Knowledge Type: Clinical Articles

The Australian Commission on Safety and Quality in Health Care (the Commission) has released four new resources to address gaps and inconsistencies in care coordination and post-sepsis support for survivors, families, and carers.

Sepsis is a life-threatening condition triggered by an abnormal and extreme response to infection. This complex clinical syndrome involves organ dysfunction as a result of this overwhelming, systemic inflammatory response. Patients can quickly progress to septic shock with profound circulatory and metabolic abnormalities. The mortality rate is high for both conditions, although it is particularly high for septic shock compared to sepsis.

The rapid initiation of appropriate antibiotic therapy, organ support and resuscitation reduces mortality. Therefore, early recognition of sepsis is key.

Australian data

Data from the 2025 National Sepsis Program Extension Epidemiology Report* demonstrates the impact of sepsis in Australia:

• Over 84,000 people hospitalised with sepsis in 2022–23.
• More than 12,000 of these cases resulted in death (around 1 in 7)
• Direct hospital cost estimated to be $700 million per year.
• Indirect costs thought to exceed $4 billion per year.

*This report only contains data from publicly funded admitted care.

National Sepsis Program

The new resources introduced by the Commission include:

• Model of Care Framework– outlines essential elements for effective sepsis care and follow-up support. The framework is intended to guide health services in the implementation of the Sepsis Clinical Care Standard. It focuses on providing high-value healthcare across all stages of the sepsis journey with an emphasis on transitions of care.
• Business case – supports investment in coordinated care and post-sepsis services.
• Coordination of care and post-sepsis support – interactive PDF – illustrates the Model of Care Framework to support local conversations about the sepsis patient journey and the opportunities for quality and safety improvements across transitions of care.
• Coordination of care and post-sepsis support – Supporting evidence and implementation ideas – offers practical steps for applying the framework in different healthcare settings.

These resources form part of the National Sepsis Program, a program designed to improve the awareness, recognition and support for people at risk of or diagnosed with sepsis in Australia.

Other key components of the program include:

1. Sepsis Clinical Care Standard

The goal of the Sepsis Clinical Care Standard is to ensure that any patient presenting with signs and symptoms of sepsis is recognised early and receives coordinated, best-practice care to reduce the risk of death or ongoing morbidity. It does this by providing national guidance on early recognition, treatment, outcomes, and post-discharge support.

2. Public Awareness Campaigns

Public awareness campaigns are run each year: Sepsis Awareness Month (September) and World Sepsis Day (13 September). These campaigns aim to increase community understanding of the signs of sepsis to promote early action.

3. Education and Resources

The Commission, in partnership with the George Institute for Global Health, Sepsis Australia and Medcast, has developed a free online education module for primary health professionals. This one-hour (CPD accredited) course supports health professionals in recognising and responding to sepsis and post-sepsis syndrome.

Challenges

While progress has been made in the management of sepsis, ongoing challenges include:

• Rates of readmission within 30 days remain high at around 22%.
• Health inequities persist
  • Aboriginal and Torres Strait Islander people experience double the sepsis hospitalisation rates of non-Indigenous Australians.
  • Patients living in rural settings and those at greater socio-economic disadvantage have a higher risk of readmission within 30 days.
• Rising costs (estimated average cost per sepsis separation increased by 50% in the 10 years to 2022-23).
• Access to coordinated and comprehensive follow-up care.

When looking at sepsis survivors, up to 50% experience post-sepsis syndrome (PSS). This is a complex condition with long-term physical, cognitive, and psychological impacts. Extreme fatigue, muscle and joint pain, and memory issues are common. Patients may also experience anxiety, depression, and symptoms of post-traumatic stress disorder. While the symptoms of PSS may be different for each patient, the condition often has a significant impact on quality of life.

Future Directions

Australian data shows that 28.7% of sepsis cases in admitted care occurred in patients with diabetes, 15.8% in patients with renal disease, and 13.4% in patients with cancer. Partnerships with chronic disease associations has been suggested to more efficiently deliver information to people at greatest risk.

Potential partners include Diabetes Australia, Kidney Health Australia, and Cancer Australia.

Other priorities include:

• Enhancing data collection and surveillance
• Expanding culturally safe care models
• Strengthening community-based follow-up care.

Summary:

Sepsis is a medical emergency requiring rapid recognition and treatment to minimise organ damage and prevent death. While mortality is significant, survivors often face long-term impacts from PSS.

The National Sepsis Program provides resources to improve care coordination and outcomes for patients and their families. Health services are encouraged to adopt the new resources and integrate the Sepsis Clinical Care Standard into practice to improve patient outcomes.

Further resources:  Sepsis in primary care online learning module.

Parkinson’s disease is a progressive disorder characterised by bradykinesia, resting tremor, rigidity, and postural instability. Dopaminergic medications, such as levodopa and dopamine agonists, are standard treatments for the motor symptoms of Parkinson’s disease.

Parkinson’s disease is associated with many complications. Dopamine dysregulation syndrome (DDS) is one such condition that can arise during the long-term treatment of Parkinson’s disease. This condition is characterised by an addictive pattern toward the use of dopaminergic medicines. Patients may take doses far in excess of what has been prescribed and beyond what is required to manage their motor symptoms.

This excessive use of dopaminergic medicines can lead to dyskinesias and psychiatric adverse effects, such as mania and psychosis. Withdrawal symptoms can also occur which may present with dysphoria and anxiety. However, even when severe drug-induced adverse effects occur, patients with DDS are typically unwilling to reduce their use of these medicines.

The pathogenesis of DDS is poorly understood. One theory is that it may be related to stimulation of the mesolimbic pathway, a central part of the brain’s reward system. In susceptible individuals, stimulation of this pathway by dopaminergic medications may lead to addictive disorders such as DDS.

Behavioural disturbances associated with DDS

Studies suggest that two thirds of patients with DDS have impulse control disorder (ICD). Common ICDs in Parkinson’s disease include pathological gambling, hypersexuality, compulsive shopping, and compulsive eating.

Punding is another behavioural disturbance often associated with DDS. Punding is a complex stereotyped behaviour typified by repetitive, non-goal-oriented activities. Examples could include compulsively assembling and disassembling objects or sorting and re-sorting collections. While people may be aware of the disruptive and unproductive nature of their behaviour, they often exhibit intense fascination with their activity and become frustrated if interrupted.

The prevalence of punding in patients with Parkinson’s disease has been reported to be between 1.4% and 14%. This wide range reflects the different populations used in various studies. The lower prevalence rate was reported in a large study of unselected Parkinson’s patients, while the higher rate was found in a study specifically looking at patients taking high doses of dopaminergic medicines. However, this behaviour is likely to be underreported due to a lack of awareness and a reluctance of patients to discuss the issue.

Risk factors

The most important risk factor for DDS appears to be chronic high doses of dopaminergic medications. Other potential risk factors were highlighted in a retrospective longitudinal study of patients with Parkinson’s disease. This study suggest the following factors may be associated with a higher risk of DDS:

• Younger age of Parkinson’s disease onset;
• A personal history of depression;
• A personal or family history of substance abuse;
• A positive family history of Parkinson’s disease in a first-degree relative; and
• Greater change in motor performance between ‘Off’ and ‘On’ states.

Contrary to some earlier studies which found a higher prevalence in males, this study did not find any gender differences in the prevalence of DDS.

A greater understanding of risk factors is important as this could be used to identify patients predisposed to developing this disorder. Preventative strategies, such as supervision of medication use, have been suggested as a means of preventing DDS in high-risk patients.

