Ruth L. Savage

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.

Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports

Background: Pneumonitis has very rarely been observed in patients taking leflunomide in clinical trials. Evidence is emerging that it is more frequent in clinical practice.

Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly?

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease.The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5mg, celecoxib 100–200mg, valdecoxib 10mg and etoricoxib 60mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly.Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown.Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation.Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor.A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.

Cardiovascular Events in Patients taking Varenicline

AbstractBackground: The smoking cessation medicine varenicline has been associated with an increased risk of cardiovascular adverse events compared with placebo in clinical trials. Cases of cardiovascular events, including myocardial infarction (MI) and cardiac dysrhythmias, have been noted from spontaneous reporting systems. Objective: The aim of this study was to summarize and describe cardiovascular adverse reactions identified in a general population during intensive postmarketing surveillance of varenicline in New Zealand. Methods: Observational prospective cohort study using prescription event monitoring methods. The patient cohort was established from pharmacy dispensing data sent directly to the Intensive Medicines Monitoring Programme (IMMP) for all New Zealand patients prescribed varenicline. Adverse cardiovascular events were identified from follow-up questionnaires completed by doctors, spontaneous reports and by record linkage to national datasets. Cardiovascular events were organized into clinical groupings for further clinical assessment, and key cases were identified. Results: All New Zealand patients dispensed a prescription for varenicline from 1 April 2007 to 30 November 2010 were included in this study. At 31 January 2011, the IMMP varenicline events dataset included a total of 172 adverse events in the IMMP circulatory System Organ Class. There were 48 reports of myocardial ischaemia, including 12 reports of MI and 8 reports of angina. Two key cases of myocardial ischaemia suggested that this may have been induced by coronary artery spasm secondary to varenicline treatment. There were 50 reports of hypotensive events, with two key cases having documented hypotension associated with chest pain/tightness, and a further 27 reports of dysrhythmia events, including two unexplained sudden deaths. Conclusions: This paper presents a series of cases of cardiovascular events in patients taking varenicline. Whilst there were multiple confounding factors in some patients, key cases were identified that suggested a possible mechanism of dysregulation of blood pressure leading to vasospasm or hypotension.

Cutaneous reactions to labetalol

thyrotrophin (TSH) responses in three cases are reminiscent of primary hypothyroidism rather than hypothalamic disease. We have evaluated the growth and hormonal status of 14 children now aged 7-15 years who have been off leukaemia treatment for at least 1 1 years. In the year after stopping chemotherapy these children had a mean growth rate of 8 cm year (range 4-9-11 2 cm,iyear) and their linear growth has been maintained in all cases. We have not found any significant hormonal disturbance in those children who agreed to undergo a combined hypothalamic-anterior pituitary function test, and the older children are passing normally through puberty. We agree that long-term careful surveillance of these children is mandatory but suggest that endocrine investigation is necessary only when their growth or development gives cause for concern. PETER SWIFT D C L SAVAGE M G MOTT J A BULLIMORE

Leflunomide in Combination Therapy for Rheumatoid Arthritis

Alcorn et al. have provided a welcome benefit-risk assessment of leflunomide use in the treatment of rheumatoid arthritis based on a review of the literature to 2008. The adverse reaction profile is discussed with specific reference to hepatotoxicity, interstitial lung disease (ILD), infection, peripheral neuropathy, weight loss and hypertension; however, there is more information about leflunomide use in combination therapy that should be considered. Leflunomide has been widely used in Australia andNew Zealand and has beenmonitored closely by the medicines regulators in each country. As Alcorn et al. stated, there was early concern about leflunomide and hepatotoxicity that almost led to the withdrawal of leflunomide in the US. A regular comprehensive pharmacovigilance review of leflunomide conducted by the New Zealand Pharmacovigilance Centre and the regulator, Medsafe, was undertaken as it was considered a timely and proactivemeans of evaluating a newly introduced medicine intended for chronic use with an emerging profile of serious adverse reactions. The review, from 2006 to 2008, used national and international spontaneous reporting data, prescription data, literature review and review of international regulatory actions. Thematerial gathered was considered by the New Zealand Medicines Adverse Reactions Committee and contributed to national decision making, information for prescribers and identification of emerging signals. The adverse reaction profile of leflunomide as monotherapy that became apparent is similar to that found by Alcorn et al; however, as the use of leflunomide in combination with other disease modifying anti-rheumatic drugs (DMARDs) increased, assessment of spontaneous reporting data and the literature provided further insights, particularly with regard to pneumonitis, pancytopenia and infection.

Impact of New Genomic Technologies on Understanding Adverse Drug Reactions

It is well established that variations in genes can alter the pharmacokinetic and pharmacodynamic profile of a drug and immunological responses to it. Early advances in pharmacogenetics were made with traditional genetic techniques such as functional cloning of genes using knowledge gained from purified proteins, and candidate gene analysis. Over the past decade, techniques for analysing the human genome have accelerated greatly as knowledge and technological capabilities have grown. These techniques were initially focussed on understanding genetic factors of disease, but increasingly they are helping to clarify the genetic basis of variable drug responses and adverse drug reactions (ADRs). We examine genetic methods that have been applied to the understanding of ADRs, review the current state of knowledge of genetic factors that influence ADR development, and discuss how the application of genome-wide association studies and next-generation sequencing approaches is supporting and extending existing knowledge of pharmacogenetic processes leading to ADRs. Such approaches have identified single genes that are major contributing genetic risk factors for an ADR, (such as flucloxacillin and drug-induced liver disease), making pre-treatment testing a possibility. They have contributed to the identification of multiple genetic determinants of a single ADR, some involving both pharmacologic and immunological processes (such as phenytoin and severe cutaneous adverse reactions). They have indicated that rare genetic variants, often not previously reported, are likely to have more influence on the phenotype than common variants that have been traditionally tested for. The problem of genotype/phenotype discordance affecting the interpretation of pharmacogenetic screening and the future of genome-based testing applied to ADRs are also discussed.

