Evaluation of Bayesian Forecasting Methods for Prediction of Tacrolimus Exposure Using Samples Taken on Two Occasions in Adult Kidney Transplant Recipients.

BACKGROUND: Bayesian forecasting-based limited sampling strategies (LSSs) for tacrolimus have not been evaluated for the prediction of subsequent tacrolimus exposure. This study examined the predictive performance of Bayesian forecasting programs/services for the estimation of future tacrolimus area under the curve (AUC) from 0 to 12 hours (AUC0-12) in kidney transplant recipients. METHODS: Tacrolimus concentrations were measured in 20 adult kidney transplant recipients, 1 month post-transplant, on 2 occasions one week apart. Twelve samples were taken predose and 13 samples were taken postdose at the specified times on the first and second sampling occasions, respectively. The predicted AUC0-12 (AUCpredicted) was estimated using Bayesian forecasting programs/services and data from both sampling occasions for each patient and compared with the fully measured AUC0-12 (AUCmeasured) calculated using the linear trapezoidal rule on the second sampling occasion. The bias (median percentage prediction error [MPPE]) and imprecision (median absolute prediction error [MAPE]) were determined. RESULTS: Three programs/services were evaluated using different LSSs (C0; C0, C1, C3; C0, C1, C2, C4; and all available concentrations). MPPE and MAPE for the prediction of fully measured AUC0-12 were <15% for each program/service (with the exclusion of when only C0 was used), when using estimated AUC from data on the same (second) occasion. The MPPE and MAPE for the prediction of a future fully measured AUC0-12 were <15% for 2 programs/services (and for the third when participants who had a tacrolimus dose change between sampling days were excluded), when the occasion 1-AUCpredicted, using C0, C1, and C3, was compared with the occasion 2-AUCmeasured. CONCLUSIONS: All 3 Bayesian forecasting programs/services evaluated had acceptable bias and imprecision for predicting a future AUC0-12, using tacrolimus concentrations at C0, C1, and C3, and could be used for the accurate prediction of tacrolimus exposure in adult kidney transplant recipients.

Prednisolone Concentrations in Plasma (Total and Unbound) and Saliva of Adult Kidney Transplant Recipients.

BACKGROUND: Prednisolone displays significant pharmacokinetic variability and exposure-outcome relationships in renal transplant recipients, suggesting a role for drug monitoring in some scenarios. It is highly protein-bound, and the free form is pharmacologically active but cumbersome to measure. Saliva concentrations might reflect free plasma prednisolone and present an alternative measurement. The aim of this study was to examine the correlation between total and free plasma and saliva prednisolone in adult renal transplant recipients. METHODS: Total and free plasma and saliva prednisolone concentrations were measured in 20 patients receiving oral prednisolone 1-2 months after transplant, between pre-dose and 12 hours post-dose. Prednisolone was determined using high-performance liquid chromatography mass spectrometric detection. The Pearson coefficient was used to assess the association between plasma and salivary prednisolone concentrations and area under the concentration-time curves (AUC0-12). RESULTS: When considering all time points, the total and free plasma prednisolone concentrations correlated well (r = 0.81), but there was poor correlation between saliva and free (r = 0.003) and total (r = 0.01) plasma concentrations. When concentrations before the maximum free prednisolone plasma value were excluded, the correlation between free plasma and saliva concentrations improved (r = 0.57). There was a moderate correlation between free and total plasma prednisolone AUC0-12 (r = 0.62) using all time points, but a poor correlation between free and total plasma prednisolone AUC0-12 and saliva AUC0-12 (r = 0.07; r = 0.17). CONCLUSIONS: Total and free plasma prednisolone measurements correlated poorly with saliva measurements; however, correlation improved when concentrations early in the dosing interval were excluded.

Evaluation of Multiple Linear Regression-Based Limited Sampling Strategies for Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients.