Treatment

Dopamine dysregulation syndrome can cause significant functional impairment. Therefore, early identification and appropriate management are important. However, this condition is difficult to treat and likely to recur.

Optimisation of dopaminergic therapy is recommended as the first step in the management of DDS, although any changes to dopaminergic therapy should be managed by a specialist. Possible strategies that could be considered include reducing the dose of dopaminergic medicine and optimising adjunct therapies. Adjuncts include monoamine oxidase (MAO) B inhibitors (e.g. rasagiline) and catechol-O‑methyltransferase (COMT) inhibitors (e.g. entacapone). However, optimisation of oral dopaminergic medicines has only been shown to resolve DDS in less than 10% of cases, and may be associated with worsening motor symptoms and features of withdrawal.

When optimisation of oral therapy fails, more advanced treatment options could be considered. In one study, long-lasting resolution of DDS was achieved by 80% of patients switched to duodenal levodopa infusion and 57% of patients undergoing deep brain stimulation. However, sample sizes were small, and further research is required in this area. Case studies suggest that aripiprazole could have a potential place in the management of DDS. Aripiprazole is a partial agonist at dopamine D₂ receptors and also exhibits agonist activity at serotonin 5HT_1A receptors and antagonist activity at serotonin 5HT_2A receptors. This partial D₂ agonist activity has been trialled in other substance abuse disorders with some success, although further studies are required.

The support of family or carers has been found to be a significant factor in achieving optimal outcomes for these patients. Monitoring of compliance with dopaminergic therapy by caregivers is associated with long-lasting remission of DDS. This may include delivering medications directly to the patient and ensuring the patient does not have any hidden medications or additional healthcare providers.

Summary

Dopamine dysregulation syndrome is a complex condition that can significantly affect quality of life for people with Parkinson’s disease. Unfortunately, the condition remains poorly understood, and there is limited evidence to guide effective management. Existing studies have often yielded inconsistent results. This is likely due to variations in follow-up duration, assessment tools, and study populations. Effective supervision and support from caregivers should be encouraged in both the prevention and management of DDS.

Correct use of medicine is a crucial factor in effective patient self-care and hence positive outcomes in any chronic disease. Different concepts have evolved from the notion of correct use of medicine, such as compliance, adherence and concordance.  Compliance is defined as “the extent to which the patient follows the health professionals’ advice and takes the treatment”. This concept is being replaced by the term ‘adherence’, as compliance may imply a submissive, uninvolved patient in a paternalistic setting. Adherence is defined as “…the extent to which a person’s behaviour – taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health-care provider”. Concordance is a new concept which has evolved and is defined as “agreement between the patient and healthcare professional, reached after negotiation that respects the beliefs and wishes of the patient in determining whether, when and how their medicine is taken, and (in which) the primacy of the patient’s decision (is recognized)”. For the purposes of this article, the term ‘adherence’ will be used to discuss contributing factors and influences in  medicine-taking behaviour, consequences of poor adherence, and strategies to improve  medicine adherence, thereby demonstrating the shift towards the concept of concordance.

The literature shows that adherence is a complicated notion, the culmination of the interaction of a variety of aspects such as the features of the condition, social background, access, and patient beliefs and characteristics. Factors that can influence adherence to medicines include gender, age, ethnicity, education, social support, marital status, mood impairment or cognition, number of prescribing doctors and visiting more than one pharmacy; and it has been found that patients with a higher income and lower medicine expenses tend to be more adherent. There are several reasons cited for patients not adhering such as simply forgetting to take the medicine, affordability, concern about safety or effectiveness, fear of or experiencing adverse effects, confusion over the directions, no longer feeling unwell or not feeling any different, feeling that they cannot manage with the number of medicines they should take and how to coordinate them, having dexterity challenges, or being simply too unwell.

Adherence to medicines is a variable aspect of treatment, as daily influences impact upon everyday choices, and chronic illnesses involve symptoms, exacerbations, and future impacts, each of which are frequently changing. In a study by Elliott et al (2007) the team concluded that continuing communication with patients about their medicines is necessary, and requires collaboration across disciplines for patients with chronic conditions. In order to positively guide patient decision-making regarding medicine use, health professionals need to be informed of the patients’ current as well as previous choices, as they may place importance on different issues from the prescribers; and with each newly introduced drug the new decisions made by the patient may not always be shared with the prescriber. Hence, when new medicines are initiated, good practice would indicate that a health professional is available to discuss medicines with patients.

Adherence is an important area to consider, as patients are generally poorly adherent to medicines, particularly in chronic disease states. Lack of adherence can lead to medicine wastage, morbidity and hospitalisation. Rates of adherence for a number of chronic medicine regimens have been found to be between 40-50%, and non-adherence is linked to more frequent doctor consultations, and increased rates or duration of hospitalisation. Medicine non-adherence is reported in the literature at a rate of approximately 50% in developed nations, with around half of this proportion being deliberate and the remainder due to ignorance of not taking medicine as they should or due to a complicated regimen. In a study by Lewis (1997), it was found that sickness due to non-adherence to medicines in the United States costs approximately US$100 billion per year. The National Audit Office reported that returned medicines in England for 2007 approximate to £100M annually. Noens et al (2009) found that significantly more chronic myeloid leukaemia patients (CML) with an unsatisfactory response had not taken their imatinib (23.2%) compared those who achieved peak response (7.3% imatinib not taken). In addition, the team found there were significantly fewer missed tablets (9%) in patients who demonstrated a complete cytogenic response, in comparison to the 26% with an incomplete cytogenic response, in a patient group who underwent treatment for a minimum of 12 months with imatinib.

The fact that a disease may possibly be life-threatening does not appear to increase medicine adherence, and findings indicate that adherence can decrease over time. A study by von Mehren and Widmer (2011) found that the population of patients who adhered to imatinib for CML and gastrointestinal stromal tumours decreased from almost 100% during the first four months of treatment to 23% at the 14^th month. It was also reported that nearly 30% of patients ceased their medicines for 30 or more days during year one of treatment in patients prescribed imatinib for CML or gastrointestinal stromal tumours. In another study conducted by Partridge et al (2003), it was shown that long-term adherence to tamoxifen reduced from 83% in the first year of treatment to 50% when the fourth year milestone was reached.

Encouraging open and equal discussion about medicines can facilitate a more beneficial discussion for both the health professional and the patient, leading to improved prescribing practices and better patient adherence. Many studies demonstrate the intervention of a pharmacist enhances medicine adherence rates. Carter et al (2005) report that support networks, the active participation of patients, and advocating self-care are significant contributors to positive treatment outcomes. Furthermore, patients report an enhanced quality of life when they are contented with the level of information regarding their medicines that is provided to them, and Cassileth et al (1980) similarly mention that patient mechanisms for managing can be derived from the information they provide.

Concordance refers to a consultative procedure where a collaborative approach between doctor and patient leads to prescribing. Pharmacists can have a role in facilitating this process, thereby alleviating the doctor to focus on diagnosis and formulating a treatment plan. The concordance approach can lead to a more empowered patient as their feelings have been discussed and respected, an open forum encouraged to discuss any ensuing treatment challenges, and hence there is a greater likelihood of the patient following the prescribed treatment and therefore commit to a more transparent decision-making process within which they have played a role. The philosophy is founded upon delivery of information and viewpoints on the part of the prescriber, and in valuing patient autonomy in reaching decisions rather than imposing directions upon them without further discussion.

