Knowledge Type: Clinical Articles

Monkeypox has been declared a Communicable Disease Incident of National Significance in Australia. As of 16 August 2022, 82 probable or confirmed cases of monkeypox have been reported to the National Notifiable Diseases Surveillance System (NNDSS).

Monkeypox is a zoonotic viral disease endemic in several African countries. In countries where monkeypox is endemic, outbreaks have historically been restricted to rural populations living within or adjacent to tropical rainforests. However, since May 2022, the World Health Organization (WHO) has received reports of monkeypox from 12 member states that are not endemic for the virus and in people with no established travel links to endemic areas.

Monkeypox infection

The virus that causes monkeypox belongs to the orthopoxvirus genus of the Poxviridae family. This is the same genus as the smallpox virus.

The incubation period for monkeypox is thought to be around 7-14 days but may be as long as 21 days. Patients may experience a prodromal phase with fever, headache, and fatigue before the characteristic rash appears. The lesions are often deep and evolve from macular to papular, vesicular, and pustular before crusting. The lesions may be painful in the initial stages and then itchy once they have crusted over. Pitted scars or pigmentation changes may remain after the lesions have healed.

The severity of infection varies significantly. Some people may develop a single lesion, while others develop multiple lesions which may coalesce and result in large regions of skin disease. Complications such as secondary infections, bronchopneumonia, sepsis, encephalitis, and infection of the cornea with vision loss can also occur. People at higher risk of severe infection include people who are immunocompromised, pregnant women, infants and young children.

While smallpox and monkeypox share some similarities, monkeypox has a much lower fatality rate. The WHO reports that the recent case fatality ratio for monkeypox is around 3-6%. However, the current global outbreak is seeing few deaths. This may be due to the reporting of mild cases that were previously not diagnosed, different demographics affected, or a less deadly strain circulating.

Isolation

The infectious period is thought to extend from the onset of rash until all scabs have healed. Human-to-human transmission may occur following close physical contact during this infectious period. Transmission is via contact with lesions, body fluids (including respiratory droplets), and contaminated materials (such as towels and bedding).

People with a suspected infection should isolate until a negative result is obtained; people with confirmed infection should isolate until the infectious period is over. Household members should avoid physical contact with the infected person and objects that have been in contact with the infected person (e.g. towels). Careful hand and respiratory hygiene are important. If the infected person cannot isolate alone, a face mask should be worn when they are around other people.

Vaccination

As smallpox and monkeypox are closely related, smallpox vaccines can protect against monkeypox. Studies suggest that vaccination against smallpox provides around 85% effectiveness against monkeypox.

There are two smallpox vaccines available in Australia:

• Jynneos® is a live vaccine produced from an attenuated, non-replicating orthopoxvirus. The vaccine is administered subcutaneously as a two-dose schedule given at least 28 days apart. This vaccine is considered a third-generation vaccine. As it is non-replicating, it is safe for people with compromised immune systems or atopic dermatitis. It is associated with fewer adverse effects compared to earlier smallpox vaccines.
  • Jynneos® is not currently registered with the Therapeutic Goods Administration (TGA). However, it is available under section 18A of the Therapeutic Goods Act 1989 (exemption because of emergency). Limited supplies have been secured by the Commonwealth and some States and Territories.
• Acam2000™ is also a live-attenuated vaccine. It is administered via the percutaneous route using 15 jabs of a bifurcated needle. A single dose is required, although revaccination may be considered every three years for people at continued high risk of exposure to live pox viruses. Acam2000™ is a second-generation vaccine that is replication competent. It must not be used in pregnancy, severe immunocompromise, or active atopic dermatitis. Patients must also be advised of the risk of self-inoculation and spread to close contacts due to viral shedding. The virus sheds from the cutaneous lesion that forms at the site of inoculation from around day three until scabbing occurs. During this time, accidental infection of skin at other sites (self-inoculation) or infection of close contacts can occur. To avoid this, the vaccination site must be kept covered during this period of viral shedding.
  • Acam2000™ is registered with the TGA and included in the National Medical Stockpile.

