Indapamide-Induced Rhabdomyolysis: An Evaluation of Case Reports in VigiBase Using the Bradford Hill Criteria.

BACKGROUND: Indapamide can cause hypokalaemia and hyponatraemia. Rhabdomyolysis associated with these electrolyte abnormalities has been reported. OBJECTIVE: The aim of this study was to assess causal association between the use of indapamide and the occurrence of rhabdomyolysis using the Bradford Hill criteria. METHODS: Variables in the rhabdomyolysis case reports and literature were reviewed. Bradford Hill criteria were used in the assessment of causal association. RESULTS: Up to 11 November 2020, there were 28 unique cases in VigiBase from 13 countries reporting indapamide-associated rhabdomyolysis. In 18 of these cases, hypokalaemia (n = 14) or hyponatremia (n = 8) was a co-reported event, including four cases where both of these events were reported. Indapamide was the only suspected drug in nine of these 18 cases and positive dechallenge was mentioned in 13 of them. In addition, there were risk factors such as falls, concomitant drugs with risk of hypokalaemia, or muscle injury. In two cases, liquorice (containing glycyrrhizin) was concomitantly used with indapamide before hypokalaemia and rhabdomyolysis occurred. Thiazide diuretics, known to cause hypokalaemia, showed similar disproportionality patterns as indapamide regarding rhabdomyolysis and myopathy, while calcium channel blockers (not causing hypokalaemia), had lower disproportionality values than indapamide. CONCLUSIONS: Based on the review of case series and causality assessment using Bradford Hill criteria, indapamide may cause rhabdomyolysis due to hypokalaemia or hyponatremia. Considering the seriousness of the reported cases, health care professionals should be aware of this potential risk following indapamide intake, particularly when there are risk factors for hypokalaemia and hyponatremia such as excessive liquorice consumption. A similar risk of muscle injuries may apply to thiazide diuretics as well.

E-Learning in Pharmacovigilance: An Evaluation of Microlearning-Based Modules Developed by Uppsala Monitoring Centre.

INTRODUCTION: An increasing global need for pharmacovigilance training cannot be met with classroom courses alone. Several e-learning modules have been developed by Uppsala Monitoring Centre (UMC). With distance learners and technological challenges such as poor internet bandwidth to be considered, UMC opted for the microlearning approach based on small learning units connected to specific learning objectives. The aim of this study was to evaluate how this e-learning course was received. METHODS: The course was evaluated through usage data and the results of two user surveys, one for modules 1-4, signal detection and causality assessment, and the other for module 5, statistical reasoning and algorithms in pharmacovigilance. The evaluation model used was based on the Unified Theory of Acceptance and Use of Technology (UTAUT). A questionnaire was developed, divided into demographic profile, performance expectancy, effort expectancy, educational compatibility and behavioural intention. The two surveys were disseminated to 2067 learners for modules 1-4 and 1685 learners for module 5. RESULTS: Learners from 137 countries participated, predominantly from industry (36.6%), national pharmacovigilance centres (22.6%) and academia (16.3%). The overall satisfaction level was very high for all modules, with over 90% of the learners rating it as either 'excellent' or 'good'. The majority were satisfied with the learning platform, the course content and the lesson duration. Most learners thought they would be able to apply the knowledge in practice. Almost 100% of the learners would recommend the modules to others and would also study future modules. Suggested improvements were an interactive forum, more practical examples in the lessons and practical exercises. CONCLUSION: This e-learning course in pharmacovigilance based on microlearning was well received with a global coverage among relevant professional disciplines.

Drug Safety in Geriatric Patients: Current Status and Proposed Way Forward.

Elderly patients are the main users of drugs and they differ from younger patients. They are a heterogeneous population that cannot be defined only by age but should rather be stratified based on their frailty. The elderly have distinctive pharmacokinetic and pharmacodynamic characteristics, are frequently polymorbid, and are therefore treated with multiple drugs. They may experience adverse reactions that are difficult to recognize, since some of them present non-specific symptoms easily mistaken for geriatric conditions. Paradoxically, the elderly are underrepresented in clinical trials, especially the frail individuals whose pharmacological response and expected treatment outcome can be different from those of non-frail patients. This means that the benefit-risk balance of drugs used in frail elderly patients is frequently unknown. We present some proposals to overcome the barriers preventing the enrollment of frail elderly patients in clinical trials, and strategies for monitoring their therapy to minimize the risk of adverse reactions. Automated alerts for drug and drug-disease interactions could help appropriate prescribing but should flag only clinically relevant interactions. Pharmaceutical forms should be designed to allow easy dose adjustment and, together with packaging and labeling, should account for the physical and cognitive limitations of frail elderly patients. Aggregate pharmacovigilance reports should summarize the safety profile in the elderly, but rather than presenting the results by age they should focus on patients' frailty, perhaps using the number of comorbidities as a proxy when information on frailty is not available.

Paediatric safety signals identified in VigiBase: Methods and results from Uppsala Monitoring Centre.

