Knowledge Type: Clinical Articles

Tirzepatide is a new drug for the treatment of type 2 diabetes mellitus (T2DM). While it is not yet available in Australia, it has recently gained Therapeutic Goods Administration (TGA) approval for adults with insufficiently controlled T2DM as an adjunct to diet and exercise, where monotherapy with metformin alone has not been tolerated or contraindicated, or in addition to other pharmacotherapies for the treatment of T2DM (1). Though not yet TGA approved for the indication of obesity, tirzepatide also offers promising outcomes in substantially reducing body weight.

It is a unique and “first in its class” medication as it is both a glucagon-like peptide–1 (GLP-1) receptor agonist, as well as a long-acting glucose-dependent insulinotropic peptide (GIP) receptor agonist. Its action on the GLP-1 receptor stimulates insulin secretion in hyperglycaemic states, suppresses glucagon secretion, delays gastric emptying and decreases appetite. GIP receptors are widespread in adipose tissue and also have a role in increasing insulin sensitivity. Thus this dual mechanism functioning on both the GLP-1 and GIP incretins significantly reduces glycaemic levels and improves insulin sensitivity, whilst reducing body weight and improving lipid metabolism. Its C20 fatty-diacid moiety, which can bind to albumin, prolongs its half-life, enabling it to be dosed once a week via subcutaneous injection.

The pre-filled subcutaneous pen is presented in multiple different strengths, as the starting dose is 2.5mg once weekly and increasing to 5mg once weekly after four weeks. The dose can be increased in further 2.5mg increments after a minimum of four weeks, with the recommended maintenance doses being either 5mg, 10mg or 15mg, with the maximum dose being 15mg once weekly. Common side effects of tirzepatide are comparable to other GLP-1 agonists and include gastrointestinal side effects such as nausea, vomiting and diarrhoea, and the incidence of hypoglycaemia appears to be low.

Compared to semaglutide, which is currently on the market, studies have shown that tirzepatide has significantly superior therapeutic efficacy. A higher percentage of those using tirzepatide reached the glycated haemoglobin (HbA1c) target level of less than 7% compared to those on semaglutide, and the patients who received tirzepatide 15mg attained almost twice the weight loss of those who received semaglutide 1mg.

Thus, tirzepatide is an emerging and promising option for those with T2DM and obesity, showing superior effects compared to semaglutide.

Crohn’s disease is a type of inflammatory bowel disease (IBD) that causes chronic and progressive inflammation of the gastrointestinal tract (GIT). It can affect any part of the GIT from the mouth to the anus, but most often affects the ileum and the beginning of the colon, leading to symptoms such as diarrhoea, abdominal pain, fatigue and weight loss. The exact cause of Crohn’s disease is not well understood, but it is believed that a combination of a genetic predisposition, environmental exposure and infectious factors may all contribute to a subsequent dysregulated immune response, leading to chronic inflammation.

There is currently no known cure for Crohn’s disease and the main goals of treatment are to relieve symptoms, improve quality of life, induce and maintain remission of the disease, heal the mucosa, and prevent complications and nutritional deficiencies. Thus, management is lifelong and multimodal, involving pharmacotherapy, dietary modifications, nutritional supplementation and sometimes surgery.

Pharmacotherapy for Crohn’s disease has changed, developed, and emerged over the years as more is understood about the disease, and improved diagnostic tools have been developed. Traditionally, a “step-up” approach was adopted for the treatment of IBD inflammation, where a milder class of medications were tried first, such as 5-aminosalicylates, before progressing to stronger medications if required. Severe disease states warranted the use of corticosteroids before surgery was considered, and immunomodulators and/or biological therapies were only considered as a last resort.

The newer approach to treating IBD is a “top-down” approach, whereby more aggressive therapy with biological drugs is started first, sometimes in combination with immunosuppressants and then following a plan for maintenance therapy once remission is achieved. In using more aggressive therapies earlier on, more complete remission with mucosal healing is more likely to be achieved, and the natural course of the disease can change, lessening the number of flare-ups and preventing long-term complications.

Treatments are also individualised for the patient based on the severity of the disease, location of the inflammation, the patient’s prognosis, response to previous treatment and presence of comorbidities, and often a combination of therapies are required to increase the effectiveness of the treatment.

The main classes of drug treatments available for Crohn’s disease in Australia include aminosalicylates, corticosteroids, immunomodulators, thiopurines, and biological immunotherapy agents. Antibiotics may also be used for associated complications, such as simple perianal fistulas, and enteral nutritional therapy is used in certain circumstances.

