Knowledge Type: Clinical Articles

Introduction:

Pharmacist prescribers have been utilised in the United Kingdom, Canada and New Zealand, with American pharmacists now allowed to prescribe Paxlovid^®. Pharmacist/doctor prescribing began in the UK in 2003 and independent pharmacist prescribing commenced in 2006. The latter development meant that pharmacists were “responsible for the assessment and consequent management, including prescribing of both undiagnosed and diagnosed conditions.”

However, the acceptance of this extension to a pharmacist’s scope of practice has been slow to come to fruition in Australia. The following is a brief review of key papers on this topic.

Literature:

More than 12 years ago, it was established that prescription errors account for 70% of medication errors that could potentially result in adverse effects. One teaching hospital reported a mean for prescribing errors with the potential for adverse effects in patients of about 4 per 1000 prescriptions.

In an attempt to reduce prescribing errors in hospitals, numerous studies have been conducted to determine the potential need and possible merits of integrating pharmacists into the prescribing process for patients.

A prospective, multi-center study was conducted by Weant et.al (2014) at four US Emergency Departments (EDs). It investigated the various functions performed by pharmacists and their impact upon medication-error detection in the ED. During 1,000 hours of recorded time and 16,446 patients seen, pharmacists detected 364 medication errors. Computerised orders (54.4%) and verbal orders (32.7%) were the most commonly detected errors. This study demonstrated that clinical pharmacists in the ED can have a significant impact on medication-error detection.

Work by Tong et al. (2015) reported similar advantageous outcomes from credentialed pharmacist charted pre-admission medications with “significantly reduced inpatient medication errors (including errors of high and extreme risk) among general medical and emergency short-stay patients with complex medication regimens or polypharmacy.”

Taking the involvement of hospital pharmacists deeper into the prescribing chain, Poh and colleagues (2018) reported that pharmacists as prescribers made 20 to 25 times less prescribing errors and 3 to 116 times less omissions than doctors when prescribing patients’ usual medications on admission to hospital or in the preoperative setting.

This innovative program is known as a partnered pharmacist medication charting (PPMC) model. It involves a pharmacist taking a medication history, reconciling medications, assessing the risk of venous thromboembolism (VTE), collaboratively making decisions with the admitting medical officer and then charting the medication.

Charting errors are a ubiquitous clinical issue with medication errors among the most common incidents reported in hospitals as well as during the pre-admission stage. Failing to record a patient’s medication history accurately can lead to poor health outcomes and increased costs because the admission errors can easily flow through the patient’s hospital stay and transfers. The initial charting errors can penetrate into and be perpetuated throughout the whole patient’s hospital stay and emerge undetected on the discharge notes which the general practitioner receives. It has been estimated that there only needs to be greater than a 10% reduction in medication discrepancies on discharge for the program cost to be covered.

Addressing these problems, Nguyen et al. (2020) showed that a PeRiopErative and Prescribing (PREP) pharmacist has a significant impact on health outcomes. The benefits included:

• The PREP pharmacist group had fewer errors than the control group: 9% (5/53) versus 96% (49/51; P< 0.001).
• Discharge prescriptions prepared by the PREP pharmacist had fewer errors than control group: 25% versus 78% (P< 0.001).
• More PREP pharmacist patients received a discharge summary with a complete medication list: 75% versus 33% (P= 0.001).
• Inpatient prescribing was more accurate in the PREP pharmacist patients: 0.64 versus 1.31 errors per patient (P= 0.047).

In 2015, Alfred Health piloted the PPMC model with support from the Department of Health and Human Services’ Workforce Innovation Grants program. Through this randomised controlled trial, medication errors fell from 35.5% to 0.5%.

In 2016-2017, the trial was expanded across five health services (seven hospitals) and included 8648 patients. Results included:

• Reduced proportion of patients with at least one medication error (19.2% to 0.5%)
• Reduced length of stay (6.5 days to 5.8 days)
• The estimated savings of $726 per PPMC patient.
• The total savings from the 2,840 admissions where the PPMC model was used for medication charting was, therefore, approximately $1.95M.
• Cost modelling of the number of general medical patients admitted that could be expected to benefit from state-wide roll-out of the PPMC model operating suggested potential savings on inpatient costs of $202M per annum.

In 2020 a multicentre prospective cohort study deploying partnered pharmacist medication charting (PPMC) admitted to public hospitals in Victoria, Australia, compared patient outcomes before and after the intervention of the charting pharmacist.

Patients who had a PPMC were found to have:

• A half-day reduction in the length of stay (LoS) from 4.7 days to 4.2 days (P < 0.001).
• Medication charts that had at least one error were reduced from 66% to 3.6%.
• The number-needed-to-treat to prevent one error was 1.6 patients. (95% Cl:1.57-1.64).
• On average, one pharmacist would be expected to undertake the PPMC model for 5–10 patients per day. This equates to potential savings of $4725 to $9450 per pharmacist per day, with the estimated average cost of a pharmacist of $460 per day.

It was concluded that the expansion of the partnered pharmacist charting model across multiple organisations was effective and feasible and is recommended for adoption by health services.

Importantly, the expansion of the PPMC model of care to enable pharmacist charting of new medications has been shown to be safe in a study by Hua and co-workers (2022).

Further evidence of significantly lower rates of medication errors, lower severity of errors and shorter inpatient length of stay allied to the use of the PPMC model in the regional setting was provided by Tong et al (2022) who studied 669 patients who received standard medical charting during the pre-intervention period. Of this total, 446 (66.7%) had at least one medication error identified compared to 64 patients (9.5%) using PPMC model (p < 0.001). Also, from an economic perspective the median LoS was reduced from 4.8 in the pre-intervention group to 3.7 days (2.0-7.0) for those patients who received PPMC (p < 0.001).

Barriers to PPMC:

Despite the evidence of both a significant clinical and economic benefit from the use of PPMC, barriers to pharmacist prescribing are substantial. These include developing a positive socio-political milieu as well as a credible level of pharmacist prescriber (PP) competency. Hence there is a need for sophisticated training courses of a high academic merit, improvements in the perceptions of the role of a PP within the medical fraternity, and “identifying specific funding, infrastructure and resourcing needs to ensure the smooth integration of pharmacist prescribers within interprofessional clinical teams.”

Conclusion:

The initiation of a PPMC has a proven set of advantages. These include a reduced length of stay in hospital, a decrease in both the errors and the severity of errors, an increased hospital savings of $726 per PPMC patient and 92% patient acceptance of PPMC.

Thus, there appears to be no disadvantages to expanding the scope of practice for pharmacists into the partnered prescribing domain.

Three national quality use of medicines (QUM) publications have recently been updated. These publications are the:

• Guiding principles for medication management in residential aged care facilities 
• Guiding principles for medication management in the community; and
• Guiding principles to achieve continuity in medication management

These updated publications build upon previous versions and aim to improve the quality and safety of medication management in Australia. These guiding principles align with the National Medicines Policy with a focus on person-centred care in aged care facilities, the community and at transitions of care.