PURPOSE: The purpose of this study is to uncover previously unrecognised risks of medicines in paediatric pharmacovigilance reports and thereby advance a safer use of medicines in paediatrics. METHODS: Individual case safety reports (ICSRs) with ages less than 18 years were retrieved from VigiBase, the World Health Organization (WHO) global database of ICSRs, in September 2014. The reports were grouped according to the following age spans: 0 to 27 days; 28 days to 23 months; 2 to 11 years; and 12 to 17 years. vigiRank, a data-driven predictive model for emerging safety signals, was used to prioritise the list of drug events by age groups. The list was manually assessed, and potential signals were identified to undergo in-depth assessment to determine whether a signal should be communicated. RESULTS: A total of 472 drug-event pairs by paediatric age groups were the subject of an initial manual assessment. Twenty-seven drug events from the two older age groups were classified as potential signals. An in-depth assessment resulted in eight signals, of which one concerned harm in connection with off-label use of dextromethorphan and another with accidental overdose of olanzapine by young children, and the remaining signals referred to potentially new causal associations for atomoxetine (two signals), temozolamide, deferasirox, levetiracetam, and desloratadine that could be relevant also for adults. CONCLUSIONS: Clinically relevant signals were uncovered in VigiBase by using vigiRank applied to paediatric age groups. Further refinement of the methodology is needed to identify signals in reports with ages under 2 years and to capture signals specific to the paediatric population as a risk group.

Varenicline and abnormal sleep related events.

STUDY OBJECTIVES: To assess adverse drug reaction reports of "abnormal sleep related events" associated with varenicline, a partial agonist to the α4ß2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. DESIGN: Twenty-seven reports of "abnormal sleep related events" often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. MEASUREMENTS AND RESULTS: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. CONCLUSIONS: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events.

Uterine perforation with the levonorgestrel-releasing intrauterine device: analysis of reports from four national pharmacovigilance centres.

BACKGROUND: Levonorgestrel-releasing intrauterine devices (LNG-IUD) are commonly used for contraception and other indications in many countries. National pharmacovigilance centres have been receiving reports from healthcare professionals and patients of uterine perforation associated with the use of these LNG-IUDs. METHODS: National pharmacovigilance centres in the Netherlands, New Zealand, Switzerland and Germany did a search on their adverse drug reaction databases for reports of cases of uterine perforation after insertion of a LNG-IUD received between the introduction of the LNG-IUD onto the market in the late 1990s and 15 July 2007. The number of women affected and patient characteristics such as age, parity and breastfeeding status were examined. In addition, the method of detection of the perforation and the time until discovery of the perforation were analysed. RESULTS: Between the introduction of the LNG-IUD onto the market in each country and 15 July 2007, 701 cases of uterine perforation with a LNG-IUD were reported; 8.5% of the perforations were detected at the time of insertion. Abdominal pain and control/check-up visits were the most common events that lead to the detection of a perforation. Of 462 women known to be parous, 192 (42%) were breastfeeding at the time the perforation was discovered. CONCLUSIONS: Uterine perforations can be asymptomatic and may remain undetected for a long time after IUD insertion. Abdominal pain, control/check-up visits or changes in bleeding patterns are triggers for detection of perforation and should therefore be taken seriously.

[Extreme sinus bradycardia (30/min) with acute right heart failure under tizanidine (Sirdalud). Possible pharmacological interaction with rofecoxib (Vioxx)]. / Extreme Sinusbradykardie (30/min) mit akuter Rechtsherzbelastung unter Tizanidin (Sirdalud) Mögliche Arzneimittelinteraktion mit Rofecoxib (Vioxx).

CASE RECORD: The case of a 59-year-old healthy woman is described, who developed an extreme sinus bradycardia (30/min) with chest pain and acute right heart failure associated with gastrointestinal symptoms and elevation of the liver enzymes while simultaneously taking tizanidine (Sirdalud), diclofenac (Voltaren), and rofecoxib (Vioxx). The symptomatology resolved promptly after stopping the medication. DISCUSSION: The usual causes of sinusbradycardia like hypothyroidism, hypothermia, intracranial pressure elevation, typhoid fever, sick sinus syndrome, hyperreactive carotid sinus reflex, organic heart disease, electrolyte disorders, and pharmacotherapy with beta-blockers, digitalis, and antiarrhythmics have been excluded in this case. Bradycardia can occur as a side effect of tizanidine. As this substance is metabolized by cytochrome P450 1A2 and rofecoxib inhibits this enzyme, an interaction between these drugs is probable. Liver function disorders and gastrointestinal symptoms, in the present case mainly due to the acute right heart failure, have also been described as side effects under tizanidine, diclofenac as well as rofecoxib. Supposedly, the combination of tizanidine/rofecoxib used to be prescribed frequently for lumbar pain as selective cyclooxygenase-(COX-)2 inhibitors are visibly replacing the nonsteroidal antirheumatics due to their better side effect profile. An augmented risk of cardiovascular events under rofecoxib led to its withdrawal from the market at the end of September 2004. RESULTS: When prescribing Sirdalud, the possible pharmacological side effects and interactions should be taken into careful account.