Vedolizumab and ustekinumab are relatively newer biological drugs used for inducing and maintaining remission in moderate to severe Crohn’s disease if there is inadequate response or failed response to conventional or conventional or TNF-alpha antagonist therapies (other biological agents). These potent monoclonal antibodies target proteins that may cause the inflammation associated with Crohn’s disease symptoms. However, their use has often been limited due to high costs, primary non-responders, secondary loss of response in some people, restricted routes of administration and adverse effects. Clinical pre-screening is essential prior to a patient commencing a biological agent, to assess historic risk of exposure to tuberculosis or viral infections, and immunisation status.

Vedolizumab is considered a “gut selective” integrin blocker, binding to alpha 4-beta7-integrin which is present on the surface of leukocytes, including T-lymphocytes. It reduces inflammation in the GIT by inhibiting the adhesion of T-lymphocytes to gastrointestinal tissues. It may cause fewer side effects than anti-TNF drugs due to only targeting the gut rather than the whole body. Vedolizumab is given with an induction treatment when the patient is acutely unwell, followed by maintenance treatment. The induction schedule for adults over 18 years old is 300mg IV infusion at weeks 0, 2 and 6. If there is no response after three doses, then the patient may benefit from a dose at week 10 as well. The maintenance schedule for adults over 18 years old is 300mg IV infusion at week 14, then every eight weeks. If subcutaneous (SC) maintenance treatment is to be used, then the IV dose at week six can be replaced with the first SC dose, and the maintenance schedule for adults over 18 years old is 108mg SC every two weeks. Vedolizumab is stopped if there is no clinical response by week 14, and if there is a loss of response to vedolizumab, 300mg is often given every four weeks instead.

Ustekinumab is a human IgG1k monoclonal antibody that inhibits the activity of the cytokines interleukin-12 and -23, which are involved in inflammatory and immune responses and are found to be elevated in Crohn’s disease. An induction treatment is also followed by maintenance treatment every eight weeks. A single IV infusion is given a week 0. For patients less than 55kg: IV 260mg is used. For patients between 55-85kg: IV 390mg is used. And for patients greater than 85kg: IV 520mg is used. A maintenance dose of SC 90mg is used at week eight and then once every eight weeks. If the response is adequate, then reducing the frequency of dosing to every 12 weeks is considered. If there is no clinical response by week 16, then ustekinumab should be stopped.

Side effects of both vedolizumab and ustekinumab include opportunistic infections, infusion reactions (e.g. pain, erythema, nausea, fever, dyspnoea, urticaria), reactivation of latent infections (e.g. tuberculosis) and potentially increased risk of malignancy and lymphoma.

As there is generally a lack of comparative studies between the biological therapies, treatment initiation is often based upon the clinician’s preference and familiarity, the disease severity, patient characteristics, and the price and availability of the drug.

Gestational diabetes is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. In pregnancy, the placenta produces hormones to support and sustain the developing baby. However, some of these hormones, such as human placental lactogen, can cause insulin resistance in the pregnant mother, resulting in a higher need for insulin whilst the mother is pregnant. If the body is unable to cope with the extra demand for insulin production, then this results in gestational diabetes. Most patients who have gestational diabetes return to normal glucose tolerance parameters postpartum and can still have a healthy baby. However, gestational diabetes needs to be managed in order to reduce the risk of developing complications during pregnancy, such as macrosomia of the baby, which means the fetus grows excessively large.

Risk factors for gestational diabetes include:

• Gestational diabetes in a previous pregnancy
• Previously elevated blood glucose concentrations prior to pregnancy
• History of abnormal glucose tolerance
• Age over 40 years
• Ethnicity (Aboriginal and Torres Strait Islander, Maori and Pacific Islander, Indian, Asian, Middle Eastern, non-white African)
• First-degree relative with diabetes
• Obesity pre-pregnancy (BMI over 30kg/m²)
• Fetal macrosomia in a previous pregnancy (birthweight more than 4500g or over the 90^th percentile for gestational age)
• Polycystic ovarian syndrome
• Use of drugs that can cause hyperglycaemia (such as corticosteroids)

All pregnant women should be screened for gestational diabetes between 24-28 weeks’ gestation (unless they already have a diagnosis of diabetes) using a 75g oral glucose tolerance test (OGTT), with the preference for testing closer to 28 weeks’ gestation as testing earlier may miss some women who may develop abnormal glucose tolerance at a later date. Testing should occur earlier for those at higher risk for hyperglycaemia in pregnancy.

An oral glucose tolerance test involves the pregnant patient having their fasting blood glucose level measured, then drinking a 75g sugary drink, and then having their blood glucose levels remeasured one hour and two hours later. Diagnostic limits for gestational diabetes are listed in Table 1 below.