Optimising patient outcomes from taking medicine is a multi-faceted concept which relies on the interplay of many ever-changing factors. Ultimately, medicine adherence is founded in an open and trusting relationship between the patient and members of the healthcare team, and the establishment of a positive rapport to foster a team approach involving the patient at the centre. In order to establish a sincere collaboration, then a mindfulness of, and pledge to respecting patient autonomy and exercising competent communication skills are required to facilitate the interaction. Greater success in achieving patient adherence may occur by eliciting patient opinions, truly listening to them and assisting them to rationalise difficulties in order to complete the decision-making process, compared to simply dictating how patients should proceed.

 

The recently published Dementia in Australia report highlights the growing burden of dementia in Australia. In 2023, dementia was the leading cause of death, responsible for around 9.5% of all deaths.

While there are many forms of dementia, Alzheimer’s disease is the most common, accounting for 60-80% of all cases. Management primarily involves supportive care and non-pharmacological interventions, although medications are available that may help manage symptoms and slow disease progression.

Four medications are available on the Pharmaceutical Benefits Scheme (PBS) for Alzheimer’s disease: the anticholinesterases (donepezil, galantamine, and rivastigmine) and the N-methyl-D-aspartate (NMDA) antagonist, memantine. These medications may provide modest benefits, although this often comes at the expense of significant adverse effects. More recently, targeted therapies have been developed which are hoped to modify the disease process.

Donanemab

The pathological hallmark of Alzheimer’s disease is the accumulation of amyloid beta protein plaques, which occurs early in the disease. Other characteristic brain changes include the development of neurofibrillary tangles composed of tau protein. While the role of these protein aggregates in Alzheimer’s disease is not entirely understood, they are accompanied by neuronal loss and brain atrophy.

Donanemab, approved in Australia in May 2025, is indicated for mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s dementia. Donanemab binds to a form of amyloid beta that is only present in brain amyloid plaques, triggering the immune system to remove these toxic deposits via microglial-mediated phagocytosis.

Donanemab has been shown to significantly reduce the amount of amyloid in the brain. In the TRAILBLAZER-ALZ 2 trial, patients with early symptomatic Alzheimer disease were randomly assigned to receive donanemab or placebo. At 76 weeks, brain amyloid plaque levels reduced by 87.0 Centiloids (95% CI, −88.90 to −85.17) in the donanemab group compared to a reduction of 0.67 Centiloids (95% CI, −2.45 to 1.11) in the placebo group. Amyloid clearance (defined as a level of <24.1 Centiloids) was achieved in 76.4% (95% CI, 72.87%-79.57%) of the donanemab group and 0.3% (95% CI, 0.08%-1.05%) of the placebo group.

The gradual reduction in plaque load is thought to slow the progression of Alzheimer’s disease. The primary outcome of the TRAILBLAZER-ALZ 2 trial was the change in the integrated Alzheimer Disease Rating Scale (iADRS). This score combines assessments of cognition and daily function, providing a better measure of clinical efficacy.. The majority of participants (68%) in this study was classified as having low/medium tau pathology, while the remainder (32%) had high tau pathology. Donanemab was associated with a 35.1% slowing of disease progression in the low/medium tau population compared to placebo. In the combined population, disease progression was slowed by 22.3%. A slowing of clinical progression that is greater than 20% is considered clinically meaningful.

Donanemab is administered as an intravenous infusion every four weeks. It is recommended to continue treatment until amyloid plaques are cleared, up to a maximum of 18 months. If monitoring of amyloid plaques is not possible, 18 months is the recommended treatment duration.

Safety concerns

Anti-amyloid antibodies, such as donanemab, can cause amyloid-related imaging abnormalities (ARIA). These events can be classified as ARIA with oedema (ARIA-E) or ARIA with hemosiderin deposition (ARIA-H).

While ARIA events are usually asymptomatic, serious events can occur. Major intracerebral haemorrhages, including some fatal events, have been reported in patients treated with this class of medications. Focal neurologic deficits similar to those observed in an ischaemic stroke have also been associated with ARIA-E.

In the TRAILBLAZER-ALZ 2 trial, ARIA-E and ARIA-H occurred in 24.0% and 19.7% of the donanemab group, respectively (compared to 1.9% and 7.4% of the placebo group). Around a quarter of the ARIA-E events in the donanemab group were symptomatic. Serious symptoms of ARIA-E were reported in 1.5% of patients receiving donanemab.

While donanemab is approved for use in Australia, it is not subsidised on the PBS. The Pharmaceutical Benefits Advisory Committee (PBAC) recently rejected an application for PBS listing citing the small and uncertain benefits along with the high burden of the treatment on patients and the health system.

Prevention

Ageing is considered the main risk factor for dementia. While this is a non-modifiable risk factor, it is thought that 45% of a person’s dementia risk is potentially modifiable by addressing the following risk factors:

• Less education
• Hearing loss
• Hypertension
• Smoking
• Obesity
• Depression
• Physical inactivity
• Diabetes
• Excessive alcohol consumption
• Traumatic brain injury
• Air pollution
• Social isolation
• Untreated vision loss
• High LDL cholesterol.

In the 2024 update of the Lancet Commission on dementia, specific actions are provided to address these risk factors. These actions include individual interventions as well as population-based policy change. It has been demonstrated that engaging in protective factors (e.g. social engagement, cognitively stimulating work) and avoiding risk factors (e.g. excessive alcohol consumption) can prevent or significantly delay a large proportion of dementia cases.

Summary

While there is no cure for dementia, there are strategies (pharmacological and non-pharmacological) that can help manage symptoms and may improve quality of life for people living with dementia.

Medications provide modest benefits for dementia but may be associated with serious adverse effects. Therefore, minimising modifiable risk factors should be considered an important strategy to prevent dementia.

Further information: Dementia Australia offers professional development and training courses for healthcare workers supporting people living with dementia.

The Therapeutic Guidelines: Antibiotic has recently updated their recommendations for the prevention of infective endocarditis.

Infective endocarditis refers to infection of the endocardial surfaces of the heart and is typically of bacterial origin. While a healthy endocardium is resistant to bacterial colonisation, infection can occur when endocardial injury coincides with bacteraemia. Endocardial injury may be related to turbulent flow (e.g. due to diseased valves), mechanical trauma (e.g. during insertion of intravascular catheters), or intravenous drug abuse (i.e. due to the repeated injection of particulate matter). The bacteraemia required for the development of infective endocarditis may be the result of oral flora introduced into the bloodstream (i.e. during dental procedures or daily oral hygiene activities) or from an established, distant source of infection.

While infective endocarditis is a relatively uncommon condition, it is associated with high morbidity and mortality. Therefore, antibiotic prophylaxis may be appropriate for certain individuals prior to procedures with a high risk of bacteraemia.

Key updates to the guidelines:

• Ventricular assist devices (VADs) added to the list of conditions warranting prophylaxis
• Clindamycin is no longer recommended for endocarditis prophylaxis prior to dental procedures
• Antibiotics with enterococcal activity should be considered for institutions with high rates of endocarditis following transcatheter aortic valve implantation (TAVI) or cardiac implantable electronic device (CIED) procedures using an inguinal approach.

Ventricular assist devices

Ventricular assist device-related infections have been reported to occur in between 18% and 59% of patients after implantation. This can include bloodstream infection, relapsing bacteraemia, sepsis, and endocarditis. When endocarditis occurs in these patients, the mortality rate has been reported to be 50%.

Due to this high risk and poor outcomes, VADs are now included among the conditions for which prophylaxis is recommended.

Clindamycin

Clindamycin is no longer recommended for endocarditis prophylaxis for dental procedures as it is associated with a higher frequency of severe adverse drug reactions (ADR) compared to other antibiotics.

