MedsScan Issue 4, 2024

These reviews provide updates on the international literature on therapeutics. Expert pharmacy practitioners — via AdPha’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 Clinical trials SPG: June Challen

Pharmacists are integral to clinical trials in primary care

The role of pharmacists in clinical trials being conducted in tertiary health facilities is well entrenched, however this is not the case in the primary care sector. This article in The Pharmaceutical Journal describes a unique example of a primary care network in the United Kingdom, where pharmacists have taken on a role in research. The hurdles faced by the pharmacist in the newly appointed role as a research pharmacist are discussed. Initially, pharmacy standard operating procedures had to be established. Other issues to be addressed included the details of the management of the investigational product, it’s storage and management and accountability.

The paper discusses the benefits of bringing clinical trials to patients in primary care. The wealth of benefits for the research pharmacist include increasing the scope for professional development, including multidisciplinary interactions within the research team. The research pharmacist requires an expanded skillset applying Good Clinical Practice standards to the research being conducted in the clinic.

This paper should encourage pharmacists in primary care to be involved in research roles. It outlines both the personal and professional benefits that can be gained by working in a research environment.  The enhanced healthcare outcomes for patients in the community setting are vital in driving this new era in healthcare provision.

Lalji K. Pharmacists are integral to launching more clinical trials in primary care. The Pharmaceutical Journal 2024; 312: 7981. Available from https://pharmaceutical-journal.com/article/opinion/pharmacists-are-integral-to-launching-more-clinical-trials-in-primary-care.

Is more always better in cancer drug dosing?

This article was written by members of the team of the Patient-Centered Dosing Initiative (PCDI). PCDI was launched in 2019 to advocate for a more balanced approach to cancer treatment for metastatic cancer patients. This paper acknowledges that dose finding for drugs used to treat cancer is historically based on clinical trial data using ascending doses with the aim to reach a Maximum Tolerated Dose (MTD).

PCDI question the practice of using the MTD, indicating that it can result in severe side effects, particularly for those with metastatic breast cancer who undergo long-term treatment. Instead, they advocate for patient centred dosing where both the effectiveness of the therapy and the patient’s quality of life are considered. The authors argue that drug dosages should be personalised for each patient based upon a standard set of criteria to be discussed between the patient and their doctor. The paper includes an educational flyer that provides patients with guidance to initiate such a conversation with their doctor. 

Given that currently approved oncology drugs are prescribed in doses based on the MTD, the authors acknowledge that patient centred optimised dosing will take time for such drugs.  The authors suggest that ongoing dialogue between patients and their doctors, as well as analysis of post-marketing studies focusing on long-term safety and efficacy will drive this shift.

PCDI is focused on metastatic breast cancer, however the authors discuss that questioning the ‘more is better’ approach has a place in treating those with other cancers. By considering each patient’s unique characteristics and treatment history, PCDI believe that effective cancer control is possible with reduced side effects and ultimately improved overall patient wellbeing.

Maués J, Loeser A, Cowden J, Johnson S, Carlson M, Lee S. The patient perspective on dose optimization for anticancer treatments: a new era of cancer drug dosing–Challenging the “more is better” dogma. Clin Trials 2024; 21:358–362

Artificial intelligence and the transformation of drug discovery

Drug discovery is a lengthy and costly process, with a high degree of uncertainty. Despite latest-generation experimental technologies, many discovery programs struggle. Even if successful, programs often take many years to complete. This feature article looks at how big pharmaceutical companies and startup companies are utilising artificial intelligence (AI), with the aim of reducing this time. Currently, there are no approved drugs that have originated from AI tools.

The author of this article first discusses the development of generative AI with a representative of a company that is applying advanced AI to accelerate biopharma drug discovery, blending science and technology with a focus on finding solutions for complex diseases. The article then examines the earliest uses of AI, where repurposing existing drugs was the driver and then focuses on the decision by a number of biotechnology startup companies, to pursue precision oncology by training AI models to find novel oncology biomarkers and targets.

The role that AI plays in drug discovery by large pharmaceutical companies is extensively reviewed, noting that not all companies are using AI as they instead focus on traditional drug discovery methods. Of interest is a comment from a former director of a big pharma company: “[p]eople feel there’s a risk that a computer designed compound is not patentable, because it’s lacking the inventive step by a human.” However, these companies are exploring the use of AI in clinical trial design, with interest shown in stratifying clinical trial populations into subsets that are more likely to benefit from the clinical trial. 

The article discusses ethical considerations of this approach to drug discovery and as a conclusion it acknowledges that AI is not yet able to solve all of the complexities of drug discovery.

Brazil R. How AI is transforming drug discovery. The Pharmaceutical Journal 2024; 313: 7987. Available from https://pharmaceutical-journal.com/article/feature/how-ai-is-transforming-drug-discovery.

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CRITICAL CARE

MedsScan Editors for Critical care SPG: Melissa Faehrmann and Grainne Hughes

Changes to β-lactam administration in the intensive care unit

Special Contributor: Georgia Clark

Sepsis, a life-threatening condition that develops from a dysregulated immune response to infection, has unacceptably high mortality rates despite extensive research. Early intervention with broad spectrum antibiotics, such as piperacillin-tazobactam or meropenem, improves mortality. Traditionally administered intermittently, β-lactams demonstrate time-dependent kill characteristics. This forms the theoretical basis that continuous infusions may improve outcomes, including mortality. Prior research on the impact of continuous versus intermittent administration is inconclusive.

BLING (Beta-Lactam Infusion Group) III trial was an international, open-label, randomised controlled trial, conducted across 104 intensive care units (ICUs). The primary outcome compared the effects of continuous versus intermittent β-lactam infusion on 90-day all-cause mortality in critically ill adults with sepsis. Participants were randomly assigned to receive a 24-hour dose of either piperacillin-tazobactam or meropenem via continuous or intermittent infusion, with the treatment duration determined by clinicians or until ICU discharge.

Seven thousand and thirty-one participants were included. The primary outcome of 90-day mortality did not reach statistical significance (24.9% continuous vs. 26.8% intermittent, 95% confidence interval [CI] 0.81–1.01, p = 0.08), however, the continuous infusion group showed an ~2% relative risk reduction. The secondary outcome of clinical cure at 14 days, demonstrated a statistically significant improvement in the continuous infusion arm. Ten adverse reactions were reported, of which one event potentially contributed to a single death in the continuous infusion arm.