The Guiding principles to achieve continuity in medication management is particularly relevant to the hospital environment and aims to promote the quality use of medicines during transitions of care.

Transitions of care are situations where all or part of a patient’s care is transferred between healthcare locations, providers, or levels of care, including:

• Between healthcare providers (e.g. clinical handover in a hospital where one nurse hands over the responsibility for a patient’s health care to another nurse);
• Between levels of care in the same location (e.g. transfer of a patient from an emergency department to a ward in a hospital);
• Between healthcare locations or settings (e.g. transfer of care from ambulance service to an acute care service);
• When care needs change (e.g. transfer from an acute care service to an aged care home);
• When an individual’s preferences change (e.g. transfer of a patient from an oncology ward to a palliative care service due to end-of-life care preferences);
• When access to services changes (e.g. transfer of ongoing care from paediatric services to adult services); and
• Between levels of healthcare (e.g. an individual is discharged from a mental health inpatient facility back to the care of their GP).

These transitions of care form an integral part of the patient experience in the healthcare system. However, care transitions are also recognised as high-risk situations for patient safety. Studies demonstrate that more than 50% of medication errors occur at transitions of care, although this figure may be higher in some settings.

The Australian Commission on Safety and Quality in Healthcare (the Commission) highlights four transition points as being particularly prone to error. These are admission to the hospital, transfer from the emergency department (i.e. to a ward, intensive care, home), transfer from the intensive care unit to the ward, and transfer from the hospital (i.e. to home, aged care home, or another hospital).

The risk of medication errors and the potential for harm from those errors will vary depending on the patient. An individual’s risk of experiencing a medication error increases as the number of medicines they take increases. Patients at higher risk of harm from these errors include those taking high-risk medications (e.g. opioids, chemotherapy, anticoagulants) and patients with comorbidities (e.g. renal impairment).

Potential consequences of these errors include increased adverse effects, preventable readmissions, and increased morbidity and mortality. There is also likely to be significant dissatisfaction for both patients and healthcare providers alike.

Due to the significant nature of these potential outcomes, improving medication safety at transitions of care was identified as a key priority of the Medication without harm – WHO Global Patient Safety Challenge – Australia’s response. The Guiding principles to achieve continuity in medication management address this through its ten principles. Guiding principles one to four set the overarching system requirements, while the remaining principles outline specific activities.

These guiding principles, based on Commonwealth of Australia (Department of Health and Aged Care) material, are shown below.

Guiding Principle 1: Clinical governance and leadership “Leaders of healthcare services have responsibilities in ensuring the safe and quality use of medicines and in ensuring the ongoing continuity of medication management.” Guiding Principle 2: Responsibility for medication management “Providers of healthcare services, managers and healthcare professionals have a responsibility to participate in all aspects of medication management in partnership with the individual receiving care, their carer and/or family.” Guiding Principle 3: Accountability for medication management “Providers of healthcare services, managers and healthcare professionals are jointly and individually accountable for making sure that activities to support the continuity of medication management are implemented.” Guiding Principle 4: Safety and quality systems “Safety and quality systems are integrated within governance processes to enable providers of healthcare services and healthcare professionals to actively manage and improve the safety and quality of health care for and with individuals receiving care.” Guiding Principle 5: Medication reconciliation “Accurate and complete medication reconciliation should be performed at the time of presentation or admission, or as early as possible in the episode of care. Medication reconciliation needs to be performed at all transitions of care.” Guiding Principle 6: Review of current medicines “Throughout each episode of care, the safe and quality use of current medicines needs to be assessed and reviewed in partnership with the individual receiving care.” Guiding Principle 7: Medication management plan “A medication management plan needs to: Be developed by healthcare professionals, in collaboration with the individual receiving care, to develop strategies to manage the individual’s medications medicines Form an integral part of care planning for the individual receiving care Be reviewed during the episode of care and before transition of care.” Guiding Principle 8: Sharing decision-making and information about medicines with the individual receiving care “As early as possible in the episode of care, the individual receiving care, their carers and/or family should receive sufficient information, in a form they can use and understand, to enable them to safely and effectively use all medicines in accordance with the agreed medication management plan.” Guiding Principle 9: Collaborating and communicating medicines-related information with other healthcare professionals “When an individual is transitioned to another episode of care, the transferring healthcare professional needs to supply comprehensive, complete and accurate information to the healthcare professional responsible for continuing the individual’s medication management in accordance with their medication management plan.” Guiding Principle 10: Ongoing access to medicines “The individual receiving care, their carer and/or family needs to receive sufficient supplies of medicines and information about how to obtain further supply of medicines, to enable them to fulfil or comply with their medication management plan. This should consider person-specific circumstances and equity of access.”

The complete guiding principles document is available for download here; a condensed version can be accessed here.

From 1 December 2022, vericiguat was made available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of symptomatic heart failure.

The criteria for initial PBS supply requires patients to:

• Have a left ventricular ejection fraction (LVEF) of less than 45%;
• New York Heart Association (NYHA) class II, III, or IV;
• No clinical signs of fluid overload and not have received intravenous treatment for fluid overload in the preceding 24 hours;
• Systolic blood pressure ≥ 100mmHg;
• Be receiving optimal standard therapy for chronic heart failure that includes a beta-blocker (unless contraindicated or not tolerated); and
• Be receiving optimal standard therapy that includes either an angiotensin converting enzyme (ACE) inhibitor, angiotensin II antagonist, or angiotensin receptor with neprilysin inhibitor combination (unless contraindicated or not tolerated).

Vericiguat is a stimulator of soluble guanylate cyclase (sGC), a receptor normally activated by nitric oxide (NO). Stimulation of sGC leads to the synthesis of cyclic guanosine monophosphate (cGMP), a signalling molecule that is essential for the normal functioning of the cardiovascular system. This system plays an important role in regulating cardiac contractility, vascular tone, and cardiac remodelling. The synthesis of NO and the activity of sGC are both reduced in heart failure.

Efficacy

The safety and efficacy of vericiguat were evaluated in the VICTORIA trial. This double-blind study randomly assigned patients with chronic heart failure (NYHA class II-IV) and LVEF of less than 45% to receive vericiguat or placebo, in addition to standard guideline-based therapy. Over 5,000 adult patients participated in this study over a median follow-up period of 10.8 months. The primary outcome was a composite of death from cardiovascular causes or first hospitalisation for heart failure.

Some of the main findings of the study include the following:

• A primary-outcome event occurred in 35.5% of the vericiguat group and 38.5% of the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.02);
• Hospitalisation for heart failure occurred in 27.4% of the vericiguat group and 29.6% of the placebo group (hazard ratio, 0.90; 95% CI, 0.81 to 1.00);
• Death from cardiovascular causes occurred in 16.4% of the vericiguat group and 17.5% of the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06); and
• The composite of death from any cause or hospitalisation for heart failure occurred in 37.9% of the vericiguat group and 40.9% of the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P=0.02).