A UK study looking at antibiotic prophylaxis found that clindamycin was associated with 13 fatal and 149 non-fatal ADR reports per million prescriptions. The majority of serious events were related to Clostridioides difficile infection. In contrast, amoxicillin was associated with zero fatal and 22.62 non-fatal ADR reports per million prescriptions.

Where endocarditis prophylaxis is indicated prior to dental procedures, amoxicillin is the first-line option. Cefalexin can be used for patients who have experienced a non-severe penicillin hypersensitivity reaction. For patients who have had a severe penicillin hypersensitivity reaction, doxycycline or azithromycin are the recommended alternatives.

Consideration must still be given to the potential for these alternative agents to cause adverse reactions. For example, doxycycline can cause oesophageal irritation and ulceration, and azithromycin can prolong the QT interval.

Enterococcal activity

A large international cohort study found high rates of postoperative infective endocarditis following TAVI. This study found Enterococcus spp. to be the most commonly isolated species in patients presenting with early peri-procedural infective endocarditis. While this pattern has not been observed in Australia, the updated guidelines recommend considering antibiotics with enterococcal activity in centres with high infection rates following TAVI and cardiac device implantation using an inguinal approach.

First and second generation cephalosporins do not have enterococcal activity. However, amoxicillin and ampicillin are active against enterococci. Oral doses should be administered 60 minutes before the procedure, intramuscular doses 30 minutes before, and intravenous doses 60 minutes before. Vancomycin or teicoplanin could be considered alternatives for patients with penicillin hypersensitivity. These agents should be administered in addition to any standard surgical prophylaxis required.

Conclusion

The current recommendations from the Therapeutic Guidelines: Antibiotic for the prevention of infective endocarditis are shown in Table 1. Prophylaxis is recommended for patients undergoing one of the procedures listed in column A if they also have a condition listed in column B.

Table 1. Indications for antibiotic prophylaxis for infective endocarditis (adapted from eTG)

Procedures requiring prophylaxis (Column A)	Conditions for which prophylaxis is recommended (Column B)
Dental procedures (involving manipulation of the gingival or periapical tissue, or perforation of the oral mucosa )	Prosthetic cardiac valve
Dermatological or musculoskeletal procedures (involving infected skin, skin structures or musculoskeletal tissues)	Prosthetic material used for cardiac valve repair
Respiratory tract or ear, nose and throat procedures (only for tonsillectomy or adenoidectomy; or invasive respiratory tract or ear, nose and throat procedures to treat an established infection).	Previous infective endocarditis
Genitourinary or gastrointestinal tract procedures (only if surgical antibiotic prophylaxis is required, or for patients with an established infection)	Ventricular assist devices
	Congenital heart disease (involving unrepaired cyanotic defects or repaired defects with residual defects at or adjacent to the site of a prosthetic patch or device)
	Rheumatic heart disease

 

 

Pruritus is a common and distressing symptom in patients receiving palliative care. The itch-scratch cycle can compromise skin integrity, increasing the risk of infection. People with advanced, life-limiting illness often already have fragile skin. This can be due to a range of factors such as reduced blood flow, nutritional deficiencies, medications, immobility, and age-related changes.

There are many potential causes of itch in this population, including:

• Dry skin;
• Uraemia related to advanced kidney disease;
• Cancer;
• Opioid analgesics; and
• Comorbid conditions unrelated to the life-limiting illness.

Itch may also be related to cholestasis due to biliary obstruction, intrahepatic disease, or adverse drug effects.

The pathogenesis of pruritus in cholestasis is not entirely understood. It is thought that impaired bile flow leads to the accumulation of pruritogenic substances. These substances may then interact with sensory nerve fibres in the skin, producing the sensation of itch. Substances that may be acting as pruritogens include bile acids, endogenous opioids, and lysophosphatidic acid (LPA).

Cholestatic itch can be treated with biliary drainage. However, this may not be appropriate for all patients with a life-limiting illness. Where systemic drug treatment is required, the Therapeutic Guidelines recommend the following therapies:

• Rifampicin 150mg orally at night (maximum of 600mg daily); or
• Sertraline 50mg daily (maximum of 100mg daily).

These first-line agents are interesting as they are not traditionally thought of as anti-itch medications. Their use in this setting would be considered off-label.

Rifampicin

Rifampicin is an antibiotic that is typically reserved for the treatment of infections due to mycobacteria or methicillin-resistant Staphylococcus aureus (MRSA) and for the prevention of meningitis and epiglottitis. However, it may also be effective in relieving itch in cholestatic pruritus.

One of the proposed mechanisms for this involves the phospholipid, LPA. This molecule is involved in many physiologic and pathologic processes, some of which can lead to the production of pruritogenic interleukins. While LPA is primarily produced intracellularly for the purposes of cell membrane synthesis, it is its extracellular production that is thought to be important in pruritus. When LPA is produced extracellularly, autotaxin is the rate-limiting enzyme involved. Therefore, inhibition of autotaxin could relieve pruritus by reducing the production of LPA.

Rifampicin is a potent agonist of the pregnane X receptor (PXR). Activation of this receptor has been shown to reduce autotaxin expression on hepatocytes. Other theories on the action of rifampicin relate to changes in the intestinal microbiome which may influence the reabsorption of pruritogens.

A Cochrane review found that rifampicin may relieve cholestatic pruritus in palliative care patients, although the certainty of evidence is very low. Rifampicin was associated with a significant reduction in pruritus compared to placebo, with a mean difference of −42.00 (95% confidence interval: −87.31 to 3.31).

Rifampicin therapy does carry a risk of hepatitis. Therefore, caution is required when used in patients with cholestatic conditions. Serum aminotransferases should be monitored at regular intervals.

Sertraline

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that may be used off-label for the management of cholestatic pruritus. Its mechanism of action in pruritus may be related to the role that serotonin plays in nociception and perception of pruritus. As sertraline inhibits the reuptake of serotonin, it may modify itch signalling.

In a study by Ataei et al., the efficacy of sertraline and rifampicin were compared in patients with cholestatic pruritus. Patients were randomised to receive either sertraline 100mg daily or rifampicin 300mg daily. A similar reduction in pruritus scores was seen in each group (-46% for sertraline vs -43% for rifampicin). However, sertraline was considered safer than rifampicin regarding hepatobiliary enzyme levels. This study had some limitations, including the small sample size and the single-blind design.

Sertraline is generally well tolerated. More commonly experienced adverse effects include nausea, diarrhoea, insomnia, and dizziness.

Colestyramine

Pruritus due to partial biliary obstruction is a registered indication for colestyramine. However, it is not currently recommended by the Therapeutic Guidelines in the palliative care setting. This is due to limited evidence to support its use in this population as well as poor tolerance.

Colestyramine is a bile acid sequestrant. It combines with bile acids in the intestine to form insoluble complexes that are excreted in the faeces. Preventing the reabsorption of bile acids results in a continuous, but incomplete, removal of bile acids from the enterohepatic circulation.

Colestyramine is presented as powder that must be mixed with water, juice or highly fluid food before administration. The usual dose for the relief of itch is 4g (one sachet) once or twice daily.

Constipation is the most commonly reported adverse event. This is often mild and easily managed, although severe cases have occurred. In rare cases, this may be accompanied by faecal impaction or haemorrhoids. Other common adverse effects include abdominal pain, dyspepsia, nausea, and anorexia

Colestyramine can reduce the absorption of other orally administered drugs. To avoid this issue, other oral medicines should be taken at least one hour before or four hours after colestyramine.

