MedsScan Issue 2, 2024

These reviews provide updates on the international literature on therapeutics. Expert pharmacy practitioners — via SHPA’s Specialty Practice Groups — scan major peer-reviewed journals in areas relevant to Australian pharmacy practice and present precis on major clinical trials, important pharmacoepidemiology studies and pharmacoeconomic research, and other updates relevant to practice. Interested readers are encouraged to explore the original publications in greater detail.

CLINICAL TRIALS

MedsScan editor for #SHPAClinTrials: June Challen

Measuring complexity of investigational drugs Services

As clinical trial pharmacists, we are all aware that the demands made on pharmacy investigational drugs services for managing clinical trials are increasing. The complexity of clinical trials, training requirements, documentation, complex preparation of investigational products and stringent storage conditions contribute to this increased demand.

In 2016, pharmacists from Vizient, an American healthcare performance improvement company, developed an Investigational Drugs Service Complexity Scoring Tool (CST) to assess the workload of pharmacy staff in clinical trials necessitated by the growing complexity of these trials. CST scores are categorised into complexity categories of low, medium or high.

This paper discusses a prospective study designed to identify numerical cut off scores for the complexity categories (low, medium and high) for both initiating and maintaining a clinical trial involving investigational drugs. In addition, the study attempted to validate the CST-assigned categories against complexity categories perceived by a practitioner-based group of pharmacists, pharmacy technicians and pharmacy leaders specialising in research clinical trials.

The paper acknowledges that the tool is useful to distinguish between those studies perceived as low and high complexity. Those studies perceived as medium complexity showed bigger discrepancies between subjective ratings and the complexity tool.

Song K, Yu M, McLuckie R, O’Brien K, Harrison M, Nguyen V, et al.  Development of complexity categories for an investigation drug services complexity scoring tool to assess pharmacy effort in clinical trial initiation and maintenance. Am J Health Syst Pharm 2023; 80: 1557–1563.

Decentralised investigational drug service pharmacist in a cancer trial infusion unit

Like many Australian cancer centres and hospitals conducting cancer clinical trial research, the University of Texas Southwestern Medical Centre research participants receive their investigational product (IP) in an infusion suite with the investigational drug service (IDS) pharmacy centralised in the infusion pharmacy unit, geographically isolated from the infusion suite. Any patient care is provided remotely to research participants by the IDS pharmacist.

This publication describes a pilot study of a decentralised IDS pharmacist to facilitate clinical consultation provision by the IDS pharmacist. This quasi-experimental study conducted a retrospective chart review for 6 months in June 2022 documenting pharmacy consults completed by the IDS centralised service.  A decentralised IDS pharmacist was then piloted, and data collected for pharmacy consults provided by the decentralised pharmacist. The study also attempted to assess the research team’s satisfaction with the decentralised service.

Despite the limitations of this pilot study, it demonstrates the potential value of decentralising IDS pharmacists. The researchers documented increased interventions by the pharmacist on patient-related issues as well as increased infusion nurse-initiated consults.  The noted increase in education sessions provided by the decentralised IDS pharmacist was an expected outcome given the convenience of their location in the infusion suite.

The authors note that responses to the satisfaction questionnaire indicate that implementing a decentralised IDS service would be well received. They acknowledge that further research should be conducted to collect data on patient related outcomes and to assess the financial impact on pharmacy budgets.

Baroody C, Sandler M, Hong C, Madanat YF, Conley S. Evaluation of a decentralized investigational drug service pharmacist in a cancer clinical trial infusion unit. J Oncol Pharm Practice 2023; [online ahead of print]. https://journals.sagepub.com/doi/10.1177/10781552231207854.

Telehealth, teletrials and decentralised clinical trials

The authors of this special communication discuss the uptake of digital technology in the conduct of clinical trials, outlining the benefits both to sponsors and participants. The terminology used now includes the terms teletrials (TT), decentralised clinical trials (DCT), digital trials and networked trials.

The Victorian Teletrials Collaborative (VTC) identified the need to refine the definitions of these terms. The publication presents a glossary of terms provided by an international literature review.

The term teletrial refers to a clinical trial conducted using telehealth technology to facilitate communications between a primary site and a satellite site. This model  enables patients who are not located near the primary site to participate in the clinical trial without relocating. The Australian Teletrial Program (ATP) is funded through the Federal Government and aims to improve access for patients, particularly those living in regional, rural and remote locations, by expanding the use of the teletrial model. The model operates with a principal investigator from the primary site who supervises associate investigators at a satellite site to conduct a clinical trial at a geographically remote location.

In decentralised clinical trials, patients can visit local facilities for health treatments and laboratory tests. Interactions between healthcare providers and patients can be conducted either through virtual tools or via face-to-face interactions. Teletrials thus can be viewed as a subset of decentralised clinical trials.

This special communication article presents a table that provides the main differences between the Teletrial Model and decentralised clinical trials. Underhill et al., discuss the added advantage of the networked approach and supervision plan embedded into teletrials. The recommendation from the authors is that globally, decentralised clinical trials should include a networked, supervised approach. This approach could have the benefits of improved patient safety, as well as developing the skills of clinical trial staff.

Underhill C, Freeman J, Dixon J, Buzza M, Long D, Burbury K, et al. Decentralized clinical trials as a new paradigm of trial delivery to improve equity of access. JAMA Oncol 2024; 10: 526–530.

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COMPOUNDING SERVICES

MedsScan editors for #SHPACompound: Rachel Berry and Tammy Nguyen

Syrspend SF PH4 Oral Suspension Formulations

Syrspend SF PH4 is a starch based ready-to-use preservative containing suspending agent free from sorbitol, sucrose, alcohol and other potentially harmful excipients with a dry powder version, Syrspend SF NEO, available for neonates. This study investigated the stability of a range of active pharmaceutical ingredients compounded into suspensions using Syrspend SF PH4.