The Australian Technical Advisory Group on Immunisation (ATAGI) provides guidance on the use of these vaccines. The current advice is that Jynneos® is preferred for both pre-exposure prophylaxis and post-exposure prophylaxis. This is due to the more favourable safety profile and simpler method of administration.

The global supply of Jynneos® is limited, and demand is high. The overall risk of contracting monkeypox in Australia is currently low and widespread vaccination is not recommended. Initial access to the vaccine will prioritise groups at higher risk. The key risk groups identified by ATAGI include:

• Anyone categorised by public health authorities as a high-risk monkeypox contact in the past 14 days;
• Gay, bisexual and other men who have sex with men (GBMSM) with a high number of sexual contacts;
• Sex workers (especially those whose clients are in high-risk categories);
• Anyone in the above risk categories who is planning to travel to a country experiencing a significant outbreak (vaccination recommended 4-6 weeks before travel); and
• Immunisation providers who administer the ACAM2000™ vaccine.

Treatment

Monkeypox is generally a self-limiting condition. Most people will not require treatment other than simple supportive care such as over-the-counter analgesics. In some cases, complications of monkeypox may require treatment, e.g. antibiotics for the management of secondary cellulitis.

Specific therapy for monkeypox may be considered in the following cases:

• People presenting with severe disease (e.g., haemorrhagic disease, confluent lesions, sepsis, encephalitis, or other conditions requiring hospitalisation); and
• People at risk of severe disease.
  • Immunocompromised
  • Children (especially those <8 years of age)
  • Pregnant or breastfeeding
  • People with one or more complications

Two treatment options are tecovirimat and vaccinia immunoglobulin. These agents are investigational, and their use requires a thorough assessment of the risks and benefits.

Tecovirimat

Tecovirimat is an orally-active antiviral indicated for the treatment of monkeypox, cowpox, and smallpox. It can also be used for the treatment of complications following vaccination against smallpox. The efficacy of tecovirimat is based on animal studies. In non-human primates, tecovirimat demonstrated a significant mortality benefit (95% survival in the tecovirimat group, compared to 5% in the placebo group). A Phase 1 study conducted in healthy human volunteers did not identify any safety concerns. Adverse events commonly reported in the study included headache, nausea, and diarrhoea.

Tecovirimat is available in 200mg capsules. The usual adult dose is 600mg twice daily for 14 days. Weight-based dosing advice is available for children ≥13kg in the guidelines. Dose adjustment is not required for renal or hepatic failure.

While tecovirimat is not approved by the TGA, it is currently the preferred first-line drug option for severe monkeypox infection according to the Australian Human Monkeypox Treatment Guidelines. Supplies of tecovirimat are held in the National Medical Stockpile.

Vaccinia immunoglobulin

Vaccinia immunoglobulin is the second-line choice for the treatment of monkeypox, although it may be preferred in pregnant patients.

Vaccinia immunoglobulin is also the first-line option for the treatment of complications following vaccination with a replication-competent vaccinia vaccine (i.e. Acam2000™). Indications for the use of this product following vaccination include:

• Eczema vaccinatum (widespread pustular or erosive lesions from the vaccinia virus, occurring particularly in areas affected by atopic dermatitis);
• Generalised vaccinia (results from viraemia and presents with a generalised vaccinia virus rash which may be accompanied by fever, myalgia, and headache. This reaction is self-limiting in immunocompetent hosts);
• Progressive vaccinia (presents with delayed or absent local wound healing and widespread lesions originating from the inoculation site that can become necrotic. The risk is highest in severe immunocompromise);
• Vaccinia infections in individuals who have skin conditions; and
• Atypical infections induced by vaccinia virus (excluding isolated keratitis).

Vaccinia immunoglobulin is not considered to be effective in the treatment of postvaccinial encephalitis.