General measures

General skincare measures are important and may avoid the need for systemic drug therapy. The following measures are recommended for all patients with pruritus and are particularly valuable for patients with dry skin:

• Generous use of emollients twice a day, particularly after bathing
  • Options include aqueous cream, glycerine 10% in sorbolene, and paraffin ointment (liquid paraffin 50% + white soft paraffin 50%)
• Bathe using warm water and gently pat skin dry
• Avoid soap and shampoos
  • Soap substitutes can be used, e.g. aqueous cream, or soap-free washes
  • Dispersible oils may be preferred if the skin is very dry
• Avoid scratching, keep fingernail and toenails short, consider use of cotton gloves and socks at night.

The product information documents for paracetamol are being updated to include warnings of high anion gap metabolic acidosis. Metabolic acidosis is a pathological process or condition that leads to a reduction in blood pH.

There are three major mechanisms that can produce metabolic acidosis:

• Increased acid generation
  • Lactic acidosis
  • Ketoacidosis
  • Ingestions or infusions (e.g. toxic alcohols, chronic paracetamol use)
• Loss of bicarbonate
  • Severe diarrhoea
  • Complication following urinary diversion surgery
  • Proximal (type 2) renal tubular acidosis (RTA)
• Reduced renal acid excretion
  • Renal failure
  • Distal (type 1) RTA and type 4 RTA

There are also two distinct types of metabolic acidosis: high anion gap metabolic acidosis (HAGMA) and normal anion gap metabolic acidosis (NAGMA). Calculation of the anion gap can be used to distinguish between the two.

Anion gap

For electrical charge to be neutral, the total number of positive charges (from cations) must equal the total number of negative charges (from anions). However, not all ions are easy to measure. Therefore, the anion gap equation uses only the dominant cations (i.e. sodium +/- potassium) and the dominant anions (i.e. chloride and bicarbonate). The rest of the ions in the blood can be considered “unmeasured”.

Anion gap = (Na⁺ + K⁺) – (Cl^– + HCO₃^–)

The anion gap is, therefore, the difference between measured cations and measured anions in the blood (which can be used to evaluate the presence of unmeasured anions).

The typical adult reference ranges for these measured ions is shown below:

• Sodium 135 to 145 mmol/L
• Potassium 3.5 to 5.2 mmol/L
• Chloride 95 to 110 mmol/L
• Bicarbonate 22 to 32 mmol/L.

The normal anion gap is often quoted as 8-16 mmol/L (or 4-13 mmol/L if potassium is excluded from the equation). This figure largely represents unmeasured anions like organic acids and negatively charged plasma proteins, such as albumin.

In both HAGMA and NAGMA there is a reduction in bicarbonate. This can be due to increased use of bicarbonate as a buffer, reduced bicarbonate production, or increased loss. However, as electrochemical neutrality must be maintained, there is always a corresponding increase in anions (either chloride or unmeasured anions). If it is the chloride level that increases, a normal anion gap would be seen. However, if it is unmeasured anions that increase, the anion gap increases.

Calculation of the anion gap can be useful to help identify the cause of metabolic acidosis and, therefore, the most appropriate treatment.

Paracetamol and HAGMA

Metabolic acidosis is associated with paracetamol overdose. However, metabolic acidosis can also occur during chronic therapy when therapeutic doses are used. This may also be referred to as pyroglutamic acidosis as it is related to a buildup of pyroglutamic acid.

Pyroglutamic acid (also known as 5-oxoproline) is an intermediate in glutathione metabolism. Glutathione is present in most cells, where it functions as an antioxidant. The γ-glutamyl cycle is responsible for the synthesis and degradation of glutathione, and can be summarised in the following steps:

• Glutathione utilisation
  • Glutathione donates its γ-glutamyl group to amino acids via the enzyme γ-glutamyl transpeptidase (GGT).
  • This forms γ-glutamyl amino acids and cysteinylglycine.
• Transport and conversion
  • γ-glutamyl amino acid is transported into the cell and converted to pyroglutamic acid by γ-glutamyl cyclotransferase.
• Recycling
  • Pyroglutamic acid is converted to glutamate by 5-oxoprolinase.
  • Glutamate then combines with cysteine (via γ-glutamylcysteine synthetase) to form γ-glutamylcysteine.
• Glutathione resynthesis
  • γ-glutamylcysteine combines with glycine (via glutathione synthetase) to regenerate glutathione.

5-oxoprolinase, the enzyme responsible for breaking down pyroglutamic acid, operates at low capacity. Therefore, pyroglutamic acid will accumulate when its rate of production is high.

There are many factors that can interrupt this cycle, including inherited enzyme defects and acquired deficiencies in cellular glutathione and cysteine. Prolonged use of paracetamol can cause depletion of both glutathione and cysteine which may disrupt this cycle.

Risk factors

There are many other factors that increase the risk of metabolic acidosis during prolonged paracetamol use, including:

• Malnutrition;
• Infection;
• Antibiotics;
• Renal failure; and
• Pregnancy.

These risk factors are common, and it has been suggested that the incidence of this condition may be under-reported.

Flucloxacillin, in particular, has been highlighted as the antibiotic more likely to contribute to this condition. This antibiotic can inhibit 5-oxoprolinase, thereby promoting the accumulation of pyroglutamic acid. Caution is advised when flucloxacillin and paracetamol are co-administered, especially when the maximum paracetamol dose is used and where other risk factors for HAGMA exist.

Ciprofloxacin is another antibiotic that may impair this pathway, along with the anticonvulsant vigabatrin.

Presentation

Pyroglutamic acidosis has a fatality rate of around 20%. Prompt recognition is essential as the condition is reversible if the causative agents are ceased.

Signs and symptoms may include:

• Reduced consciousness;
• Kussmaul breathing (rapid, deep breathing);
• Nausea and vomiting;
• High anion gap;
• Low bicarbonate levels (often < 10 mmol/L);
• Hypokalaemia; and
• Severe deterioration of kidney function.

Treatment

Treatment of paracetamol-induced HAGMA involves cessation of paracetamol and any other causative agent (i.e. any medication that can inhibit enzymes involved in the γ-glutamyl cycle).

Supportive measures, such as intravenous fluids and respiratory support, may be sufficient for the management of mild cases. A sodium bicarbonate infusion may be considered for patients with more severe disease (i.e. serum pH < 7.1).

As glutathione depletion is thought to be key in the pathogenesis of this condition, administration of N-acetylcysteine (NAC) may also be considered. A recently published systematic review found that NAC was associated with a lower fatality rate (11% with NAC vs 24% without). Case reports have also shown that haemodialysis may hasten the removal of pyroglutamic acid.

Reports in Australia

In the past ten years, the Therapeutic Goods Administration (TGA) has received 96 reports of metabolic acidosis in patients taking paracetamol. While many of these patients were taking multiple medications, paracetamol was the only suspected medicine involved in 32 of these reports.

Demographics of reports to the TGA:

• 7% related to children (< 17 years);
• 41% occurred in people aged 18-64;
• 26% in people > 64 years
• 57% related to females and 36% to males.

The patient age was unknown for 26% of the reports and gender was not specified in 6% of cases.

Summary

Pyroglutamic acid accumulation is a rare cause of metabolic acidosis and may occur in association with chronic therapeutic use of paracetamol. Risk factors are common in hospitalised patients, and it is thought to be an underdiagnosed condition. Awareness is essential as untreated cases can progress to severe acidosis.

Patients presenting with HAGMA in association with paracetamol are typically women with chronic illness and malnutrition. The co-administration of flucloxacillin is thought to be a significant contributing factor.

The possibility of paracetamol as a causative agent should be considered in patients with HAGMA who are taking long-term paracetamol, particularly if additional risk factors exist.