Safety

There was a slight reduction in systolic blood pressure noted in each group over the first 16 weeks of the VICTORIA study (greater effect in the vericiguat group than in the placebo group). However, readings returned to baseline by week 32. Patients with a systolic blood pressure of less than 100mmHg or symptomatic hypotension at treatment initiation were excluded from the study.

Symptomatic hypotension and syncope were prespecified adverse events of clinical interest in the VICTORIA trial. Symptomatic hypotension was more commonly reported in the vericiguat group (9.1% versus 7.9%), as was syncope (4.0% versus 3.5%).

The manufacturer advises that if symptomatic hypotension occurs, prescribers should consider dose adjustment of concomitant diuretics and treatment of other causes of hypotension. If symptomatic hypotension continues, a temporary reduction or interruption of vericiguat dosing should be considered.

Anaemia was also more commonly reported in the vericiguat group (7.6% versus 5.7%). While anaemia was common at baseline (35.7% of patients met the World Health Organization criteria for anaemia), vericiguat was associated with a modest reduction in haemoglobin at week 16. This reduction did not progress further over the 96 weeks of follow-up. Analysis demonstrates that patients with lower baseline haemoglobin levels were at higher risk for the primary end point of death from cardiovascular causes or hospitalisation for heart failure.

Reduced haemoglobin is a finding similar to studies conducted with riociguat, another sGC stimulator. The mechanism of this adverse effect is currently unknown. It has been postulated that anaemia could be a result of vasodilator effects that could lead to bleeding from unidentified sources. Alternatively, animal models suggest there may be a link between haemoglobin and the sGC pathway.

Contraindications and precautions

Vericiguat is contraindicated with other sGC stimulators. The other sGC stimulator available in Australia is riociguat, which is approved for the treatment of pulmonary hypertension.

Although not contraindicated, combined use with phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil) is not recommended. This combination of medications has not been studied in patients with heart failure, and it may increase the risk of symptomatic hypotension.

Administration

Vericiguat has a longer half-life (around 30 hours in heart failure patients) than riociguat and can be administered as a single daily dose. Dosing is usually initiated at 2.5mg daily. This can be doubled every two weeks to a target maintenance dose of 10mg once daily, or as tolerated. Tablets are available in 2.5mg, 5mg, and 10mg strengths to facilitate titration.

The manufacturer does not recommend dose adjustments for patients with mild or moderate hepatic impairment or severe renal impairment (eGFR ≥ 15 mL/min/1.73 m² without dialysis). However, vericiguat is not recommended for use in patients with severe hepatic impairment or an eGFR <15 mL/min/1.73 m^2, as it has not been studied in these populations.

For optimal bioavailability, vericiguat tablets should be taken with food. For patients who have difficulty swallowing, tablets may be crushed and mixed with water immediately before administration. This provides comparable bioavailability and peak plasma levels to swallowing a whole tablet.

When given with food, vericiguat exposure is not affected by coadministration with medications that increase gastric pH. This includes proton pump inhibitors, H₂ receptor antagonists, and antacids.

Place in therapy

Vericiguat is indicated as an adjunct to standard of care therapy for symptomatic chronic heart failure with reduced ejection fraction (HFrEF). The National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand recommend the following medications for all patients with HFrEF: an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist.

In the VICTORIA trial, more than 99% of patients were treated with other heart failure therapies at baseline. This included beta-blockers (93%), ACE inhibitors or angiotensin II receptor blockers (73%), and a mineralocorticoid receptor antagonist (70%). The majority of patients (91%) were taking two or more heart failure medications, and 60% were receiving triple therapy (i.e. a beta-blocker, any renin-angiotensin system inhibitor, and a mineralocorticoid antagonist.

Patients were also included who were taking an angiotensin receptor and neprilysin inhibitor (ARNI) combination (15%) or ivabradine (6%), or had an implantable cardiac defibrillator (28%) or biventricular pacemaker (15%).

Only 3% of patients were on a sodium glucose co-transporter 2 (SGLT2) inhibitor. Therefore, the study authors declined to comment on any potential additional benefit of vericiguat to SGLT2 inhibitor therapy. The SGLT2 inhibitors approved for the treatment of heart failure are empagliflozin and dapagliflozin.

In Australia, more than 26,000 babies are born preterm each year. The World Health Organization (WHO) classifies preterm as babies born alive before 37 weeks of pregnancy are completed. This can be further categorised as moderate to late preterm (32-37 weeks), very preterm (28-32 weeks), or extremely preterm (<28 weeks).

In the developed world, preterm birth is the leading cause of death and disability in children up to five years of age. It is associated with a wide range of complications, including long-term neurological disability, prolonged hospital stay after birth, readmission to hospital in the first 12 months of life, and chronic lung disease. For this reason, the care of preterm and low-birth-weight infants is a global priority.

On World Prematurity Day (17 November 2022), the WHO launched its recommendations for the care of preterm or low-birth-weight infants. The WHO recommendations for care of the preterm or low-birth-weight infant (henceforth referred to as ‘WHO recommendations’) cover preventive care, management of complications, and family involvement and support.

One of the new recommendations applies to the use of probiotics. This recommendation, based on moderate certainty evidence, states that “probiotics may be considered for human-milk-fed very preterm infants (< 32 weeks’ gestation).”

Infant microbiome

The human gastrointestinal tract is normally colonised by many microorganisms. This complex and diverse ecosystem is established through vertical transmission (i.e. from mother to infant) and environmental exposure. However, the intestinal microbiota of a preterm infant is typically quite different to that of a healthy full-term infant. A preterm infant is more likely to be colonised by potentially pathogenic facultative anaerobes, such as Enterobacter, Escherichia, and Klebsiella. In addition, levels of commensal strictly anaerobic microbes, such as Bifidobacterium, Bacteroides, and Clostridium, are reduced. These differences are largely related to gestational age, but may also be affected by the mode of delivery, exposure to antibiotics, and feeding practices.

The gut microbiome appears to play an important role in the development of many diseases in preterm infants, including serious conditions such as necrotising enterocolitis (NEC). Necrotising enterocolitis is a gastrointestinal condition that affects around 5% of very preterm or very low birth weight infants. It has a mortality rate of around 20-40%, although this may be closer to 50% in infants that require surgery. In addition, infants who develop NEC have a higher risk of other infections, slower growth, and longer hospital stays compared to gestation-comparable infants who do not develop NEC.

While the exact pathogenesis of NEC is not completely understood, studies demonstrate that feeding with human milk reduces the risk compared to feeding with cow’s milk formula. The apparent protective effect of human milk is postulated to be related to the prebiotic and probiotic substances it contains.

Probiotics are live microorganisms that provide beneficial health effects when administered in adequate amounts. Prebiotics, on the other hand, are substances that feed intestinal microbes to selectively promote the growth of non-pathogenic microorganisms. In particular, prebiotics in human milk may promote the growth of lactobacilli and bifidobacteria that play a role in maintaining mucosal barrier functions.

Infant probiotics

Due to the serious nature of conditions associated with microbial imbalances, strategies to address this have been investigated. Supplemental probiotics are one such measure.

