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Hiba EL Masri,1 Treasure M McGuire,1– 3 Mieke L van Driel,4 Helen Benham,5,6 Samantha A Hollingworth1 1School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia; 2Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; 3Mater Pharmacy, Mater Health, Brisbane, Queensland, Australia; 4Primary Care Clinical Unit, Faculty of Medicine, The University of Queensland, Brisbane, Australia; 5Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia; 6Department of Rheumatology, Princess Alexandra Hospital, Brisbane, Queensland, AustraliaCorrespondence: Hiba EL Masri, School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, Queensland, 4102, Australia, Tel +61 478512234, Email h.elmasri@uqconnect.edu.auBackground: A critical gap exits in understanding the dynamics of patient-based benefit-risk assessment (BRA) of medicines in chronic diseases during the disease journey.Purpose: To systematically review and synthesize current evidence on the changes of patients’ preferences about the benefits and risks of medicines during their disease journey including the influence of disease duration and severity, and previous treatment experience.Methods: A systematic review of studies identified in PubMed and Embase, from inception to November 2020, was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Articles were eligible if they analyzed adult patient-based BRA of medicines with a chronic disease, based on at least one of the pre-specified dimensions: disease severity, disease duration, or previous treatment experience.Results: A total of 26,228 articles were identified and 105 were eligible for inclusion. Of these, 85 detected a variation in patient-based BRA of medicines with at least one of the pre-specified criteria. Patients with higher disease severity and more treatment experience have increased risk tolerance. It remains inconclusive whether disease duration directly affects the relative importance of a patient’s preference.Conclusion: Factors important for patients’ BRA of their medicines during a chronic disease journey vary more with their clinical situation and previous treatment experience than with time since diagnosis. Due to the importance of these factors on patients’ perspectives and potential impact on their decision-making and eventually their clinical outcomes, there is a need for more studies to assess the dynamics of patients’ BRA in every disease.Keywords: patient preference, choice behavior, decision making, health knowledge, attitudes, practice, attributes, risk tolerance

Objective: Atypical antipsychotic medications that are primarily used to treat schizophrenia and bipolar disorder cost the Pharmaceutical Benefits Scheme (PBS) AUD$334.4m in 2007. There are indications that they have also been used outside the approved indications to treat behavioural disturbances in the elderly. The aim of the present study was therefore to examine (i) trends in prescribing of subsidized atypical antipsychotic drugs in the Australian population from 2002 to 2007; and (ii) gender and age differences in the utilization of these drugs. Methods: Government (Medicare Australia) data on numbers of prescriptions, quantity and doses for atypical and typical antipsychotics from 2002 to 2007 were analysed. Defined daily dose per 1000 population per day were estimated for age and sex groups using Australian Bureau of Statistics population data. Results: The proportion of prescribed antipsychotics that were atypical increased from 61% in 2002 to 77% in 2007. In male subjects, olanzapine was most often prescribed between the ages of 25 and 55 years. In female subjects, in contrast, the highest rates of prescribing were in those >=75 years. Lower doses of these drugs were prescribed in older adults. Conclusions: Atypical antipsychotic drugs were most commonly used to treat schizophrenia in younger men and behavioural disturbances in older women with dementia. They appear to have been used outside of the approved indication for schizophrenia and bipolar disorder with significant financial costs to the PBS. Research into the reasons for their extensive use in elderly women is needed to inform more rational prescribing of these medicines. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteoporosis is a common cause of disability and death in elderly men and women. Until 2007, Australian Government-subsidized use of oral bisphosphonates, raloxifene and calcitriol (1[alpha],25-dihydroxycholecalciferol) was limited to secondary prevention (requiring x-ray evidence of previous low-trauma fracture). The cost to the Pharmaceutical Benefits Scheme was substantial (164 million Australian dollars in 2005/6). OBJECTIVE: To examine the dispensed prescriptions for oral bisphosphonates, raloxifene, calcitriol and two calcium products for the secondary prevention of osteoporosis (after previous low-trauma fracture) in the Australian population. METHODS: We analysed government data on prescriptions for oral bisphosphonates, raloxifene, calcitriol and two calcium products from 1995 to 2006, and by sex and age from 2002 to 2006. Prescription counts were converted to defined daily doses (DDD)/1000 population/day. This standardized drug utilization method used census population data, and adjusts for the effects of aging in the Australian population. RESULTS: Total bisphosphonate use increased 460% from 2.19 to 12.26 DDD/1000 population/day between June 2000 and June 2006. The proportion of total bisphosphonate use in June 2006 was 75.1% alendronate, 24.6% risedronate and 0.3% etidronate. Raloxifene use in June 2006 was 1.32 DDD/1000 population/day. The weekly forms of alendronate and risedronate, introduced in 2001 and 2003, respectively, were quickly adopted. Bisphosphonate use peaked at age 80-89 years in females and 85-94 years in males, with 3-fold higher use in females than in males. CONCLUSIONS: Pharmaceutical intervention for osteoporosis in Australia is increasing with most use in the elderly, the population at greatest risk of fracture. However, fracture prevalence in this population is considerably higher than prescribing of effective anti-osteoporosis medications, representing a missed opportunity for the quality use of medicines. [ABSTRACT FROM AUTHOR]