While the primary outcome wasn’t statistically significant, the relative risk reduction suggests there are potential benefits of continuous β-lactam infusions in critically ill patients. The study evaluated a patient focused outcome, using a low-cost intervention that required minimal training to implement. Where appropriate intravenous access is available, the low-risk intervention may benefit critically ill patients, and should be considered where possible.

Dulhunty JM, Brett S, Waele J, Rajbhandari D, Billot L, Cotta MO, et al. Continuous vs intermittent β-Lactam antibiotic infusions in critically ill patients with sepsis: The BLING III randomized clinical trial. JAMA 2024; 332: 629–637.

Pantoprazole for stress ulcer prophylaxis in patients undergoing invasive ventilation

Special Contributor: Kathlin Tunnah

Critically ill patients receiving mechanical ventilation are at risk for stress-induced gastrointestinal ulceration and bleeding. While proton pump inhibitors (PPIs) are commonly used for prophylaxis, their benefits compared to potential harms remain unclear. Recent studies have suggested both a reduction in clinically important upper gastrointestinal bleeding and a potential increase in mortality associated with PPI use, leading to weak recommendations in guidelines.

The REVISE (Re-Evaluating the Inhibition of Stress Erosions) trial was an international, randomised, double-blind trial conducted at 68 ICUs across eight countries. Critically ill adults undergoing mechanical ventilation were randomly assigned to receive 40 mg daily of intravenous pantoprazole or a placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the ICU at 90 days, and the primary safety outcome was death from any cause at 90 days. Secondary outcomes included ventilator-associated pneumonia, Clostridium difficile infection and patient-important bleeding.

The trial enrolled 4821 patients. Pantoprazole significantly reduced the risk of clinically important upper gastrointestinal bleeding compared to the placebo (1.0% vs. 3.5%, hazard ratio [HR] 0.30, P < 0.001). There was no significant difference in mortality at 90 days between the two groups (29.1% vs. 30.9%, HR 0.94, p = 0.25). Patient-important bleeding was reduced with pantoprazole, while other secondary outcomes showed no significant difference.

The REVISE trial demonstrated that intravenous pantoprazole effectively reduces clinically important upper gastrointestinal bleeding in patients undergoing mechanical ventilation without a significant impact on mortality. These findings provide valuable evidence to support clinical decision-making regarding stress ulcer prophylaxis in critically ill, ventilated patients. This high-quality evidence from a large, international trial may lead to stronger recommendations for PPI use in updated guidelines. The trial also highlights the importance of considering patient-important outcomes in clinical research.

Cook D, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L, et al. Stress ulcer prophylaxis during invasive mechanical ventilation. N Engl J Med 2024; 391: 9–20.

Does a pharmacist have a pharmacoeconomic and clinical impact in an ICU?

Contributor: Gráinne Hughes

The presence of clinical pharmacists in hospitals and their impact has been well documented in literature. This systematic review evaluated the clinical impact and pharmacoeconomic benefit that pharmacists have in the intensive care unit (ICU). A qualitative evaluation of 11 articles including a total of 18 718 patients was performed using the CHEERS grid (Consolidated Health Economic Evaluation Reporting Standards).

The pharmaceutical interventions were grouped into several categories and pharmaceutical analysis was the most frequent type of assignment: global for six and more specialised for five of the studies. Resources averaged 0.5 full-time equivalent (FTE) per 10 ICU beds and ten of the studies included pharmacist experience in critical care which ranged from 6 months to 13 years.

Five studies were cost-benefit analyses, five were cost-analyses and one was a cost-consequence analysis. All studies showed economic benefit. The cost-benefit analysis expressed the benefit as a ratio — per €1 invested in pharmacist time. The economic gain generated ranged from €2.65 to €24.20. Avoided drug-related costs were reported as averages per patient per year ranging from €29.73 to €194.24. The clinical benefit highlighted optimisation of therapeutic management alongside the reduction of drug-related iatrogenesis.

The overall CHEERS compliance score for the 11 studies was 63% +/- 17% which reveals the heterogenous quality of the studies. Most of the studies poorly described the rationale and model used, and the least reported items across all studies was analysis and hypothesis, with only five using sensitivity analysis. The economic evaluation of the studies had to be reworked in some cases for comparison and they were all converted to euros at the 2022 exchange rate. Some studies were very specific in their field of focus and did not include all drugs prescribed without distinction.

Overall, the study highlights the valuable role of clinical pharmacists in enhancing ICU care quality and economic efficiency, by optimising medication use and preventing costly complications.

Simonetti L, Lefrant JY, Cireașă B, Poujol H, Leguelinel-Blache G. Pharmacoeconomic and clinical impact of pharmaceutical service in the intensive care unit: a systematic review. Eur J Hosp Pharm 2024: ejhpharm-2024-004208 [online ahead of print].  

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GERIATRIC MEDICINE

MedsScan Editors for Geriatric medicine SPG: Anna Jennings, Gauri Godbole and Richard Bolitho

A new way to measure medication literacy

Special contributor: Alexandra Brown

Medication literacy is an integral component of safe medication use and is a predictor of adverse patient outcomes. Despite being a cornerstone of medication safety, validated instruments to measure this construct are hard to come by and not commonly used in pharmacy practice. As medication literacy decreases with age and is compounded by more complex medication regimens, older adults are a priority population for assessment and improvement of medication literacy. This study aimed to evaluate the psychometric properties of The Medication Literacy Test for Older Adults (TELUMI) to determine its adequacy for measuring medication literacy in older adults. The TELUMI assessment is a performance-based measure of 33 items, theoretically representing the four dimensions of medication literacy: functional, communicative, critical and numeracy.

The study was a cross-sectional methodological study conducted with 334 older adults from community and hospital outpatient settings in Brazil. TELUMI psychometric properties were assessed using descriptive item-analysis, exploratory factor analysis (EFA), item response theory (IRT), reliability and convergent validity analysis. The psychometric analysis demonstrated support for a one-dimensional structure of the TELUMI as opposed to the theoretical four-dimensional focus. The one-dimensional structure implies a single score can reflect medication literacy as a global construct. However, this structure makes it impossible to generate individual scores for each of the four dimensions proposed theoretically. The IRT demonstrated that a majority of the items showed adequate discrimination potential.