There is currently a range of commercially available probiotics. These products typically contain one or more bacterial strains but may also contain fungi (e.g. Saccharomyces boulardii). They may be formulated as drops, powders, or capsules.

Infloran® is one example of an infant probiotic. This product contains Bifidobacterium bifidum and Lactobacillus acidophilus in a capsule presentation. Capsules can be opened, and the contents added to a small amount of liquid (e.g. expressed breast milk or formula).

Efficacy

A systematic review of 56 trials (totalling 10,812 infants) provided evidence on the efficacy of probiotics. This study looked at the potential for probiotics to reduce the risk of NEC in infants who were very preterm or very low birth weight (<1.5kg). This review included studies that investigated the enteral administration of probiotics (single or multi-strain) for at least one week using a comparator of placebo or no treatment.

This study suggested the following outcomes:

• Reduced all-cause mortality by hospital discharge (moderate-certainty evidence from 51 trials totalling 10,170 participants [RR 0.76, 95% CI 0.65 to 0.89]);
• Decrease in NEC by hospital discharge (low-certainty evidence from 54 trials totalling 10,604 participants [RR 0.54, 95% CI 0.45 to 0.65]);
• Decrease in invasive infection by hospital discharge (moderate certainty evidence from 47 trials totalling 9,762 participants [RR 0.89, 95% CI 0.82 to 0.97]);
• Decreased length of hospital stay (from 22 trials totalling 5,458 infants [mean difference -1.93 days, 95% CI -3.78 to -0.08]); and
• Little or no effect on neurodevelopment between 18 months and 3 years (low-certainty evidence from five trials totalling 1,518 participants assessing severe neurodevelopmental impairment using a validated test [RR.1.03, 95% CI 0.84 to 1.26]).

The type of probiotics used in these trials varied. Single‐genus probiotics were used in 33 trials (most commonly Bifidobacterium spp. or Lactobacillus spp.), while multi‐genus products were used in 23 trials (most commonly Bifidobacterium spp. plus Lactobacillus spp.).

There was no evidence of subgroup differences depending on probiotic genus for the outcomes of mortality, invasive infection, length of hospital stay after birth, visual impairment, or hearing impairment. However, there was some evidence of subgroup differences for the incidence of NEC.

For NEC, the largest effect size was seen for probiotics that contain:

• Lactobacillus spp.;
• Bifidobacterium spp. plus Lactobacillus spp.;
• Bifidobacterium spp. plus Streptococcus spp.; or
• Bifidobacterium spp. plus Lactobacillus spp. plus Streptococcus spp.

Only five trials (totalling 254 subjects) included formula-fed infants exclusively. Therefore, the WHO recommendations have not been applied to these infants. However, the authors of the systematic review conclude that the findings are likely to be broadly applicable to infants fed enterally with human milk, formula, or a mixture of the two. The risk-benefit equation may differ as the risk of NEC is higher in formula-fed infants.

Safety

The WHO recommendations advise that there is little evidence of harm associated with the use of probiotics in preterm infants. However, there are case reports of probiotic-derived bacteraemia and fungaemia occurring in preterm infants.

Summary

The WHO recommends that only probiotics specifically formulated for preterm or low birth-weight infants should be used in this population. In addition, products should conform to the relevant regulatory standards. In Australia, this would be indicated by the inclusion of the product on the Australian Register of Therapeutic Goods (ARTG).

The WHO recommendations concede that there is currently insufficient evidence to advise on the most appropriate probiotic type (i.e. genera, species or strain), formulation type, dose, or duration of administration. Parents should be involved in the decision-making and be adequately informed of the potential benefits and risks as well as the need for further research.

The eviQ resource, established by the Cancer Institute NSW, has developed an International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD). This guideline, created in collaboration with an international, multidisciplinary working party, aims to be a decision-support tool for cancer clinicians treating patients with chronic kidney disease (CKD).

It is estimated that 15-20% of cancer patients have an eGFR of 30-59mL/min/1.73m². Accurate assessment of renal function is particularly important for these patients as minor differences in estimated renal function may significantly impact prescribed therapy. This could be in the form of dose adjustments or avoidance of first-line therapies.

Recommendations from the ADDIKD guideline include significant changes to clinical practice regarding the assessment of renal function and dosing recommendations for 59 anticancer drugs in kidney dysfunction.

Key changes:

Standardised categories for kidney dysfunction

The Kidney Disease Improving Global Outcomes (KDIGO) CKD categories are recommended to guide dose adjustments and monitor drug-related adverse events for anticancer drugs. These categories are shown in Table 1.

Table 1. KDIGO kidney function categories based on measured/estimated GFR

GFR stage	GFR (ml/min/1.73m2)	Kidney function
G1	≥ 90	Normal or high GFR
G2	60-89	Mildly reduced GFR
G3A	45-59	Mild-moderately reduced GFR
G3B	30-44	Moderate-severely reduced GFR
G4	15-29	Severely reduced GFR
G5	< 15	Kidney failure without KRT*
G5D	< 15	Kidney failure with KRT*

*KRT = kidney replacement therapy

While there are limited studies investigating the use of KDIGO CKD categories in the oncology setting, standardisation of kidney dysfunction classification is expected to reduce complexity and promote uniformity.

Method of assessing kidney function

The preferred method of estimating kidney function in cancer patients is the estimated glomerular filtration rate via the Chronic Kidney Dysfunction-Epidemiology Collaboration 2009 equation (eGFR_CKD-EPI). This equation provides a more accurate and precise estimate of the directly measured glomerular filtration rate (mGFR) compared to other estimation methods, such as the Cockcroft-Gault equation. However, directly mGFR may be required in some clinical situations.

Directly mGFR remains the most accurate method to evaluate renal function in cancer patients. Direct methods measure the clearance of exogenous filtration markers such as inulin or iohexol. These agents are freely filtered by the glomerulus but not reabsorbed or secreted by the tubules. While direct mGFR is more precise, its use is limited by cost, time, and access issues.

Dosing modifications

The eGFR_CKD-EPI is recommended to guide the dosing of anticancer drugs that are dosed according to renal function. Exceptions have been made for specific clinical situations and specific anticancer drugs where this method may be unreliable.

The eGFR_CKD-EPI equation is not suitable for use in pregnant women, patients younger than 18 years, and kidney replacement therapy. Alternative methods of assessing renal function should be used in these patients.

In addition, there are many clinical scenarios where eGFR_CKD-EPI may be considered unreliable, including:

• Extremes of body size or muscle mass;
• Amputees;
• Persons with paraplegia;
• Skeletal muscle conditions;
• Advanced liver disease;
• Untreated hypothyroidism;
• Ureteric obstruction;
• People taking creatine supplements or drugs that interfere with creatinine secretion or creatinine assay; and
• Dosing of certain anticancer drugs, including carboplatin, methotrexate (doses ≥ 500 mg/m²), and cisplatin.

Directly mGFR is preferred for initial dosing in the above scenarios.