Vaccinia immunoglobulin is administered as an intravenous infusion. The usual dose is 6,000 U/kg, given as soon as symptoms appear. Repeat doses may be required depending on symptom severity and response to treatment. Higher doses may be considered if the initial response is poor.

Common adverse reactions reported in clinical trials include headache, nausea, rigors, and dizziness.

Caution is required when monitoring blood glucose in patients receiving vaccinia immunoglobulin. This product contains maltose which some blood glucose monitoring systems falsely interpret as glucose. Clinical decisions based on incorrect blood glucose readings can lead to serious events. Therefore, only glucose monitors and test strips that are glucose-specific should be relied upon during treatment with vaccinia immunoglobulin.

Other potential therapies

Cidofovir is a potential therapeutic agent. While there is currently no human data to support its use in the treatment of monkeypox, in vitro and animal studies show efficacy against orthopoxviruses. Cidofovir is associated with significant adverse effects, which may outweigh the potential benefits.

Cidofovir is currently TGA registered for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The Australian Human Monkeypox Treatment Guidelines advise careful consideration of the use of cidofovir for monkeypox in order to preserve supply for patients with difficult-to-treat CMV disease and other viral infections in transplant patients.

Brincidofovir is another potential therapy for monkeypox. This antiviral is not registered by the TGA. It is approved by the US Food and Drug Administration (FDA) for the treatment of smallpox. There is currently no human data to support its use in the treatment of monkeypox. Brincidofovir has shown efficacy against orthopoxviruses in in vitro and animal studies. It is currently undergoing clinical trials in Australia.

Summary

Most people are not at high risk of contracting monkeypox, and mass vaccination is not recommended. Vaccine supplies are currently limited and will be directed toward people at the highest risk of contracting the infection.

For most people, monkeypox is a self-limiting infection that does not require specific treatment. However, severe disease can occur, and treatment may be deemed necessary. The Australian Human Monkeypox Treatment Guidelines should be referred to for information on specific therapies.

The monkeypox situation is evolving in Australia and health advice may change. The Department of Health can be accessed for current medical advice, official reports, and case numbers.

Background

Anticholinergic burden is defined as the cumulative effect of taking multiple anticholinergic medications resulting in an increased risk of adverse effects. High, long-term cumulative exposure has been linked to an increased risk of mortality and poor cognitive and physical function, such as poor grip strength, slower walking speeds and poor appetite. These poor outcomes have been associated with increased hospital admissions, longer hospital stays and increased GP visits.

Anticholinergic burden is a prominent issue, particularly in the older population, due to the presence of polypharmacy. It is estimated that about 35% of adults over 60 years take more than five medications at a time, and anticholinergic drugs are often the most prescribed medications. A previous study identified approximately 8.9 drug-related problems per patient in the older population.

Medications used to treat common chronic conditions such as pain, allergies, depression, and cardiovascular disease can have weak anticholinergic properties. These can be overlooked as they are typically not recognised as anticholinergic drugs.

Understanding the effects of anticholinergic drugs and their cumulative effect is essential to assessing anticholinergic burden and preventing poor clinical outcomes.

Anticholinergic Medications

 Examples of anticholinergic medications may include: 

High Potency	Low Potency
•       Doxepin •       Orphenadrine •       Benztropine •       Solifenacin* •       Oxybutynin •       Atropine •       Nortriptyline* •       Chlorpromazine •       Clozapine •       Amitriptyline •       Clomipramine	•       Loratadine •       Amantadine •       Codeine •       Oxycodone •       Metoprolol •       Loperamide •       Haloperidol •       Olanzapine* •       Quetiapine* •       Temazepam •       Citalopram •       Paroxetine* •       Warfarin

*Varied classification of potency dependent on assessment scale

Side effects

 The side effects of anticholinergic medications can be classified as central or peripheral.

• Central effects: cognitive dysfunction, delirium, confusion, falls, brain atrophy.
• Peripheral side effects: dry mouth, urinary retention, visual disturbance, tachycardia, constipation, increased risk of pulmonary infections.