Angiotensin-converting enzyme (ACE) inhibitors are used in the management of many conditions, including hypertension, heart failure, myocardial infarction, and diabetic nephropathy. Around 30% of individuals are intolerant to these medications, most commonly due to symptomatic hypotension or the development of a persistent dry cough. Angioedema is a less frequent but potentially serious adverse effect associated with this class.

Angioedema is characterised by non-pitting oedema of subcutaneous or submucosal tissues. It often affects the face, lips, tongue and throat. Where angioedema affects the bowel wall, gastrointestinal symptoms, may also be present. While some cases are mild and self-limiting, airway involvement can be life-threatening.

There are many potential causes of angioedema, including:

• Allergic reactions;
• Genetic disorders (e.g. hereditary angioedema);
• Acquired disorders (e.g. B cell lymphoproliferative disorders);
• Autoimmune disorders;
• Certain infections; and
• Medications (via allergic and non-allergic mechanisms).

Medication-induced angioedema

Allergic causes of angioedema are related to mast cell degranulation and may also be referred to as histaminergic angioedema. This may be accompanied by other signs and symptoms of mast cell mediator release, e.g. urticaria, flushing, generalised pruritus, and hypotension. Allergic angioedema may also be accompanied with anaphylaxis. In general, mast-cell mediated angioedema begins within minutes of exposure to an allergen, peaks within a few hours, and resolves in 24 to 48 hours.

In contrast, symptoms of non-allergic angioedema tend to develop over a more prolonged period. These reactions are related to activation of the kallikrein-kinin cascade (a key regulatory system involved in the maintenance of blood pressure, haemostasis, inflammation, and renal function). Bradykinin, a potent vasodilator produced in this cascade, increases vascular permeability and contributes to angioedema. Non-allergic angioedema is typically not associated with urticaria, bronchospasm, or other symptoms of allergic reactions.

ACE inhibitors

All medications in the ACE inhibitor class are associated with non-allergic angioedema. This is an infrequent adverse event, with an estimated incidence of around 0.1-0.42%. However, as ACE inhibitors are widely prescribed, they represent a significant cause of non-allergic angioedema.

One small Australian study found that 32% of patients presenting to the emergency department with angioedema were taking an ACE inhibitor. While causation was not confirmed in this study, the attributable risk factor for ACE inhibitors in patients with ACE-inhibitor-associated angioedema is thought to be 80%.

Bradykinin accumulation is thought to be the cause as ACE inhibitors block bradykinin degradation. Symptoms of ACE inhibitor-associated angioedema typically affect the face, lips, tongue, and upper airway. Gastrointestinal involvement is less common but may present with abdominal pain, vomiting, or diarrhoea.

Angioedema can occur at any stage during ACE inhibitor therapy. Around half of all cases occur in the first month of treatment. However, a first presentation can occur after months or years of therapy without incident. This variability can lead to the ACE inhibitor being overlooked as the causative agent.

Before the cause is correctly identified, patients may experience multiple episodes of angioedema with long symptom-free periods. If administration of the ACE inhibitor continues, the episodes will usually get worse. Patients with mild initial presentations can go on to develop life-threatening angioedema. Therefore, early recognition is crucial to prevent serious events.

Risk factors

While ACE inhibitors can cause angioedema on their own, combination with other medications may increase the risk.

Medications associated with a heightened risk include:

• Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin);
• Mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, sirolimus); and
• Neprilysin inhibitors (i.e. sacubitril – combination contraindicated by manufacturer).

Other factors that may increase the risk of ACE inhibitor-induced angioedema include:

• Smoking;
• History of ACE inhibitor-induced cough (~9x increased risk); and
• African American background (~4x increased risk).

Management

As ACE inhibitor-induced angioedema is mediated by bradykinin rather than histamine, it often does not respond to standard treatments used for histaminergic angioedema. However, initial management may still include these therapies, as distinguishing between the two forms can be challenging at presentation.

The primary management of ACE inhibitor-induced angioedema is airway management (if required) and discontinuation of the drug. Mild cases may not require treatment. However, patients should be monitored for several hours in case of symptom progression. Antihistamines are sometimes used to relieve symptoms, although their efficacy in this setting is likely limited.

Angioedema caused by ACE inhibitors typically resolves within 24-72 hours. Some patients may experience recurrent episodes in the weeks to months after discontinuing the ACE inhibitor due to lingering effects of the discontinued drug. However, if the angioedema persists, alternative causes should be considered.

When a patient presents with angioedema and is taking an ACE inhibitor, discontinuation is generally recommended even if the cause is unclear. This is because continuing the ACE inhibitor puts the patient at risk of more frequent and severe episodes.

Alternatives

Patients who experience angioedema attributed to an ACE inhibitor should not be rechallenged with any other ACE inhibitor in the future. A history of ACE inhibitor-induced angioedema is also listed as a contraindication for the angiotensin receptor neprilysin inhibitor, sacubitril with valsartan.

An angiotensin II receptor blocker (ARB) may be considered as a replacement for the discontinued ACE inhibitor. While angioedema has been reported with ARBs, recent studies suggest that these drugs do not have a higher risk compared with other antihypertensives.

A large registry-based cohort study investigated the safety of ARBs in people with a history of angioedema during ACE inhibitor therapy. The study included over one million users of ACE inhibitors, and angioedema was reported to occur in 0.5% of users. Of the individuals who experienced angioedema during ACE inhibitor therapy, the highest recurrence rate was seen in the group who continued to take an ACE inhibitor (adjusted hazard ratio of 1.45 (95% CI, 1.19 to 1.78)). However, the lowest incidence occurred in patients switched to an ARB (adjusted hazard ratio, 0.39; 95% CI, 0.30 to 0.51).

Summary

While ACE inhibitor-induced angioedema is infrequent, this adverse effect is potentially serious. Prompt recognition and management is essential to improve patient outcomes and prevent progression to life-threatening complications. ACE inhibitors may be overlooked as the cause of angioedema due to the highly variable timing of the initial event. Discontinuation of the ACE inhibitor is recommended for all patients with ACE inhibitor-associated angioedema. Alternative therapies, such as ARBs, may be considered in these patients.

The management of coronavirus disease 2019 (COVID-19) continues to evolve as new therapies become available and new virus variants emerge. A recently published meta-analysis, including data from over 166,000 patients, examined the efficacy of antivirals in mild to moderate COVID-19. The analysis provides insights into the effectiveness of therapies in reducing hospital admissions.

This study ranked the following from most to least effective in reducing hospital admission:

• Nirmatrelvir + ritonavir (OR_SC 0.15 (95% CI 0.07 to 0.32)) – moderate certainty
• Remdesivir (OR_SC 0.25 (95% CI 0.07 to 0.77)) – moderate certainty
• Systemic corticosteroids (OR_SC 0.43 (95% CI 0.20 to 0.90)) – low certainty
• Molnupiravir (OR_SC 0.66 (95% CI 0.44 to 0.92)) – low certainty

Abbreviations: OR_SC, odds ratio compared with standard care; CI, credible interval

The study authors concluded that nirmatrelvir + ritonavir and remdesivir probably reduce admission to hospital, while systemic corticosteroids and molnupiravir may reduce admission to hospital. Evidence to support a mortality benefit for these agents compared to standard care is inconsistent.

Choice of therapy

The National COVID-19 Clinical Evidence Taskforce provides information on the management of COVID-19 in the Australian context. While this resource is no longer being updated, it will remain online until it no longer reflects the evidence or recommended practice.

Antivirals that target the virus that causes COVID-19 are intended to reduce the risk of severe illness and are prescribed to patients with risk factors for developing serious complications.