Four items were recommended for exclusion due to low discrimination potential and unacceptable guessing indices. All items had an adequate difficulty index. The 29-item version of the TELUMI is psychometrically adequate for measuring medication literacy in older adults and should be considered for use in clinical practice to identify patients requiring assistance in improving medication literacy and safety. Psychometric evaluation in an Australian setting should be considered.

Neiva Pantuzza LL, Moreira Reis AM, Ferreira Botelho S, Pereira de Rocha AL, Parreiras Martins MA, Gonzaga do Nascimento MM, et al. Medication Literacy Test for Older Adults: psychometric analysis and standardization of the new instrument.  Int J Clin Pharm 2024; 46: 1124–1133

Does introduction of antihypertensives increase risk of fractures in older adults?

Special contributor: Vidya Menon

Falls are a common cause for injuries and hospitalisations in elderly patients. This large retrospective cohort study focused on determining whether initiating antihypertensives in elderly nursing home patients was associated with an increased risk of falls and fractures, given the potential for these medications to induce orthostasis. It is crucial that such modifiable risk factors are taken into consideration for the wellbeing of our elderly population. 

Data was procured from Veterans Health Administration (VA) corporate data warehouse — a national repository for electronic health records for all VA facilities in the United States — between the period of 1 January 2006, and 31 October 2019. The treatment group included patients who had an increase in the number of antihypertensive medication groups. They were observed for 30 days post initiation of medication, considered as the high-risk period.

1:4 Propensity Score matching was applied due to the large number of participants in the control arm, compared to the treatment arm. The study concluded that the incidence rate (per 100 person-years) of fractures was higher (5.4) for the antihypertensive group compared with 2.2 for the control group. The antihypertensive group was also noted to be at an increased risk of severe falls (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.53–2.13), syncope (HR 1.69, 95% CI 1.30–2.19), and traumatic brain injury hospitalisations (HR 2.30, 95% CI 1.44–3.69).

Limitations of the study included the fact that due to the VA nursing home residents being largely male, the data including incidence of certain fractures like hip fractures, which are more common in females, is not as robust as it could be. The study also lacked factors that could determine the differences in fracture risk associated with each drug class or dose changes. The study highlights the importance of close monitoring of older patients in nursing homes when started on a new antihypertensive, especially during the high-risk period.

Dave CV, Li Y, Steinman MA, Lee SJ, Liu X, Jing B, et al. Antihypertensive Medication and Fracture Risk in Older Veterans Health Administration Nursing Home Residents. JAMA Intern Med 2024; 184: 661–669.

The effect of deprescribing in older people

Special contributors: Hui Wen Quek, Amy Page

The use of multiple medications (known as polypharmacy) is prevalent among older people with multimorbidity. Inappropriate medication use can lead to harmful patient outcomes. Deprescribing involves discontinuing one or more medications that are potentially harmful or no longer required. Over the past decade, new ways of implementing deprescribing interventions have been implemented and evaluated across all settings.

A 2024 systematic review and meta-analysis identified 153 new deprescribing studies published since 2015. This paper investigated the effect of deprescribing on health-related outcomes in older people. It included 259 studies involving people aged 65 years and older taking at least one regular medication at the start of the study and excluded patients who were at the end of their lives or receiving end-of-life care.

Overall, deprescribing to reduce polypharmacy did not significantly change mortality, falls, fractures, adverse drug events, emergency room presentations or unplanned hospital admissions in randomised controlled trials (RCTs). However, deprescribing to reduce polypharmacy significantly improved survival in people aged 65 to 79 in RCTs. A limitation of the review is that mortality was assessed as a secondary outcome in many studies, and the studies could be inadequately powered to detect a clinically significant difference between groups.

While more high-quality research is needed, this study highlights that medications can be safely reduced or stopped when closely supervised by healthcare professionals using a patient-centred process. To many pharmacists, the concept of deprescribing is not new. As experts in pharmacotherapy, pharmacists can identify medication-related problems through medication reviews and propose changes to prescribers. Pharmacists in hospital settings in particular, are ideally placed to review and reconcile patients’ medication lists during care transitions to ascertain the clinical appropriateness of each medicine and alignment with patient goals. Deprescribing is a part of medication optimisation to improve the safety and quality of medication use.

Quek HW, Page A, Lee K, Lee G, Hawthorne D, Clifford R, et al. The effect of deprescribing interventions on mortality and health outcomes in older people: An updated systematic review and meta-analysis. Br J Clin Pharmacol 2024; 90: 2409–2482.

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NEPHROLOGY

MedsScan editor for Nephrology SPG: Laura Johnstone

Changing the FLOW of diabetic kidney disease with semaglutide

New therapies to slow progression of diabetic kidney disease have emerged such as glucagon-like peptide-1 (GLP-1) agonists, with trials largely focusing on cardiovascular outcomes. No trial has examined renal outcomes with GLP-1 agonist use in high-risk diabetic kidney disease, until now.

The FLOW trial was a randomised (1:1), double-blind, placebo-controlled trial of adults with type 2 diabetes (T2DM) with an estimated glomerular filtration rate (eGFR) of 25 to <50 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio (UACR) of >100 to <5000 mg/g or eGFR 50 to 75 mL/min/1. 73m2 and a UACR of >300 to <5000 mg/g. Patients also had to be on a stable maximal dose of an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless intolerant. Participants received semaglutide (starting dose 0.25 mg weekly titrating up to 1 mg weekly) or placebo. Primary outcomes were major kidney disease events composite of kidney failure onset, sustained reduction of eGFR from baseline (≥50% for ≥28 days), or death (kidney-related or cardiovascular causes). Secondary outcomes included total eGFR slope, major cardiovascular events and death from any cause. Safety outcomes looked at adverse events – serious, those that led to discontinuation of intervention or of special interest.

The trial was ceased early after a planned interim analysis of efficacy, with median participant follow up at 3.4 years. The semaglutide group had a 24% lower relative risk of major kidney disease events compared to placebo (331 vs 410) (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.66– 0.88, p = 0.0003), events including persistent reduction of baseline eGFR (≥50% for ≥28 days)  (165 vs 213; HR 0.73, 95% CI 0.59–0.89) and death from cardiovascular causes (123 vs 169; HR 0.71, 95% CI 0.56–0.89). Overall, participants using semaglutide reported less serious adverse events such as serious infection, infestations or cardiovascular disorders compared to placebo (49.6% vs 53.8%), however discontinuation of treatment was more common in the semaglutide group (4.5% vs 1.1%), primarily due to gastrointestinal side effects.