The ingredients tested were amoxicillin, clozapine, indometacin, levodopa/carbidopa, levothyroxine, lomustine, methyldopa and procarbazine. Active ingredients were supplied as active ingredient powder, apart from clozapine where a powder was unavailable, so tablets were ground to produce a fine powder. Indometacin was prepared in Syrspend SF NEO. Suspensions were protected from light and studied under both refrigeration (4–8oC) and room temperature (20–25oC) storage conditions, apart from lomustine, procarbazine and methyldopa, which were only studied under refrigeration. The study period was 90 days for all suspensions except amoxicillin, which was tested over 30 days due to antibiotic courses usually being of shorter duration. Chemical stability was tested using high-performance liquid chromatography, apart from amoxicillin where titration was used.

Amoxicillin 5 mg/mL was stable for 30 days, noting a 5.62% decline in concentration when stored at room temperature. Clozapine 25 mg/mL, indometacin 5 mg/mL and levodopa 5 mg/mL /carbidopa 1.25 mg/mL were found to be chemically stable for 90 days at both storage temperatures. Lomustine (4 mg/mL and 10 mg/mL) and methyldopa 25 mg/mL were chemically stable for 90 days refrigerated. Procarbazine 10 mg/mL showed a loss of 5% between day 30 and 60 refrigerated. Levothyroxine sodium 25 µg/mL suspensions, formulated with SyrSpend SF PH4 as the vehicle, were demonstrated to be stable for 90 days when stored under refrigerated conditions. The study was funded by the manufacturer of Syrspend.

These results are of particular interest in relation to the increased stability of levothyroxine and indometacin suspensions, compared to previous studies with alternative suspending agents, and data to support an indometacin formulation in a suspending agent with fewer excipients provides a viable option for neonates, while noting that this formulation used active pharmaceutical ingredient powder. The results from this study have been added to the Syrspend SF compatibility table available from Fagron.

Mansourian M, Dijkers E, Silva CCV, Polonini HC. Compatibility of commonly used active pharmaceutical ingredients in a ready-to-use oral suspending vehicle. Pharmaceutics 2023; 15: 2388.

Fosfomycin stability in elastomeric pumps

Fosfomycin is a phosphonic antibiotic with activity against aerobic gram-positive (gram +ve) and gram-negative (gram -ve) bacteria with a potential role in the treatment of multi-drug resistant bacteria. An added benefit of fosfomycin is that it also exhibits low toxicity. Previous studies indicate there may be enhanced clinical efficacy from administration by continuous infusion. Elastomeric infusors can be used to deliver continuous intravenous (IV) antibiotics in a community setting.

The aim of this study was to investigate chemical and physical stability of fosfomycin at both refrigerated (4oC) and body temperature (34oC). A concentration of 16 g/250 mL in water for injection was prepared for the refrigerated (4oC) study. Two concentrations were prepared for the body temperature study at 34oC: 16 g/250 mL in glucose 5% and 24 g/250 mL in glucose 5%. All samples were protected from light. Samples were compared to a freshly prepared sample for 5 consecutive days with further observations made at 9 days. A polyisoprene elastomeric infusor was used.

Fosfomycin was chemically stable for 5 days refrigerated at a concentration of 16 g/250 mL and for 6 days at 34oC at a concentration of 16 g/250 mL. The higher 24 g/250 mL concentration was stable for the 9-day study period and therefore, an exact shelf life cannot be determined. Outpatient parenteral antibiotic therapy allows patients to be managed in the home environment, freeing up hospital beds and reducing costs.

This study marks the first-time extended pre-administration storage of Fosfomycin at 4oC and in-use storage at 34oC have been studied. Further stability studies are warranted to test a range of elastomeric infusors made from different materials, higher dosages and potentially alternative diluents. The IV form of fosfomycin is not readily available in Australia but can be obtained via the Special Access Scheme.

Manca A, Palermiti A, Mula J, Cusato J, Maiese D, Simiele M, De Nicoló A, D’Avolio A. Stability study of fosfomycin in elastomeric pumps at 4oC and 34oC: technical bases for a continuous infusion for outpatient parenteral antibiotic therapy. Pharmaceutics 2023; 15: 2347.

Extended in-vial stability of durvalumab concentrate

Durvalumab is an immunotherapy agent used in the treatment of solid organ tumours, in particular, lung cancer. Stability of the dilution solution for infusion in the product information was extended in 2021, but in-use stability of the concentrate vials was not extended. This study aimed to determine the physical and chemical stability of in-use concentrate vials.

Fourteen durvalumab (Imfinzi) 50 mg/mL concentrate vials were spiked with a Codan microspike. Seven vials were refrigerated (2–8oC) and 7 vials were stored at room temperature (20–25oC). All vials were protected from light. The vials were sampled on days 0, 7, 14, 21 and 28 by withdrawing volume with a syringe via the vial spike. Physical and chemical stability was measured using size-exclusion high-performance liquid chromatography (HPLC), ion-exchange HPLC, pH analysis and visual inspection.

During the 28-day study period, the appearance of the solution and pH remained unchanged, no substantial changes were observed by HPLC and no degradation products or impurities were detected. It was therefore concluded that durvalumab concentrate solution remains physically and chemically stable over 28 days both refrigerated and at room temperature when protected from light in a punctured vial. From a microbiological point, refrigerated storage is preferable to room temperature storage. Durvalumab can either be given as flat dosing or as a mg/kg dose depending on the protocol used. When given as a mg/kg dose, there is the potential for wastage of part vials. The results of this study indicate potential for vial sharing as a cost minimisation strategy, noting that this data is for physical and chemical stability only and that the microbiological stability and probability of microbial contamination must be considered as part of the risk assessment prior to extending expiries.

Almasi J, Thiesen J, Krämer I. Physicochemical stability of durvalumab (Imfinzi®) concentrate for solution in original vials after first opening. Pharm Technol Hosp Pharm 2023; 8: 2023008.

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CRITICAL CARE

MedsScan editors for #SHPACritCare: Grainne Hughes and Melissa Faehrmann

ACORN: cefepime vs piperacillin-tazobactam and the effect on renal outcomes in acutely ill adults

Special contributor: Megan Richardson

Cefepime and piperacillin/tazobactam are frequently prescribed in acutely ill patients at risk of resistant gram-negative infections. Their spectrums of activity are similar but they are thought to differ in adverse effect profiles, especially in relation to neurotoxicity and acute kidney injury (AKI).