Risk factors for disease progression include:

• Older age (> 65 years, or > 50 years for Aboriginal and Torres Strait Islander people);
• Diabetes requiring medication;
• Obesity (BMI >30 kg/m²);
• Renal failure;
• Cardiovascular disease, including hypertension;
• Respiratory compromise, including COPD, asthma requiring steroids, or bronchiectasis; and
• Immunocompromising conditions (i.e. primary or acquired immunodeficiency or immunosuppressive therapy).

Where antivirals are considered necessary, treatment should be initiated as soon as possible after symptom onset.

Nirmatrelvir + ritonavir (Paxlovid®)

Paxlovid® is the preferred oral treatment for COVID-19, unless contraindications are present. This product contains nirmatrelvir tablets co-packaged with ritonavir tablets.

Nirmatrelvir inhibits the main protease of the SARS‑CoV‑2 virus, preventing viral replication. Ritonavir is included to increase nirmatrelvir levels by inhibiting its metabolism.

The approved indication is:

• COVID-19 in adults ≥18 years who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death.

Administration

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet). These tablets should be taken together every 12 hours for five days. Failure to correctly take nirmatrelvir with ritonavir will result in subtherapeutic plasma levels of nirmatrelvir.

No dose adjustment is required for mild renal impairment (eGFR 60 to < 90 mL/min/1.73m²). For patients with moderate impairment (eGFR 30 to < 60 mL/min/1.73m²), the nirmatrelvir dose should be reduced to 150 mg (taken with ritonavir 100 mg) every 12 hours for 5 days. Paxlovid® is currently contraindicated in severe renal impairment as data for appropriate dosing is not yet available. Its use is also contraindicated in severe hepatic impairment, although no dose adjustment is required in mild to moderate hepatic impairment.

It is recommended that the tablets be swallowed whole without regards to food. However, studies suggest that administering nirmatrelvir + ritonavir as an oral suspension does not alter its pharmacokinetic parameters. The guidelines advise that nirmatrelvir + ritonavir tablets can be crushed or split and mixed with food or liquid, where necessary. Alternatively, they may be administered via a nasogastric tube, as indicated.

Adverse effects

Common adverse effects include taste disturbance, headache, diarrhoea, and nausea.

Nirmatrelvir and ritonavir are both metabolised by CYP3A4, and this contributes to many clinically significant drug interactions. Coadministration with medicines that induce this enzyme may reduce the concentration and efficacy of the antiviral. Use with strong CYP3A4 inducers is contraindicated as this may be associated with loss of virologic response and potential resistance. Paxlovid® may also increase the levels of medications that are metabolised by CYP3A. Use is contraindicated with medicines that are highly dependent on CYP3A for clearance and for which elevated levels may result in serious or life-threatening events.

The interactions of ritonavir can be difficult to predict, as it inhibits and induces CYP3A4 and other CYP enzymes. It also inhibits P‑glycoprotein and is a strong inducer of UGTs (which mediate glucuronidation). A full medication history should be taken before initiating therapy, ensuring that complementary and over-the-counter products are included.

Many medications are contraindicated with Paxlovid®, including:

• Drugs that may result in serious or life-threatening reactions, e.g. amiodarone, flecainide, colchicine, simvastatin, diazepam, and sildenafil.
• Drugs that may result in loss of virologic response and potential resistance, e.g. apalutamide, carbamazepine, phenytoin, rifampicin, St John’s wort.

The product information should be consulted for comprehensive advice on drug interactions.

Molnupiravir (Lagevrio®)

Molnupiravir has provisional approval for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death.

Molnupiravir inhibits viral replication following incorporation into viral RNA. It is less effective than nirmatrelvir + ritonavir and is not routinely recommended for the treatment of COVID-19. Molnupiravir is only recommended if an oral agent is required and the nirmatrelvir + ritonavir combination is contraindicated.

Administration

The recommended dose is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. Doses may be taken with or without food.

Adverse effects

Diarrhoea, nausea, and dizziness were the most commonly reported adverse events in clinical trials. These were of mild to moderate severity. No serious drug-related adverse events were reported.

Molnupiravir is not a substrate of any major drug metabolising enzymes or transporters and is considered unlikely to cause drug interactions.

Remdesivir (Veklury®)

Remdesivir is an intravenously administered agent that may also be considered for patients with mild to moderate disease, as well as more severe cases where ventilation is not required.

The approved indications are for the treatment of COVID-19 in:

• Adults and paediatric patients (at least 4 weeks of age and weighing at least 3 kg) who have pneumonia due to SARS-CoV-2, and who require supplemental oxygen; and
• Adults and paediatric patients (weighing at least 40 kg) who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.

Remdesivir is metabolised to remdesivir triphosphate (an adenosine analogue). This pharmacologically active form is then incorporated into viral RNA, preventing its replication. Remdesivir is used in both outpatient and hospital settings and treatment should begin within seven days of symptom onset.

Administration:

Remdesivir is administered daily via IV infusion. For adults and patients >40kg, the usual dose is 200mg on day 1, then 100mg on subsequent days. The usual treatment duration is three days for patients who do not require supplemental oxygen, and 5-10 days for patients with pneumonia who do need supplemental oxygen.

Remdesivir is supplied as a powder for injection. The powder is reconstituted with water for injection and then further diluted with 0.9% sodium chloride. The final volume is typically 250mL, although a volume of 100mL may be used for patients with severe fluid restrictions. The infusion should run over 30-120 minutes.

Dose adjustment is not required for patients with renal impairment (including those on dialysis) or hepatic impairment.

Adverse effects

Common adverse effects include nausea, vomiting, headache, rash, increased aminotransferases, and prolonged prothrombin time (PT). While prolonged PT has been observed in clinical trials, no difference has been reported in the incidence of bleeding events compared to placebo.

Hypersensitivity reactions (including infusion-related and anaphylactic reactions) have been associated with remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates (up to 120 minutes) may reduce the risk of these events. Remdesevir must only be administered in settings where there is immediate access to medications to treat a severe infusion or hypersensitivity reaction and access to an emergency medical response.

Table 1. Comparison of COVID-19 antiviral agents.

Drug	Route	Timing of initiation	Comments
Remdesivir	IV	≤7 days	30-120 minute infusion
Nirmatrelvir + ritonavir	Oral	≤5 days	1st line oral agent Many drug interactions + contraindications
Molnupiravir	Oral	≤5 days	Less effective

Summary

If an antiviral is considered appropriate for COVID-19, therapy should be promptly initiated following diagnosis. Where an oral agent is required, nirmatrelvir + ritonavir is preferred as it is more effective than molnupiravir. Remdesivir remains a valuable option for reducing the risk of hospitalisation. However, as it requires IV administration, its use in the community is limited.

INTRODUCTION:

Migraine headaches impose a substantial level of pain and disruption to a person’s quality of life. (Malmberg-Ceder, Soinila et al. 2022) Common triggers for migraine included physical activity, poor sleep hygiene, physical and mental fatigue, and emotional anxiety and stress. (Aderinto, Olatunji et al. 2024)

The age-adjusted prevalence of migraine is observed to be 21% in women, which is twice the rate of 10.7% seen in men (Burch, Rizzoli et al. 2021) and the economic burden is substantial. Starting from 2020 as a baseline, over the next 10 years migraine is predicted to have a in health-care costs of AU$1.67 billion, or AU$1313 per person. There could also be AU$68.13 billion loss to the GDP.(Tu, Liew et al. 2020)

Historically, acute migraine treatment has involved triptans as the leading clinical option. Preventive treatments include propranolol, metoprolol, amitriptyline and anti-epileptics such as sodium valproate and topiramate (Zobdeh, Ben Kraiem et al. 2021) as well as botulinum toxin.  (Kępczyńska and Domitrz 2022).