The FLOW trial demonstrated that semaglutide 1 mg weekly significantly reduced the risk of major kidney disease events and the risk of death from cardiovascular causes in type 2 diabetes patients with kidney disease, yet the exact reno-protective effects of semaglutide remained unclear. Further research could explore other potential mechanisms for reno-protective effects of GLP-1 agonists in diabetic kidney disease such as effects on blood pressure, glycemia and weight, or use of GLP-1 agonists with ACE inhibitors/ARBs, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, finerenone and other GLP-1 agonists to find the most effective, safe and economical combination treatment/s including order and priority. Additionally, by completing the trial early the investigators have limited the chance to demonstrate semaglutide slowing rate of decline in eGFR long term, which would be highly valuable research given its insidious nature.  This trial was funded by Novo Nordisk, the manufacturer of semaglutide which immediately sparks bias concerns, however they did have a rigorous study design ensuring a large sample size and a well-defined control group.

Pharmacists are vital to provide education to patients with type 2 diabetes and kidney disease to ensure adherence to medicines and manage side effects, particularly GI upset (in the case of semaglutide), to prevent cessation of this medicine and maximise short- and long-term benefits of it as well as other chronic therapies.

Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med 2024; 391: 109–121.

Re-kidneyzing rejection: the Felzartamab trial

A significant gap exists in the treatment of antibody-mediated rejection (AMR), despite it being a lead cause for immune-mediated kidney transplant failure. Felzartamab, a fully human IgG1 CD38 monoclonal antibody has emerged as a promising agent to potentially fill this gap. Preliminary evidence for targeting CD38 has shown it may reverse or even prevent AMR. Targeting CD38 through plasma cell depletion leads to less production of donor-specific antibodies and natural killer (NK) cells, which are major players in microvascular inflammation.

This phase 2, double-blind, randomised, placebo-controlled trial studied 22 kidney transplant patients (11 patients received felzartamab and 11 received placebo), at least 180 days post-transplant with AMR. Treatment protocol entailed 9 infusions of felzartamab 16 mg per kilogram of body weight for 6 months or placebo and a 6-month observation period.

The safety of felzartamab over placebo was acceptable and efficacy showed promise. Significant adverse events for the felzartamab group were mild to moderate first-dose infusion-related reactions (73%, P = 0.001). While the placebo group had more serious adverse events, mainly infection-related than the felzartamab group (36% vs 9%), other events that occurred more often in the felzartamab group included infections (P = 0.31), nasopharyngitis (P = 0.03), COVID-19 (P = 0.20) and cytomegalovirus (n = 1). Over the course of the trial, felzartamab-treated patients had AMR resolution in 82% of cases vs 20% of patients treated with placebo. Additionally, microvascular inflammation, rejection-related transcript scores and plasma levels of donor-derived cell-free DNA were reduced. The researchers noted the limited power of the study for clinical outcomes, although surrogate markers for long-term transplant survival such as eGFR stabilisation were discovered.

The trial authors concluded that felzartamab shows promise for treatment of AMR in kidney transplant recipients given it met its primary outcomes with a favourable safety and side effect profile. Secondary outcomes included higher resolution of AMR and improved biomarkers. The trial limitations were small sample size, short trial duration and poor selection and matching of patient cohorts, which would limit the application to the Australian population. For example, 80% of participants were white and a 10-year median-age gap existed between groups.

Given this is an investigational phase 2 study, further research is required in larger, longer-term trials with a multiculturally diverse group, including First Nations people to confirm the findings and show improved patient outcomes such as kidney function and graft survival, prior to this medicine becoming a standard treatment option for Australian kidney transplant recipients.

Mayer KA, Schrezenmeier E, Diebold M, Halloran PF, Schatzl M, Schranz S, et al.  A randomized phase 2 trial of felzartamab in antibody-mediated rejection. N Eng J Med 2024; 391: 122–132.

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ONCOLOGY AND HAEMATOLOGY

MedsScan Editors for Oncology and haematology SPG: Hayley Vasileff and Alborz Soroush

ADAURA

The ADAURA study found that giving adjuvant osimertinib to patients with resected non-small cell lung cancer (NSCLC) that have epidermal growth factor receptor (EGFR) mutations in stages IB to IIIA with or without previous adjuvant chemotherapy adjuvant, led to significant improvements in disease free survival.

The phase 3 study involved 682 patients who were randomly assigned in a 1:1 ratio to either take osimertinib at a dose of 80 mg once daily or take a placebo for up to three years or until disease recurrence occurred. The primary end point was disease free survival in patients with stage II to IIIA cancer and secondary outcomes included overall survival, disease free survival and safety measures for all stages from IB to IIIA.

Of the 682 participants randomised in the trial, 339 participants were given osimertinib while the remaining 343 participants received placebo treatment. Notably, for individuals with stage II to IIIA cancer, the five-year overall survival rate was recorded at 85% for those taking osimertinib compared to 73% for those taking placebo. The analysis revealed a hazard ratio of death standing at 0.49 (95.03% confidence interval [CI] 0.33–0.73, P < 0.001).

The 5-year overall survival rate, for individuals in the population (stage IB to IIIA) was 88% in the group taking osimertinib compared to 78% in the placebo group. The risk of death was significantly lower in the osimertinib group with a hazard ratio of 0.49 (95.03% CI 0.34–0.70, P < 0.001). The safety profiles remained consistent with findings except for one serious case of pneumonia linked to COVID-19 that was not attributed to the trial treatment.

In summary, adjuvant osimertinib treatment demonstrated an enhancement in survival among patients, with resected EGFR mutated stage IB to IIIA NSCLC, thereby endorsing its utilisation as a standard adjuvant therapy option. This information has led to PBS approval of osimertinib in adjuvant setting stage IB to IIIA EGFR mutated NSCLC since 1 June 2024.

Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohé C, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 2023; 389: 137–147.

Keynote 868

A phase 3 research study about combining pembrolizumab and chemotherapy for patients with advanced endometrial cancer examined how effective and safe it is to use pembrolizumab, a PD-1 inhibitor, alongside chemotherapy (carboplatin+ paclitaxel) in first line settings for patients with stage III, IVA, IVB or recurrent settings. Patient populations were included from both mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) tumours. 