Table 1: Blood glucose levels in the second and third trimester of pregnancy for diagnosis of gestational diabetes (adapted from Therapeutic Guidelines: Diabetes)

Gestational diabetes
Fasting blood glucose concentration	5.1 to 6.9 mmol/L
Blood glucose concentration 1 hour after OGTT	10 mmol/L or more
Blood glucose concentration 2 hours after OGTT	8.5 to 11 mmol/L

Upon diagnosis of gestational diabetes, the patient is recommended to start a healthy eating plan and regular physical activity, whilst monitoring and maintaining their blood glucose levels within the target range whilst pregnant. Target blood glucose concentrations are listed in Table 2 below:

Table 2: Blood glucose concentration targets for gestational diabetes (adapted from Therapeutic Guidelines: Diabetes)

Second and third trimester
Fasting	4 to 5.3 mmol/L
Preprandial (before lunch and before evening meal)	4.5 to 5.5 mmol/L
1 hour postprandial	6 to 7.8 mmol/L
2 hours postprandial	5.5 to 6.7 mmol/L

 

Over half of pregnant women with gestational diabetes can be managed with dietary modifications and physical activity alone, and this is the preferred means of managing gestational diabetes. Optimal nutrition and controlled weight gain, with an emphasis on the quality, distribution and type of carbohydrates consumed, is critical. At least 20-30 minutes of exercise each day is also beneficial in lowering blood glucose levels. However, if diet and lifestyle modifications are insufficient in controlling blood glucose levels, then pharmacological therapy is initiated.

Therapeutic options include metformin and insulin.

It is preferable for pregnant women with gestational diabetes to use a basal-bolus insulin regime to allow for flexibility and tailored dosing. Mixed insulin regimes using fixed-dose combinations of insulin a few times a day can also be used for women who do not prefer multiple daily injections. However, this regime is more likely to cause both hyperglycaemia and hypoglycaemia.

Alternatively, metformin can be used for those who have a phobia of needles, those who refuse or have poor adherence with insulin, and those who have experienced excessive weight gain with insulin. A suitable metformin regime is:

• Metformin immediate release 500mg once daily (or modified release once daily at night). The dose can be increased as tolerated over 1-2 weeks according to response, up to a maximum of 2000mg daily in divided doses

Specialist advice should be sought if the patient has renal impairment.

If fasting blood glucose concentrations are 5.8mmol/L or above when metformin is initiated, then monotherapy with metformin alone is usually unlikely to be effective, and insulin will mostly be required as well.

Metformin should be avoided during pregnancy if the patient is slim and has not gained enough weight during pregnancy, where there is intrauterine growth restriction, and where the pregnant woman has preeclampsia.

Delivery is usually timed around the due date (by 41 weeks’ gestation) for women whose glycaemic targets are met with diet alone and without other complications. Early delivery (i.e. around 39 weeks’ gestation) is recommended for those whose glycaemic targets are met with antihyperglycemic drugs but have no other complicating factors. Earlier delivery (i.e. around 36-38 weeks’ gestation) is recommended for those whose glycaemic targets are not met or if complications such as elevated blood pressure or intrauterine growth restriction exist.

Women with gestational diabetes should have their insulin and metformin stopped with the onset of labour or when fasting before a caesarean section. Blood glucose concentrations should be measured every two hours during labour; if above target, insulin is used to manage this. However, most women will not require insulin during labour.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially considered well down the line of treatment options for the management of type 2 diabetes. However, updated Australian guidelines now recommend that prescribers consider them earlier to help patients lower their blood glucose levels. They are not regarded as first-line treatment in diabetes, but they can be a valuable part of the overall management plan. They can be prescribed with insulin.

Glucagon-like peptide-1 (GLP1) is a gut-derived hormone (also known as an incretin). It is released from the small intestine in response to food ingested. It has a short half-life of 1-2 minutes and is quickly broken down by the enzyme dipeptidyl peptidase 4 (DPP-4). Physiological actions of GLP1 are:

• Glucose-dependent insulin release from the pancreas
• Slowing of gastric motility, slowing down gastric emptying
• Promote satiety
• Inhibit glucagon release in a glucose-dependent manner

GLP1-RAs are based on human GLP1. However, they have been modified not to be degraded by DPP-4. They are administered subcutaneously. Physiological actions of GLP1-RAs are:

• Increase glucose-dependent insulin secretion and suppress inappropriate glucagon secretion
• Delay gastric emptying, which slows glucose absorption and decreases appetite (results in reduced calorie intake)

GLP1-RAs have a lower risk of causing hypoglycaemia but are only PBS listed for patients that have an HbA1c > 7 and have trialled other glucose-lowering medications with no success.

Apart from insulin, the glucose-lowering effects of GLP1-RAs are greater than other glucose-lowering agents. GLP1-RAs reduce HbA1c levels between 0.3% – 1.3%, with once-weekly GLP1-RAs being more effective than once or twice-daily GLP1-RAs.