More recently a new class of drugs, the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), have become available as an effective preventative treatment for chronic migraine. (Ray, Dalic et al. 2024) In Australia eptinezumab, fremanezumab, galcanezumab and erenumab are available. The first three act directly against CGRP whilst erenumab acts against the CGRP receptor. (de Vries, Villalón et al. 2020). They are collectively referred to as CGRP antagonists. (AMH, 2025).

Briefly, the pathophysiology of migraine involves the triggering of the trigeminovascular system. Divisions of the trigeminal nerve innervate the face and as well as the meninges, which also includes intracranial blood vessels and the dura. These nerve branches release calcitonin-gene related peptide (CGRP), which acts as a potent vasodilator of cerebral and dural vessels, leading to neurogenic inflammation, and CGRP facilitates pain transmission from trigeminal vessels to the CNS.(Pescador Ruschel and De Jesus 2025)

Proof of concept for the role of CGRP has been demonstrated by the venous infusions of CGRP which results in migraine-like headaches. (de Vries, Villalón et al. 2020). Calcitonin gene-related peptide is reported to be most potent known vasodilator of both cerebral and peripheral blood vessels. (ACOG. 2022)

It is important to note that CGRP monoclonal antibodies (mAbs), due to their molecular size, exhibit only 0.1% presence in the brain as they are unable to cross the blood-brain barrier. Therefore, their mechanism of action primarily involves the trigeminal network located outside the brain. (Edvinsson and Warfvinge 2019). Two studies using radiolabelled mAbs have confirmed that these drugs act mainly peripherally, due to their large size.(Labastida-Ramírez, Caronna et al. 2023)

USE IN LACTATION:

For lactating mother’s, the current approved product information for erenumab (Aimovig) in eMIMS (2025) states:

“It is not known whether Aimovig is present in human milk. There are no data on the effects of Aimovig on the breastfed child or the effects of Aimovig on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from Aimovig, a decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the potential benefit of Aimovig to the mother and the potential benefit of breast feeding to the infant.”

However, a more forensic analysis of the pharmacokinetics of CGRP drugs, understood as the timeline of the drug’s absorption, bioavailability, distribution, metabolism and excretion, is important in assessing the suitability of administering these drugs to pregnant and lactating mothers. (Ernstmeyer and Christman 2023)

THE RESEARCH:

Erenumab (Aimovig), a biosynthetic immunoglobulin G monoclonal antibody (mAb), is a large protein molecule with a weight of 150,000 Da. (Bussiere, Davies et al. 2019, Kothari, Wanjari et al. 2024).

Because of the size of erenumab, presentation via maternal milk to a newborn infant faces a number of physical barriers.

First, erenumab (and other mAbs) must cross the mammary epithelium from maternal blood into milk. A review of the research by LaHue, Anderson et al. (2020) of 155 women using the mAbs certolizumab, rituximab or natalizumab across 30 studies reported that “a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.”

These researchers applied the relative infant dose (RID), a metric comparing the infant and maternal drug dose, where <10% is generally considered safe, and found that certolizumab and rituximab were present in maternal milk at <1%.

A second “barrier’ is the digestion of a mAb in the infants GIT. A study of the IgG1 mAb palivizumab presence in neonatal intestinal fluid found a variably level of destruction of 50%. (Sah, Lueangsakulthai et al. 2020) As a guide to understanding the poor GI abruption, “native” IgG is only 0.01% absorbed intact from the GIT. (Anderson 2021)

Other “barriers” to infant exposure include the extent to which the drug is bound by maternal plasma proteins, the degree of drug ionisation, lipid solubility and most pertinently, the molecular weight of the drug, which for CGRP drugs is 150,000 Da. (Hotham and Hotham 2015).

Once a CRGP drug enters the infant GIT there are added impediments to the drug entering its bloodstream. These include the infant gut immune barrier (GIB) (Daneman and Rescigno 2009), as well as infant acidic denaturing. (Tashima 2021). 

The implications of this low rate of infant GI tract absorption of mAbs is readily demonstrated by another mAb, natalizumab, for which there is considerable pharmacokinetic data.

Natalizumab is given at a 300mg dose and, according to the official information, will achieve an average patient plasma concentration of 110mg/L. Applying the aforementioned 0.01% GIT absorption and an estimated volume of distribution of 0.25L (Anderson 2021), the infant would be exposed to a concentration of approximately 0.04% of the mother’s serum level.

This is a trivial level when measured against the WHO Working Group of experts of drug use during breastfeeding, who consider an infant: maternal ratio of less than 10% to be safe.

Indeed, many medicines enter breast milk, but usually the amount received by the infant is less than 10% of the maternal dose.(Amir, Pirotta et al. 2011)

In summary, Rayhill (2022) has noted: “The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this has not been adequately studied.”

PREGNANCY IMPLICATIONS:

The positive implications associated with a putative low foetal concentration are supported by a 2021 analysis of WHO pharmacovigilance date for erenumab, galcanezumab and fremanezumab when given during pregnancy and lactation. (Noseda, Bedussi et al. 2021) The researchers reported that there were “no specific maternal toxicities, patterns of major birth defects or increased reporting of spontaneous abortion…”

There are various case reports of erenumab given during pregnancy. For example, Vig, Garza et al. (2022) referenced a case of a woman who used erenumab for migraine through her pregnancy with no harm to her child.

In another report of three pregnancies with gestational exposure to erenumab, two women ceased erenumab during the first trimester with no adverse sequalae for their babies.

One woman ceased erenumab 1 month before conception and experienced a first trimester spontaneous abortion due to gestational trophoblastic neoplasia, however a subsequent pregnancy was uneventful. No plausible drug-related explanation could be offered by the authors for the spontaneous abortion. (Bonifácio, de Carvalho et al. 2022)

An updated safety analysis on erenumab, galcanezumab, fremanezumab and eptinezumab use in pregnancy by  Noseda, Bedussi et al. (2023) “ showed no signals of foeto-maternal toxicity according to VigiBase® safety reports.”

A case series and literature review by Elosua-Bayes, Alpuente et al. (2024) focused on the periconceptional period of CGRP therapies that were ceased prior to conception. They reported that “database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates.”

They concluded that “CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.”

A reasonable explanation for foetal safety is that mAbs likely do not cross the blood brain barrier secondary to their molecule size. (de Vries, Villalón et al. 2020).

In contrast to these positive reports, Rayhill (2022) advise that CGRP mAbs should be ceased 5-6 months pre-conception due to their long half-life and a lack of safety data.

EFFICACY:

All four CGRP therapies have been reported to possess long-term safety, making them “effective and well-tolerated for the prevention of migraines.” (Muddam, Obajeun et al. 2023)

Summarising the current research, Oliveira, Gil-Gouveia et al. (2024) reported that “Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6–61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29–88% of the patients stopped medication overuse.”

CONCLUSION:

Based upon the preceding literature review, the use of erenumab and other CGRP medications in lactation is an option that can be positively considered by a clinician when balancing the maternal benefits against potential foetal harms. However caution is necessary because longer-term studies are still required, (Burch, Rizzoli et al. 2021) notably in its cardiovascular impact, since CGRP has protective properties in cardiovascular disease. (González-Hernández, Marichal-Cancino et al. 2016).

Their use in pregnancy currently has contradicting research findings.   (Elosua-Bayes, Alpuente et al. 2024) (Moisset, Demarquay et al. 2024)