This open label, single centre study aimed to directly compare the safety of these agents. Adult patients in whom antipseudomonal cover was indicated were randomised 1:1 to receive cefepime 2 g push or piperacillin/tazobactam 3.375 g extended infusion, with dose and frequency adjusted based on estimated glomerular filtration rate. In each group, patients received the assigned antibiotic for a median of 3 days (interquartile range [IQR] 1–4 days).

Of the 2511 patients included, there was no significant difference between the two arms (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.8–1.13, p = 0.56) for the primary outcome of the incidence of AKI or death with 75% and 73.4% of patients respectively remaining alive and experiencing no AKI as defined by laboratory markers. A large proportion of patients in each arm (82.7% vs 80.9%) did receive vancomycin during the study, however the authors were not able to quantify the impact of this.

The secondary outcomes that investigated the proportion of patients with a major kidney adverse effect (as a less laboratory-focused composite endpoint) was also not statistically different with an absolute difference of 1.4% (95% CI -1.0%–3.8%). However, patients randomised to cefepime had a significantly lower number of alive, delirium/coma-free days (11.9 vs 12.2 days, OR 0.79, 95%CI 0.65–0.95), which was used as a measurable way of assessing neurological dysfunction.

This study demonstrated the risk of developing AKI was not increased with piperacillin/tazobactam when compared with cefepime in acutely ill patients. It is important to note that these findings may not be generalisable to the Australian setting, as it was administered as an extended infusion, at a lower dose than is used in Australian practice. Cefepime was associated with an increased risk of neurological adverse events, however the neurological markers chosen didn’t include seizures.

Qian ET, Casey JD, Wright A, Wang L, Shotwell MS, Siemann JK, et al. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: the ACORN randomized clinical trial. JAMA 2023; 330: 1557–67.

Combining rifaximin with systemic antibiotics in critically ill, encephalopathic patients

Although rifaximin is often used acutely for the treatment of hepatic encephalopathy (HE), it is only licensed for the prevention of recurrent HE in Australia. Some previous research has reported reduced mortality and length of hospital stay in HE patients with sepsis, when they are treated with rifaximin as well as broad-spectrum antibiotics. This is thought to be due to a possible synergistic effect between antibiotics and rifaximin as well as the effect of rifaximin on modulating the gut microbiome. In this double-blind trial, 184 critically ill patients with HE were evenly randomised to receive appropriate systemic antibiotics alone, or antibiotics as well as 550 mg rifaximin enterally twice daily for up to 14 days (antibiotics + rifaximin). All patients were also treated with lactulose, targeting 2–3 loose bowel motions per day, as part of standard care.

The study found that combining rifaximin with broad-spectrum antibiotics in critically ill patients with HE did not lead to earlier resolution, or reduced severity, of HE compared to standard treatments of lactulose and broad-spectrum antibiotics for infection and HE respectively. Of the patients with decompensated cirrhosis, the rifaximin + antibiotics group had reduced rates of hospital-acquired infections and in-hospital mortality, in comparison to those with acute on chronic liver disease where there was no difference in endpoints between the groups. The authors speculated that the benefit of rifaximin, on inflammation and liver disease progression, may be seen with longer-term therapy.

This small-scale study demonstrated that combining rifaximin and systemic antibiotics in critically ill patients with presumed sepsis and HE may provide a small benefit only to those patients with decompensated cirrhosis. While rifaximin is often used in the acute treatment of HE in critically ill patients, the licensed and evidence-based indication remains longer-term use for the prevention of recurrent HE.

Kulkarni AV, Avadhanam M, Karandikar P, Rakam K, Gupta A, Simhadri V, et al. Antibiotics with or without rifaximin for acute hepatic encephalopathy in critically ill patients with cirrhosis: a double-blind, randomised controlled (ARiE) trial. Am J Gastroenterol 2024; 119: 864–74.

Meropenem therapeutic drug monitoring in the intensive care unit

Special contributor: Negin Nasseh

Critically ill patients experience suboptimal antibiotic concentrations due to altered renal clearance. Previous studies in intensive care unit (ICU) patients have reported subtherapeutic concentrations for antibiotics with intermittent bolus infusions.

This study aimed to examine meropenem pharmacokinetic/pharmacodynamic (PK/PD) target attainment with a 30 min intermittent infusion, dosed at 1 g every 6 hours in ICU patients with variable renal function, and 8 hourly dosing in the continuous venovenous hemodialysis (CVVHD) group. There were 87 patients included, 34 of these patients received continuous renal replacement therapy (CRRT). Samples were taken for meropenem pre-, post- and mid-infusion at 24, 48 and 72 hours of therapy. Of the 87 patients, 42 patients had a pathogen identified. A population PK model using a non-parametric approach in p-metrics, identified a 2- compartment model with significant covariates of serum creatinine and CRRT on clearance, to best describe the pharmacokinetics.

Meropenem trough concentrations differed between the CRRT and non-CRRT groups (median 15.5 mg/L and 5.9 mg/L respectively, p < 0.001). Troughs were lower in patients with augmented renal clearance (ARC), and higher in patients receiving continuous venovenous haemofiltration (CVVHF) (p < 0.001). C-reactive protein (CRP) was reduced in 85% of patients, with a median initial value of 175 (down trending after 72 hours) to 70, and a greater reduction in the ARC group (p < 0.001). Forty-two (48%) patients had a blood culture positive infection. Mortality at 90 days was 32% overall, specifically 41% in the CRRT group, 26% in the non-CRRT group and 13% in the ARC group.

This study showed 100% median target attainment for intermittent infusions of meropenem across all groups except those with ARC. This may in part be explained by the 6-hourly dosing, in contrast with standard 8-hourly dosing. Extended infusions should be considered for patients with ARC. The observed minimum inhibitory concentration (MIC) for speciated pathogens was lower than the EUCAST MIC used in the PK/PD calculations, which may lead to an underestimation of overall drug exposure and may explain the lack of correlation between target attainment and clinical outcomes. This study was not powered to evaluate the statistical significance of differences in clinical outcomes between each group. Australian Guidelines at present recommend 8-hourly dosing for meropenem, however this study suggests improved target attainment in ICU patients when 6-hourly dosing is used.