Background: Policymakers in sub-Saharan Africa (SSA) face challenging decisions regarding the allocation of health resources. Economic evaluations can help decision makers to determine which health interventions should be funded and or included in their benefits package. A major problem is whether the evaluations incorporated data from sources that are reliable and relevant to the country of interest. We aimed to review the quality of the data sources used in all published economic evaluations for cardiovascular disease and diabetes in SSA., Methods: We systematically searched selected databases for all published economic evaluations for CVD and diabetes in SSA. We modified a hierarchy of data sources and used a reference case to measure the adherence to reporting and methodological characteristics, and descriptively analysed author statements., Results: From 7,297 articles retrieved from the search, we selected 35 for study inclusion. Most were modelled evaluations and almost all focused on pharmacological interventions. The studies adhered to the reporting standards but were less adherent to the methodological standards. The quality of data sources varied. The quality level of evidence in the data domains of resource use and costs were generally considered of high quality, with studies often sourcing information from reliable databases within the same jurisdiction. The authors of most studies referred to data sources in the discussion section of the publications highlighting the challenges of obtaining good quality and locally relevant data., Conclusions: The data sources in some domains are considered high quality but there remains a need to make substantial improvements in the methodological adherence and overall quality of data sources to provide evidence that is sufficiently robust to support decision making in SSA within the context of UHC and health benefits plans. Many SSA governments will need to strengthen and build their capacity to conduct economic evaluations of interventions and health technology assessment for improved priority setting. This capacity building includes enhancing local infrastructures for routine data production and management. If many of the policy makers are using economic evaluations to guide resource allocation, it is imperative that the evidence used is of the feasibly highest quality., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We examined the patterns of antibiotic prescribing by medical and non-medical prescribers (dentists, nurse practitioners, and midwives) in Australia. We explored trends in the dispensed use of antibiotics (scripts and defined daily dose [DDD] per 1000 population/day) by Australian prescribers over the 12-year period, 2005-2016. We obtained data on dispensed prescriptions of antibiotics from registered health professionals subsidized on the Pharmaceutical Benefits Scheme (PBS). There were 216.2 million medical and 7.1 million non-medical dispensed prescriptions for antibiotics over 12 years. The top four antibiotics for medical prescribers were doxycycline; amoxicillin, amoxicillin plus clavulanic acid, and cefalexin, constituting 80% of top 10 use in 2005 and 2016; the top three for non-medical were amoxicillin, amoxicillin plus clavulanic acid and metronidazole (84% of top 10 use in 2016). The proportional increase in antibiotic use was higher for non-medical than medical prescribers. While medical prescribers preferentially prescribed broad-spectrum and non-medical prescribers moderate-spectrum antibiotics, there was a large increase in the use of broad-spectrum antibiotics over time by all prescribers. One in four medical prescriptions were repeats. Overprescribing of broad-spectrum antibiotics conflicts with national antimicrobial stewardship initiatives and guidelines. The proportional higher increase in antibiotic use by non-medical prescribers is a concern. To reduce inappropriate use of antibiotics and antimicrobial resistance, educational strategies targeted at all medical and non-medical prescribers are needed to align prescribing with current best practice within the scope of practice of respective prescribers., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Introduction: In Australia, the available published literature demonstrated a spike in dispensed prescription medicines after the onset of the COVID-19 pandemic that subsequently returned to expected levels. Smoking cessation medicines may not follow this pattern because quit attempts are influenced by a range of factors. Knowledge of whether dispensing of these medicines has changed since the pandemic is lacking. We explored the change in dispensing of publicly subsidised smoking cessation medicines since the pandemic., Methods: Australia's universal health-care system provides access to government-subsidised medicines via the Pharmaceutical Benefits Scheme and records of dispensed medicines are publicly available on a nationally aggregated level. We retrieved Pharmaceutical Benefits Scheme data from January 2016 to January 2021. We used interrupted time series modelling to quantify the impact of COVID-19 on dispensing of nicotine replacement therapy (NRT) patches, varenicline and all smoking cessation treatments combined separately., Results: After an initial spike in medicines at the onset of the pandemic, the monthly rate of prescriptions dispensed for varenicline was predominantly within predicted ranges, while that of NRT patches was predominantly below predicted ranges., Discussion and Conclusions: There has been a differential change in the number of subsidised smoking cessation medicines supplied in Australia since the COVID-19 pandemic, with varenicline prescriptions largely within, and NRT patches largely lower than, expected ranges. The reasons for the apparent change in dispensing of subsidised smoking cessation medicines are unclear., (© 2022 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Background: Non-communicable diseases are a growing burden in many African countries; cardiovascular disease is the main disease. Antihypertensive medicines (AHM) are a common treatment option but we know little about community use in most low- and medium-income countries (LMIC). We aimed to describe the use of antihypertensive medicines (AHM) in Ghana and Nigeria using a novel data source., Methods: We used data from mPharma-a health and pharmaceutical company which distributes pharmaceuticals to hospital and retail pharmacies. We extracted data using the anatomical therapeutic chemical (ATC) classification codes and calculated use in defined daily doses and explored patterns by class, medicines, dose, and originator or generic product., Results: AHM use differed between Ghana and Nigeria. The most used classes in Ghana were angiotensin receptor blockers (ARB) followed by calcium channel blockers (CCB) and angiotensin-converting-enzyme inhibitors (ACEi). The five most used products were 16 mg candesartan, 30 mg nifedipine, 10 mg lisinopril, 5 mg amlodipine and 50 mg losartan. In Nigeria ARB, CCB and diuretics were widely used; the top five products were 50 mg losartan, 10 mg lisinopril, 30 mg nifedipine, 40 mg furosemide, and 5 mg amlodipine. More originator products were used in Ghana than Nigeria., Conclusion: The differences between Ghana and Nigeria may result from a combination of medical, contextual and policy evidence and reflect factors related to clinical guidance (e.g. standard treatment guidelines), accessibility to prescribers and the role of community pharmacies, and structure of the health system and universal health coverage including funding for medicines. We show the feasibility of using novel data sources to gain insights on medicines use in the community., (© 2022. The Author(s).)

Introduction Antidepressant use has increased over the last two decades, with Australia and New Zealand among the highest antidepressant users in Organisation for Economic Co-operation and Development (OECD) countries. Comorbidity and polypharmacy are common in antidepressant users, increasing the likelihood of interaction-related adverse drug events, which are frequently preventable. Aim We aimed to identify, profile, and analyse potential antidepressant drug-drug interactions in information-seeking antidepressant users. Methods We retrospectively analysed antidepressant-related drug-drug interaction enquiries from patients or carers who contacted a pharmacist-led Australian national medicines call centre over an 8-year period to determine patient characteristics, concomitant drugs involved, prevalence and type of antidepressant-related drug-drug interaction across life stages, and associated risks. Results Of 3899 antidepressant drug-drug interaction calls, the most frequent concomitant drugs were antipsychotics, opioids, benzodiazepines, and complementary medicines. Narrative analyses of 2011 calls identified 81.0% of patients with potential drug-drug interactions and 10.4% categorised with worrying symptoms. The most frequent drug-drug interaction risks were excessive sedation, increased anticholinergic effects, serotonin syndrome, and suicidal thoughts. Carers of children aged Discussion Antidepressant users often have information gaps and safety concerns regarding drug-drug interactions that motivate help-seeking behaviour. Symptoms and drug-drug interaction consequences may be underestimated in these patients. Primary care health professionals have a role in proactively addressing the risk of drug-drug interactions to support benefit-risk assessment and shared decision-making.

Data on antifungal utilization trends are important for encouraging antifungal stewardship. This study explored the use of antifungal agents for systemic application and the impact of reimbursement policy changes in Australia. We analyzed national data from the Australian Pharmaceutical Benefits Scheme (PBS) (2005-2016) and determined patterns of use over time and the impact of reimbursement decisions using an interrupted time-series model. From 2005-2016, there was an increase in the use of most antifungals, especially fluconazole, itraconazole, and posaconazole. Ketoconazole was the most commonly dispensed systemic antifungal agent (46.0%) prior to being removed from the PBS list and being replaced by fluconazole (69.8%). The PBS event "Fluconazole and itraconazole restrictions eased" led to the immediate increased use of fluconazole (0.025/1,000 per day), with both the highest rates and numerical increases attributed to obstetricians and gynecologists (1,969%; 1,851 dispensed prescriptions), as well as dermatologists (1,723%; 1,689 dispensed prescriptions) in 2010 and 2016. This is the first Australian national longitudinal estimate of systemic antifungal use. Our findings show an overall increase in the prescription of most antifungals during the investigated period, with reimbursement decisions impacting utilization. These data provide a baseline to inform the development of national antifungal guidelines and policies to encourage more targeted antifungal stewardship.