BACKGROUND: Although multiple linear regression-based limited sampling strategies (LSSs) have been published for enteric-coated mycophenolate sodium, none have been evaluated for the prediction of subsequent mycophenolic acid (MPA) exposure. This study aimed to examine the predictive performance of the published LSS for the estimation of future MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) in renal transplant recipients. METHODS: Total MPA plasma concentrations were measured in 20 adult renal transplant patients on 2 occasions a week apart. All subjects received concomitant tacrolimus and were approximately 1 month after transplant. Samples were taken at 0, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours and 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 hours after dose on the first and second sampling occasion, respectively. Predicted MPA AUC0-12 was calculated using 19 published LSSs and data from the first or second sampling occasion for each patient and compared with the second occasion full MPA AUC0-12 calculated using the linear trapezoidal rule. Bias (median percentage prediction error) and imprecision (median absolute prediction error) were determined. RESULTS: Median percentage prediction error and median absolute prediction error for the prediction of full MPA AUC0-12 were <15% for 4 LSSs, using the data from the same (second) occasion. One equation (1.583C1 + 0.765C2 + 0.369C2.5 + 0.748C3 + 1.518C4 + 2.158C6 + 3.292C8 + 3.6690) showed bias and imprecision <15% for the prediction of future MPA AUC0-12, where the predicted AUC0-12 from the first occasion was compared with the full AUC0-12 from the second. All LSSs with an acceptable predictive performance included concentrations taken at least 6 hours after the dose. CONCLUSIONS: Only one LSS had an acceptable bias and precision for future estimation. Accurate dosage prediction using a multiple linear regression-based LSS was not possible without concentrations up to at least 8 hours after the dose.

Psychiatric adverse events in oseltamivir prophylaxis trials: Novel comparative analysis using data obtained from clinical study reports.

PURPOSE: Estimating the rate of adverse events (AEs) caused by a treatment in clinical trials typically involves comparing the proportions of patients experiencing AEs in intervention and control groups. However, potentially important information, including duration, recurrence, and intensity of events, is lost. In this study, we illustrate how the additional information can be obtained and incorporated into analyses of AEs. METHODS: Data on psychiatric AEs were extracted from clinical study reports (CSRs) provided by the manufacturer of oseltamivir in 4 prophylaxis randomised trials in adults and adolescents. We analysed the incidence, recurrence, duration, and intensity of events, using logistic regression models where the outcome compared was proportion of days suffering from an event, and developed novel presentation techniques. RESULTS: Psychiatric AEs were generally more frequent, longer, and more intense in the treatment than placebo arms. Logistic regression models confirm the apparent association overall (odds ratio [OR] 3.46, 95% confidence interval [CI] 1.28 to 9.32), particularly for events classified as severe (OR 34.5, 95% CI 3.66 to 325). However, the absolute difference in proportion of days suffering from severe psychiatric AEs between groups was small. CONCLUSIONS: This example analysis shows evidence of a causal effect of oseltamivir on psychiatric AEs, not apparent in the published versions of the same trials and a Cochrane review which showed a nonsignificant 81% increased odds of experiencing a psychiatric event. This unique and important finding was dependent on obtaining previously unavailable data from clinical study reports and using novel analyses and presentation methods.

Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis.

AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.

Actions following adverse drug events - how do these influence uptake and utilisation of newer and/or similar medications?

BACKGROUND: Over the last decade, actions following some adverse drug events received major publicity. This study investigated changes in usage patterns of medications in Australia following two examples - rofecoxib market withdrawal (2004) and warnings about jaw necrosis following bisphosphonates (2007). METHODS: Dispensing data for COX-2 inhibitors (2000-2008) and anti-osteoporosis medications (2003-2012) were obtained from the Australian Pharmaceutical Benefits Scheme database. For bisphosphonates, data on Australian marketing expenditures were purchased from Cegedim(R). RESULTS: For COX-2 inhibitors, celecoxib dispensing halved after rofecoxib withdrawal, but meloxicam dispensing increased by 60 %. When lumiracoxib was introduced (2006) there was uptake of prescribing at a faster rate than meloxicam in 2002, its first year of use. For bisphosphonates, alendronate had highest use at the time of the warnings (8.3 DDD/1000/day), dropping to 4.9 DDD/1000/day by 2012. In contrast, risedronate use rose 2007-2012 from 4.1 to 4.9 DDD/1000/day. There was 49 % increase in reported annual expenditure on detailing for risedronate from 2007 to 2008 (to AUD$7.3 million) and only 29 % increase for alendronate (to AUD$3.1 million). CONCLUSIONS: The rapid uptake of prescribing of lumiracoxib and increased use of meloxicam flagged a concern, especially after rofecoxib withdrawal due to safety issues. Bisphosphonates are useful drugs, however the dramatic rise in expenditure on detailing, followed by a rise in utilisation of risedronate could suggest that adverse publicity triggered a marketing response. These examples highlight the importance of tracking utilisation of medication classes in real time, using different data as needed, to ensure that due caution is exercised (and quick intervention provided if needed) for medications in the same class.