Assessing Anticholinergic Burden

Several validated tools based on expert opinions and literature review have been developed to quantify anticholinergic burden. Utilisation of these tools can be useful as part of clinical reviews and assessing the risk/benefit ratio when prescribing or deprescribing.

Incorporated aspects such as the number of medications included and dose consideration vary greatly amongst the scales. As such, calculated exposure to anticholinergic prescribing can vary as much as 8 to 17.6% depending on the assessment scale used.

Some of the more widely used scales include:

Scale	Scale Points	Medications Included	Includes dose consideration
Anticholinergic Drug Scale (ADS)	0-3	520	Yes
Anticholinergic Cognitive Burden Scale (ACB)	1-3	88	No
Anticholinergic Rating Scale (ARS)	1-3	49	Yes
Anticholinergic Loading Scale (ACL/ALS)	0-3	292	No
Modified Anticholinergic Cognitive Burden Scale (mACB)	1-3	82	No
Drug Burden Index (DBI)	DBI = Σ[D/(D+δ)]   D = daily dose taken δ = minimum licensed daily dose

To date, there is no consensus on a standardised tool to quantify anticholinergic risk. For clinicians and pharmacists wanting to assess anticholinergic risk, an online tool (http://www.anticholinergicscales.es/) that comprises of several scales may be used to assess the anticholinergic risk comprehensively.

Summary

Anticholinergic burden is largely present in cases of polypharmacy. Often, medications with strong anticholinergic properties are recognised as inappropriate medications in the older population. However, there is widespread use of low potency anticholinergic drugs in common chronic conditions, and its additive effects may be overlooked.

Quantifying anticholinergic burden is important to identify patients at risk and evaluate the risk and benefit ratios of prescribed medications. Pharmacists can incorporate quantification of anticholinergic burden into clinical care to help identify patients at risk, refer patients as needed or monitor patients for adverse effects.

The ubiquitous belief that a course of antibiotics should be taken until finished has its origins in the Nobel prize speech in 1945 by John Fleming when he advocated: “If you use penicillin, use enough!” This mantra has become embedded in national and international public awareness antibiotic programs. However, the research does not support this decree in all clinical cases.

For example, uncomplicated community-acquired pneumonia (CAP) in children treated with either cephalosporins or penicillins showed no difference in treatment failure with a median 6 days versus a median 10 days and readmission rates for CAP for 5 versus 10-day therapy were significantly lower with the short-course.

Similarly, a median treatment of 9 days for P. aeruginosa bacteraemia showed no significant difference in the 30-day reoccurrence risk, compared to a median treatment of 15 days (HR = 0.68, 95% CI =0.34-1.36, P = 0.28) whilst a short course (6-10 days) treatment in low-risk methicillin-susceptible Staphylococcus aureus bacteraemia (n=141) showed no significant difference in 90-day mortality when compared to long course treatment (11-16 days).

For uncomplicated gram-negative bacteraemia (GNB), a randomised controlled trial (n=604) showed that a 7-day course was non-inferior to 14-day treatment when assessed for clinical failure, readmissions, extended hospitalisation at 90 days or mortality. Similarly, a systematic review and meta-analysis by Li et al. (2021) reported no significant differences for 30-day mortality or recurrent bacteraemia, 90-day mortality or recurrence, adverse events, Clostridium difficile infection or the development of resistance for short versus long-term treatment for uncomplicated GNB. As a summary of antibiotic use for GNB, Le Fevre has noted that the personalising and individualising of antibiotic treatment duration is “… a promising approach, in need of further research.”

A more nuanced approach is required for certain types of infections, with a shorter duration of therapy for uncomplicated intra-abdominal infections such as appendicitis, but a longer duration for complex infections such as faecal peritonitis.