Introduction: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area., Methods: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis., Results: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer., (Copyright © 2022 Hiba El Masri, Treasure M. McGuire, Christine Dalais, Mieke van Driel, Helen Benham, Samantha A. Hollingworth.)

Background: While women are taking a greater role in decisions about menopause symptom management, the legacy of the Women's Health Initiative (WHI) studies persist. Despite hormone therapy (HT) being effective in reducing all-cause mortality, many women seeking relief of menopausal symptoms exaggerate HT harms and overstate the perceived benefits or ignore the risks of alternative therapies. We aimed to explore the longitudinal impact of the widely-publicised WHI 2002 study on women's information-seeking and describe determinants of decision-making about managing menopausal symptoms., Methods: In a longitudinal analysis of both quantitative and qualitative data, we explored consumer questions about menopause-related medicines received by two Australian medicines call centres (1996-2010) before, during, and after WHI 2002. We analysed calls by age and gender of caller and patient, their relationship, postcode, enquiry type, and motivation to help-seek. We compared calls regarding HT and herbal medicines (HM) with the rest of calls, and thematically analysed question narratives across the three time-periods., Results: There were 1,829 menopause-related calls received of over this time-period, with a call surge, primarily from women in their mid-fifties, in the two months after the WHI 2002 publication. Two in three calls were motivated by negative media reports as women sought support for decision-making, primarily reassurance to cease HT. While HT safety concerns persisted for eight years post-publication, the nature of information-seeking changed over time. Callers subsequently sought reassurance to use menopause treatments together with their other medicines; and pursued HT substitutes, including HM, in response to HT product discontinuation., Conclusions: Women sought information or reassurance to support a decision, based on dynamic changes in internal (symptom or risk intolerance, attitude towards menopause and treatment preferences) and external factors (perceived source trust and changes in treatment availability). In assessing HT benefit versus risk, women tend to overestimate risk with HT safety concerns persisting over time. Decision-making in managing menopause symptoms is complex and dynamic. Reassurance to reach or justify decisions from a perceived trusted source can support informed decision-making., (© 2021. The Author(s).)

The correction factor (CF) is a critical parameter in wastewater-based epidemiology (WBE) that significantly influences the accuracy of the final consumption estimates. However, most CFs have been derived from a few old pharmacokinetic studies and should be re-evaluated and refined to improve the accuracy of the WBE approach. This study aimed to review and estimate the CFs for atenolol, carbamazepine, and naproxen for WBE using the daily mass loads of those pharmaceuticals in wastewater and their corresponding dispensed prescription data in Australia. Influent wastewater samples were collected from wastewater treatment plants serving approximately 24% of the Australian population and annual national dispensed prescription data. The estimated CFs for atenolol and carbamazepine are 1.37 (95% CI: 1.17-1.66) and 8.69 (95% CI: 7.66-10.03), respectively. Due to significant over-the-counter sales of naproxen, a reliable CF could not be estimated based on prescription statistics. Using an independent dataset of 186 and 149 wastewater samples collected in an urban catchment in 2011 and 2012, WBE results calculated using the new CFs matched well with the dispensed data for atenolol and carbamazepine in the catchment area.

Background: New disease modifying therapies (DMT) to control relapsing-remitting multiple sclerosis (RRMS) have been introduced to the market in the past few years and are now widely used in Australia., Objective: To analyse the dispensed use of government subsidised RRMS DMTs in Australia from 1996 to 2019., Methods: We obtained data of dispensed use of DMTs from the Australian Government's Pharmaceutical Benefits Scheme (PBS) administered by Medicare Australia. We measured use as defined daily dose (DDD) per 100,000 population per day. We obtained jurisdictional population data from the Australian Bureau of Statistics., Results: Total DMT use increased by an average of 18% annually, from 2.4 (in 1996) to 69.9 DDD/100,000/day in 2019. Interferon β1B was the most commonly used medicine between 1996 and 2000, Interferon β1A between 2001 and 2014, and fingolimod subsequently. Among Australian states, Tasmania (the southernmost state) had the highest dispensed DMT use of 94.6 DDD/100,000/day in 2019. Concession beneficiaries under the Government's PBS had both lower use and cost per patient than general beneficiaries did. Fingolimod and ocrelizumab accounted for 55% of total expenditure on MS drug therapy in 2019., Conclusion: The use of oral DMTs might increasingly replace parenteral treatments in the near future. Given the current substantial government expenditure on oral DMTs, it will be imperative to examine the real world effectiveness of DMTs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To compare the dispensed use of antidepressants in Australia and Sweden., Methods: We analysed publicly available data from Australia and Sweden on dispensed use of antidepressants from 2006 to 2018., Results: The dispensed use of antidepressants has increased in both Australia and Sweden. Australia had a more rapid increase resulting in a higher total use. The utilisation profile was similar in both countries; SSRIs were the most commonly used group, "other antidepressants" were the group that increased the most, and seven of the eight most used substances were the same. There were differences in which antidepressants were most used, with the three most prescribed antidepressants being escitalopram, sertraline, and venlafaxine in Australia; and mirtazapine, sertraline, and citalopram in Sweden., Conclusion: Dispensed use of antidepressants has increased remarkably in both Australia and Sweden between 2006 and 2018. Although similar with regard to economic status and health care system, use of antidepressants differs between both countries. This may be a result of a combination of factors related to medical, contextual and policy evidence. The differences displayed in this study may reflect varying accessibility of treatments, national programmes enhancing mental health literacy in the population, clinical prescribing guidelines and timing of approval of new antidepressants., (© 2020 John Wiley & Sons Ltd.)

Background Prescription opioids are a central aspect of pain management and as the prevalence of pain is increasing so is the rate of use of prescription opioids. Increased opioid prescriptions increases the risk of deaths and morbidity. Objective To (a) describe the 22-year trend of prescription opioid dispensing in Queensland, (b) examine the effect of opioid dose, formulation and socioeconomic status on the number of prescriptions dispensed. Design/setting Retrospective analysis of data from the Monitoring of Drugs of Dependence system of the Monitored Medicines Unit of Queensland Health, Australia. Participants Queensland residents (3.3 million) from 18 years old dispensed 18.8 million opioid prescriptions from January 1997 to December 2018. Results Opioid prescriptions dispensed annually increased to over two million in 2018 from about 150,000 prescriptions in 1997. The number of prescriptions for modified-release formulations dispensed annually was three times higher compared to the immediate-release formulations. Oxycodone accounted for over 60% of prescriptions for pharmaceutical opioids since 2013. There was an increase in the number of prescriptions dispensed as socioeconomic status decreased and modified-release opioid formulations positively affects the pattern of dispensing. The highest increase in number of prescriptions dispensed (for all opioids) was observed among the high socioeconomic status (IRR = 1.25, 95% CI 1.25, 1.26). The disparities in the annual number of prescriptions across dose categories are wider in the modified-release than the immediate-release formulations. Conclusion The dispensing of opioids increased significantly in Queensland. There was a positive relationship between the increased dispensing of opioids and locations of lower socioeconomic status.