Osteoporosis medication dispensing for older Australian women from 2002 to 2010: influences of publications, guidelines, marketing activities and policy.

PURPOSE: Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76-81 years at baseline) from 2002 to 2010. METHODS: Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921-1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. RESULTS: Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. CONCLUSIONS: Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy.

Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update.

This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.

Differences in utilisation of gastroprotective drugs between 2001 and 2005 in Australia and Nova Scotia, Canada.

PURPOSE: This study aimed to compare use of histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), 2001-2005, in the elderly and social security beneficiaries in Australia (AUS) and Nova Scotia, Canada (NS). METHODS: Prescription dispensing data were collected for all subsidised H2RAs and PPIs. In AUS, dispensing data for concession beneficiaries were obtained from the Pharmaceutical Benefits Scheme database. In NS, data were sourced from the Pharmacare database. Relevant population data were used to convert to World Health Organisation Anatomic Therapeutic Chemical defined daily doses (2005) per 1000 beneficiaries per day (DDD/1000/day). RESULTS: Overall use of gastroprotective agents was similar and rising in NS and AUS (100-160 DDD/1000/day) over this 5-year time window. However, the proportion of this use accounted for by PPIs was far higher in AUS (over 85% by 2005) than in NS (23% rising to 35% over the 5 years). In AUS, PPI use rose from 50 to about 140 DDD/1000/day over the 5 years, whereas PPI use in NS rose slowly to less than 60 DDD/1000/day by 2005. H2RA use in NS was always high (over 100 DDD/1000/day), whereas in AUS, H2RA use fell from 54 to around 24 DDD/1000/day over this period. CONCLUSIONS: AUS had much higher use of PPIs than NS over 2001-2005. The proportion of PPIs in all gastroprotective agents rose in AUS to be nearly 90%. The differences in utilisation during this time window could lead to differences in health outcomes from either lower gastro-intestinal bleeding risk or higher long-term adverse effects of PPIs.

Consumers' experiences and values in conventional and alternative medicine paradigms: a problem detection study (PDS).

BACKGROUND: This study explored consumer perceptions of complementary and alternative medicine (CAM) and relationships with CAM and conventional medicine practitioners.A problem detection study (PDS) was used. The qualitative component to develop the questionnaire used a CAM consumer focus group to explore conventional and CAM paradigms in healthcare. 32 key issues, seven main themes, informed the questionnaire (the quantitative PDS component - 36 statements explored using five-point Likert scales.) RESULTS: Of 300 questionnaires distributed (Brisbane, Australia), 83 consumers responded. Results indicated that consumers felt empowered by using CAM and they reported positive relationships with CAM practitioners. The perception was that CAM were used most effectively as long-term therapy (63% agreement), but that conventional medicines would be the best choice for emergency treatment (81% agreement). A majority (65%) reported that doctors appeared uncomfortable about consumers' visits to CAM practitioners. Most consumers (72%) believed that relationships with and between health practitioners could be enhanced by improved communication. It was agreed that information sharing between consumers and healthcare practitioners is important, and reported that "enough" information is shared between CAM practitioners and consumers. Consumers felt comfortable discussing their medicines with pharmacists, general practitioners and CAM practitioners, but felt most comfortable with their CAM practitioners. CONCLUSIONS: This PDS has emphasized the perceived importance of open communication between consumers, CAM and conventional providers, and has exposed areas where CAM consumers perceive that issues exist across the CAM and conventional medicine paradigms. There is a lot of information which is perceived as not being shared at present and there are issues of discomfort and distrust which require resolution to develop concordant relationships in healthcare. Further research should be based on optimisation of information sharing, spanning both conventional and CAM fields of healthcare, due to both the relevance of concordance principles within CAM modalities and the widespread use of CAM by consumers.

Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration: using Monte Carlo simulations to predict doses for specified pharmacodynamic targets.

Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL(CVVHDF)) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL(CVVHDF) decreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.

How is medication prescribing ceased? A systematic review.

BACKGROUND: Medication prescribing is a complex process where the focus tends to be on starting new medication, changing a drug regimen, and continuing a drug regimen. On occasion, a prudent approach to prescribing may necessitate ending an ongoing course of medication, either because it should not have been started in the first place; because its continued use would cause harm; or because the medication is no longer effective. OBJECTIVE: To identify effective strategies for stopping pre-existing prescribing in situations where continued prescribing may no longer be clinically warranted. RESEARCH DESIGN: Systematic searches for English-language reports of experimental and quasi-experimental research were conducted in PubMed (1951-November 2009), EMBASE (1966-September 2008), and International Pharmaceutical Abstract b (1970-September 2008). A manual search for relevant review articles and a keyword search of a local database produced by a previous systematic search for prescribing influence and intervention research were also conducted. STUDY SELECTION AND DATA EXTRACTION: Following initial title screening for relevance 2 reviewers, using formal assessment and data extraction tools, independently assessed abstracts for relevance and full studies for quality before extracting data from studies selected for inclusion. RESULTS: Of 1306 articles reviewed, 12 were assessed to be of relevant, high-quality research. A variety of drugs were examined in the included studies with benzodiazepines the most common. Studies included in the review tested 9 different types of interventions. Effective interventions included patient-mediated interventions, manual reminders to prescribers, educational materials given to patients, a face-to-face intervention with prescribers, and a case of regulatory intervention. Partially effective interventions included audit and feedback, electronic reminders, educational materials alone sent to prescribers, and distance communication combined with educational materials sent to prescribers. CONCLUSIONS: It appears possible to stop the prescribing of a variety of medications with a range of interventions. A common theme in effective interventions is the involvement of patients in the stopping process. However, prescribing at the level of individual patients was rarely reported, with data often aggregated to number of doses or number of drugs per unit population, attributing any reduction to cessation. Such studies are not measuring the actual required outcome (stopping prescribing), and this may reflect the broader ambiguity about when or why it might be important to end a prescription. Much more research is required into the process of stopping pre-existing prescribing, paying particular attention to improving the outcomes that are measured.

A quality improvement initiative to improve adherence to national guidelines for empiric management of community-acquired pneumonia in emergency departments.

OBJECTIVE: The objective of this study was to improve the concordance of community-acquired pneumonia management in Australian emergency departments with national guidelines through a quality improvement initiative promoting concordant antibiotic use and use of a pneumonia severity assessment tool, the pneumonia severity index (PSI). DESIGN: and INTERVENTIONS: Drug use evaluation, a quality improvement methodology involving data collection, evaluation, feedback and education, was undertaken. Educational interventions included academic detailing, group feedback presentations and prescribing prompts. SETTING AND PARTICIPANTS: Data were collected on 20 consecutive adult community-acquired pneumonia emergency department presentations by each hospital for each of three audits. MAIN OUTCOME MEASURES: Two process indicators measured the impact of the interventions: documented PSI use and concordance of antibiotic prescribing with guidelines. Comparisons were performed using a Chi-squared test. RESULTS: Thirty-seven hospitals, including public, private, rural and metropolitan institutions, participated. Twenty-six hospitals completed the full study (range: 462-518 patients), incorporating two intervention phases and subsequent follow-up audits. The baseline audit of community-acquired pneumonia management demonstrated that practice was varied and mostly discordant with guidelines. Documented PSI use subsequently improved from 30/518 (6%, 95% confidence interval [CI] 4-8) at baseline to 125/503 (25%, 95% CI 21-29; P < 0.0001) and 102/462 (22%, 95% CI 18-26; P < 0.0001) in audits two and three, respectively, while concordant antibiotic prescribing improved from 101/518 (20%, 95% CI 16-23) to 132/462 (30%, 95% CI 26-34; P < 0.0001) and 132/462 (29%, 95% CI 24-33; P < 0.001), respectively. CONCLUSIONS: Improved uptake of guideline recommendations for community-acquired pneumonia management in emergency departments was documented following a multi-faceted education intervention.