A problem with prolonged antibiotic use is the induction of opportunistic overgrowth. Tan et al. (2021) reported that superinfection rates occur more regularly when patients received long-term treatment of non-ventilator associated hospital-acquired pneumonia, compared to short-term treatment (6.3% v. 18.2% p= 0.027).

Exceptions to the “shorter is better” approach involve persistent infections such as M. tuberculosis, H. pylori, Salmonella Typhi, T. pallidum, S. aureus (cystic fibrosis patients with bronchiectasis or pneumonia, or device-associated infections) and M. leprae. There are also some infections, for example osteomyelitis, where a shorter duration increases the risk of relapse. Intravenous antibiotics are often recommended for at least 4-6 weeks after surgical debridement, followed by 3-6 months of oral therapy.

Bacterial resistance is multilayered and can occur either through natural resistance or acquired resistance. The latter involves horizontal gene transfer (HGT) via transformation, transposition, and conjugation. HGT enables bacteria to rapidly change in response to shifting environmental circumstances, thereby providing an enhanced survival advantage. For example, HGT of vanB determinants occurs in hospital E. faecalis and E. faecium, and multi-drug resistant vancomycin-resistant enterococci (VRE) can transfer genetic determinants to methicillin-resistant S. aureus (MRSA). The inappropriate use of antibiotics has also allowed P. aeruginosa to acquire resistance via chromosomal mutations and acquisition of antibiotic resistance genes via HGT.

In summary, improper antimicrobial stewardship, including sub-therapeutic dosing, has resulted in the current problem of universal antimicrobial resistance. Therefore, reducing unjustified antibiotic use is vital to mitigating bacterial resistance. Longer duration of exposure to antibiotics for opportunistic bacteria (E. coli, E. faecium, S. aureus, K. pneumoniae, Pseudomonas spp, Acinetobacter spp and Enterobacter spp) increases both resistance and transfer of resistant strains between asymptomatic patients. Paradoxically and counter-intuitively, less is better for most patients, as a reduced use of antibiotics lowers rather than increases resistance.

Venous thromboembolism (VTE) may include a deep vein thrombosis (DVT) or a pulmonary embolism (PE). The incidence of VTEs in terminal phase palliative care patients is often difficult to determine, which may be because the focus in this setting is symptom management rather than diagnosis and undertaking further investigations – also noting that subclinical VTEs may be asymptomatic. The forms of VTE prophylaxis available include compression stockings (such as TEDS), unfractionated heparin, or low molecular weight heparin such as enoxaparin. There is limited evidence for the role of compression stockings in terminal phase palliative care patients. If pharmacological VTE prophylaxis was indicated, enoxaparin may be preferred to unfractionated heparin due to its once-daily dosing (compared to bd-tds with unfractionated heparin). The decision to use VTE prophylaxis in a palliative care patient is a difficult one in that many patients are at greater risk of thrombosis, as well as at a greater risk of bleeding.

In terms of risk factors to consider for thrombosis:

• If patients have cancer, the metastatic cancer itself is a risk factor for thrombosis, noting that the type of cancer is relevant – some types of primary cancers have a higher risk of thrombosis such as lung, pancreatic or haematological cancers, whereas other cancers such as prostate cancer may have a lower risk
• Dehydration (particularly as patients approach the terminal phase and oral intake decreases)
• Age > 60
• Reduced mobility (which will continue to reduce further in the terminal phase)
• If there is concurrent infection

In terms of risk factors to consider for bleeding:

