Risk of drug-induced photosensitivity: focus on spectroscopic and molecular characteristics.

BACKGROUND: Drug-induced photosensitivity is difficult to predict and remains a challenge for both the dermatological clinical practice and pharmacovigilance. PURPOSE: To assess the association between spectroscopic and molecular characteristics and the occurrence of photosensitivity reactions. METHODS: For 143 well-known photosensitisers (e.g. tetracyclines, diuretics), we retrieved information on spectroscopic and molecular parameters, including: absorption maximum lambda(max), molar absorption coefficient epsilon, area under the absorption curve (AUC), molecular weight and configuration, hetero and aromatic halogen atoms, lipophilicity (log P) and acid/base status (pKa). In the WHO-ADR database, all reports with suspected adverse drug reactions of the study drugs were selected. We identified all reports on photosensitivity reactions and defined them as cases. All other reports were selected as non-cases. A case-non-case approach was performed to assess the spectroscopic and molecular exposure variables as a factor for photosensitivity reactions. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: A lambda(max) between 290 and 320 nm (OR 3.74, 95% CI 3.45-4.06), and an epsilon > 20,000 M(-1) cm(-1) (OR 5.49, 95% CI 5.10-5.92) were highly associated with the reporting of photosensitivity reactions. Risk of the photosensitivity reactions was significantly increased among intermediate or high AUCs compared to low AUC. Low molecular weight and aromatic halogen atoms were associated with photosensitivity reactions (OR 2.37, 95% CI 2.07-2.71 resp. OR 3.37, 95% CI 3.15-3.61) as were log p < 1 and pKa < 7. CONCLUSION: The reporting of photosensitivity reactions to established phototoxic drug classes is strongly influenced by spectroscopic and physicochemical characteristics of individual drugs.

Can intranasal corticosteroids cause migraine-like headache?

Intranasal corticosteroids (INCs) act predominantly locally and are considered to exert minimal systemic effects. On reviewing the international data collected in the World Health Organization's global pharmacovigilance programme an unexpected cluster was found of 38 case reports of migraine in suspected connection with INCs. These reports came from five countries (May 2007) and concerned six different drugs. In all reports the INC was the sole suspect drug. In nine cases re-exposure to the drug had taken place, leading to the recurrence of the event in eight of these patients. However, INCs are mainly used for rhinitis, and there is a known connection between rhinitis and migraine. Although representing only 0.6% of the total of case reports, international pharmacovigilance data suggest that the use of INCs may cause or trigger migraine or migraine-like headache. Further study is needed to determine if the reported association is true or not and, if so, what the possible mechanism is.

The spectrum and types of adverse side effects to biological immune modulators: a proposal for new classification.

In recent years, a growing number of biological agents such as cytokines, monoclonal antibodies and fusion proteins have become available for the treatment of various autoimmune, neoplastic, cardiovascular, infectious, allergic, and other conditions. Their introduction has resulted in marked clinical improvements for many patients. Nevertheless, a variety of adverse side effects have been observed with these agents. Based on the special features of biological agents a new classification of these side effects of biological agents is proposed--related but clearly distinct from the classification of side effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions due to high cytokine levels (type alpha), hypersensitivity due to an immune reaction against the biological agents (type beta), immune or cytokine imbalance syndromes (type gamma), symptoms due to cross-reactivity (type delta), and symptoms not directly affecting the immune system (type epsilon). This classification could help to better deal with the clinical features of these side effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

Deep vein thromboembolism in malignant diseases.

Tumourous diseases are associated with haemorrhagic as well as thrombotic complications. Trousseau described in 1865 a mutual association between tumourous diseases and venous thromboembolism. As many as 15-20% patients with venous thromboembolism have an undetected malignity, which equals a prevalence of 2-3% in the population. From this ensues the relative risk of a newly diagnosed malignity which is higher during the first year after venous thromboembolism. Migrating thrombophlebitis is a relatively specific sign in tumours, in particular in pancreatic tumours. In the pathogenesis of venous thromboembolisms in tumourous diseases, the following factors play a significant part: elevated coagulation parameters, reduced fibrinolysis, frequent immobilization, surgical operations in the case history, chemotherapy, hormonal therapy and central venous catheters. Conventional long term management of VTE involves the use of vitamin K antagonists, such as warfarin, to reduce the risk of recurrence. Recent evidence-based approach in long term management of VTE in patients with tumorous disease shows that the use of LMWH offers an effective alternative to VKAs with higher efficacy, without a significantly increased risk of bleeding, and without the need for regular laboratory monitoring.

Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death.

AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS AND RESULTS: All 284,426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.

Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs.

OBJECTIVE: The aim of this paper is to demonstrate the usefulness of the Bayesian Confidence Propagation Neural Network (BCPNN) in the detection of drug-specific and drug-group effects in the database of adverse drug reactions of the World Health Organization Programme for International Drug Monitoring. METHODS: Examples of drug-adverse reaction combinations highlighted by the BCPNN as quantitative associations were selected. The anatomical therapeutic chemical (ATC) group to which the drug belonged was then identified, and the information component (IC) was calculated for this ATC group and the adverse drug reaction (ADR). The IC of the ATC group with the ADR was then compared with the IC of the drug-ADR by plotting the change in IC and its 95% confidence limit over time for both. RESULTS: The chosen examples show that the BCPNN data-mining approach can identify drug-specific as well as group effects. In the known examples that served as test cases, beta-blocking agents other than practolol are not associated with sclerosing peritonitis, but all angiotensin-converting enzyme inhibitors are associated with coughing, as are antihistamines with heart-rhythm disorders and antipsychotics with myocarditis. The recently identified association between antipsychotics and myocarditis remains even after consideration of concomitant medication. CONCLUSION: The BCPNN can be used to improve the ability of a signal detection system to highlight group and drug-specific effects.

Association between terbinafine and arthralgia, fever and urticaria: symptoms or syndrome?

PURPOSE: The antifungal agent terbinafine has been approved for marketing in The Netherlands since 1992. Adverse drug reactions (ADRs) may occur in about 10% of the patients, the majority gastrointestinal disorders and skin reactions. Since the introduction of terbinafine, the Netherlands Pharmacovigilance Foundation Lareb received eight reports of arthralgia during the use of this drug. In four reports the additional presence of skin reactions was mentioned, two of these reports concerned urticaria. Two patients who reported arthralgia also had a fever. These reports were described in more detail, and analysed statistically in order to determine whether symptoms are interrelated. METHODS: All reports with known gender and a reporting date between 1 March 1992 and 1 January 1999, concerning patients older than 10 years, were included. The extent to which the symptoms urticaria, fever and arthralgia were interrelated was examined by logistic regression modelling. RESULTS: Case series as well as the results of the statistical analysis show a clustering of symptoms among reports of patients using terbinafine. Both urticaria and arthralgia were statistically significantly associated with reports on terbinafine compared to all other reports in the database. CONCLUSION: The findings might point towards a clustering of these symptoms in patients using terbinafine. Possibly these symptoms have a shared aetiology, presumably an immunological reaction.

Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.

OBJECTIVES: To examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy. DESIGN: Data mining using bayesian statistics implemented in a neural network architecture. SETTING: International database on adverse drug reactions run by the World Health Organization programme for international drug monitoring. MAIN OUTCOME MEASURES: Reports mentioning antipsychotic drugs, cardiomyopathy, or myocarditis. RESULTS: A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation. 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.

The value of reporting therapeutic ineffectiveness as an adverse drug reaction.

Therapeutic ineffectiveness is a frequent drug-related problem that can occur in a variety of different situations and be caused by different mechanisms. Examples are inappropriate use, interactions or metabolic abnormalities. Observations in patients of unexpected ineffectiveness can provide important information with regard to such situations. Therefore, ineffectiveness--especially when unexpected or unexplained--is a potentially important reportable event in pharmacovigilance. The terms regarding ineffectiveness in the WHO Adverse Reaction Terminology (WHOART) have been recently revised in order to enable optimal coding of such case reports.

