order dependencies in the WHO data. Quantitatively unexpectedly strong relationships in the data are highlighted relative to general reporting of suspected adverse effects; these associations are then clinically assessed. [ABSTRACT FROM AUTHOR]

The detection of unknown and unexpected connections between drug exposure and adverse events is one of the major challenges of pharmacovigilance. For the identification of possible connections in large databases, automated statistical systems have been introduced with promising results. From the large numbers of associations so produced, the human mind has to identify signals that are likely to be important, in need of further assessment and follow-up and that may require regulatory action. Such decisions are based on a variety of clinical, epidemiological, pharmacological and regulatory criteria. Likewise, there are a number of criteria that underlie the subsequent evaluation of such signals. A good understanding of the logic underlying these processes fosters rational pharmacovigilance and efficient drug regulation. In the future a combination of quantitative and qualitative criteria may be incorporated in automated signal detection. [ABSTRACT FROM AUTHOR]

We define an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." Such reactions are currently reported by use of WHO's Adverse Reaction Terminology, which will eventually become a subset of the International Classification of Diseases. Adverse drug reactions are classified into six types (with mnemonics): dose-related (Augmented), non-dose-related (Bizarre), dose-related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure). Timing, the pattern of illness, the results of investigations, and rechallenge can help attribute causality to a suspected adverse drug reaction. Management includes withdrawal of the drug if possible and specific treatment of its effects. Suspected adverse drug reactions should be reported. Surveillance methods can detect reactions and prove associations. [ABSTRACT FROM AUTHOR]

Identification of harm in the form of adverse drug reactions that are caused by counterfeit or other substandard medicinal products by application of standard pharmacovigillance methods of registration, analysis and investigation could be forensic pharmacovigillance. As recent example of this type of forensic pharmacovigilance is the discovery and investigation into the adverse drug reactions caused by contaminated heparin in the USA in 2008 is discussed. [ABSTRACT FROM AUTHOR]

Conclusions: Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. The study shows the potential of bayesian neural networks in analysing data on drug safety. [ABSTRACT FROM AUTHOR]

The authors reflect on the interaction between the medical and legal fields in legal cases involving medical malpractice. They suggest that the relationship between medicine and law can be confusing because of conflicting interpretations of evidence regarding harm caused by medications. They argue that this type of confusion affects the perceptions of medical professionals and the public and their daily use of medication.

The world changes continuously and pharmacovigilance as a new discipline also must change. There are new fields opening with novel challenges whilst we are still perfecting ways to manage and improve the basic challenges such as inadequate data for decision making and under-reporting. Traditional medicines, vaccines, poisoning and medication error are all aspects of the safety of medicines that we have monitored for decades, though without perhaps paying enough attention to their special aspects. There are many new stakeholders taking serious interest in pharmacovigilance outside the regulatory sphere and they often focus on improving individual patient care, rather than the more traditional concentration on broad public health. The same stakeholders are also drawing attention to other iatrogenic outcomes that should be recognised, evaluated and their outcomes compared and contrasted with medication, such as harm from medical devices. The vigilance methods used for medication are very much applicable to all these new fields, though more and different expertise will be needed to evaluate outcomes. [ABSTRACT FROM AUTHOR]