Eight hundred and sixteen patients (225 in the dMMR cohort and 591 in the pMMR cohort) were randomly assigned to receive paclitaxel (175 mg/m2) plus carboplatin (AUC 5) along with either pembrolizumab 200 mg (n = 407) or placebo (n = 409) every 3 weeks for 6 cycles, which was followed by 400 mg pembrolizumab or placebo maintenance every 6 weeks for up to 14 cycles. The main goal of the study was to assess progression free survival (PFS). Key secondary outcomes included safety and overall survival (OS).

In the 12-month analysis, progression free survival in the dMMR group was higher with pembrolizumab at 74% compared to 38% with placebo (risk ratio for progression or death 0.30, 95% CI 0.19–0.48, P < 0.001), showing a difference in relative risk of 70%. In the pMMR group, patients on pembrolizumab had a progression free survival of 13.1 months versus 8.7 months with a placebo (risk ratio 0.54, 95% CI 0.41–0.71, P < 0.001).

Similar frequencies of grade 3 or 4 adverse events (regardless of attribution) were seen in dMMR and pMMR cohorts. In the dMMR cohort, any-cause adverse events occurred in 98.2% of patients on pembrolizumab and 99.1% of patients on placebo. In the pMMR cohort, rates were 93.5% and 93.4%, respectively. Grade 3 or higher adverse events in the dMMR cohort were 63.3% for pembrolizumab and 47.2% for placebo; in the pMMR cohort, they were 55.1% and 45.3%, respectively. Grade 5 events were almost the same in both dMMR and pMMR groups (1.4% vs 1.5%), with one cardiac arrest possibly related to pembrolizumab-related in the latter. The addition of pembrolizumab did not appear to increase the frequency of adverse events that are commonly associated with combination chemotherapy.

In summary, the findings indicate that pembrolizumab, when used alongside chemotherapy and continued as maintenance treatment, resulted in a significantly increased period of progression free survival compared to placebo, for individuals, with dMMR and pMMR endometrial cancers along with a manageable safety profile.

Currently dostarlimab (PD-1 inhibitor) is Pharmaceutical Benefits Scheme-approved in conjunction with chemotherapy followed by maintenance in the dMMR group of patients only. Considering the results of Keynote 868, there is now the opportunity to combine immunotherapy and chemotherapy for both dMMR and pMMR primary advanced or recurrent endometrial cancers.

Eskander RN, Sill MW, Beffa L, Moore RG, Hope JM, Musa FB, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 2023; 388: 2159–2170.

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PAEDIATRICS AND NEONATOLOGY

MedsScan Editor for Paediatrics and neonatology SPG: Rachael Worthington

XTENDing effective prophylaxis in paediatric hemophilia A with efanesoctocog alfa

Despite therapeutic advances in hemophilia A, multiple injections weekly with conventional standard half-life and extended half-life factor VIII concentrates are required to prevent life-threatening bleeding and bleeding into joints for paediatric patients to manage hemophilia A. Once weekly efanesoctocog alfa has been shown to provide high sustained factor VIII activity with superior bleeding prevention in patients 12 years of age or older with severe hemophilia A, with data in children under 12 years of age limited. This open-label, international, single-group, phase 3 study enrolled previously treated patients younger than 12 years of age with severe hemophilia A.

Patients received prophylaxis with once weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary endpoint was the presence of factor VIII inhibitors, with secondary endpoints of annualised rates of treated bleeding episodes, bleeding treatment, safety and pharmacokinetics. A total of 74 male patients were enrolled, 38 less than 6 years of age and 36 with an age of 6 to <12 years, with 72 (97%) patients completing the study.

No factor VIII inhibitors developed. Most adverse events were non serious, and no serious adverse events were reported as being related to efanesoctocog alfa. In the 73 patients treated according to the protocol, the median and model-based mean annualised bleeding rates were 0.00 (interquartile range [IQR] 0.00– 1.02) and 0.61 (95% confidence interval [CI] 0.42–0.90), respectively. A total of 47 patients (64%) had no bleeding episodes, with no spontaneous bleeding episodes in 65 (88%) and no episodes of bleeding into joints in 61 (82%). A total of 41 (95%) of 43 bleeding episodes resolved with one injection of efanesoctocog alfa. Pharmacokinetic analysis demonstrated mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours.

The authors concluded that once weekly prophylaxis with efanesoctocog alfa provided effective bleeding prevention, as well as effective treatment of bleeding episodes with a single injection. Efanesoctocog alfa was deemed safe, with mainly non serious adverse events which did not lead to discontinuation of therapy.

Malec L, Peyvandi F, Chan AKC, Königs C, Zulfikar B, Yuan et al. for the XTEND-Kids Trial Group. Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A. N Engl J Med 2024; 391: 235-246.

Risky business: medication administration errors in children

Medication errors among paediatric inpatients continue to be a significant safety issue in hospitals around the world and the risk of medication administration errors, compared to prescribing errors remains high with less opportunities for detection and prevention. This prospective, direct observational study sought to identify nurse, medication and work-environment factors associated with medication administration errors among paediatric inpatients. 

The study was conducted in a paediatric referral hospital and involved direct observation of 298 nurses, with details of 5137 doses prepared and administered to 1530 children recorded and compared to medication charts to identify errors, which were assessed for potential severity and actual harm. Nurse characteristics, medication type and work variables were also collected. Multivariable models were used to assess medication administration error risk factors.

Errors occurred in 1899 (37.0%, 95% CI 35.7–38.3%)  administrations, 489 (25.8%, 95% CI 23.8–27.9%) of which were rated as potentially serious. Intravenous infusions (n = 514) and injections (n = 188) had high error rates (64.7%, 95% CI 61.3–68.0% and 77.4%, 95% CI 71.7–82.2% respectively), and 59.7% (95% CI 53.4–65.6%) of intravenous injections had potentially serious errors. No nurse characteristics were associated with medication administration errors. However intravenous route, early morning and weekend administrations, patient aged ≥ 11 years, oral medications requiring solvents/diluents and electronic medication management system use were all significant risk factors. When comparing paper charts to an electronic medication management system, medication administration errors causing actual harm were 45% lower using an electronic medication management system.

The authors concluded that medication error prevention strategies should focus on intravenous administrations and that older children in hospital required attention as a risk factor. Improvement in the design and integration of medication technologies in nurses’ work environments is also warranted.