An intervention to improve benzodiazepine use--a new approach.

OBJECTIVE: To design, implement and evaluate a novel intervention, utilizing electronic media, to improve benzodiazepine use in specific geographical areas in Australia. METHODS: An educational intervention about benzodiazepine use, using email, a website and bookmarks, targeted consumers, GPs, nurses (in aged care facilities) and pharmacists in two areas in Australia over a 6-month period. Two control areas, which received no aspect of the intervention, were used to compare and contrast. A drug use evaluation was conducted in aged care facilities before and after the study (in the intervention areas) and after the intervention (in the control areas) to assess quality of benzodiazepine use. Benzodiazepine dispensing data were obtained for each area before, during and after the intervention to quantitate use. Interviews were conducted with nurses and pharmacists involved in the intervention and website statistics were recorded. RESULTS: A significantly smaller number of aged care residents were on benzodiazepines for 6 months or more (P < 0.05) after the intervention compared with before. However, other indices, such as number of residents taking benzodiazepines or taking them for a long time, did not change significantly before compared to after the intervention and there were no significant differences between the control and intervention areas after the intervention. Quantitative use of benzodiazepines did not change after the intervention. Many health care professionals in the intervention areas remembered seeing the electronic educational material for benzodiazepines. The website was viewed 115 times during the study. CONCLUSIONS: The study was easy and inexpensive to administer and attracted high participation rates by health care professionals. There was a change in the use of benzodiazepines in aged care facilities (less long-term benzodiazepine use) in the intervention areas. The electronic educational materials (emails and website) were read and informations (especially the key messages) were able to be recalled after the intervention. However, no large changes in benzodiazepine overall use (either between control and intervention areas or before and after the intervention) were recorded.

Improving the use of benzodiazepines--is it possible? A non-systematic review of interventions tried in the last 20 years.

BACKGROUND: Benzodiazepines are often used on a long term basis in the elderly to treat various psychological disorders including sleep disorders, some neurological disorders and anxiety. This is despite the risk of dependence, cognitive impairment, and falls and fractures. Guidelines, campaigns and prescribing restrictions have been used to raise awareness of potentially inappropriate use, however long term use of benzodiazepine and related compounds is currently increasing in Australia and worldwide. The objective of this paper is to explore interventions aimed at improving the prescribing and use of benzodiazepines in the last 20 years. METHODS: Medline, EMBASE, PsychINFO, IPA were searched for the period 1987 to June 2007. RESULTS: Thirty-two articles met the study eligibility criteria (interventions solely focusing on increasing appropriate prescribing and reducing long term use of benzodiazepines) and were appraised. Insufficient data were presented in these studies for systematic data aggregation and synthesis, hence critical appraisal was used to tabulate the studies and draw empirical conclusions. Three major intervention approaches were identified; education, audit and feedback, and alerts. CONCLUSIONS: Studies which used a multi-faceted approach had the largest and most sustained reductions in benzodiazepines use. It appears that support groups for patients, non-voluntary recruitment of GPs, and oral delivery of alerts or feedback may all improve the outcomes of interventions. The choice of outcome measures, delivery style of educational messages, and requests by GPs to stop benzodiazepines, either in a letter or face to face, showed no differences on the success rates of the intervention.

Gastroprotective drugs in Australia: utilization patterns between 1997 and 2006 in relation to NSAID prescribing.