Calculating carboplatin doses

Carboplatin is predominantly excreted via glomerular filtration. Most of the dose is excreted within the first six hours, with 65% eliminated in the urine within 24 hours of administration. As renal function declines, urinary elimination decreases, and the area under the curve (AUC) increases. There is a strong correlation between carboplatin AUC, kidney function, and the severity of thrombocytopenia and, to a lesser degree, leucopenia.

In the case of carboplatin, directly mGFR is the preferred option in most cases. Body surface area-adjusted eGFR_CKD-EPI is a suitable alternative to use in the Calvert formula, especially where the eGFR falls between 45 and 125 mL/min/1.73 m², treatment intent is non-curative, and the patient is neither an amputee, paraplegic nor has conditions of skeletal muscle or an extreme of body size or muscle mass.

A new carboplatin dose calculator is available on the eviQ website. This calculator employs the Calvert formula with a target AUC. There are currently three options for the input of kidney function: directly mGFR, BSA-adjusted eGFR_CKD-EPI, and creatinine clearance calculated via the Cockcroft-Gault equation. The option of using creatinine clearance is included to support practice during the transition but will be phased out in the future.

Implications

The ADDIKD guideline is intended to guide clinical decision-making for the use of anticancer drugs in CKD; it is not meant to be prescriptive.

It should also be stressed that the new guideline does not apply to:

• Dose adjustment in kidney dysfunction beyond the first cycle of treatment (dosing for subsequent cycles requires an assessment of the patient’s tolerance to the initial dosing regimen);
• Dosing in acute kidney injury or unstable kidney function;
• Dose adjustment for kidney dysfunction in stem cell mobilisation, bone marrow transplantation and cellular therapies;
• Specific dosing instructions in kidney failure (eGFR < 15 mL/min/1.73 m² with or without KRT);
• Dosing in patients < 18 years of age with kidney dysfunction; and
• Dosing in pregnant women with kidney dysfunction

Current status

The ADDIKD guideline is published and available on the eviQ website. However, eviQ protocols have not yet been updated to align with the recommendations of the ADDIKD. In 2023, eviQ will begin progressively updating protocols by cancer type. This process is expected to take between 12 and 18 months. A link to the full guideline has been added to each eviQ protocol to avoid confusion during this interim phase.

eviQ has added two new calculators to its website to support the adoption of the ADDIKD guideline recommendations. The first is the eGFR calculator with the option to adjust for BSA. The second is the carboplatin dose calculator.

More detailed information, along with online learning modules, are also available at eviQ.

A study has shown that pharmacists and physicians seldom discuss a patient’s ability to swallow medications. Only a few of the affected patients with swallowing difficulties seek advice from their physicians or pharmacists. Older individuals may not be aware of their inability to swallow, as they could perceive it to be a normal aging process. As a result, they do not seek appropriate advice from a healthcare professional. Some signs and symptoms of medication swallowing difficulties include coughing, choking and gagging during or immediately after swallowing the solid oral dose form. Some individuals with medication swallowing difficulties may be asymptomatic and not display signs or symptoms. This does not necessarily rule out any risk of medication swallowing difficulties.

More than 70% of medications are administered orally. More than 60% of active pharmaceutical ingredients are formulated as solid oral forms e.g. tablets and capsules. Hence, there is a need to create awareness in providing the appropriate recommendations.

Swallowing solid dosage forms whole goes against the innate chewing reflex. This may trigger a gag reflex in some people when the tablet or capsule touches the tongue. Successful swallowing of a solid dose depends on an individual’s ability to overcome their chewing and gag reflex. Swallowing tablets and capsules without chewing is a skill and it can be taught.

Contributing factors:

• Females are more likely to experience medication-swallowing difficulties than males as they have a shorter interval between swallows, and a smaller volume in each swallow.
• Aging, as swallowing flow and volume capacity decreases with age.
• Tablets and capsules that are too small may be difficult to swallow, as some individuals may be unable to feel them once they are in the mouth.
• Rough textures, irregular shapes and unpleasant tastes or smells of solid oral medications.
• Past traumatic events, e.g. choking episodes associated with swallowing solid dose forms.
• Medical conditions e.g. stroke, Parkinson’s disease, xerostomia.

Issues that arise due to swallowing difficulties:

• Individuals may not receive the full therapeutic dose due to medication non-adherence.
• An increase in medication retention time in the throat may result in oesophagitis especially when taking doxycycline, NSAIDs or bisphosphonates.
• The uncoordinated swallowing process may force the medication to penetrate the lungs, causing aspiration pneumonia.
• Prolonging the swallowing process may lead to solid medications to disintegrate in the mouth releasing a bitter taste, which may further aggravate the swallowing issues.

Management strategies for medication swallowing difficulties:

• Provide appropriate advice on dose form modification e.g. oral liquids, disintegrating tablets, wafers, patches, and injections. The pharmacist should initiate discussion with the prescriber before amendment to the dose form is made. When a formulation is not commercially available, pharmacists can contact a compounding pharmacy to check availability of an extemporaneous product.
• Modifying solid forms to ease swallowing e.g. splitting, crushing or chewing tablets and opening capsules. Spoons, syringes, knives, pill crushing devises, pill cutters, a mortar and pestle can be recommended. Consider potential drug loss when modifying dose forms. Certain modified release preparations can be halved but not crushed or chewed, while some cannot be halved, crushed or chewed.
• Postural adjustment – changing the head and neck position to alter the speed and flow of solid dose forms making it easier to swallow and reducing the risk of aspiration and laryngeal penetration. Consultation with the physician or speech pathologist to determine suitability is necessary.
• Mixing medication with foods like fruit puree, applesauce, yoghurt, honey, custard, pudding. A speech pathologist or dietician could advise on the most appropriate food textures and liquid consistencies to ensure a safe swallow. Complete consumption of medication containing food is necessary to avoid under dosing. Food –drug interactions when mixing medications with food and beverage should be taken into account.
• Recommending appropriate swallowing aids as this eliminates the need to modify dosage form e.g. use of medication lubricating gels (Gloup®).
• Recommend to swallow solid medications with at least 50 – 60 ml of water.

Pharmacists need to proactively approach patients and incorporate a discussion about medication swallowing difficulties when providing medication counselling to all patients. However, inappropriate dose form modifications may be harmful and result in serious health and legal consequences.

There are two key issues related to the use of vancomycin in arthroplasty patients:

1. Is the drug appropriate, and
2. Is the dose appropriate.

In arthroplasty, vancomycin is indicated for patients:

• Colonised or infected with methicillin-resistant  aureus(MRSA), or
• At increased risk of being colonised or infected with MRSA, e.g. patients undergoing a joint arthroplasty procedure that is a reoperation (return to theatre or early revision),
• Patients with immediate non-severe or delayed non-severe hypersensitivity to penicillins, use cefazolin, with or without vancomycin.
• Patients with immediate severe or delayed severe hypersensitivity to penicillins, use vancomycin as monotherapy.

As can be seen, vancomycin is not a ‘just in case’ therapy.