Westbrook JI, Li L, Woods A, Badgery-Parker T, Mumford V, Merchant A, et al. Risk Factors Associated with Medication Administration Errors in Children: A Prospective Direct Observational Study of Paediatric Inpatients. Drug Saf 2024; 47: 545–556.

STOP long courses of oral Antibiotic therapy for peadiatric febrile urinary tract infections

Febrile urinary tract infections in children that appear well are conventionally treated with oral antibiotics, with most guidelines recommending 7–14 days of treatment. The Short-course oral antibiotic Therapy Of acute Pyelonephritis in children (STOP) trial sought to determine the noninferiority (5% threshold) of a 5-day amoxicillin-clavulanate course compared with a 10-day regimen to treat febrile urinary tract infections.

This multi-centre, investigator-initiated, parallel-group, randomised, controlled trial randomly assigned children aged 3 months to 5 years with uncomplicated febrile urinary tract infections to receive amoxicillin-clavulanate 50 + 7.12 mg/kg/day orally in 3 divided doses for 5 or 10 days. The primary endpoint was the recurrence of a urinary tract infection within 30 days after the completion of therapy. Secondary endpoints were the difference in prevalence of clinical recovery, adverse drug-related events and resistance to amoxicillin-clavulanic acid and/or to other antibiotics when a recurrent infection occurred.

From May 2020 through September 2022, 175 children were assessed for eligibility and 142 underwent randomisation. Of 72 patients in the 5-day group the recurrence rate of all urinary tract infections (febrile and nonfebrile) within 30 days of the end of therapy was 2.8% (n = 2) and of 70 patients in the 10-day group, the recurrence rate was 14.3% (n = 10), with a difference between the two groups of -11.51% (95% CI –20.54 to –2.47). The recurrence rate of febrile urinary tract infections within 30 days from the end of therapy was 1.4% (n = 1) in the 5-day group and 5.7% (n = 4) in the 10-day group (95% CI –10.4 to 1.75). Resolution of clinical signs and symptoms was similar between the groups, as was the need for further antibiotic therapy. Only one patient in the 5-day group had an adverse event (diarrhoea).

The authors concluded that a 5-day course is non-inferior to a 10-day course of oral amoxicillin-clavulanate, with no difference in resistance or emergence of opportunistic pathogens noted between the groups. The authors also acknowledged the small sample size, due to low recruitment rates during the COVID-19 pandemic.

Montini G, Tessitore A, Console K, Ronfani L, Barbi E, Pennesi M. STOP Trial Group. Short Oral Antibiotic Therapy for Pediatric Febrile Urinary Tract Infections: A Randomized Trial. Pediatrics 2024; 153: e2023062598.

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PALLIATIVE CARE

MedsScan Editors for Palliative care SPG: Vicki Poulier, Gauri Godbole and Annette Bush

Feasibility of methadone rotation compared to other opioid rotations in patients with refractory cancer-induced bone pain

Cancer-induced bone pain (CIBP) is common in patients with malignancies. This condition significantly impacts patients’ functional capacity and quality of life, yet there is limited evidence to guide the choice of opioids in this patient cohort. This pilot randomised controlled study investigated the feasibility, tolerability and potential efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in patients with refractory CIBP.

The study included adult inpatients with CIBP already on strong opioids, who had a worst pain intensity of ≥4/10 and/or opioid toxicity graded ≥2. Participants were randomised 1:1 to either methadone or another opioid rotation. Standardised assessment tools were used at predefined time points over 14 days.

Of 51 eligible participants, 38 patients consented, and 29 patients completed the follow up. Both groups showed significant reductions in average and worst pain scores, as well as total pain interference scores. The methadone group had a more significant reduction in oral morphine equivalent daily dose compared to the OOR group. However, the incidence of opioid-related adverse events was unchanged in the MR group, but lower in the OOR group. Satisfaction with analgesia did not differ significantly between the groups.

While this pilot study demonstrated that both MR and OOR are feasible, safe and acceptable for patients with refractory CIBP, the authors note that methadone must be prescribed by clinicians familiar with its complex kinetics. The study highlights the need for larger, multi-centre randomised controlled trials to confirm these findings and better understand the efficacy of MR and OOR in this patient cohort.

The study’s limitations include its small sample size and short follow up period, which may affect the generalisability and robustness of the results. Moreover, the study could not provide definitive conclusions on the observed difference in reports of opioid toxicity between groups nor how anxiety impacted pain perception.

Sulistio M, Gorelik A, Tee HJ, Wojnar R, Kissane D, Michael N. Methadone versus other opioids for refractory malignant bone pain: a pilot randomized controlled study. Support Care Cancer 2024; 32: 495.

Pharmacists in specialist palliative care telehealth

Globally, only a small portion of patients in need of palliative care receive it, with rural and remote populations facing particularly limited access. In Australia, the majority of palliative care is provided in hospitals rather than in patients’ homes, despite evidence that home-based care is a cost-effective alternative to hospital admissions and enhances patient outcomes. Palliative care patients are at high risk of experiencing medicine related harm, yet pharmacists are underrepresented in community palliative care teams.

This observational study explored the impact of the inclusion of a pharmacist in a telehealth-based specialist palliative care team with the aim of reducing medicine related harm. The study was conducted at the Gold Coast Hospital and Health Service, where the pharmacist participated in telehealth sessions twice weekly over a 6-month period. Data collected included identified drug–drug interactions, medication-disease interactions, adverse drug effects, recommendations to optimise symptom management, and recommendations to optimise medication administration and access.

Ninety-five patients were included with an age range of 43–96 years. At referral, 88.4% of patients were taking five or more medications and 56.8% of patients were taking potentially inappropriate medications. One hundred and forty-two medication recommendations were accepted by the prescribing team, with 34.5% related to deprescribing, 14% to medicine-related problems, 24.7% to symptom management and 26.8% to medication administration.

This study demonstrated the value of a specialist palliative care pharmacist in improving symptom management and reducing medicine related harms in a community telehealth service. Limitations include the brief intervention timeframe, potential bias due to the self-reporting of interventions and the inclusion of only one pharmacist. Despite these limitations, this Australian study offers valuable insights for developing a model of care that integrates specialist pharmacist reviews in community palliative care, including support for services delivered via telehealth.

Chess-Williams LM, Broadbent AM, Hattingh L. Cross-sectional study to evaluate patients’ medication management with a new model of care: incorporating pharmacist into a community specialist palliative care telehealth service. BMC Pall Care 2024; 23: 172.