• Active bleeding would be a contraindication. Platelet levels should be considered, for example, a decrease of 30-50% of the initial platelet count, or platelets < 50 x 10⁹/L may be a contraindication to VTE prophylaxis. Consideration of the possibility of heparin-induced thrombocytopenia as an adverse effect should also be considered.
• Significant liver impairment – also consider factors such as previous/current alcohol abuse
• Significant renal impairment – if VTE prophylaxis is indicated, a dose reduction would be appropriate (e.g. enoxaparin 20mg daily for creatinine clearance < 30mL/minute)
• Severe malnutrition may increase bleeding risk. For patients with low body weight (males < 57kg and females < 45kg), guidelines suggest to reduce the dose of enoxaparin to 20mg daily (if VTE prophylaxis is indicated)
• Anaemia (common in palliative care patients) may increase bleeding risk
• A recent study by Tardy et al looked at the bleeding risk of hospice patients (the majority of whom had metastatic cancer) and found that while the incidence of VTEs was low, there was quite a high incidence of significant bleeding in this patient group (9.8%), and it was identified that bleeding was associated with VTE prophylaxis (p=0.04, HR = 1.48 (1.02-2.15))

One of the main goals of palliative care therapy is improving symptoms as well as quality of life for patients. It is noted that the conditions resulting from a thrombotic event may cause unpleasant or distressing symptoms for patients such as painful swollen legs (DVT) or tachycardia/dyspnoea (PE). In addition, if it is a thrombotic event that ends up causing a patient’s death, these distressing symptoms may be present for a number of hours prior to death. However, it is also noted that end-of-life medications may be used for the management of such symptoms (e.g. morphine for dyspnoea or pain), in the event that this does occur. This is in contrast to if a patient experienced a catastrophic haemorrhage as a result of VTE prophylaxis therapy, which may be equally (or more) distressing for patients and there are no medications appropriate to provide ‘symptom relief’. Another consideration in terms of quality of life is that patients may find the daily subcutaneous enoxaparin injection uncomfortable or painful, or they may simply prefer to minimise their medication burden at the end stage of life.

The prognosis or trajectory of a palliative care patient should be considered in the prescribing of VTE prophylaxis (for example, if they have days versus weeks or months to live). The risks versus benefits of using VTE prophylaxis, as well as not using VTE prophylaxis, should be explained to the patient and ultimately their preferences will guide the decision making. Ideally, patients would have considered their preferences for VTE prophylaxis ahead of time, and have this documented on their advanced health directive, however, this would often not be the case. If the patient’s preference was to have VTE prophylaxis, this decision should be re-assessed regularly during their hospital/hospice admission, particularly if their clinical state changes with regards to the factors discussed above.

Although the oral route should be maintained for as long as possible in a palliative care setting, there are a variety of circumstances where commencing a continuous subcutaneous infusion (CSCI) may be beneficial. This may be temporary (for example, to manage significant vomiting, then once symptoms are under control, the patient may be converted back to oral medications if appropriate), or the CSCI may be ongoing as part of end-of-life care.

Indications for CSCI use include:

• Where oral administration is problematic – for example, with significant nausea and vomiting, a severely dry mouth, dysphagia (particularly in cases such as mouth, throat or oesophageal cancer), poor oral absorption, if the patient is too weak to swallow oral formulations, or they are unconscious
• Where rectal administration is problematic – for example, significant diarrhoea or a bowel obstruction
• Where IV administration is problematic – for example, due to the risk of infection and the level of invasiveness in a palliative care setting
• Where IM administration is problematic – many patients find IM injections to be uncomfortable (particularly if they are cachectic, which is common in a palliative care setting)
• If the patient requests to switch to a CSCI – for example, to minimise their tablet burden or if they are requiring repeated bolus subcutaneous injections per day
• Intractable pain may or may not be an indication for CSCI use, as there are differing viewpoints as to whether CSCIs provide superior analgesia compared to other routes of administration. There is a lack of studies in this area due to the difficulty assessing patient-reported symptom relief in end-of-life care; however a recent small study did find CSCIs did provide superior analgesia.

