First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Hypersensitivity Reaction.

RATIONALE: Transient myopericarditis has been recognised as an uncommon and usually mild adverse event predominantly linked to mRNA-based COVID-19 vaccines. These have mostly occurred in young males after the second dose of mRNA COVID-19 vaccines. OBJECTIVES: Fulminant necrotising eosinophilic myocarditis triggered by a variety of drugs or vaccines is an extremely rare hypersensitivity reaction carrying a substantial mortality risk. Early recognition of this medical emergency may facilitate urgent hospital admission for investigation and treatment. Timely intervention can lead to complete cardiac recovery, but the non-specific clinical features and rarity make early diagnosis challenging. FINDINGS: The clinical and pathological observations from a case of fatal fulminant necrotising myocarditis in a 57-year-old woman, following the first dose of the Pfizer-BioNTech vaccine, are described. Other causes have been discounted with reasonable certainty. CONCLUSION: These extremely rare vaccine-related adverse events are much less common than the risk of myocarditis and other lethal complications from COVID-19 infection. The benefits of vaccination far exceed the risks of COVID-19 infection.

The safety of cardioselective ß1-blockers in asthma: literature review and search of global pharmacovigilance safety reports.

INTRODUCTION: Beta-blockers are key in the management of cardiovascular diseases but blocking airway ß2-receptors can cause severe and sometimes fatal bronchoconstriction in people with asthma. Although cardioselective ß1-blockers may be safer than non-selective ß-blockers, they remain relatively contraindicated and under-prescribed. We review the evidence of the risk associated with cardioselective ß1-blocker use in asthma. METHODS: We searched "asthma" AND "beta-blocker" in PubMed and EmbaseOvid from start to May 2020. The World Health Organization (WHO) global database of individual case safety reports (VigiBase) was searched for reports of fatal asthma or bronchospasm and listed cardioselective ß1-blocker use (accessed February 2020). Reports were examined for evidence of pre-existing asthma. RESULTS: PubMed and EmbaseOvid searches identified 304 and 327 publications, respectively. No published reports of severe or fatal asthma associated with cardioselective ß1-blockers were found. Three large observational studies reported no increase in asthma exacerbations with cardioselective ß1-blocker treatment. The VigiBase search identified five reports of fatalities in patients with pre-existing asthma and reporting asthma or bronchospasm during cardioselective ß1-blocker use. Four of these deaths were unrelated to cardioselective ß1-blocker use. The circumstances of the fifth death were unclear. CONCLUSIONS: There were no published reports of cardioselective ß1-blockers causing asthma death. Observational data suggest that cardioselective ß1-blocker use is not associated with increased asthma exacerbations. We found only one report of an asthma death potentially caused by cardioselective ß1-blockers in a patient with asthma in a search of VigiBase. The reluctance to use cardioselective ß1-blockers in people with asthma is not supported by this evidence.

Synthetic cannabis: adverse events reported to the New Zealand Pharmacovigilance Centre.

INTRODUCTION: Synthetic Cannabinoid Receptor Agonists (SCRA) were legally available in New Zealand (NZ) prior to May 2014. During the period November 2012-November 2019, reports of adverse events associated with SCRA use from across the country were submitted to the New Zealand Pharmacovigilance Centre (NZPhvC). The purpose of this study was to investigate adverse reactions associated with SCRA reported to the NZPhvC. METHODS: The NZPhvC database was searched for adverse events involving SCRA. Cases were extracted and analysed for demographic information of users, reactions reported and SCRA involved. Summary statistics were performed using SAS 9.3. RESULTS: One hundred and thirteen cases were identified from 1 November 2012 to 31 November 2019, comprising 81 males (71.7%) and 32 females (28.3%), with a mean age of 28.4 ± 10.1 years. Ethnicity included European (51.3%, n = 58), Maori (39.8%, n = 45), Indian (1.8%, n = 2), and Polynesian (0.9%, n = 1). There were a total of 327 reactions recorded in these cases, and the majority were psychiatric (52%, n = 170), followed by nervous system (11%, n = 35), alimentary (7%, n = 24), and cardiovascular (7%, n = 23). Where the compounds could be identified, the majority of events involved AB-FUBINACA (n = 18), 5 F-PB-22 (n = 17), and PB-22 (n = 6). CONCLUSIONS: This study found that young, male and European populations frequently were involved in SCRA adverse events. A disproportionate number of Maori were present in this group. Psychiatric reactions were of clinical significance, and possibly correlated to the high potency and efficacy of SCRA compared to cannabis. Pharmacovigilance is a useful tool to measure and monitor illicit drug use, and with appropriate infrastructure and capacity has the potential to contribute to drug policy at a national level.