Identifying the evidence gap in Australia for continuous subcutaneous infusion admixtures in palliative care practice

In palliative care, symptoms are commonly managed by administering multiple drugs combined in a single continuous subcutaneous infusion (CSCI). However, for many of these drug combinations, there is very limited evidence to support chemical compatibility and physical stability. This study assessed admixtures administered in CSCIs from three inpatient and two community palliative care services in Victoria over a three-month period.

CSCIs were assessed against Australian evidence-based compatibility guidelines to identify the frequency of CSCIs not supported by data, and the most common drug combinations and concentrations which require data. Compatibility was assessed as: physical and chemical compatibility with laboratory data, physical compatibility with observational data only, mixed compatibility impacted by factors such as change in concentration or pH, no compatibility data, and incompatible.

Of 616 infusions assessed against the guidelines, 340 had 2-drug combinations, and 276 had 3-drug combinations. Almost two-thirds had laboratory data with 60% compatible and 0.2% incompatible. Further laboratory data was required for 39.7% overall, with observational data only for 18.7%, mixed compatibility data for 15.4% and no data for 5.7%. The most prescribed combinations for which further data is required were hydromorphone and haloperidol, and hydromorphone, haloperidol and midazolam. 

The majority of CSCI observational data is from the United Kingdom, which differs significantly from Australian practice in preferred diluent and drug choices. This study has identified the common CSCI drug combinations and doses prescribed in Australian clinical practice and highlighted the gaps in available compatibility data locally. This can guide future laboratory research into CSCI compatibility and stability data.

Leong MCI, Michael N, Wojnar R. Compatibility of medication admixtures in continuous subcutaneous infusions: prioritizing laboratory testing for common combinations. Int J Pharm Pract 2024; 32: 392–395.

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TECHNICIANS AND ASSISTANTS

MedsScan Editor for Technicians and assistants SPG: Bryan Walker

COVID-19 and Canadian registered pharmacy technicians

Canadian registered pharmacy technicians (RPTs) were critical during the COVID-19 pandemic in supporting pharmacies. This article explores the experiences and stressors of these RPTs and aims to develop the Canadian profession. The authors used focus groups and the Job Demands-Resources (JD-R) model to investigate the experiences of 16 participants.

The authors identified some of the critical demands that emerged during the pandemic, including increased work volumes and hours to meet patient demand, the management of drug shortages and prescriptions, the unpredictable nature of COVID-19 and ineffective communication and increased staff shortages.

The 16 participants expressed that the increased work volume and expanded scope of practice increased their exhaustion and stress levels. To manage medication shortages, Canadian provinces were required to enact dispensing limits of 30 days to prevent hoarding of medicines. Staff also expressed their fear of exposure to COVID-19 while having to maintain face-to-face contact, along with call-offs and daycare and school closures increasing the strain on pharmacy technician resources. The lack of PPE was also identified as a significant hurdle to patient and employee safety.

Despite these stressors, the RPT workforce demonstrated tremendous adaptability, particularly in relation to managing medicine shortages. The authors recommend more pharmaceutical perspectives are included in policymaking and for pharmacy professionals to be part of the decision-making process. This would help improve medication safety, patient safety and communication. The authors also advise that organisations should include RPTs in their preparedness plans to help ensure a prompt and effective response to future events. Providing adequate compensation and recognition to the RPTs would help increase morale and retention and attract more people to the profession.

Khan A, Dignos PN, Papadopoulos A, Nowrouzi-Kia B, Sivanthan M, Gohar B. Unmasking the unrecognized: exploring registered pharmacy technicians’ stressors during COVID-19 through a demands-resources inquiry and looking ahead. Inquiry 2024; 61: 469580241241391.

American pharmacy technicians and workforce retention

While professional opportunities for American pharmacy technicians have expanded, increasingly many pharmacy technicians have chosen to transition from their professional roles. This study examined how pharmacy technicians in Ohio, USA could be retained in the workforce using education and training.  The authors aimed to evaluate technician interest and participation in technician development opportunities and describe the preparedness and training of pharmacy technicians in their current roles. This cross-sectional, anonymous survey was designed to evaluate pharmacy technicians' perceptions of training, preparedness and career paths and distributed to all 24 444 licensed pharmacy technicians within the state of Ohio.

One thousand, three hundred and eight-six surveys were completed and returned: of these 41% reported not devoting time to their professional development. Almost 25% of participants reported that they would like to spend more than 4 hours per month on personal development. The most common obstacle identified by participants in developing their personal growth was the added stress on the pharmacy technician's workload for more than 50% of the respondents. Other obstacles included cost/support (40%), a lack of employer support (30%), a lack of time to attend opportunities (35%) and a perceived lack of value of the available opportunities (27%).

Participants also identified the tools they found most helpful in their professional development and readiness for their current roles. These were identified as:  on-the-job training (60%), pharmacy technician certification (48%), and guidance or mentorship from peer technicians (46%). Experiential training was the most beneficial training modality among simulation, educational and experiential training options with 53% of respondents reporting it as helpful.

As a significant portion (41%) of respondents were not devoting time to professional development, the authors conclude that there is an opportunity to create programs to determine ways to increase participation suggesting creating devoted time during the workday and increasing group opportunities for shared learning, as well as increased financial support and dedicated time to complete certifications and attend relevant conferences. The authors call on employers to invest in ongoing training beyond onboarding to show support for the continuing growth of the technician workforce.

Unfortunately, minimal studies have been done in this area, and more research is required to determine what obstacles need to be overcome to increase technician job satisfaction and help support the pharmacy technician workforce.

Summerlin J, Duvall L, Hopton S, Vasko A, Graham A, Mehta BH. Pharmacy technician development: Insight into training, preparedness, and career-path perceptions. J Am Pharm Assoc 2024; 64: 120–125.