Historically vancomycin was dosed as 1g irrespective of the patient’s weight. However, pharmacokinetics studies have shown that there is a greater deposition of vancomycin in fat tissue compared to bone. Sharareh et al. have reported that for vancomycin “a substantial difference was noted in trabecular bone concentrations with respect to patient weight with lower body mass index (BMI) achieving greater concentrations.” Furthermore, the lipophilic nature of vancomycin has direct dosing implications in obese patients compared to those with a normal range BMI.

It is relevant to determine if there is any difference in periprosthetic joint infection (PJI) for different antibiotic therapies. Kheir and colleagues (2017) reviewed the past records of 1828 patients at a single institution who underwent primary total joint arthroplasty (TJA) and who received vancomycin prophylaxis (2008 to 2014). During the same period, 5810 patients underwent primary TJA and received cefazolin monotherapy. Adequate vancomycin dosing was defined as 15 mg/kg. All patients had vancomycin infusion initiated within two hours before incision.

One of the principal findings was that primary TJA patients receiving vancomycin had double the rate of PJI (2%) compared to patients receiving cefazolin (1%), and  94% (1726 of 1828) of patients received a fixed 1-g dose of vancomycin, of whom 64% (1105 of 1726) were underdosed.

Hence, dosing all patients with 1g of vancomycin is frequently inadequate as it is only for patients weighing 66.7kg or less. The therapeutic inappropriateness of this dosing regime is underscored by a recent report from the Australian Institute of Health and Welfare (2022), which reported that 31% of the population is obese (BMI ≥ 30).

The Australian Orthopaedic Association and South Australian Health recommend vancomycin 1.5g for patients > 80kg if the patient meets the approved indications, whilst international practice, reflected in Therapeutic Guidelines, recommends a dose of 15mg/kg. With weight-based dosing, only 12% of patients have been shown to have a vancomycin level < 15mg/L, whereas 60% of patients had a vancomycin level < 15mg/L when given 1g.

It is relevant to this discussion to appreciate that the appropriate dosing of vancomycin is best determined by using the area under the curve (AUC): minimum inhibitory concentration (MIC) ratio. This ratio combines the pharmacokinetic (time course of antimicrobial concentrations) and pharmacodynamic (antimicrobial effect of the concentration) factors. Both of these factors determine efficacy.

The AUC is determined by the peak serum level (or time at incision) and trough level (time at wound closure), whereas the pharmacodynamic parameter relates to the duration of time that the drug level is above the MIC. It is essential that vancomycin concentration levels remain above the MIC for the entire surgical procedure (until complete wound closure) so as to exert a full and effective prophylactic effect.

Dosing with 1g of vancomycin, irrespective of weight will fail the AUC/MIC standard too frequently.

Various national guidelines unambiguously argue against the routine use of vancomycin. The Australian Orthopaedic Association (AOA – 2018) has stated that:

“Vancomycin should NOT routinely be used for surgical prophylaxis except for patients with immediate hypersensitivity (eg anaphylaxis) to penicillin (where it replaces the cephalosporin) or with an increased risk of postoperative infection with methicillin-resistant Staphylococcus aureus (MRSA) (where it is added to the cephalosporin). This includes patients known to be infected or colonised pre-operatively with MRSA, or with a history of infection or colonisation with MRSA.” (Their emphasis)

International research also argues against the use of alternatives to cephalosporins such as vancomycin/clindamycin.

“ … the use of a non-cephalosporin perioperative antibiotic continues to be associated with a greater risk of TKA PJI compared to cefazolin. Strategies that increase the proportion of patients receiving cefazolin rather than non-cephalosporin alternatives must be emphasized.” In this study, 10,484 knees (90.8%) received cefazolin, while 1,066 knees (9.2%) received either vancomycin or clindamycin as preoperative prophylaxis. The rate of PJI in the cefazolin group (0.5%) was half of that seen in the vancomycin or clindamycin group. (1.0%).

A key question that may arise is whether adherence to published guidelines has any clinical outcome bearing.

Chandrananth et al. studied this issue and concluded that “Non-adherence to guidelines increased the risk of SSI in patients undergoing total knee and hip arthroplasty. Dosing adjustment recommendations of prophylaxis for patients weighing >80kg was poorly adhered to, and these patients were subsequently at higher risk of infection… In patients weighing >80kg (49.5% of surgeries), guideline-concordant dosing occurred in only 58.7% of cases.”

A major consequence of the inappropriate dosing and non-indicated use of vancomycin is the development of vancomycin-resistant enterococci (VRE) and the horizontal gene transfer (HGT) of resistant genes to other enterococci species as well as other bacterial families such as S. aureus. Due to HGT, VRE isolates of the VanA phenotype have caused disease outbreaks. Moreover, the undiscerning use of vancomycin resulting in VRE and multi-drug resistance is leading clinicians to rely on “last resort antibiotics” which are increasingly ineffective and pose a particular challenge for clinical management.

To conclude, it is clinically imprudent to use vancomycin at a sub-therapeutic level and in patients for whom there is no indication.

A bisphosphonate drug holiday is a break from medication therapy following long-term treatment. Bisphosphonates are effective at reducing the risk of vertebral, non-vertebral and hip fractures in postmenopausal women and adult men. Though there are many benefits of treatment, some rare but serious side effects have been associated with the use of bisphosphonates including atypical fractures. Drug holidays may reduce the risk of serious adverse effects. Bisphosphates are long-acting medications, and therefore adequate efficacy may be maintained after discontinuation. Therefore, drug holidays may be a great option for patients to reduce the risks of treatment.

Bisphosphonate therapy has been shown superior to placebo at reducing the rate of fractures in randomised controlled trials. In one review they found therapy to be associated with a 50% reduction in hip fracture risk, 40 to 50% reduction in vertebral fractures and 20 to 30% reduction in non-spine fractures.

In the FIT study, over 2000 women were randomised to alendronate or placebo for up to five years. Many benefits of alendronate therapy were identified in the trial including a 50% reduction of vertebral fractures with five years of treatment. Also, there was significantly less non-vertebral fractures.

In another study, the HORIZON-PFT, patients received three years of annual zoledronic acid infusions. Zoledronic acid therapy was found to reduce the risk of hip fracture by 41%, reduce the risk of non-vertebral fractures by 25% and increase bone mineral density (BMD).

Adverse effects

Atypical femoral fractures (AFF) and osteonecrosis of the jaw are the two rare but potentially serious adverse effects that are associated with bisphosphonate therapy. These side effects are so rare that many trials of these medications have no cases in the study population. Of note, these serious side effects are more common in cancer patients who receive high dose bisphosphonates but still linked to patients who are using bisphosphonates for fracture prevention.

Atypical femoral fractures

AFF is often only on one side, requires surgical repair and can occur with minimal trauma. Though the cause is unknown, bisphosphonates are anti-remodelling drugs and it is thought that AFFs are exacerbated by impaired bone repair.