An ABC of drug-related problems.

The problems relating to the use of medicines are manifold. They may differ in pharmacological, pathological, epidemiological and legal respects, and may have different consequences, for example, as regards scientific study, regulation or rational use. Pharmacovigilance is concerned with all such problems: adverse effects and interactions as well as problems relating to ineffectiveness, inappropriate use, counterfeiting, dependence or poisoning. Practically all medicine-related problems can be classified in one basic system, taking into account their characteristics and distinctions. This system distinguishes between appropriate and inappropriate drug use; dose-related and dose-unrelated problems [corrected]; and types A ('drug actions'), B ('patient reactions') and C ('statistical') adverse effects. This classification may serve as an educational tool and may be useful in when choosing a study method and for the design of effective strategies in pharmacovigilance.

Anaphylactic reactions to proton-pump inhibitors.

OBJECTIVE: To report two cases of anaphylactic reactions to proton-pump inhibitors (PPIs). CASE SUMMARIES: A 54-year-old woman who had taken omeprazole in the past was treated with omeprazole 40 mg and developed periorbital edema, edema of the skin, pruritus, nausea, and vomiting about 45 minutes after taking one capsule. Five months later, she was treated with lansoprazole 30-mg capsules. Again, within 45 minutes she developed an even more serious reaction, with pruritus and urticaria on her whole body, increased sweating, facial edema, and loss of consciousness. A 61 -year-old man took one tablet of pantoprazole 40 mg one year after first being treated with the drug. Within hours after ingestion, he developed malaise, generalized pruritus and urticaria, a swollen tongue and eyes, and diffuse sweating; his blood pressure decreased to 75/50 mm Hg. DISCUSSION: Because of the acute onset of symptoms and close temporal association with exposure to the drug, as well as previous exposure to it, the reactions can be classified as anaphylactic shock to PPIs. These benzimidazole derivatives are chemically related; observations in a few patients, such as the first case above, suggest that cross-sensitivity may occur. The Uppsala Monitoring Centre (UMC) has received a total of 42 reports of anaphylactic reactions or anaphylactic shock in association with PPIs. These reports account for 0.2% of the total of reported suspected adverse drug reactions to PPIs, compared with 0.8% anaphylactic reactions in the UMC database as a whole. CONCLUSIONS: These findings suggest that the chemically related PPIs can, as a group, cause anaphylactic reactions; however, the rate is comparatively low. Since anaphylaxis is a potentially serious reaction, more precise information is needed regarding its frequency, and healthcare professionals need to be aware of this possibility when prescribing these agents.

A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database.

BACKGROUND: The detection of new drug safety signals is of growing importance with ever more new drugs becoming available and exposure to medicines increasing. The task of evaluating information relating to safety lies with national agencies and, for international data, with the World Health Organization Programme for International Drug Monitoring. RATIONALE: An established approach for identifying new drug safety signals from the international database of more than 2 million case reports depends upon clinical experts from around the world. With a very large amount of information to evaluate, such an approach is open to human error. To aid the clinical review, we have developed a new signalling process using Bayesian logic, applied to data mining, within a confidence propagation neural network (Bayesian Confidence Propagation Neural Network; BCPNN). Ultimately, this will also allow the evaluation of complex variables. METHODS: The first part of this study tested the predictive value of the BCPNN in new signal detection as compared with reference literature sources (Martindale's Extra Pharmacopoeia in 1993 and July 2000, and the Physicians Desk Reference in July 2000). In the second part of the study, results with the BCPNN method were compared with those of the former signalling procedure. RESULTS: In the study period (the first quarter of 1993) 107 drug-adverse reaction combinations were highlighted as new positive associations by the BCPNN, and referred to new drugs. 15 drug-adverse reaction combinations on new drugs became negative BCPNN associations in the study period. The BCPNN method detected signals with a positive predictive value of 44% and the negative predictive value was 85%. 17 as yet unconfirmed positive associations could not be dismissed with certainty as false positive signals. Of the 10 drug-adverse reaction signals produced by the former signal detection system from data sent out for review during the study period, 6 were also identified by the BCPNN. These 6 associations have all had a more than 10-fold increase of reports and 4 of them have been included in the reference sources. The remaining 4 signals that were not identified by the BCPNN had a small, or no, increase in the number of reports, and are not listed in the reference sources. CONCLUSION: Our evaluation showed that the BCPNN approach had a high and promising predictive value in identifying early signals of new adverse drug reactions.