Helset E, Cheng V, Sporsem H, Thorstensen C, Nordøy I, Gammelsrud KW, Hanssen G, Ponzi E, Lipman J, von der Lippe E. Meropenem pharmacokinetic/pharmacodynamic target attainment and clinical response in ICU patients: a prospective observational study. Acta Anaesthesiol Scand 2024; 68: 502–11.

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GERIATRIC MEDICINE

MedsScan co-editors for #SHPAGeri: Anna Jennings and Richard Bolitho

A multicomponent intervention to reduce hypnotic drugs in geriatric inpatients

Special contributor: Angela Shiu

Older patients are more susceptible to the adverse effects of hypnotic drugs due to lower physiological reserves, multimorbidity and polypharmacy. Additionally, the benefits of hypnotic use for insomnia in this population are modest at best, with known adverse effects. This single-centre, prospective pre- and poststudy investigated a pharmacist-led intervention to deprescribe chronic hypnotic drugs (benzodiazepines and ‘Z-drugs’) against usual care in a Belgian geriatric inpatient unit. The intervention included staff education, a standardised rapid discontinuation regimen, clinical decision support systems, patient education and communication to primary care. The primary outcome was discontinuation of hypnotic drugs one month post-discharge. Emergency use of hypnotics after discontinuation and sleep quality were also measured.

One hundred and ninety-eight patients were included with 25 patients excluded following enrolment. Hypnotic discontinuation at one month post-discharge was 21.9% in the control group and 37.7% in the intervention group (p = 0.02). No difference in sleep quality was found and both groups had similar rates of emergency hypnotic use.

A short follow-up period was unable to exclude re-uptake of hypnotics. Other limitations included a selection and follow-up bias, and a lack of generalisability across different populations. Additionally, researchers were unable to determine the effects of individual interventions on the primary outcome. Researchers also opted for a rapid withdrawal approach which may not be appropriate in the wider population. Sleep quality was also only assessed upon inclusion, at day 14 and at one month post-discharge.

While more research is needed, this study highlights the benefits of pharmacist-led hypnotic deprescribing in hospitalised patients and the positive impact that patient involvement may have on the deprescribing process.  

Van der Linden L, Hias J, Liesenborghs A, Walgraeve K, Van Brantegem P, Hellemans L, et al. The impact of a pharmacist intervention on post-discharge hypnotic drug discontinuation in geriatric inpatients: a before-after study. BMC Geriatr 2023; 23: 407.

What is the differential risk of severe hyponatraemia associated with hyponatraemia inducing medications in older people?

Special contributor: Heather Forbes

Hyponatraemia is a common electrolyte disturbance in older patients, which is associated with frailty, cognitive impairment, falls and increased mortality. Due to higher rates of polypharmacy, older people may have higher exposure to hyponatraemia-inducing medications (HIMs). It is hence important to identify the patterns of HIMs use in order to minimise risk of hyponatraemia. This large, case-controlled, population-based study investigated a random sample of patients over 65 years of age with severe hyponatraemia, using a Korean health insurance database. Multivariable logistic regression was performed to compare the risk of severe hyponatraemia between newly started, concurrently used or persistently used HIMs.

Newly started HIMs, when compared with persistently used HIMs, were significantly associated with an increased risk of severe hyponatraemia in eight classes: desmopressin (adjusted odds ratio [OR]: 3.82, 95% confidence interval [CI] 3.01–4.85); serotonin-norepinephrine reuptake inhibitors (OR 3.28, 95% CI 2.56–4.19); selective serotonin reuptake inhibitors (OR 2.48, 95% CI 2.06–2.98); thiazides (OR 2.37, 95% CI 2.09–2.69); mirtazapine (OR 1.84, 95% CI 1.15–2.95), tricyclic antidepressants (OR 1.39, 95% CI 1.15–1.67),; and proton pump inhibitors (OR 1.24, 95% CI 1.14–1.34). The number of HIMs was significantly associated with an increased risk of severe hyponatraemia compared with non-use: single HIM (OR 1.48, 95% CI 1.40–1.56); two HIMs (OR 2.07, 95% CI 1.95–2.20); and three or more HIMs (OR 3.40, 95% CI 3.19–3.62). Concurrent use of HIMs was significantly associated with an increased risk of hyponatraemia when compared with single HIM use, for all tested combinations.

Study limitations included restricted generalisability across different ethnicities, the risk of hyponatraemia misclassification and the use of diagnostic codes instead of laboratory data. This study highlights the risk of severe hyponatraemia associated with HIM use in older patients, especially when newly initiated or when multiple HIMs are used concurrently. Pharmacists are well placed to ensure safe prescribing of these medicines. This may include recommending appropriate monitoring, suggesting alternatives to a HIM if other options are available, or deprescribing HIMs that are no longer appropriate.

Jun K, Ah YM, Shin J, Lee JY. The differential risk of severe hyponatraemia based on the use patterns of hyponatraemia-inducing medications in older adults. Age and Ageing 2023; 52: afad026.

Clinical practice guidelines for the appropriate use of psychotropic medications in people living with dementia and in residential aged care

Special contributor: Nicholas Jensen

Until recently, Australian guidelines for best practice use of psychotropic medications in people living with dementia have not been available. This document addresses this gap, offering a list of 15 Conditional Recommendations and 49 Good Practice Statements developed using current best evidence by a wide range of stakeholders including pharmacists, geriatricians, nurses and many others.

Key messages include the need to individualise patient care and that shared decision-making should occur when planning to initiate a psychotropic medicine, regularly throughout the course of treatment and upon treatment withdrawal. Detail is provided about deprescribing psychotropics, with the guidelines emphasising the need to determine review dates for possible discontinuation at the point of prescribing. The guidelines also advise on frequency and role of formal medication reviews and the role of medication advisory committees within facilities.

Whilst specific details of the guidelines are beyond the scope of this summary, pharmacists working in this area are encouraged to review and become familiar with the resource. Section 3.4 outlines the existing resources available for pharmacists wanting to enhance their knowledge in this area.  Additionally, a range of supplementary materials and educational tools have been developed for patients, families, caregivers and Residential Aged Care Facilities to support implementation of the guideline.