In a study of almost 200,000 women, 277 AFF incidents occurred. The risk of AFF was higher with increased duration of therapy with a bisphosphonate. The hazard ratio of 8.86 for patients who used bisphosphonates for 3 to 5 years (when compared with use of bisphosphate under 3 months) and increased up to 43.51 for patients who received 8 years of therapy or more. Post discontinuation of therapy, the risk of AFF fell rapidly.

Osteonecrosis of the jaw

Osteonecrosis of the jaw is bone that is exposed in the facial region. To meet the criteria of medication-related osteonecrosis of the jaw, patients must have been exposed to an antiresorptive drug, antiangiogenic drug or romosozumab. They must also have no history of facial radiation therapy, and the exposed bone must have not healed over a period of greater than 8 weeks.

The condition is rare, reported in less than 1 case in 10,000 patient years in patients using bisphosphonates for fracture prevention. Whilst some serious cases require extensive jaw surgery, most cases are mild.

Drug holidays

Bisphosphonates have been shown in pharmacokinetic studies to remain in the bone for years after cessation. For example, alendronate has a similar half-life to bone mineral, about 10.5 years. So, a patient having a drug holiday may continue to benefit from past treatment for years. Another benefit of stopping bisphosphate therapy is the theoretical increase of bone turnover.

The FLEX trial (an extension of the FIT trial) included over a thousand women who had received on average five years of alendronate therapy. Patients were randomised to an additional five years of therapy with alendronate or placebo. Patients in the alendronate group maintained BMD (bone mineral density) at the total hip and had a greater increase in lumbar spine BMD and total body BMD than the placebo subjects.

Fracture rates between groups were similar. However, the rate of clinical vertebral fractures was significantly different between groups with 5.3% in placebo group and 2.4% in alendronate group.

Overall, the authors concluded that for many women, a drug holiday of up to five years after five years of treatment of alendronate was unlikely to increase fracture risk. However, continued treatment without a drug holiday may be appropriate for patients with very low BMD or for patients at high risk of vertebral fractures.

In another follow up study of the HORIZON-PFT trial, 921 women who had received three annual doses of zoledronic acid were randomised to continue for another three years or receive placebo. The primary outcome, change in femoral neck BMD, was significantly different, +0.24% in zoledronic acid group compared to -0.80% in placebo group. The difference in lumbar spine was also significantly different.

There was no significant increased risk for nonvertebral, hip or all clinical fractures between groups. However, the risk of vertebral fracture was significantly lower in the treatment group.

The authors concluded that patients who had a drug holiday had residual benefits from therapy. Patients who continued therapy were more likely to maintain gained BMD. This study also recommended that patients that are deemed high risk continue bisphosphonate therapy.

There was also a three-year extension for women from that trial who had already received 6 years of zoledronic acid, 190 patients were randomised to receive a further three years of treatment or placebo. Due to the small subject population, there were few fractures and no significant difference between groups. From this trial, it is likely that patients who receive zoledronic acid therapy for six years can have a drug holiday of up to three years.

The FLEX and HORIZON studies were important in establishing the benefits and risks of drug holidays. The risk of vertebral fractures was approximately 50% higher in patients who were in the placebo groups in these trials than the patients in the treatment groups. No significant differences were found between the risk of hip fracture or all non-spine fractures. There are concerns that these outcomes were not able to be reviewed as there were not enough patients in either study to identify a significant difference in risk of these outcomes.

There are no randomised controlled trials for drug holidays from risedronate therapy. There is a cohort analysis of over 50,000 subjects comparing subjects who had a drug holiday from either risedronate or alendronate. Subjects included had used bisphosphonate therapy for over three years and had a break of over 120 days. Follow up was up to 3 years.

Overall, patients who used risedronate prior to a drug holiday were found to be at an 18% increased relative risk for hip fracture over 3 years compared with patients who used alendronate prior to a drug holiday. This effect was more pronounced after two years of drug holiday. Of note, there were limitations of this cohort study including that not all relevant data for subjects was available (such as BMD) and therefore the investigators couldn’t rule out significant differences between subject groups. However, the trial indicates that a risedronate drug holiday has increased risks compared with an alendronate drug holiday.

Of note, if patients do have drug holidays from risedronate, this should be reviewed at the end of two years due to the potential for increased risk of hip fracture.

The ideal candidates for drug holidays are patients who do not have very low BMD, have no fracture history and patients who are younger. Contraindications of a drug holiday include history of hip fracture, vertebral fractures or if a patient has had a fracture while receiving treatment.

For patients who are in the middle ground, patients need to be advised of the risks versus benefits and allowed to make an informed decision.

Once a drug holiday has been commenced, monitoring BMD is recommended. If BMD levels drop too low, or the patient has a fracture, bisphosphonate therapy should probably be restarted. At the end of a proposed drug holiday, unfortunately there is no clear evidence to guide us. Restarting therapy with oral or IV bisphosphonate may be appropriate, or switching to denosumab might be another option.

Drug holidays may be appropriate for patients who have received five years of treatment with oral bisphosphonates or three to six years of therapy with IV bisphosphonates. Treatment with bisphosphonates needs to be regularly reviewed to assess the risks and benefits of treatment. The potential for serious adverse effects (especially AFF) that increase with increased length of treatment must be considered as well as the potential for maintained benefit during a drug holiday. It is essential for patients to be informed on the risks and benefits.

Hopefully there will be more studies in the future to guide clinicians on the best timing for drug holidays. Also, hopefully there will be studies on how to recommence patients on these treatments following a drug holiday.

Approximately one in six people worldwide are affected by iron deficiency anaemia (IDA). It is the most common nutritional deficiency. Children below five, pregnant women and women of childbearing age are at the greatest risk of IDA.

The symptoms of IDA include weakness, fatigue, dyspnoea, headache, paleness and difficulty concentrating. Symptoms often vary between age groups, and IDA may also be asymptomatic. Iron is an essential nutrient that is indispensable for lots of different cellular mechanisms, including mitochondrial function, enzymatic synthesis and processes, and DNA synthesis and repair. It is also an essential part of the synthesis of myoglobin (found in muscles) and haemoglobin (found in red blood cells). Haemoglobin is essential for the transportation of oxygen by red blood cells.

An iron study blood test with low haemoglobin and low ferritin levels is an indicator of the presence of IDA. Serum iron levels may not accurately show the availability of iron in the body which is why an iron study panel blood test is required.

There can be many different causes of IDA. IDA may be due to increased intake requirements or demand due to menstrual blood loss, pregnancy, blood donation or other blood loss. It can be caused by insufficient iron intake due to patients eating a vegan/vegetarian diet or suffering from disordered eating. IDA may also be caused by malabsorption due to coeliac disease or inflammatory bowel disease. Other potential causes of IDA include medications, genetic causes or disease-related (such as anaemia of chronic disease).

Medications that may cause IDA include non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs). NSAIDs can cause injury to the gastrointestinal tract resulting in ulcers and/or bleeding, which may precipitate IDA. PPI use can be associated with reduced absorption of other medications and nutrients. Gastric acid secretion affects the absorption of iron from the gastrointestinal tract. In a population-based case-control observational study, the use of PPIs for over one year by subjects was associated with a greater risk of iron deficiency.