Background There is an association between the duration of prescription opioids use and an increased risk of serious harm, often unintentional. Objective (1) Describe the trends in duration of prescription opioids dispensing and, (2) determine the risk of long-term use (≥4 months) based on patients' socioeconomic status, daily dose in oral daily morphine milligram equivalent, and opioid formulation. Setting Residents of Queensland (2,827,727), Australia from the age 18 years and who were dispensed pharmaceutical opioids from 1 January 1997 to 31 December 2018. Method Retrospective, longitudinal population-based analysis using data obtained from the Monitoring of Drugs of Dependence system of the Monitored Medicines Unit of Queensland Health. Main outcome measure Contribution of socioeconomic status, and daily dose and opioid formulation (modified-release or immediate-release) to the risk of long-term opioid use. Results There was little difference between the number of patients dispensed opioids for ≥4 months and ≤3 months between 1997 and 2011. Thereafter, the number for those using opioids long-term increased. The highest risk of having opioids dispensed for ≥4 months were for patients in the lowest level of socioeconomic status (adjusted odds ratio 1.36; 95% CI, 1.34, 1.38), compared to people in the highest socioeconomic status areas, followed by the low-socioeconomic status areas, mid-socioeconomic status areas, and high-socioeconomic status areas respectively. The risk of being dispensed prescription opioids for ≥4 months significantly increased as the dose increased: adjusted odds ratio 1.73; 95% CI, 1.71, 1.75, adjusted odds ratio 1.89; 95% CI, 1.87, 1.92, and adjusted odds ratio 3.63; 95% CI, 3.58, 3.69 for the ≥20 to <50 oral daily morphine milligram equivalent, ≥50 to <100 oral daily morphine milligram equivalent and ≥100 oral daily morphine milligram equivalent dose categories, respectively. Conclusion Higher doses and living in a low socioeconomic status areas were associated with increased risk of long-term dispensing of opioid prescriptions.

Background: The relationship between antibiotic use and the incidence of triazole-resistant phenotypes of invasive candidiasis (IC) in critically ill patients is unclear. Different methodologies on determining this relationship may yield different results. Methods: A retrospective multicenter observational analysis was conducted to investigate exposure to antibiotics and the incidence of non-duplicate clinical isolates of Candida spp. resistant to fluconazole, voriconazole, or both during November 2013 to April 2018, using two different methodologies: group-level (time-series analysis) and individual-patient-level (regression analysis and propensity-score adjusting). Results: Of 393 identified Candida spp. from 388 critically ill patients, there were three phenotypes of IC identified: fluconazole-resistance (FR, 63, 16.0%); voriconazole-resistance (VR, 46, 11.7%); and cross-resistance between fluconazole and voriconazole (CR, 32, 8.1%). Exposure to several antibacterial agents with activity against the anaerobic gastrointestinal flora, especially third-generation cefalosporins (mainly cefoperazone/sulbactam and ceftriaxone), but not triazoles, have an immediate effect (time lag = 0) on subsequent ICU-acquired triazole-resistant IC in the group-level ( p < 0.05). When the same patient database was analyzed at the individual-patient-level, we found that exposure to many antifungal agents was significantly associated with triazole-resistance (fluconazole [adjusted odds ratio (aOR) = 2.73] or caspofungin [aOR = 11.32] on FR, voriconazole [aOR = 2.87] on CR). Compared to the mono-triazole-resistant phenotype, CR IC has worse clinical outcomes (14-days mortality) and a higher level of resistance. Conclusion: Group-level and individual-patient-level analyses of antibiotic-use-versus-resistance relations yielded distinct but valuable results. Antibacterials with antianaerobic activity and antifungals might have "indirect" and "direct" effect on triazole-resistant IC, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Zhang, McGuire, Hollingworth, Van Driel, Cao, Wang and Dong.)

Objective This study compared the cost of an integrated primary-secondary care general practitioner (GP)-based Beacon model with usual care at hospital outpatient departments (OPDs) for patients with complex type 2 diabetes. Methods A costing analysis was completed alongside a non-inferiority randomised control trial. Costs were calculated using information from accounting data and interviews with clinic managers. Two OPDs and three GP-based Beacon practices participated. In the Beacon practices, GPs with a special interest in advanced diabetes care worked with an endocrinologist and diabetes nurse educator to care for referred patients. The main outcome was incremental cost saving per patient course of treatment from a health system perspective. Uncertainty was characterised with probabilistic sensitivity analysis using Monte Carlo simulation. Results The Beacon model is cost saving: the incremental cost saving per patient was A$365 (95% confidence interval -A$901, A$55) and was cost saving in 93.7% of simulations. The key contributors to the variance in the cost saving per patient course of treatment were the mean number of patients seen per site and the number of additional presentations per course of treatment associated with the Beacon model. Conclusions Beacon clinics were less costly per patient course of treatment than usual care in hospital OPDs for equivalent clinical outcomes. Local contractual arrangements and potential variation in the operational cost structure are of significant consideration in determining the cost-efficiency of Beacon models. What is known about this topic? Despite the growing importance of achieving care quality within constrained budgets, there are few costing studies comparing clinically-equivalent hospital and community-based care models. What does this paper add? Costing analyses comparing hospital-based to GP-based health services require considerable effort and are complex. We show that GP-based Beacon clinics for patients with complex chronic disease can be less costly per patient course of treatment than usual care offered in hospital OPDs. What are the implications for practitioners? In addition to improving access and convenience for patients, transferring care from hospital to the community can reduce health system costs.