Important take home messages: 

  1. Non-pharmacological measures remain the first-line option for people with dementia exhibiting changed behaviours.
  2. Before starting a psychotropic medication, identify and document the target symptoms, anticipated outcome and the initial date for review.
  3. Duration of antipsychotic treatment generally should not continue beyond 12 weeks unless reviewed by a psychiatrist or geriatrician, or clinically reviewed with another medical practitioner.

To many pharmacists, the recommendations in these guidelines will be unsurprising. They affirm our important role in identifying patients receiving inappropriate therapy, experiencing adverse effects, and monitoring duration of treatment.

Bell S, Bhat R, Brennan S, Clark B, Corlis M, Etherton-Beer C, et al. Clinical practice guidelines for the appropriate use of psychotropic medications in people using with dementia and in residential aged care: summary of recommendations and good practice statements. Parkville: Monash University; 2022. Available from https://app.magicapp.org/#/guideline/7881.

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MEDICINES INFORMATION

MedsScan editor for #SHPAMedsInfo: Helen Trenerry

Comparison of knowledge of potential drug-drug interactions between Egyptian hospital and community pharmacists

Pharmacists have an important role in optimising medication use in patients. The identification of potential drug–drug interactions (DDIs) can prevent adverse medicine reactions, reduce hospital admissions and length of stay and decrease the financial burden on the healthcare system.

A self-administered questionnaire was distributed to hospital and community pharmacists in Egypt. The questionnaire collected demographic data of the participant pharmacists. Nineteen pairs of common DDIs in clinical practice were used to assess the pharmacists’ knowledge. They rated the interactions as no interaction, contraindication, may be used together with monitoring and not sure. On completion of the questionnaire, answers and information about DDIs were provided.

There were 2260 community pharmacists and 2103 hospital pharmacists who completed the survey. Overall, 58.25% of DDIs were identified correctly with no significant difference in knowledge between community and hospital pharmacists. The highest number of correct answers among the community pharmacists was 17 compared with 13 for hospital pharmacists. Internet or mobile applications were the most common sources of information for pharmacists (used by 47.1% of participants).

Knowledge of DDIs among community and hospital pharmacists is comparable. Further education is required to improve identification of DDIs among pharmacists to minimise patient harm. Limitations of this study include the use of some old, infrequently used drugs for the DDIs and a lack of identification of specific internet and mobile applications used to search for information. This would be a useful study to adapt to assess Australian pharmacists’ knowledge of DDIs.

Wahsh EA, Abou Warda AE, Abdallah MS, Elsayed A, Abdel Dalem YS, Sadek EM. Assessment of potential drug-drug interaction knowledge, attitude, and practice among Egyptian hospital and community pharmacists: a cross-sectional multicenter study. Future J Pharm Sci 2024; 10: e1–e8.

Artificial intelligence (AI) potential applications in pharmacy in Saudi Arabia

The increase in chronic disease and complex health conditions requires management with multiple medications with an increased risk of adverse reactions and drug interactions. A literature search was conducted to identify articles published on the use and potential applications of artificial intelligence (AI) in polypharmacy management.

This review identified potential applications of AI to improve polypharmacy management in Saudi Arabia. There is already a role in identifying drug–drug interactions, but future potential applications or tools could be used to identify adverse reactions and optimise medication plans. AI can analyse genetic data, patient histories and current medications to individualise treatment plans, improving efficacy and minimising polypharmacy. AI can also be used to predict which patients are at risk of adverse outcomes secondary to polypharmacy and may require adjustment of their treatment plan. AI apps can monitor patients’ adherence and provide alerts and reminders to both patients and clinicians. Other applications of AI include real-time support for decision making, use in remote education and telehealth and even the design of clinical trials.

There are a range of applications for AI in polypharmacy management and patient care. Major limitations for AI applications that need to be addressed include patient acceptance and trust in the use of AI regarding the security and privacy of their data. There is also a real possibility that this advancement in knowledge will lead to less direct interaction between the patient and the health care provider; this cannot be replaced with AI applications.

Alsanosi SM, Padmanabhan S. Potential applications of artificial intelligence (AI) in managing polypharmacy in Saudi Arabia: a narrative review. Healthcare 2024; 12: 788.

Effectiveness and safety of anti-obesity medicines

Obesity is now recognised as a chronic, relapsing, remitting disease. Obesity is associated with increased morbidity and mortality largely due to complications such as Type 2 diabetes, hypertension, obstructive sleep apnoea and degenerative joint disease. The authors of this article conducted a literature review to find evidence from systematic reviews, meta-analyses and randomised controlled trials relating to the safety and efficacy of anti-obesity medicines. Recent guidelines on treatment of obesity were also included.

Anti-obesity medicines were tabulated into those approved by the United States Food and Drug Administration and those used off-label for obesity. Information was provided on the route of administration, efficacy (proportion of patients achieving 5% weight loss at 12 to 24 months), adverse effects, contraindications, choice of medication in patients with other comorbidities and cost for one month supply. The individual medicines currently available and emerging treatments are discussed in further detail.

Previous guidelines for treatment of obesity focused on lifestyle interventions and bariatric surgery. More recently, guidelines have prioritised anti-obesity medicines in their recommendations, based on evidence of clinical benefit.

This review presents an excellent summary of the effectiveness and adverse effects of anti-obesity medicines. A personalised approach to the treatment of obesity with medication is required for the best patient outcome. Limitations of current data include a lack of information on combination therapy, weight loss maintenance therapy and outcomes other than percentage weight loss, that focus on decreased morbidity and mortality from comorbid conditions.

Henderson Lewis K, Sloan CE, Bessesen DH, Arterburn D. Effectiveness and safety of drugs for obesity.  BMJ 2024; 384: e072686.