International Reports of Unexpected Low Plasma Concentrations of Dabigatran Suggest That More Frequent Measurements Will Add Value

We were interested to read the report by Chin1 recently published in this journal, suggesting that some patients may benefit from dose adjustment of non–vitamin K antagonist oral anticoagulants (NOACs), otherwise referred to as direct oral anticoagulants (DOACs). We would like to report a small case series that provides evidence for selective dose adjustment and/ormeasurement of NOACs, in particular dabigatran. The World Health Organization (WHO) Global Database of Individual Case Safety Reports (“VigiBase”) holds reports of suspected adverse drug reactions collected worldwide throughtheWHOProgramfor InternationalDrugMonitoring.2 A previous investigation of reports of thromboembolic events associated with dabigatran in VigiBase3 included a literature search, which identified four published case reports of dabigatran plasma concentrations below the expected “within therapy range” (representing the generally reported range of values identified in patients on such therapy in clinical trials). VigiBase was therefore searched for similar reports of low plasma concentrations. It is acknowledged, however, that the information provided in VigiBase is heterogeneous (i.e., it originates frommultiple sources [different countries and types of reporters] and the amount of information given, as well as the likelihood that the medicine caused the adverse reaction, may vary from case to case). Two of the published reports and 12additional reports of this unexpectedeffectwere identified, originating from five countries. While specific target therapeutic ranges for dabigatran plasma concentrations have not been validated, “within therapy” ranges identifying values that are typically seen in treated patients have been described. Thus, “expected” trough and peak dabigatran plasma levels after intake of approved dosages for atrial fibrillation are around 61 to 143 and 117 to 275 ng/mL, respectively, for 150 mg twice a day and 43 to 102 and 85 to 200 ng/mL, respectively, for 110 mg twice a day.4 Chin calculated an optimal trough range of 30 to 130 ng/mL after constructing a combined risk versus trough concentration model for a typical patient based on data from the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial.1 ►Table 1 shows the details of the four published case reports. Patients 1 and 2 had embolic stroke while taking dabigatran.5,6 Peak and trough plasma concentrations were measured thereafter using Hemoclot, a commercially available dilute thrombin time (dTT) assay, following witnessed intake. Patients 3 and 4 did not have thromboembolic events.7,8 Patient 3 had a lower than expected activated partial thromboplastin time (aPTT) shortly after starting dabigatran, so that peak concentrations at two dose levels were quantified, usingHemoclot, following confirmed intake after 31 days of treatment. Patient 4, who had undergone gastric bypass surgery, had trough concentrations quantified because another patient with gastric bypass developed a cardioembolic stroke on dabigatran and was found to have lower than expected aPTT values. The doses of dabigatran administered were appropriate for all four patients, especially after the dose increase in patient 3 who had normal

Severe muscle symptoms with lipid-lowering agents may be confused with neurogenic claudication associated with spinal canal stenosis.

BACKGROUND Screening of the WHO global individual case safety report database (VigiBase) has recently identified case reports with HMG CoA reductase inhibitors and muscle symptoms co-reported with spinal stenosis. In some reports spinal stenosis appears to have been listed as a coincidental finding. OBJECTIVE To assess reports with sufficient information to ascertain if they suggested that there may have been diagnostic confusion between muscle symptoms attributable to HMG CoA reductase inhibitors with or without ezetimibe and symptoms of spinal stenosis. METHOD Reports were examined for patient demographics, past history, clinical and investigational findings, co-prescribed medicines and outcomes. RESULTS Three case histories recorded details suggestive of diagnostic confusion between severe and disabling muscle symptoms affecting the lower limbs attributable to an HMG CoA reductase inhibitor with and without ezetimbe and symptoms of neurogenic claudication due to spinal stenosis. The statins were not discontinued promptly leading to prolonged morbidity. Serum creatine kinase levels (CK) were normal in two patients and not recorded for the third. CONCLUSION The reports include two safety issues, firstly the need to consider HMG CoA reductase inhibitors as a cause of severe lower limb muscle symptoms even in the presence of spinal stenosis and normal CK levels and the second, the need to measure serum creatine kinase when these symptoms occur to detect progression of myopathy and potentially serious outcomes.

Erratum to: Impact of New Genomic Technologies on Understanding Adverse Drug Reactions

In the online published article Section 3, para 2, lines 4–5, which previously read: …Gordon et al. applied targeted NGS of multiple genes from over 14,000 subjects, to illustrate the extent of potentially… Should read: …Gordon et al. applied targeted NGS of multiple genes from 6503 subjects, to illustrate the extent of potentially… The online version of the original article can be found under