BACKGROUND: In Australia, the prescribing of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H(2)RAs) for defined gastrointestinal disorders is approved for subsidy by the universal Australian Pharmaceutical Benefits Scheme. These agents also may be used with NSAIDs, but this prescribing is not approved for subsidy. PPI prescribing increased in Australia between 1997 and 2006, and some authorities are concerned that this increase may be due to prescriptions outside the approved indications. OBJECTIVES: The aims of this study were to quantify gastroprotective drug consumption in Australia between 1997 and 2006 and to investigate the relationship over time between this prescribing and NSAID prescribing. METHODS: Data from concession beneficiaries (seniors and welfare recipients) were included. Data on PPIs, H(2)RAs, NSAIDs, and cyclooxygenase (COX)-2 inhibitors dispensed between 1997 and 2006 were gathered from Medicare Australia and are expressed as defined daily doses (DDDs) per 1000 concession beneficiaries per day (CBPDs). Gastroprotective drugs were defined using the World Health Organization Anatomical Therapeutic Chemical classification of 2006. Drug utilization 90% and expenditures in Australian dollars (AUD $, not normalized to an index year) were calculated. RESULTS: H(2)RA prescribing was stable between 1997 and 2001, at approximately 60 DDDs/1000 CBPDs. Dispensation of H(2)RAs began to decrease in 2001 to 20 DDDs/ 1000 CBPDs in 2006. PPI consumption increased consistently, with a sharp change beginning in 2001 (from about 45 to 140 DDDs/1000 CBPDs between 2001 and 2006). The government expenditure for PPIs per concession beneficiary per year also increased from about AUD $26 in 1997 to almost AUD $74 in 2006, whereas the expenditure for H2RAs decreased from about AUD $24 to about AUD $5. Nonselective NSAID prescribing decreased with the introduction of COX-2 inhibitors in 2000. COX-2 inhibitors increased the overall consumption of total NSAIDs in the first 4 years (2000-2003) after their introduction. CONCLUSIONS: The prescribing of H(2)RAs decreased, whereas the prescribing of PPIs increased, between 1997 and 2006 in this population of concession beneficiaries in Australia. During the same period, nonselective NSAID prescribing decreased while COX-2 inhibitor prescribing increased.

Systematic review of interventions to improve prescribing.

OBJECTIVE: To update 2 comprehensive reviews of systematic reviews on prescribing interventions and identify the latest evidence about the effectiveness of the interventions. DATA SOURCES: Systematic searches for English-language reports of experimental and quasi-experimental research were conducted in PubMed (1951-May 2007), EMBASE (1974-March 2008), International Pharmaceutical Abstracts (1970-March 2008), and 11 other bibliographic databases of medical, social science, and business research. Following an initial title screening process and after selecting 6 specific intervention categories (identified from the previous reviews) in community settings, 2 reviewers independently assessed abstracts and then full studies for relevance and quality and extracted relevant data using formal assessment and data extraction tools. Results were then methodically incorporated into the findings of the 2 earlier reviews of systematic reviews. DATA SELECTION AND SYNTHESIS: Twenty-nine of 26,314 articles reviewed were assessed to be of relevant, high-quality research. Audit and feedback, together with educational outreach visits, were the focus of the majority of recent, high-quality research into prescribing interventions. These interventions were also the most effective in improving prescribing practice. A smaller number of studies included a patient-mediated intervention; this intervention was not consistently effective. There is insufficient recent research into manual reminders to confidently update earlier reviews and there remains insufficient evidence to draw conclusions regarding the effectiveness of local consensus processes or multidisciplinary teams. CONCLUSIONS: Educational outreach as well as audit and feedback continue to dominate research into prescribing interventions. These 2 prescribing interventions also most consistently show positive results. Much less research is conducted into other types of interventions and there is still very little effort to systematically test why interventions do or do not work.

The Australian rise of esomeprazole-was expenditure on samples a contributor?

BACKGROUND: Administrative data from the Australian Pharmaceutical Benefits Scheme (PBS) showed rapid growth of esomeprazole dispensing when it was launched. Australia has universal prescription medicine coverage (the PBS), which included esomeprazole from August 2002. Free samples of new medicines are commonly provided to doctors. OBJECTIVES: To determine if a relationship exists between marketing expenditure on samples and the dispensing rate for esomeprazole in Australia between June 2002 and September 2006. METHODS: Quarterly sample expenditures at product/brand level for proton pump inhibitors (PPIs) for Australian general practitioners were obtained for July 2002 to September 2006. Corresponding PBS dispensing data were obtained for all PPIs and converted to defined daily dose (DDD)/1000 population/day. Spending on samples was calculated as dollars per dispensed prescription and plotted against time on the Australian market. RESULTS: Total PPI usage increased from 34.2 to 50.8 DDD/1000 population/day over the study period. Expenditure on samples per dispensed prescription was higher when a PPI was new on the market and diminished over 5-6 years to a relatively constant level. The rapid decline in this ratio was demonstrated by a case study following esomeprazole from launch in Australia for almost 5 years clearly demonstrating the initial investment to drive sales. CONCLUSION: A relationship appears to exist between expenditure on esomeprazole samples and its usage in Australia. A high initial investment was followed by a rapid reduction in cost per prescription dispensed, predominantly due to growth in market share. This trend was consistent with other PPIs.