Pharmacovigilance in perspective.

Pharmacovigilance is more than spontaneous reporting alone, and the evaluation of marketed medicines is more than just pharmacovigilance. The positioning of a drug usually takes place during the years following introduction, when worldwide experience has accumulated. Originally a modest appendix of drug regulation, pharmacovigilance has become a major activity. The provision of the information needed for the evaluation of the benefits and risks of drugs is in the first place a scientific challenge. In addition, there are important ethical, logistical, legal, financial and commercial constraints. Good pharmacovigilance practice needs to be developed to ensure that data are collected and used in the right way and for the right purpose. Pharmacovigilance, and more generally the study of the benefits and risks of drugs, plays a major role in pharmacotherapeutic decision-making, be it individual, regional, national or international. In addition, pharmacovigilance is becoming a scientific discipline in its own right. A variety of changes are taking place in the complex system of drug development, regulation and distribution. Pharmacovigilance should be proactive in monitoring their possible consequences.

Signalling possible drug-drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole.

AIMS: In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible drug-drug interactions. We describe a method for detecting possible drug-drug interactions using logistic regression analysis to calculate ADR reporting odds ratios. METHODS: To illustrate this method, we analysed the adverse drug reaction 'delayed withdrawal bleeding' resulting from a possible interaction between itraconazole and oral contraceptives in reports received by the Netherlands Pharmacovigilance Foundation LAREB between 1991 and 1998. RESULTS: In total 5,503 reports were included in the study. The odds ratio, adjusted for year of reporting, age and source of the reports, for a delayed withdrawal bleeding in women who used both drugs concomitantly compared with women who used neither oral contraceptives, nor itraconazole, was 85 (95% CI: 32-230). CONCLUSIONS: Since spontaneous reporting systems can only generate signals concerning possible relationships, this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. This approach might be a promising tool for the development of procedures for automated detection of possible drug-drug interactions in spontaneous reporting systems.

Comparing therapeutic benefit and risk.

Theoretically, the merit of a medical drug can be quantitatively determined by calculating benefit and risks as the drug-attributed gain or loss, respectively, of quality-adjusted life years. This calculation is based on comprehensive data concerning large numbers of patients. For most drugs, however, the data available are more or less incomplete. Therefore, large-scale intensive and continuous data collection needs to become routine in medical and pharmaceutical practice. In addition, important scientific, ethical, logistic and financial obstacles need to be overcome. Preliminary evidence suggests that the 'Principle of Threes' is a useful tool for categorizing the merit of drugs and for comparing drugs of a given therapeutic class. The safety of a drug is a dynamic rather than a constant feature. The merit of a drug is not an absolute quality, but is meaningful only in a given context. It is still uncertain whether merit assessment can present the dilemma that 'a drug causes benefit in many at the cost of serious injury in some' in a way the individual user can understand. Quantitative merit assessment will be welcome but should not be expected to replace individual therapeutic decision making. It remains to be seen whether merit assessment is to result in a gold standard for the acceptability or unacceptability of drugs.

Bladder dysfunction during the use of tramadol.

The Netherlands Pharmacovigilance Foundation LAREB received five case reports concerning transient impairment of micturition or urinary retention, suspected to be induced by tramadol. In all patients--three women and two men--the symptoms occurred in temporal association with the use of tramadol and promptly recovered after stopping of the drug. Tramadol was taken orally in doses within the recommended therapeutic range (150 mg or less daily). Disturbance of micturition is not mentioned as a side-effect in the summary of product characteristics of Tramal 50 and 100. Tramadol is an opioid agonist, however, and morphine is known to increase the tonus of the bladder sphincter and to cause urinary retention.