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ONCOLOGY AND HAEMATOLOGY

MedsScan editor for #SHPAOncHaem: Hayley Vasileff

The role of mirtazapine as an appetite stimulant in patients with non-small cell lung cancer and anorexia

Special contributor: Kaiting Leong

Lung cancer is the leading cause of cancer-related deaths globally, with approximately 1.8 million fatalities each year.1 Anorexia is a common consequence of lung cancer, affecting over half of patients, leading to weight loss and reduced tolerance to treatments, ultimately impacting survival rates. Mirtazapine antagonises the central presynaptic alpha-2 autoreceptors, and postsynaptic 5-hydroxytryptamine (5HT2/5HT3) and histamine (H1) receptors and therefore favours an antidepressant effect and could exert an analgesic and antiemetic effect. It could also stimulate the appetite and increase body weight. This study aims to evaluate effects of mirtazapine on appetite and energy intake in patients with advanced non-small cell lung cancer (NSCLC) and cancer-related anorexia.

In a study involving eighty-six patients with NSCLC and anorexia, participants were randomised into placebo or mirtazapine groups, with half the number of patients in each group. The mirtazapine group received 15 mg of mirtazapine daily for the first 15 days, then increasing to 30 mg daily until completion at eight weeks. Results showed a significant increase in energy consumption, particularly from fat intake, in the mirtazapine group, which was sustained at eight weeks. Patients in this group also reported reduced fatigue, albeit with an increase in nightmares compared to the placebo group. However, adverse effects like somnolence, drowsiness, dizziness, tremors or anxiety were not reported.

The study concluded that although appetite scores did not significantly differ between the groups, the increase in energy intake, particularly from fats, suggests a potential benefit of mirtazapine in improving the nutritional status of patients with advanced NSCLC and anorexia.

References

  1. World Health Organization (WHO). Lung cancer. Geneva: WHO; 2023. Available from https://www.who.int/news-room/fact-sheets/detail/lung-cancer#:~:text=GLOBOCAN%202020%20estimates%20of%20cancer,deaths%20(18%25)%20in%202020. Accessed 14 May 2024. 

Arrieta O, Cárdenas-Fernández D, Rodriguez-Mayoral O, Gutierrez-Torres S, Castañares D, Flores-Estrada D, et al. Mirtazapine as appetite stimulant in patients with non-small cell lung cancer and anorexia: a randomized clinical trial. JAMA Oncol 2024;10: 305–314.

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PALLATIVE CARE

MedsScan editors for #SHPAPallCare: Vicky Poulier, Gauri Godbole and Annette Bush

Deprescribing antithrombotics in palliative care patients with cancer

Deprescribing antithrombotics in patients with palliative care needs is a complex process. Studies indicate that these are often continued until shortly before death.

In this study a deprescribing tool — the antithrombotics scheme — is evaluated. This retrospective, single-centre clinical cohort observational study included 111 patients with solid tumors who were taking antithrombotics when they were seen by a palliative support team. Rates of antithrombotic deprescribing, adherence to the antithrombotics scheme and differences in clinical outcomes between adherence and non-adherence were analysed.

The median age of the study population was 70 years. Most patients (79.3%) took only one antithrombotic medication, with low molecular weight heparin (LMWH) the most prescribed. The rate of major bleeding events in patients with scheme adherence compared to non-adherence was 9.9% vs 13.8% and was not statistically significant. The differences in median time until event (after the first palliative care consultation) were 56 days and 31 days, respectively. Limitations of this study include the single site and the documentation of prognosis and decision-making on antithrombotics use was not standardised. The palliative care team was most often consulted within just 15 days of death.

Future prospective research is still needed to analyse and validate the antithrombotics scheme, and to investigate if the timing of first palliative consultation can influence the occurrence of thrombotic or bleeding events. This study demonstrates that the antithrombotics scheme can aid healthcare professionals to evaluate appropriateness of antithrombotics in palliative cancer patients, providing a stepwise algorithm to guide deprescribing and thus optimise care in the last phase of life.

Riveras A, Crul M, Kloes J, Steegers M, Huisman B. A Tool for Deprescribing Antithrombotic Medication in Palliative Cancer Patients: A Retrospective Evaluation. J Pain Palliat Care Pharmacother 2024; 38: 20–27.

Transdermal rotigotine dose and Parkinson’s disease at end of life

Patients with Parkinson’s disease nearing end-of-life (EOL) are commonly prescribed transdermal rotigotine when the oral route becomes non-viable. Recent studies suggest dopaminergic medicines may worsen distress, confusion, delirium, agitation and hallucinations, and that lower levodopa equivalent daily dose (LEDD) may be better tolerated. Evidence to guide dosing of rotigotine at EOL remains limited.

This Australian study retrospectively reviewed medical records of 60 patients with Parkinson’s disease (PWP) who died during January 2019 to May 2022 to determine if rotigotine dose impacted occurrence of distress at EOL. Proxy measures for distress were benzodiazepine (BZ) and morphine doses required in the last 72 hours. Clinical practice tools were used to calculate oral morphine equivalent (OME), benzodiazepines as midazolam equivalent doses; and OPTIMAL for LEDD conversion.

Most (83%) patients with a median age of 81.5 years were eligible for conversion to rotigotine, with 13% given the calculated dose, 38% a lower dose, 12% a higher dose and 37% receiving no rotigotine. Higher rotigotine dose was associated with higher total BZ dose (r = 0.334, p = 0.016) and PRN BZ dose (r = 0.289, p = 0.037). Higher LEDD on admission was associated with higher total BZ dose (r = 0.305, p = 0.018) and total oral morphine equivalent (OME) dose (r = 0.258, p = 0.046). There were no significant differences in total OME or BZ use in those taking these regularly prior to admission and those who were not, or those with pre-existing dementia and those without.

The study concluded rotigotine doses should be conservative when initiated as replacement dopamine agonists at EOL to minimise risk of worsening delirium and distress.

Hewer C, Richfield E, Halton, C, Alty J. Transdermal rotigotine at end-of-life for Parkinson’s Disease: Association with measure of distress. J Pain Symptom Manage 2024; 67: e121–e128.

Survey of palliative care patient acceptance of analgesic-induced sedation

Sedation from opioids and other analgesics is a known adverse effect, however studies exploring patient expectations and acceptance of sedation are limited. This study investigated the level of analgesic-induced sedation accepted by palliative care patients. Seventy-six inpatients and day patients from a single palliative care service in the United Kingdom completed a survey during 2018–2021.