Background: Accessing multiple prescribers for opioid prescription, referred to as doctor-shopping, is associated with an increased risk of opioid overdose and fatalities., Aim: The primary aim of this study was to assess the probability of accessing multiple prescribers among patients dispensed prescription opioids., Method: A retrospective population-based study using the Monitoring of Drugs of Dependence system of the Medicines Monitoring Unit (MMU) of Queensland Health, Australia. We assessed the odds of accessing multiple prescribers across both -short-term (≤1 month, 2-3 months) and longer-term (4-6 months and ≥7 months). We examined the relationship between multiple doctor visits, the dispensed dose of opioid and patient's residential socioeconomic status (SES)., Result: Compared to those dispensed opioid prescriptions for ≥7-12 months, those dispensed opioids for ≤1 month were more likely to have visited ≥3 prescribers (adjusted odds ratio (aOR)) 4.06, 95% CI 4.01, 4.10, while for 2-3 months and 4-6 months the odds were aOR 2.36, 95% CI 2.33, 2.39 and aOR 1.79, 95% CI 1.74, 1.79 respectively. Patients dispensed opioid doses of ≥100 oral morphine milligram equivalent per day (MME/day) were more likely to obtain prescriptions from ≥3 prescribers compare to those receiving a dose of <20MME/day (aOR 1.90; 95% CI 1.87, 1.94). The probability of obtaining opioid prescriptions from multiple prescribers increased as the socioeconomic status decreased: aOR 1.41; 95% CI 1.38, 1.44 for lowest SES compared to the highest SES., Conclusion: Patients were more than four time likely to be dispensed opioid prescriptions from multiple prescribers within the first 30 days of initiating opioid treatment, possibly as part of multidisciplinary referral post-hospital discharge. High dose opioid and low SES was associated with higher probability of accessing multiple prescribers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Disease-modifying antirheumatic drugs (DMARDs) have transformed the treatment of numerous autoimmune and inflammatory diseases but their perceived risk of harm may be a barrier to use., Methods: In a retrospective mixed-methods study, we analysed conventional (c) and biologic (b) DMARDs-related calls and compared them with rest of calls (ROC) from consumers to an Australian national medicine call center operated by clinical pharmacists from September 2002 to June 2010. This includes the period where bDMARDs became available on the Pharmaceutical Benefits Scheme, the government-subsidized prescription medicines formulary. We compared caller and patient demographics, enquiry types and motivation to information-seek for both cDMARDs and bDMARDs with ROC, using a t-test for continuous data and a chi-square test for categorical data. We explored call narratives to identify common themes., Results: There were 1547 calls involving at least one DMARD. The top three cDMARD enquiry types were side effects (27.2%), interactions (21.9%), and risk versus benefit (11.7%). For bDMARDs, the most common queries involved availability and subsidized access (18%), mechanism and profile (15.8%), and side effects (15.1%). The main consumer motivations to information-seek were largely independent of medicines type and included: inadequate information (44%), wanting a second opinion (23.6%), concern about a worrying symptom (18.8%), conflicting information (6.9%), or information overload (2.3%). Question themes common to conventional and biological DMARDs were caller overemphasis on medication risk and the need for reassurance. Callers seeking information about bDMARDs generally overestimated effectiveness and focused their attention on availability, cost, storage, and medicine handling., Conclusion: Consumers have considerable uncertainty regarding DMARDs and may overemphasise risk. Patients cautiously assess the benefits and risks of their DMARDs but when new treatments emerge, they tend to overestimate their effectiveness., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Health technology assessment (HTA) is an effective tool for supporting priority setting (PS) in health. Stakeholder groups need to understand HTA appropriate to their role and to interpret and critique the evidence produced. We aimed to rapidly assess current health system priorities and policy areas of demand for HTA in Sub-Saharan Africa, and identify key gaps in data and skills to inform targeted capacity building. Methods: We revised an existing survey, delivered it to 357 participants, then analysed responses and explored key themes. Results: There were 51 respondents (14%, 30 full completions) across 14 countries. HTA was considered an important and valuable PS tool with a key role in the design of health benefits packages, clinical guideline development, and service improvement. Medicines were identified as a technology type that would especially benefit from the application of HTA. Using HTA to address safety issues (e.g. low-quality medicines) and value for money concerns was particularly highlighted. The perceived availability and accessibility of suitable local data to support HTA varied widely but was mostly considered inadequate and limited. Respondents also noted a need for training support in research methodology and data gathering. Conclusions: While important in raising awareness of HTA as a tool for PS, this study had a low response rate, and that respondents were self-selected. A more refined survey will be developed to support engagement strategies and capacity building., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hollingworth SA et al.)

Background: Evidence-based decision-making for prioritising health is assisted by health technology assessment (HTA) to integrate data on effectiveness, costs and equity to support transparent decisions. Ghana is moving towards universal health coverage, facilitated mainly by the National Health Insurance Scheme (NHIS) established in 2003. The Government of Ghana is committed to institutionalising HTA for priority-setting. We aimed to identify and describe the sources of accessible data to support HTA in Ghana., Methods: We identified and described data sources encompassing six main domains using an existing framework. The domains were epidemiology, clinical efficacy, costs, health service use and consumption, quality of life, and equity. We used existing knowledge, views of stakeholders, and searches of the literature and internet., Results: The data sources for each of the six domains vary in extent and quality. Ghana has several large data sources to support HTA (e.g. Demographic Health Surveys) that have rigorous quality assurance processes. Few accessible data sources were available for costs and resource utilisation. The NHIS is a potentially rich source of data on resource use and costs but there are some limits on access. There are some data on equity but data on quality of life are limited., Conclusions: A small number of quality data sources are available in Ghana but there are some gaps with respect to HTA based on greater use of local and contextualised information. Although more data are becoming available for monitoring, challenges remain in terms of their usefulness for HTA, and some information may not be available in disaggregated form to enable specific analyses. We support recent initiatives for the routine collection of comprehensive and reliable data that is easily accessible for HTA users. A commitment to HTA will require concerted efforts to leverage existing data sources, for example, from the NHIS, and develop and maintain new data (e.g. local health utility estimates). It will be critical that an overarching strategic and mandatory approach to the collection and use of health information is developed for Ghana in parallel to, and informed by, the development of HTA approaches to support resource allocation decisions. The key to HTA is to use the best available data while being open about its limitations and the impact on uncertainty.

Purpose: The study's aim was to compare the use of proton pump inhibitors (PPIs), histamine 2-receptor antagonists (H 2 RAs) and mucoprotective medicines (MPs) used for gastric acid-related disorders (GARD) in Australia and South Korea (Korea) from 2004 to 2017., Methods: Prescription data for PPIs, H 2 RAs and MPs for Australian outpatients were extracted from the Australian Statistics on Medicines annual reports, with dose-specific and expenditure data obtained from Medicare. Similar data were obtained from Korean National Health Insurance Service claims data. We analysed the volume and expenditure of medicines use annually using the defined daily dose per 1,000 population per day. We calculated which medicines accounted for 90% of use and estimated the proportions of use for low- and high-dose PPIs., Results: While total utilisation for GARD medicines increased over time in both countries, patterns of use differed. Overall, use was somewhat higher in Australia but increased more rapidly in Korea. PPIs were used more extensively in Australia, while more MPs and H 2 RAs were used in Korea. Expenditure and use of low-dose PPIs is escalating in Korea., Conclusion: There were substantial differences in the use of GARD medicines in Australia and Korea over 14 years. Both countries face similar challenges to promote rational medicines use and contain medical care costs. The discrepant prescribing patterns can be attributed to differences in healthcare systems, pharmaceutical policies and demographics. This study provides a baseline to influence more rational use of these medicines. It provides insight into medicines policies for other countries that face similar challenges.