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WOMEN'S AND NEWBORN HEALTH

MedsScan Editor for Women’s and newborn health SPG: Kate Luttrell

To treat or not to treat: managing bipolar disorder during pregnancy

Background: Bipolar disorder affects approximately 2–3% of the Australian population, and it is known that pregnant and postpartum women are particularly at risk of bipolar mood episodes. This is likely due to an overlap in the onset of bipolar disorder during peak reproductive years, and the additional stress, hormonal and physiological changes that occur during this period.1

Uncontrolled bipolar disorder during pregnancy has been associated with severe mood imbalances postpartum, a 25–50% increased risk of postpartum psychosis, and increased risk of preterm birth, intrauterine growth restriction, caesarean and instrumental delivery, as well as adverse neonatal and neurodevelopmental outcomes.2,3

However, many patients with bipolar disorder discontinue treatment while pregnant, possibly due to concerns about the safety of their medicine during pregnancy or misinformation they have received from healthcare providers. This places the woman at a 71% chance of recurrence of bipolar disorder episodes during pregnancy.4,5

Aim: This retrospective chart review aimed to evaluate pregnancy and neonatal outcomes in women with untreated bipolar disorder compared to women treated with lamotrigine, lurasidone or other atypical antipsychotics at an American tertiary teaching institution, located in Missouri.

Method: Data was extracted from electronic medical records of pregnant patients, over 14 years of age with a history of bipolar disorder, and their neonates. Eligible patients had two documented prenatal visits at a Maternal and Fetal Care clinic after 1 January 2014, and delivered by 31 October 2017. Mothers were identified by their ICD-9 and ICD-10 codes for bipolar disorder diagnosis, and through medication reports of pregnant women prescribed a single mood stabiliser medication; lithium, antiepileptics or atypical antipsychotics were included.

Results: After reviewing data from 198 pregnancies, it was found that patients receiving a mood stabiliser during pregnancy had significantly lower rates of preterm delivery and low birth weight compared to patients with untreated bipolar disorder. No significant differences were observed between groups for gestational age, length, rates of caesarean section delivery, neonatal intensive care unit admissions, APGAR (Appearance, Pulse, Grimace, Activity and Respiration) scores or malformation rates. Mood stabilisers observed in this study included lamotrigine, lurasidone and other atypical antipsychotics, and no significant differences were found in outcomes between agents. The results of this study suggested that the use of mood stabilisers for bipolar disorder during pregnancy is not associated with adverse pregnancy or neonatal outcomes or foetal malformations.

Key limitations: Being a retrospective chart review, the study relied heavily on thorough clinical documentation during each patient’s episode of care. Confounding factors were not recorded or controlled for due to the study design including dose, adherence to therapy, concurrent medications or substance use and maternal comorbidities that may have impacted results.

The safety of medicines during pregnancy was assessed based on neonatal outcomes at time of birth, and no data was collected on adverse outcomes presenting later, such as neurodevelopmental or behavioural challenges. The sample size of this study was also likely too small to reliably detect any possible associations between untreated bipolar disorder or medication use and rare malformations or adverse outcomes.

Impact on practice: Current clinical guidelines recommend continuation of mood stabiliser therapy for bipolar disorder during pregnancy, with the exception of valproate and carbamazepine given their known teratogenic potential.6 Findings from this study add to the existing body of evidence supporting this practice.5,7,8 Despite this, we know many women are concerned about continuing psychiatric medications during their pregnancy, and if healthcare providers are not experienced in managing perinatal mental health, there is a risk of cessation of therapy and recurrence of bipolar disorder episodes.4,9

By continuing to research the appropriate management of psychiatric and chronic health conditions during pregnancy, we can better inform health care practitioners and patients to make treatment decisions that optimise maternal and neonatal outcomes. Pharmacists can play an important role in facilitating evidence-based discussions with patients on the safety and risks of medication exposure balanced against the risk of poorly controlled medical conditions. In this setting, providing reassurance to pregnant women regarding the continued use of their mood stabilisers during pregnancy is likely to result in improved outcomes for both them and their baby.

With limited data available on the safety of lurasidone use during pregnancy, this study also provides reassuring evidence that it may be an acceptable option for the treatment of bipolar disorder in pregnancy, with a similar neonatal risk profile to lamotrigine and other atypical antipsychotics. This is consistent with other research and pregnancy registries data, which suggest an absolute risk of malformations of 2.19% with lurasidone, within the expected background malformation rate of 3–5%.10,11

References

  1. Masters GA, Hugunin J, Xu L, Ulbricht CM, Simas TAM, Ko JY, et al. Prevalence of bipolar disorder in perinatal women: a systematic review and meta-analysis. J Clin Psychiatry 2022; 85: 21r14045.
  2. Clark CT, Wisner KL. Treatment of peripartum bipolar disorder. Obstet Gynecol Clin North Am 2018; 45: 403–417.
  3. Sit DK, Wisner KL. Identification of postpartum depression. Clin Obstet Gynecol 2009; 52: 456–468.
  4. Park Y, Huybrechts KF, Cohen JM, Bateman BT, Desai RJ, Patorno E, et al. Antipsychotic medication use among publicly insured pregnant women in the United States. Psychiatr Serv 2017; 68: 1112–1119.
  5. Viguera AC, Whitfield T, Baldessarini RJ, Newport J, Stowe Z, Reminick A, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 2007; 164: 1817–1824.
  6. Malhi GS, Bell E, Bassett D, Boyce P, Bryant R, Hazell P, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guideline for mood disorders. Aust N Z J Psychiatry 2021; 55: 7–117.
  7. Wang Z, Chan AYL, Coghill D, Ip P, Lau WCY, Simonoff E, et al. Association between prenatal exposure to antipsychotics and attention-deficit/hyperactivity disorder, autism spectrum disorder, preterm birth, and small for gestational age. JAMA Intern Med 2021; 181: 1332–1340.
  8. Bodén R, Lundgren M, Brandt L, Reutfors J, Andersen M, Kieler H. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilizers for bipolar disorder: population based cohort study. BMJ 2012; 345: e7085
  9. Masters GA, Xu L, Cooper KM, Simas TAM, Brenckle L, Mackie TI, et al. Perspectives on addressing bipolar disorder in the obstetric setting. Gen Hosp Psychiatry 2022; 77: 130–140.
  10. Montiel C, Newmark RL, Clart CT. Perinatal use of lurasidone for the treatment of bipolar disorder. Exp Clin Psychopharmacol 2022; 30: 249–252.
  11. Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev 2022; 24: 91–101.

Kernizan N, Forinash A, Yancey A, Kruger S, Chavan NR, Mathews K. Mood stabilizers for treatment of bipolar disorder in pregnancy and impact on neonatal outcomes. Bipolar Disord 2024; [online ahead of print]. DOI: https://doi.org/10.1111/bdi.13481.  

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