IDA can have serious long-term outcomes. Children with IDA may have delayed cognitive development or difficulty concentrating. Adults with IDA may have reduced physical performance, including work productivity, and IDA is associated with a reduced quality of life, especially for women with heavy menstrual bleeding. Pregnant women with IDA are more likely to go into preterm labour, have neonates with lower weights, and IDA is also associated with an increased risk of neonatal and maternal mortality. Elderly people with IDA may experience cognitive decline.

Treatment of IDA should include investigation of the underlying causes and management where possible. For example, if IDA is due to blood loss during menstruation, consider options to reduce blood loss, such as contraceptive therapy. Treatment with iron therapy (oral or parenteral) is usually required to adequately and quickly replenish iron stores. Serum ferritin levels should be monitored to ensure adequate response to therapy. For long-term prevention of future IDA, patients may need to adjust their diets to include more iron-rich foods.

Oral iron therapy is inexpensive, simple to administer and is often more convenient for patients. Oral iron therapy’s side effects include black stools, constipation and nausea. Oral iron therapy is not suitable for patients with absorption issues.

The usual dose is 100mg to 210mg of elemental iron daily. It is best to take at least one hour before food, and it may interact with tea, calcium supplements, PPIs and antacids. Vitamin C assists iron absorption, and vitamin C/iron combination products are available. If gastrointestinal side effects occur, patients can try divided dosing or take iron supplements with food.

Children with IDA may be administered 3 to 6mg elemental iron per kg per day with a maximum dose of 210mg. There are less side effects with doses at the lower end of the range, and it may be beneficial to administer doses with juice containing vitamin C to increase absorption. Iron absorption is inhibited in children who consume a lot of milk and other dairy products (including bottle feeding). Where possible, it is recommended to reduce milk consumption to under 500mL per day in children aged between 1 and 5.

IV therapy is indicated for use in patients who cannot use oral therapy or where a quick response is required. IV is preferred over IM as absorption is poor from IM injection. IM injection may also be painful and discolour the skin. IV iron is more effective than oral iron at improving quality of life for patients with chronic medical conditions and pregnancy. IV iron is indicated for patients receiving dialysis and for IDA induced by chemotherapy. In a meta-analysis of over 10 000 subjects, iron infusions were not associated with severe side effects or an increased rate of infections. IV site reactions may occur, and there is a very small risk of anaphylaxis.

Ferric carboxymaltose (Ferinject^®) is suitable for rapid infusion and is generally well tolerated. This medication is indicated for patients 14 years and older. Iron polymaltose (Ferrosig^® / Ferrum H^®) has a long infusion time (typically around five hours) and is indicated for hospital inpatients. Iron sucrose (Venofer^®) is used for haemodialysis patients and other specialist settings. Please refer to dosing guides and local hospital protocols.

In summary, IDA is a common but potentially serious condition that requires iron therapy. Oral iron therapy is often used first line, but adverse effects may decrease patient compliance. IV iron therapy is indicated for severe IDA, patients with absorption issues, patients with chronic disease and for patients unable to tolerate oral therapy.

Background

An electrocardiogram (ECG or EKG) is a non-invasive test that is used to evaluate electrical activity of the heart. The P wave represents atrial depolarisation which occurs prior to atrial contraction. The QRS complex represents ventricular depolarisation which occurs prior to ventricular contraction. The T wave represents ventricular repolarisation. The duration of time between the onset of ventricular depolarisation and end of repolarisation is described as the QT interval.

Figure 1. Normal sinus rhythm as seen on ECG (Credit: Agateller (Anthony Atkielski) licensed under Public Domain via Wikimedia Commons)

A prolonged QT interval on the ECG is used as a marker for increased risk of Torsades de Pointes, a potentially life-threatening form of polymorphic ventricular tachycardia. In some cases, brief episodes may self-terminate. However, in severe cases, it may cause sudden cardiac death. Torsades de Pointes is associated with a high mortality risk of 10%.

Hospital patients are at greater risk of drug-induced QT interval prolongation and Torsades de Pointes, due to the increased likelihood of being prescribed high-risk medications during an admission. Additional risk factors include concomitant heart disease, advanced age, electrolyte imbalances, bradycardia and kidney or liver disease.

Importantly, drug-induced QT interval prolongation can be preventable. Understanding the risk factors, medications related to QT interval prolongation and assessing the risk is essential to preventing poor clinical outcomes.

QT drugs

Certain medications are associated with varying risk levels of Torsades de Pointes. Medications considered as conditional risk are only associated with Torsades de Pointes under certain conditions of use (e.g. overdose, hypokalaemia, drug interactions).

The risk of developing QT interval prolongation can also be affected by the administration method, such as in cases of rapid IV dosing.

Table 1. Examples of medications and associated risk of Torsades de Pointes (source: Credible Meds)

Class	Known Risk	Possible Risk	Conditional Risk
Antibiotics	Moxifloxacin Clarithromycin Roxithromycin Azithromycin Ciprofloxacin Erythromycin	Norfloxacin	Metronidazole
Antidepressants	Escitalopram Citalopram	Nortriptyline Mirtazapine Venlafaxine	Amitriptyline Doxepin
Antifungal	Fluconazole		Voriconazole Ketoconazole
Antipsychotic	Haloperidol Droperidol Chlorpromazine	Clozapine Asenapine Lurasidone	Olanzapine Risperidone Ziprasidone
Antiemetic	Droperidol Chlorpromazine Ondansetron	Granisetron Promethazine	Metoclopramide
Anaesthetic	Cocaine Propofol
Antiarrhythmic	Sotalol Flecainide Amiodarone
Analgesic	Methadone	Tramadol Buprenorphine
Other	Hydroxychloroquine	Levetiracetam

Assessing QT interval prolongation risk  

The Tisdale Risk Score for QT interval prolongation may be a useful predictive tool to assess the risk in hospitalised patients.

The use of the Tisdale Risk Score was studied in a cardiac care unit, in which 13% of alerts resulted in additional ECG/laboratory monitoring or treatment of modifiable risk factors and discontinuation of 17.9% of medication orders.

Figure 2. Tisdale Risk Score for QT interval prolongation

Risk Factor	Points
Age ≥ 68 years	1
Female sex	1
Loop diuretic	1
Potassium Serum K+≤ 3.5 mEq/L	2
Admission QTC  ≥450 ms	2
Acute myocardial infarction	2
1 QTC interval-prolonging drug	3
≥ 2 QTC interval-prolonging drugs	3
Sepsis	3
Heart failure	3
Maximum risk score	21

Risk score category: Low risk = <7; Moderate risk = 7 to 10; High risk = >11

Role of Pharmacist

Pharmacists can help minimise the risk of QT interval prolongation and Torsades de Pointes in hospitalised patients through:

• Awareness of risk factors
• Monitoring serum electrolyte concentrations
• Identifying high-risk drug interactions
• Providing dose adjustments for renally cleared QT interval prolonging drugs in renally impaired patients