Background: Opioid analgesic (OA) and anxiolytic, hypnotic and sedative (AHS) medicines use raise community concerns about risks of dependence: dose escalation, unintentional misuse. Objectives: We aimed to identify common consumer OA and AHS information gaps and concerns that led to information seeking from a hotline. Methods: We conducted a retrospective, mixed-method observational study of consumers' OA and AHS-related calls to an Australian national medicines call center (September 2002-30 June 2010). We analyzed these medicines' call characteristics compared to their respective rest of calls (ROC) and thematically explored narratives concerning withdrawal and misuse. Results: Of 123,217 calls, 7,395 (6.0%) involved OA and 7,789 (6.2%) AHS, with consistency between call characteristics. While female middle-aged callers predominated, more males called for these medicines than their complementary ROC. Uncertainty about unresolved OA and AHS concerns led to help-seeking that was consistent over eight years. Main motivations were inadequate information (OA 44.5%; AHS 41.2%), seeking a second opinion (OA 24.2%; AHS 24.2%), worrying symptoms (OA 21.6%; AHS 23.1%), and conflicting information (OA 4.9%; AHS 5.1%). Callers focused on withdrawal and issues related to inadvertent overuse or deliberate misuse (OA 9.2% vs. non-OA ROC 2.9%; AHS 12.6% vs. non-AHS ROC 2.7%). Primary themes were similar for both cohorts: concern about harm or aiming to minimize harm by information seeking, requesting a strategy, or reassurance. Conclusions: Consumers have under-recognized perceptions of harm from OA and AHS use, particularly withdrawal and misuse. Resources based on real world consumer concerns can encourage open dialogue between patients and their prescribers.

Objectives: Recommendations in clinical practice guidelines (CPG) may differ and cause confusion. Our objective was to appraise CPGs for antifungal treatment of invasive candidiasis (IC) in non-neutropenic critically ill adult patients., Methods: We systematically searched the literature for CPGs published between 2008 and 2018. We assessed the quality of each guideline using six domains of the AGREE II instrument. We extracted and compared recommendations for different treatment strategies and assessed content quality., Results: Of 19 guidelines, the mean overall AGREE II score was 58%. The domain 'clarity of presentation' received the highest scores (88%) and 'applicability' the lowest (18%). CPGs provided detailed recommendations on antifungal prophylaxis (n = 10), with fluconazole recommended as initial prophylaxis in all seven CPGs citing a specific drug. Echinocandin was recommended as the initial drug in all 16 CPGs supporting empirical/pre-emptive treatment; and in 18 of 19 for targeted invasive candidiasis treatment. However, it remains unclear when to initiate prophylaxis, empirical or pre-emptive therapy or when to step down., Conclusions: The methodological quality of CPGs for antifungal treatment of IC in non-neutropenic critically ill patients is suboptimal. Some treatment recommendations were inconsistent across indications and require local guidance to help clinicians make better informed decisions., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to examine the longitudinal impact of evidence changes on menopausal hormone therapy (MHT) use in Australia. Methods: We analyzed two datasets of subsidized and total MHT use (2000-2016) using segmented regression analysis to explore the impact of the Women's Health Initiative (WHI) 2002 and 2007 studies. Analyses were stratified by class, route, and strength. Use was measured in defined daily dose/1000 women/day (DDD/1000/day) or packs/1000 women/month (packs/1000/month). Results: The drop in total MHT use after the WHI 2002 was substantial. The biggest decreases in class, route, and strength were estrogens (28.99 DDD/1000/day, 95% confidence interval [CI] 23.97, 34.01), oral (46.07 DDD/1000/day, 95% CI 41.13, 51.01), and medium strength (34.95 packs/1000/month, 95% CI 30.17, 39.73), respectively. However, vaginal use remained stable (-1.83 DDD/1000/day, 95% CI -3.83, 0.17). Profiles of total and subsidized use were similar over time. Utilization levels were relatively unchanged after 2007. Decreased utilization contributed to product discontinuation, with a lag of up to 4 years. Product discontinuation in 2009 further decreased utilization. Discussion and conclusions: MHT use remained low after 2002 despite evidence favoring its use in women younger than 60 years or within 10 years postmenopause. Continued low use could relate to the WHI 2002 media coverage, therapy objectives, key stakeholder uncertainty, health policies, and medicine availability.

Background: Consumers have questions about their medication but the nature of these concerns and how they reflect medication use is unknown., Objectives: To determine the characteristics and medicines interests of callers to an Australian medicines call center and whether the medicines interest of callers corresponds with medicines utilization., Methods: Data from consumers who contacted a national medicines call center between September 2002 and June 2010 were analyzed. Patterns of consumer medicines interest were described. Medicines were class-matched by Anatomical Therapeutic Classification, and compared with dispensed use (January 2006-June 2010)., Results: In total 125,951 calls were received between 2002 and 2010. Callers were mainly female (76.8%), median age 48 years, calling for themselves (71.7%). Motivation to call related to safety (34.7%), efficacy (24.1%) and interactions (14.9%). For the comparison with medicines utilization, 85,416 calls with 124,177 individual medicine counts were analyzed (2006 and 2010). There were 976 unique 'medicines of interest'. Half (49.4%) of these questions involved just fifty unique medicines. Nervous system medicines (antiepileptics, psycholeptics, analgesics) and antibacterials consistently ranked highest for interest compared with use. Conversely, agents acting on the renin-angiotensin system, statins and drugs for acid related disorders ranked low for interest despite widespread use., Conclusions: Consumer questions about medicines correlate poorly with overall medicines utilization. To promote quality health outcomes, clinicians should target their education to the relatively small number of medicines of real concern to patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Medicine use as part of multimodal management for whiplash-associated disorders (WAD) is common: neck pain is the cardinal symptom, mental health conditions are common, and some individuals may have neurological signs and symptoms. Almost half of the individuals with WAD have ongoing pain and disability. However, medicine use during acute and chronic recovery periods for WAD management is unknown. We analysed medicine use during acute (<12 weeks) and chronic (12 weeks to 2 years) postinjury periods in adults claiming compensation for WAD in the no-fault jurisdiction of Victoria, Australia (n = 2871). Compared with males, females were more likely to have only nonopioid analgesic and/or NSAID claims during the acute postinjury period (odds ratio = 1.35 [95% confidence interval: 1.08-1.68]). However, high medicine use was more likely in males (1.39 [1.16-1.67]), middle-aged claimants (35-44 years) (1.74 [1.12-2.56]), and claimants with a common law claim (2.96 [2.38-3.68]). During both acute and chronic postinjury periods, over half of the pharmaceutical claimants were prescribed NSAIDs and weak opioid medicines, and over one quarter were prescribed benzodiazepines. Antidepressant use was high during the chronic period. The proportion of strong opioid claimants quadrupled between 2000/2001 (5.5%) and 2012/2013 (23.4%). Opioid consumption, expressed as oral morphine equivalent, was double in males than in females (z = -5.4, P < 0.001), and higher in middle-aged than in younger or older claimants (χ = 13.9, P < 0.001). The high opioid, benzodiazepine, and antidepressant medicine use in this study is concerning and highlights the need for pharmaceutical approaches that balance pain management while minimising risk.