Suspected Hepatotoxicity With a Supercritical Carbon Dioxide Extract of Artemisia annua in Grapeseed Oil Used in New Zealand.

A case series of hepatotoxicity associated with an extract of Artemisia annua L. was identified through the New Zealand spontaneous adverse drug reaction reporting system. A. annua extract, produced using a supercritical carbon dioxide extraction method and formulated with grapeseed oil, has been marketed in New Zealand as a natural product for joint health. As of 31 January 2019, the New Zealand Pharmacovigilance Centre had received 29 reports of hepatic adverse reactions occurring in patients taking A. annua extract in grapeseed oil. The case reports were assessed for patient and adverse reaction characteristics, patterns of A. annua extract use and causality (based on the WHO-UMC system for standardized case causality assessment). Patients were aged 47 to 93 years (median 67). Time to onset of hepatotoxicity from starting A. annua extract was 7 days to approximately 12 months in the 23 reports with this information. Nineteen of these reports indicated onset within 12 weeks. A. annua extract was the sole suspect medicine in 27 reports. A few patients had possible predisposing conditions. Twenty-seven patients were reported to have recovered or improved on stopping A. annua extract. Nine patients required hospital admission. The pattern of hepatic injury varied. Jaundice, often with pruritus and dark urine, was experienced by 16 patients. There was considerable consistency across case reports from various reporters. We assessed the case reports as a series using the Bradford Hill guidelines for causal inference and concluded that there was a safety signal of a causal association between the A. annua extract and hepatotoxicity sufficient to be communicated and investigated further.

Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin.

INTRODUCTION: We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. METHODS: To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. RESULTS: Thirty patient reports were identified. The age range was 23-88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3-16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. Serious infection occurred in 54.5% (12 of 22 patients with information). Polypharmacy (five or more medicines daily) was used by 36.7% of patients long term, increasing acutely to 83.3%, including additional potentially interacting medicines. Warfarin daily dose (1.5-13.0 mg, mean 4.4, median 4.0, standard deviation 2.2) was moderate to low. Pre-roxithromycin international normalised ratio values ranged from 1.4 to 3.7, mean and median 2.5, standard deviation 0.5. A high proportion of interactions were observed between warfarin and roxithromycin compared with other macrolides and compared with cytochrome P450 3A4-related macrolide interactions. The pattern was similar to published Australian data. CONCLUSION: In this case series, the high prevalence of acute polypharmacy, including potentially interacting medicines, and serious infection suggests that they may have contributed to warfarin potentiation and increased the clinical significance of a roxithromycin/warfarin interaction.

A new web-based Medication Error Reporting Programme (MERP) to supplement pharmacovigilance in New Zealand--findings from a pilot study in primary care.

AIMS: To determine if primary care clinicians would report medication errors using a new web-based system, and to obtain data illustrating the potential of the information collected to improve medication safety. METHOD: The New Zealand Pharmacovigilance Centre led the development of the Medication Error Reporting Programme (MERP) which was then piloted over an 8- month period involving 38 general practice and 28 community pharmacy staff. The Pharmacy Defence Association also contributed dispensing error claims. An analysis of the characteristics of errors was undertaken. RESULTS: A total of 376 reports were submitted; 55 (15%) reported patient harm, 1 of which required lifesaving intervention. The therapeutic groups most commonly implicated were medicines for managing 'nervous' and 'cardiovascular' systems. Wrong dose (25%) and wrong medicine (22%) were the most common error types, occurring predominantly with the prescribing and dispensing of medications. The most frequent contributing factors to errors in general practice were problems in the process of prescribing whereas in community pharmacy they related to product name and packaging factors. Time pressures, workload and interruptions were commonly cited for both settings. CONCLUSION: Primary care clinicians who volunteered for the pilot were willing and able to use the MERP system to report medication errors. The standardised data obtained through MERP enables rapid analysis and has the potential to inform initiatives for improving patient safety.

Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future.

The utility of wild-type outer membrane vesicle (wtOMV) vaccines against serogroup B (MenB) meningococcal disease has been explored since the 1970s. Public health interventions in Cuba, Norway and New Zealand have demonstrated that these protein-based vaccines can prevent MenB disease. Data from large clinical studies and retrospective statistical analyses in New Zealand give effectiveness estimates of at least 70%. A consistent pattern of moderately reactogenic and safe vaccines has been seen with the use of approximately 60 million doses of three different wtOMV vaccine formulations. The key limitation of conventional wtOMV vaccines is their lack of broad protective activity against the large diversity of MenB strains circulating globally. The public health intervention in New Zealand (between 2004-2008) when MeNZB was used to control a clonal MenB epidemic, provided a number of new insights regarding international and public-private collaboration, vaccine safety surveillance, vaccine effectiveness estimates and communication to the public. The experience with wtOMV vaccines also provide important information for the next generation of MenB vaccines designed to give more comprehensive protection against multiple strains.