Various hypothetical scenarios were described, including severe pain present in the last days to short weeks of life that limited ability to eat, mobilise and maintain personal care.  Participants were asked how likely they would accept increasing levels of sedation: dozing, dozing and difficulty concentrating, asleep for most of the day, and asleep all of the time.

The majority of patients had malignant disease (92%) with at least half (56.5%) admitted due to active symptom exacerbation. Most patients (89.47%) indicated they would accept mild sedation to control pain, while significantly, almost two-thirds (59.21%) would not accept high levels of sedation (p = 0.0001). If the expected prognosis was extended to weeks to months, 40.79% would amend their answers with a preference for less sedation. Patients who had seen severe pain in others were more likely to accept higher sedation levels (p = 0.025).

The study suggests patients appear less likely to accept increasing sedation from analgesics, particularly if their expected prognosis is longer. Notably, few patients were neutral in their answers, highlighting the emotive and subjective nature of patients’ desires to maintain personal activities and interactions. The study is limited in that scenarios were simplified and only explored analgesic-induced sedation, and thus were not reflective of clinical practice.

Burdon J, Fingas S, Parry R, Pitsillides C, Taylor P. Sedation from analgesics: patient preference survey. BMJ Support & Pall Care 2024; [online ahead of print]. doi: 1136/spcare-2023-004759.

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RURAL AND REMOTE

MedsScan editors for #SHPARuralRemote: Kelly Beswick and Mitchell Rigby

Hospital staff perceptions on virtual clinical pharmacy services

Special contributor: Caitlin Hardman

Background: Virtual clinical pharmacy services (VCPS) focus on the core role of hospital pharmacists, including medication reconciliation, medication review and patient education delivered virtually by utilising existing videoconferencing technology, the electronic medical record and electronic medication platforms. It is an established model of care to support rural and remote Australian hospitals to increase the safe and effective use of medicines and improve compliance with national accreditation standards.1 Few studies have evaluated the role of hospital staff in the implementation of virtual pharmacy services.

Aim: To understand healthcare staff perspectives of the VCPS in rural and remote New South Wales and identify areas for improvement.

Method: This qualitative study utilised Appreciative Inquiry which is an action research approach. Appreciative Inquiry is usually described as using a four-stage version of the action research cycle, known as the ‘4D cycle’. The study employed focus groups of hospital healthcare staff three months after the implementation of VCPS. The questions focused on the strengths of the VCPS and envisioned improvements by concentrating on discovery (valuing current strengths), dream (envisioning what might be), design (discussing enhancements) and destiny (applying innovations).

Results: A total of 67 health care staff participated in fifteen focus groups. Participants noted VCPS value to patients, staff and the health service. The ease of use, model of delivery, availability, local knowledge and responsiveness of highly skilled pharmacists was the key to user satisfaction. Suggested improvements included extending virtual service hours, widening patient eligibility and maintaining training and education to staff on VCPS.

Key limitations: A notable limitation was the study cohort size. In addition, focus groups were short and scheduled at shift changes which may have limited participation and/or contributions.

Impact on practice: This study has demonstrated that VCPS are an acceptable and effective model of care to improve medication management in small rural hospitals. It highlights the possibilities of virtually delivered clinical pharmacy services across rural and remote health facilities in Australia and potentially worldwide.

References

  1. Chambers B, Fleming C, Packer A, Botha L, Hawthorn G, Nott S. Virtual clinical pharmacy services: A model of care to improve medication safety in rural and remote Australian health services. Am J Health Syst Pharm 2022; 79: 1376–1384.

Allan J, Webster E, Chambers B, Nott S. “This is streets ahead of what we used to do”: staff perceptions of virtual clinical pharmacy services in rural and remote Australian hospitals. BMC Health Serv Res 2021; 21: 1306.

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TECHNICIANS AND ASSISTANTS

MedsScan editor for #SHPATechnicians: Bryan Walker

The American experience: advancing pharmacy technician training opportunities

The United States healthcare system is grappling with urgent and complex challenges, including escalating costs, variable quality and unequal access. These issues are influenced by internal factors such as hospital consolidation and technological advancements, external pressures such as an aging population, high healthcare costs compared to other developed countries and increasing consumer demands. These factors necessitate a re-evaluation of existing pharmacy models.

The future of all healthcare professions is moving towards interprofessional collaborative teams. Extensive documented evidence shows that pharmacy technicians are essential for advancing clinical services. Recently, the focus on how pharmacy technicians’ roles would change with new practice models has increased dramatically. Examples of newer tasks include completing medical histories, taking vital signs and facilitating care transitions. Universities have not contributed significantly to solving this problem of training technicians since only two universities have pharmacy schools offering pharmacy technician classes. Additionally, few pharmacists are involved in formalised pharmacy technician training programs.

The need for more universities and schools of pharmacy to become accredited institutions is imperative. By offering pharmacy technician classes, these institutions could provide the necessary opportunities for technicians, such as in compounding, pharmacy calculations, management and law. These efforts would be fruitful in providing a constant pool of technicians and increasing the number of individuals wanting to advance by getting a graduate degree in pharmacy.

Adopting standard definitions of pharmacy technicians, national standards of education and training programs, the skills required for credentialing technicians and requirements for a national certification will be crucial in shaping the clinical services needed to progress to improved medication outcomes and a direct positive impact on patient care. The active involvement of pharmacy boards, pharmacy schools, and employers in this process is not just vital; it is essential for the success of these new solutions.

 Wheeler JS, Gray JA, Gentry CK, Farr GE. Advancing pharmacy technician training and practice models in the United States: historical perspectives, workforce development needs, and future opportunities. Res Social Adm Pharm 2020; 16: 587–90.

The impact of a pharmacy technician training program within a college of pharmacy

The objective of this article was to assess the outcomes and effectiveness after completing the pharmacy technician training program. The American Journal of Health-System Pharmacy assessed this from December 2021 to March 2023. A survey was distributed to participants who completed the program three months after their estimated completion date. The survey assessed enrolment and academic progression, utilisation of educational resources, self-perceived proficiency on pharmacy technician core competencies, employment information, program recommendations and student demographics.