Objective: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features)., Research Design and Methods: A Markov decision model was developed to estimate incremental costs and quality-adjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA 1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework., Results: Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%., Conclusions: Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus., (© 2018 by the American Diabetes Association.)

Prescription opioid use has increased rapidly in developed countries, as have fatalities and other related adverse events. This review examines the intrinsic characteristics of opioids, including their mechanisms of action and pharmacokinetic and pharmacodynamic properties, to determine how the use of a regonised pharmacological remedy for a medically confirmed ailment could result in an accidental fatality. Opioids trigger biological processes that inhibit their own therapeutic effect. Prolonged use of opioids can result in activation of pronociceptive systems, leading to opioid-induced hyperalgesia and tolerance, while opioid metabolites can antagonise the antinociceptive action of the parent drug, also leading to opioid-induced hyperalgesia and tolerance. Pain stimulates respiration and counteracts the respiratory depression effect of opioids. Analgesia from opioids leads to loss of this protective mechanism, leading to increased risk of death due to respiratory failure. Increased patient counseling during opioid prescribing and dispensing, and limiting prescription to short-term use in non-malignant pain, may decrease the adverse effects of opioids. The vast majority of patients who unintentionally experience serious adverse events from pharmaceutical opioids do not start out as drug seekers. Even opioid use within prescribing guidelines can place some patients at risk of death and may prevent patients from seeking help for prescription opioid dependence.

Erlotinib is used to treat non-small-cell lung cancer (NSCLC). Erlotinib was subsidized on the Pharmaceutical Benefits Schedule in Australia for the treatment of advanced stage (IIIB or IV) NSCLC (August 2008). In the pivotal trial supporting initial subsidy, erlotinib increased overall survival (OS) by 2 months compared with placebo (adjusted hazard ratio, 0.70; 95% confidence interval: 0.58-0.85). We examined the effectiveness of erlotinib in a 'real-world' setting by measuring survival outcomes in NSCLC patients treated in two tertiary metropolitan public hospitals in Queensland. We extracted data from the electronic oncology prescribing system (CHARM) for NSCLC patients prescribed erlotinib (1 September 2009 to 1 February 2015). Survival estimates and analyses were generated using Kaplan-Meier curves. 134 patients received at least one dose of erlotinib during the study period. At the date of data extraction 113 patients had died. The median patient age was 64 years and 55% were men. The median duration of treatment was 2.0 months. The median OS was 5.8 months. The median progression-free survival (time from start of erlotinib to disease progression or death from any cause) was 3.6 months. The use of erlotinib in the two Queensland sites was consistent with the pivotal trial used to support subsidy. The median OS was somewhat less than the trial (5.8 vs. 6.7 months), which could be because of the hospital cohort including frailer patients who were unsuitable for parenteral chemotherapy, and the mixed epidermal growth factor receptor mutation status of the hospital cohort.

Rationale: Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia., Methods: Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia., Results: There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively., Conclusions: The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.

The authors would like to change the statement found in the results section of the abstract from "There were five reported deaths from neutropenia and cardiomyopathy." to "There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively."

Background: The rate of an unintentional drug overdose involving prescription opioids continues to rise. An understanding of the threshold dose and dose(s) associated with unintentional prescription opioid overdose will help to mitigate this epidemic., Objective: The objective of this systematic review is to systematically synthesise and meta-analyse studies on doses of prescription opioids and ascertain the doses of opioids that are associated with increased risk of severe opioid poisoning or mortality., Data Sources: A search of PubMed, EMBASE, CINAHL and Web of Science from inception to 16 January 2017 was conducted using search strategies and the MeSH (Medical Subject Headings) terms for studies of adult patients using prescription opioids who experienced an accidental overdose., Study Selection: Of the 1332 studies identified, 117 were selected for full article review. Ten met the inclusion criteria for qualitative analysis, but only seven studies were meta-analysed. The included studies were in English, and participants met predetermined International Classification of Diseases (ICD) codes. Studies were excluded if they included only paediatric participants or the participants met the ICD code for intentional self-harm., Data Extraction and Synthesis: Two researchers elaborated and validated a data extraction form. Data were then independently extracted by both reviewers as per this form. We assessed study quality using the Newcastle-Ottawa Scale (NOS) for non-randomised studies in meta-analyses. We performed a meta-regression using a random-effect model and summarised the results using relative risk (RR) and 95% confidence intervals (CIs). The threshold dose for an unintentional overdose is 20 morphine milligram equivalents (MME)/day. There were higher risks with larger doses: (1) ≤ 20 versus ≥ 21 MME/day: RR 2.81, 95% CI 1.09-7.22, p < 0.001; (2) ≤ 50 versus > 50 MME/day: RR 3.87, 95% CI 2.36-6.33, p < 0.001; (3) ≤ 100 versus > 100 MME/day: RR 4.28, 95% CI 2.61-7.1, p < 0.001; and (4) ≤ 50 versus > 50-100 MME/day: RR 3.09, 95% CI 1.84-5.18, p < 0.001). Heterogeneity was explained by the type of overdose event, inpatient or outpatient status, and length of observation. Type of pain (cancer or non-cancer pain) had no impact on heterogeneity., Limitations: The definition of exposure in studies included in the meta-analysis was heterogeneous. Some studies defined exposure as the filling of a prescription while others defined exposure as the prescription of an opioid to the patient, and all studies assumed that patients took the prescribed opioid. Medications that may contribute to overdose, such as benzodiazepines and other drugs, were not considered., Conclusions: A significantly increased risk of inadvertent prescription opioid overdose was found with 20-50 MME/day, with fatality more likely with opioid doses above 50 MME/day, although extensive heterogeneity was found with the dose comparisons. Clinicians should inform patients of this risk and monitor them closely., Protocol Registration: This protocol was registered with PROSPERO 2017: CRD42017058426.

Objective: To explore the nature of the bidirectional relationship between vasomotor symptoms (VMS) and depression, and to determine whether hot flashes and night sweats differentially affect the association between VMS and depression through their effect on sleep disruption., Methods: Multiple databases were searched from 1961 until July 31, 2016, and a manual search of reference lists of identified articles was conducted. Sixteen articles that involved 10,008 participants were identified and analyzed., Results: The methods of analyses and measurement of VMS and depression varied across the studies. Two studies explored the bidirectional association, but only one was significant in both directions (odds ratio [OR] depression to VMS 3.06, 95% confidence interval [CI] 1.43-6.58; OR VMS to depression 8.88, 95% CI 2.57-30.68). In both cases, the association between VMS leading to depressive symptoms was stronger than the opposite. Eleven studies examined VMS leading to depression, but only five showed a significant effect (OR 1.57-1.81, P ≤ 0.02). Treating VMS and depressive symptoms as continuous variables (n = 3) diminished the relationship. Three studies showed a significant association of depression leading to VMS (OR 1.62-1.94, P ≤ 0.01). We found little evidence for a specific effect of night sweats on the association between VMS and depressive symptoms. The effect might not be related to sleep disruption., Conclusions: There is a bidirectional association between VMS and depressive symptoms. The menopausal transition appears to increase the risk of recurrent episodes of depression that might not be explained only by VMS. Further investigation is needed to explain the differential effect of night sweats and hot flashes on depression.