A comparison of mycophenolate use in Australia and Northern Europe, and the impact on the pharmaceutical benefits scheme.

PURPOSE: The aim of this study was to characterise utilisation of mycophenolate in Australian transplant recipients from 2001 to 2007; to identify specific patterns of mycophenolate mofetil and enteric-coated mycophenolate sodium usage; to examine expenditure on mycophenolate prescription and to compare Australian usage with Danish, Finish and Netherlands populations. METHODS: Data on mycophenolate usage were obtained from Medicare Australia, Finish and Danish Medicines Agency and Netherlands Healthcare Insurance Board databases. Utilisation of mycophenolate was described as daily defined dose (DDD/per 1000 population/day). RESULTS: From 2001 to 2007, utilisation of mycophenolate in Australia increased approximately 30-fold. In 2007, mycophenolate sodium accounted for 8.3% of mycophenolate total DDDs. In 2007, AUD$4,890,000 was spent on mycophenolate prescription. In 2006, utilisation of mycophenolate was five- to eight-fold higher in Northern Europe compared to Australia. Renal transplant rates per 1000 population/year were similar across countries. CONCLUSIONS: Differences in the rate of mycophenolate utilisation between Northern Europe and Australia exist and may be due to differences in approved indications between countries, prescribing habits, or because of a more mature market in Europe. If the Australian market increases to that of North Europe the cost of prescribing mycophenolate will eventually be in the vicinity of AUD$20-80 million.

The Queensland experience of participation in a national drug use evaluation project, Community-Acquired Pneumonia Towards Improving Outcomes Nationally (CAPTION).

BACKGROUND: Multicentre drug use evaluations are described in the literature infrequently and usually publish only the results. The purpose of this paper is to describe the experience of Queensland hospitals participating in the Community-Acquired Pneumonia Towards Improving Outcomes Nationally (CAPTION) project, specifically evaluating the implementation of this project, detailing benefits and drawbacks of involvement in a national drug use evaluation program. METHODS: Emergency departments from nine hospitals in Queensland, Australia, participated in CAPTION, a national quality improvement project, conducted in 37 Australian hospitals. CAPTION was aimed at optimising prescribing in the management of Community-Acquired Pneumonia according to the recommendations of the Australian Therapeutic Guidelines: Antibiotic 12th edition. The project involved data collection, and evaluation, feedback of results and a suite of targeted educational interventions including audit and feedback, group presentations and academic detailing.A baseline audit and two drug use evaluation cycles were conducted during the 2-year project. The implementation of the project was evaluated using feedback forms after each phase of the project (audit or intervention). At completion a group meeting with the hospital coordinators identified positive and negative elements of the project. RESULTS: Evaluation by hospitals of their participation in CAPTION demonstrated both benefits and drawbacks. The benefits were grouped into the impact on the hospital dynamic such as; improved interdisciplinary working relationships (e.g. between pharmacist and doctor), recognition of the educational/academic role of the pharmacist, creation of ED Pharmacist positions and enhanced involvement with the National Prescribing Service, and personal benefits. Personal benefits included academic detailing training for participants, improved communication skills and opportunities to present at conferences. The principal drawback of participation was the extra burden on already busy staff members. CONCLUSION: A national multicentre drug use evaluation project such as CAPTION allows hospitals which would otherwise not undertake such projects the opportunity to participate. The Queensland arm of CAPTION demonstrated benefits to both the individual participants and their hospitals, highlighting the additional value of participating in a multicentre project of this type.