• Liraglutide was slightly more effective at reducing HbA_1cthan exenatide
• Dulaglutide appears to be as effective as liraglutide or exenatide
• Semaglutide appears slightly more effective at reducing HbA_1cthan liraglutide or dulaglutide

In trials comparing the addition of an injectable GLP1-RA or insulin in patients needing further glucose lowering, glycaemic efficacy of GLP1-RA was similar or greater than that of basal insulin. GLP1-RAs have an advantage over insulin for their weight loss ability and simplicity. They can be administered within 2-3 days if a dose is missed. They can be confused with insulin because of similar presentation and administration.

The combination of insulin and GLP1-RA has been shown to reduce HbA1c, weight, insulin doses and number of injections per day. In combination with SGLT2 inhibitors, there is a beneficial effect in glucose lowering and weight loss. However, the combination of GLP1-RA and SGLT2 inhibitors together is not PBS listed.

It is not recommended to use a GLP1-RA and a dipeptidyl peptidase-4 (DPP-4) inhibitor together as there are no additional glycaemic or other benefits, and both are incretin mimetics. If a patient is already taking a DPP-4 inhibitor and a GLP1-RA is to be started, guidelines advise ceasing the DPP-4 inhibitor.

GLP1-RAs have shown improvements in major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) but not in heart failure. They have also proved to be beneficial in reducing the risk of renal failure, though they are likely inferior to SGLT2 inhibitors.

GLP1-RAs provide greater weight loss compared to other glucose-lowering medications. Although weight loss is advantageous in people living with type 2 diabetes, pharmacists need to be aware that using GLP1-RAs can lead to excessive weight loss, especially in people who experience nausea and vomiting. Referral to a dietician may be necessary to ensure adequate nutrition.

• Semaglutide has greater HbA1c and weight improvement compared to other GLP1-RAs
• Exenatide (recently discontinued in Australia) is short-acting and needs to be administered twice a day just before meals for maximum efficacy
• Liraglutide is administered once daily
• Semaglutide and dulaglutide are longer-acting and administered once weekly, independent of food intake

Once weekly injections were more consistent and effective in lowering HbA1c. Twice daily GLP1-RAs were more effective in slowing down gastric emptying (hence increased nausea and vomiting) and lowering glucose levels postprandial. Once weekly GLP1-RAs are also marketed and approved for weight loss.

Dulaglutide uses a simpler self-injection auto device compared to semaglutide and exenatide, which require additional steps for administration (e.g. attachment of a needle). This may be advantageous for people who are fearful of needles or who require a simple administration device. Dulaglutide has a simple dose regime too. Semaglutide and exenatide require dose titration. Semaglutide has the added complexity of requiring prescriptions of different pens to achieve the target dose.

Precautions:

• Monitor and use with caution in people with gastroparesis or severe gastro-oesophageal reflux disease as they delay gastric emptying
• There is limited evidence in the safety for use in terminal renal failure and severe hepatic dysfunction.
• Semaglutide should be used with caution in patients with pre-existing retinopathy
• Use with caution in patients with a previous history of pancreatitis or risk factors for pancreatitis (e.g. excessive alcohol intake, hypertriglyceridemia)
• Use with caution if there is a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome.

Adverse effects:

• Up to 50% of patients experience nausea and/or This usually improves with continued treatment. More frequent in exenatide.
• Diarrhoea – more common with once-weekly GLP1-RA
• Constipation
• Dyspepsia
• Gastro-oesophageal reflux disease (GORD)
• Abdominal pain
• Fatigue – reduces with continuous treatment
• Injection site reactions
• Hypoglycaemia – if used in combination with sulfonylureas and/or insulin
• Increased heart rate

Gradual dose titration can help patients to achieve tolerance to the adverse effects.

Healthcare professionals can help manage the gastrointestinal side effects by advising patients to:

• Eat smaller portions
• Eat lower fat foods
• Avoid food and smells that worsen feelings of nausea
• Drink plenty of fluids to manage constipation or prevent dehydration in diarrhoea

Recommended dosages for type 2 diabetes:

• Exenatide – 5mcg twice a day within 60 minutes before morning and evening meals. If tolerated, increase to 10mcg twice a day after 1 month.
• Dulaglutide – 1.5mg weekly
• Semaglutide – 0.25mg weekly for 4 weeks, then5mg weekly for at least 4 weeks. May increase to 1mg weekly thereafter (usually 4-6 weeks after 0.5mg)
• Liraglutide – 0.6 mg once daily. Can increase to 8 mg daily in increments of 0.6 mg with at least one-week intervals to improve gastrointestinal tolerability.

Overall potential benefits of GLP-1 RAs outweigh many of the older second-line therapy options. This medication class can be considered a useful option in the treatment of type 2 diabetes for patients with HbA1c levels that are not at target, or for patients with established cardiovascular disease (CVD) or a high risk of CVD. The convenience of a once-weekly therapy may also appeal to many patients over the additional burden imposed by adding an extra tablet.

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.