Thirty-six participants completed the survey. This correlated with a 60% response rate. The participants were attracted by the programs’ affiliation with a college of pharmacy, affordability and the ability to learn the content online. Approximately half of the participants were employed as pharmacy technicians, and the self-reported certification exam rates averaged around 78%, compared to the national average of 71%. Participants’ evaluation of their effectiveness was high, with a rating of 4.12 out of 5. Ninety-seven per cent of the participants felt the program prepared them to become pharmacy technicians.

With these results, having a well-structured and resourced pharmacy technician program affiliated with a college of pharmacy or a university can provide higher-quality pharmacy technicians and help create a pathway to solving the staff shortages presently experienced across many healthcare professions. Since the group sample was small, more extensive research with larger groups will need to be done to help support these findings.

Wheeler JS, Martin N, Barenie RE. Evaluating the impact of a pharmacy technician training program within a college of pharmacy. Am J Health Syst Pharm 2024; 81: 634–40.

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WOMEN'S AND NEWBORN HEALTH

MedsScan editor for #SHPAWomenNewborn: Kate Luttrell

Neurokinin-3 receptor antagonists for the management of vasomotor symptoms of menopause

Special contributor: Treasure McGuire

Background: Vasomotor symptoms (VMS) of menopause occur in up to 80% of postmenopausal persons and can significantly negatively impact on quality of life.1 Symptoms are a strong motivation for seeking treatment.2 While menopausal hormone therapy (MHT) is standard of care, use remains controversial due to findings from the Women's Health Initiative.3

The physiology of hot flushes involves changes in the central thermoregulatory zone of the hypothalamus, with hypothalamic neurons expressing KNDy neurons (kisspeptin, neurokinin B, and dynorphin).4  During menopause, as  estrogen levels fall, KNDy neurons lack inhibition, and this heightened neuronal activity seems to contribute to VMS.4 It has led to neurokinin-3 receptor (NK3R) antagonists such as fezolinetant and elinzanetan being trialled as non-hormone alternatives to MHT to manage VMS.

Aim: The aim of this systematic review was to assess the literature describing the safety and efficacy of NK3R antagonists approved and in development for postmenopausal persons with VMS.

Method: A search of MEDLINE, EMBASE and International Pharmaceutical Abstracts was conducted using the search terms and permutations of NK3R antagonists, elinzanetant, fezolinetant and osanetant to 1 March 2023. Inclusion criteria were full-text studies in English, reporting on efficacy or safety studies in participants identifying as female. Extracted data were synthesised to allow comparison of reported study characteristics, efficacy outcomes (VMS frequency and severity) and safety events. Eligible records were evaluated for risk of bias via the Cochrane Risk of Bias 2 tool for randomised studies and the certainty of evidence by outcome was calculated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This study was neither funded nor registered.

Results: After screening, the search returned 186 records. Seven randomised controlled trials (RCTs) and one post hoc analysis of two NK3R antagonists (fezolinetant and elinzanetant) met the inclusion criteria (n = 3503 with sample sizes ranging from 76 to 1831 participants).

Three fezolinetant RCTs demonstrated a reduction in VMS frequency/severity, improvement in Menopause-Specific Quality of Life scores and improvement in sleep quality at weeks 4 and 12 compared with placebo without serious adverse events. The two RCTs on elinzanetant also showed improvements in VMS frequency and severity. All studies evaluated safety through treatment-emergent adverse events, with the most common reports being COVID-19, headache, somnolence and gastrointestinal upset. Each record evaluated had a low risk of bias. There is a strong certainty of evidence as per the GRADE system.

Key strengths and limitations: The participants evaluated had similar demographics, and the studies had the same primary outcomes to assess the efficacy and safety of VMS frequency and severity at specific time points. In addition, they had very similar exclusion and inclusion criteria, simplifying data comparison. All participants across the studies recorded their VMS daily in a diary using the same definitions of mild, moderate and severe symptoms.

While there were no serious safety concerns in the included trials, it should be noted that exclusion criteria were stringent. Women with medical conditions or chronic diseases were not eligible for study inclusion. This may have limited the applicability of findings to women who are healthy with no comorbidities. As only English language studies were included, this may have also led to exclusion of relevant records.

Impact on practice: The 2023 North American Menopause Society non-hormone position statement added fezolinetant as a potential prescription treatment option for VMS.7 Fezolinetant 45 mg film coated tablets were also listed on the Australian Register of Therapeutic Goods on 26 February 2024, paving the way for NK3R antagonists being prescribed for menopausal symptoms.  Due to the high-quality evidence supporting the efficacy of fezolinetant and elinzanetant in reducing VMS frequency and severity, these agents may provide an effective option for women seeking non-hormone treatment of VMS, with a mild short-term side-effect profile. However, as most trials were of 3-to-15-week duration, with only two trials extending to 40 and 52 weeks, respectively, the long-term safety of these agents still needs to be evaluated.  

References

  1. Pinkerton JV, Santen RJ. Managing vasomotor symptoms in women after cancer. Climacteric 2019; 22: 544–52.
  2. Williams RE, Kalilani L, DiBenedetti DB, Zhou X, Fehnel SE, Clark RV. Healthcare seeking and treatment for menopausal symptoms in the United States. Maturitas 2007; 58: 348–58
  3. Chlebowski RT, Aragaki AK. The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context. Menopause 2023; 30: 454–61.
  4. Faubion SS, Stuenkel CA. Neurokinin 3 receptor antagonists for treatment of vasomotor symptoms: a new panacea or just a flash in the pan? Menopause 2018; 25: 859–61.
  5. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ 2019; 366: l4898.
  6. Schünemann H, Brożek J, Guyatt G, Oxman A (eds). GRADE handbook: handbook for grading quality of evidence and strength of recommendations using the GRADE approach. The GRADE Working Group; 2013. Available at https://gdt.gradepro.org/app/handbook/handbook.html. Accessed 1 April 2024.
  7. The 2023 nonhormone therapy position statement of the North American Menopause Society advisory panel. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause 2023; 30: 573–90.

Cieri-Hutcherson NE, Marji EK, Hutcherson TC. Systematic review of neurokinin-3 receptor antagonists for the management of vasomotor symptoms of menopause. Menopause 2024; 31: 342–54.

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