Objectives: The aim of this study was to characterise the use and costs of subsidising conventional disease-modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs in Australia from 2004-2014 through pharmaceutical benefits schemes., Methods: Dispensing and expenditure data on conventional and biologic DMARDs were extracted from Medicare Australia and temporal trends were analysed. Medicine use was standardised in terms of the defined daily dose (DDD) per 1,000 population per day (DDD/1,000 population/day)., Results: Conventional and biologic DMARD use increased 74% over the study period (4.86 to 8.46 DDD/1,000 population/day; average annual increase 6.7%). Conventional DMARDs accounted for the vast majority of total use and increased 55% (4.81 to 7.43 DDD/1,000 population/day), while biologic DMARD use increased 1,784% (0.055 to 1.030 DDD/1,000 population/day). The most frequently used conventional DMARD was methotrexate (56% total conventional DMARD use) and use increased 95%. Hydroxychloroquine and leflunomide use increased marginally while sulfasalazine use declined 4.2%. Etanercept was the most commonly used biologic DMARD in 2004 and adalimumab in 2014. Conventional DMARD expenditure decreased 4.2% to AUD$33.3 million but biologic DMARD expenditure increased 2,089% to AUD$585.4 million., Conclusions: The use of conventional and biologic DMARDs increased substantially over a decade in Australia. Patterns of use of conventional DMARDs have changed, and costs have decreased. In contrast a significant escalation in both the use and cost of biologic DMARDs has occurred. Further research is required to address cost-effectiveness, regulation and quality use of these medicines in clinical practice.

Aim: Metastatic colorectal cancer has a large burden of disease in Australia. Medical therapy is fundamental to extending survival and improving quality of life. The benefits of two costly medicines, bevacizumab and cetuximab, used in Australia remain unclear. The aim of this study was to retrospectively examine the use of these two medicines in metastatic colorectal cancer across five public hospitals in south east Queensland and to compare clinical outcomes to those of published clinical trials., Methods: We extracted data from the chemotherapy prescribing database for patients planned for bevacizumab or cetuximab therapy between 2009 and 2013. Median overall survival was estimated using Kaplan-Meier methods., Results: There were 490 bevacizumab-containing protocols planned and 292 patients received at least one dose of bevacizumab. Median overall survival was 17.2 months (95% confidence interval [CI], 15.4-19.3). Of 208 planned cetuximab-containing protocols, 134 patients received at least one dose of cetuximab. Median overall survival was 9.1 months (95% CI, 7.6-12.0). Thirty-day mortality rates from date of first dose were 0.7% for bevacizumab and 7.5% for cetuximab., Conclusion: Overall survival of patients receiving bevacizumab and cetuximab was consistent with clinical trials, providing some assurance that benefits seen in trials are observed in usual practice. This study provides a methodology of using routinely collected health data for clinical monitoring and research. Because of the high cost of these medicines and the lack of toxicity data in this study, further analysis in the postmarketing setting should be explored., (© 2016 John Wiley & Sons Australia, Ltd.)

Background Health records can be used to measure medicine use and health outcomes. The public subsidy of lenalidomide in Australia was based on two phase III trials showing improved survival. Objective To use hospital pharmacy information management systems to determine survival outcomes for lenalidomide as a second line treatment in relapsed or refractory multiple myeloma (RRMM) patients. Setting Five public hospitals in Queensland, Australia. Method We extracted data on medicine use and survival for RRMM patients planned to start lenalidomide from pharmacy management and pathology databases. Descriptive statistical analyses (Kaplan-Meier curves) were used to calculate overall survival. Main outcome measure Overall survival. Results There were 136 patients who received at least one lenalidomide dose and 2234 cycles were ordered. The median age was 69 years and 54% were male. Two lenalidomide containing protocols were considered: 90% of patients had lenalidomide plus dexamethasone; 18% had lenalidomide plus dexamethasone with cyclophosphamide. The median starting lenalidomide dose was 20 mg (range 4.3-25 mg) on days 1-21 of a 28-day cycle. Median time on treatment 9.4 months (range 0.5-71.7 months). Median overall survival was 45.4 months (range 12.0-70.5 months). Conclusion The median survival in our study compared favourably to clinical trials. Patients and clinicians can be reassured that outcomes in this clinical setting are as good as those observed in trials.

Aim: To estimate potential savings for Australia's health care system through the implementation of an innovative Beacon model of care for patients with complex diabetes., Methods: A prospective controlled trial was conducted comparing a multidisciplinary, community-based, integrated primary-secondary care diabetes service with usual care at a hospital diabetes outpatient clinic. We extracted patient hospitalisation data from the Queensland Hospital Admitted Patient Data Collection and used Australian Refined Diagnosis Related Groups to assign costs to potentially preventable hospitalisations for diabetes., Results: 327 patients with complex diabetes referred by their general practitioner for specialist outpatient care were included in the analysis. The integrated model of care had potential for national cost savings of $132.5 million per year., Conclusions: The differences in hospitalisations attributable to better integrated primary/secondary care can yield large cost savings. Models such as the Beacon are highly relevant to current national health care reform initiatives to improve the continuity and efficiency of care for those with complex chronic disease in primary care., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background Increasing use of opioid analgesics (OA) has been reported worldwide. Objective To compare the use of OA in two countries in order to better understand these trends. Setting Outpatient settings in Australia and The Netherlands. Method We analysed publicly available government data on outpatient OA dispensing over 15 years (2000-2014). We compared dispensing trends for specific OA and explored medical (national clinical guidelines), contextual and policy-related factors to explain differences in use between the two countries. Main outcome measure OA prescribing in Australia and The Netherlands, absolute volume of use, preferred types of opioids and changes over time. Results The average annual increase in OA prescribing was 10% in Australia and 8% in The Netherlands between 2000 and 2014. In 2014, the total use of OA was 10.0 daily defined doses (DDD)/1000 population/day in Australia and 9.4 DDD/1000 population/day in The Netherlands. In Australia, the most commonly prescribed opioids were oxycodone and tramadol, compared to fentanyl and tramadol in The Netherlands. We found differences in prescribing guidelines, culture of prescribing and regulatory frameworks that could explain some of the observed differences. Conclusion OA prescribing has increased remarkably in both countries between 2000 and 2014 but the types of prescribed OA vary. Differences in national evidence-based guidelines influenced the types of OA used. Prescribing culture as well as regulatory policies and costs, may also contribute to the different patterns of OA use.