Detecting medication errors in the New Zealand pharmacovigilance database: a retrospective analysis.

BACKGROUND: Despite the traditional focus being adverse drug reactions (ADRs), pharmacovigilance centres have recently been identified as a potentially rich and important source of medication error data. OBJECTIVE: To identify medication errors in the New Zealand Pharmacovigilance database (Centre for Adverse Reactions Monitoring [CARM]), and to describe the frequency and characteristics of these events. METHODS: A retrospective analysis of the CARM pharmacovigilance database operated by the New Zealand Pharmacovigilance Centre was undertaken for the year 1 January-31 December 2007. All reports, excluding those relating to vaccines, clinical trials and pharmaceutical company reports, underwent a preventability assessment using predetermined criteria. Those events deemed preventable were subsequently classified to identify the degree of patient harm, type of error, stage of medication use process where the error occurred and origin of the error. RESULTS: A total of 1412 reports met the inclusion criteria and were reviewed, of which 4.3% (61/1412) were deemed preventable. Not all errors resulted in patient harm: 29.5% (18/61) were 'no harm' errors but 65.5% (40/61) of errors were deemed to have been associated with some degree of patient harm (preventable adverse drug events [ADEs]). For 5.0% (3/61) of events, the degree of patient harm was unable to be determined as the patient outcome was unknown. The majority of preventable ADEs (62.5% [25/40]) occurred in adults aged 65 years and older. The medication classes most involved in preventable ADEs were antibacterials for systemic use and anti-inflammatory agents, with gastrointestinal and respiratory system disorders the most common adverse events reported. For both preventable ADEs and 'no harm' events, most errors were incorrect dose and drug therapy monitoring problems consisting of failures in detection of significant drug interactions, past allergies or lack of necessary clinical monitoring. Preventable events were mostly related to the prescribing and administration stages of the medication use process, with the majority of errors 82.0% (50/61) deemed to have originated in the community setting. CONCLUSIONS: The CARM pharmacovigilance database includes medication errors, many of which were found to originate in the community setting and reported as ADRs. Error-prone situations were able to be identified, providing greater opportunity to improve patient safety. However, to enhance detection of medication errors by pharmacovigilance centres, reports should be prospectively reviewed for preventability and the reporting form revised to facilitate capture of important information that will provide meaningful insight into the nature of the underlying systems defects that caused the error.

Pharmacovigilance in New Zealand: the role of the New Zealand Pharmacovigilance Centre in facilitating safer medicines use.

The New Zealand Pharmacovigilance Centre (NZPhvC) is the national centre responsible for monitoring adverse reactions to therapeutic products in New Zealand(NZ). The NZPhvC operates three pharmacovigilance programmes and this article explains how each of these programmes operate, focuses on their strengths and limitations, and looks to the future for medicines safety monitoring in NZ.

The Intensive Vaccines Monitoring Programme (IVMP): an electronic system to monitor vaccine safety in New Zealand.

New Zealand introduced a tailor-made vaccine (MeNZB) for epidemic control of Group B meningococcal disease. The Intensives Vaccine Monitoring Programme (IVMP), which prospectively collected data electronically on a cohort of children receiving vaccinations in sentinel practices across NZ, was developed as part of a national multi-faceted safety strategy. The main aim of the IVMP was to identify the presence of unexpected adverse events occurring with MeNZB vaccination. We describe the methodology and success factors plus consider the limitations encountered in this system which shows potential as a means for post-marketing vaccine and medicine surveillance in the future.

Post-marketing safety monitoring of a new group B meningococcal vaccine in New Zealand, 2004-2006.

New Zealand introduced a new outer membrane vesicle vaccine in 2004 to combat an epidemic of group B meningococcal disease. An Independent Safety Monitoring Board oversaw intensive safety monitoring, which included hospital surveillance, health professional reporting (passive and active) and mortality monitoring. With over three million doses administered to individuals aged under 20 years, the monitoring results provide consistent evidence supporting the vaccine's safety.

Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents.

The HMG-CoA reductase inhibitors ('statins') have come into widespread use internationally. There has been a long history of their use in New Zealand and this use has increased in recent years. There has also been an increase in the number of reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) of suspected psychiatric adverse reactions associated with statins. The reactions mentioned in these reports include depression, memory loss, confusion and aggressive reactions. Convincing reports to CARM of recurrence of these reactions upon rechallenge add weight to recent studies reporting serious psychiatric disturbances in association with statin treatment. Aggressive reactions associated with statins are poorly documented in the literature. These observations emphasise the need to be vigilant in looking for these reactions as they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.