There are a number of advantages of CSCI use which include:

• Giving medications via CSCI rather than bolus subcutaneous injections decreases the number of injections for a patient. This is more comfortable for them and is more convenient (for patients, nursing staff, or family/carers if in a home setting) as a CSCI is normally only changed every 24 hours
• CSCIs may allow a combination of medications to be given in the one syringe driver (taking into account drug compatibility)
• If a CSCI is used at the patient’s home (versus in hospital/hospice care), it may allow them to remain at home for end-of-life care which may align better with their preferences and goals of care
• The use of a CSCI may result in more stable plasma levels of medications, thereby minimising fluctuating/withdrawal symptoms and resulting in improved symptom control. Also, noting that in a hospital or hospice setting, there are often delays to patients receiving bolus subcutaneous doses in a timely manner – in other words, this is another way the use of a CSCI may improve symptom control
• If patients are still ambulant, the use of CSCI can help to maintain their mobility rather than leaving them bed-bound

In terms of considerations around patient selection:

• If the CSCI is to be used in a home setting, there are a number of factors to consider in terms of an ‘appropriate’ patient to receive a CSCI:
  – That the home environment is suitable/safe for palliative care staff to attend the house to change the CSCI (normally once daily) and to review the patient
  – Ideally, there would be a family member/carer at home who would be willing and able to administer subcutaneous ‘prn’ breakthrough doses. This person(s) should receive appropriate education regarding the correct administration and disposal of medications. Patients or their family members should also be able to manage ‘technical problems’, for example knowing how to change the batteries if necessary, or how to manage a leaking infusion
• A CSCI may be difficult to connect and change for some patients, for example, those who are highly agitated, although placement of the cannula around the scapula may be helpful in this regard
• A CSCI may not function optimally in patients with impaired lymphatic drainage (for example, patients with significant oedema)
• Some patients feel that the use of a CSCI takes away their sense of control of their medications – again, to consider the individual patient’s preferences and goals of care

A final consideration with regards to patient selection is that patients and their families should have clear education provided with regards to the role of a CSCI, as well as its advantages/disadvantages for that specific patient. An open discussion between patients, their family and members of the palliative care team will give patients and their family the opportunity to ask any further questions prior to commencing a CSCI, and can help to dispel some myths surrounding CSCI use (for example, that their use may hasten death.

HPS Pharmacies is delighted to share the following study overview written by Natansh Modi, a pharmacist at HPS Pharmacies St Andrew’s. The study, conducted by Natansh and her colleagues,  looked at patient-reported outcomes in advanced breast cancer. Click here to read the full study.

1. What was the main purpose of your study?

The study aimed to evaluate the prognostic performance of pre-treatment patient-reported outcomes for prognosis and toxicity in patients initiating anticancer treatment for HER2-positive advanced breast cancer.

2. What was the rationale behind the study? Why is it important to do research on this topic?

Shared decision making is the process in which the clinician and the patient collate and discuss the available evidence on the benefits and harms of treatments to make the most appropriate informed health decisions for the patient. Shared decision making is an essential component of providing patient-centred care.

Eastern Cooperative Oncology Group performance status (ECOG PS) is a clinician-interpreted tool used to evaluate the daily living abilities of patients. Patient-reported outcomes (PROs) are structured self-reported tools that provide the patients’ perspective and voice to their physical, social, emotional, and functional abilities.

PROs have shown to be of prognostic importance in other cancer types (including bladder cancer, non-small-cell lung cancer, and melanoma), with some studies demonstrating patient-reported physical function/well-being as more prognostic than ECOG PS. Additionally, PROs have shown the potential to detect serious adverse events earlier than clinician reporting. However, the prognostic value of PROs in HER2-positive advanced breast cancer has been minimally explored.

3. What was the key finding of your study?

Patient-reported physical well-being, trial outcome index score, total FACT-B score, functional well-being, and BC subscale score were identified as significantly and independently associated with overall survival. This study found that both patient-reported physical well-being and clinician-interpreted ECOG PS provide independent prognostic information.

4. What are the implications of your findings for patient care?

The present study demonstrates that patient-reported physical well-being has independent, and potentially superior, prognostic performance to the clinician-interpreted ECOG PS. It is, therefore, essential that clinical practice transforms to place a greater emphasis on the patient’s perspective and voice.

5. What are the key limitations of your study?

Randomised controlled trials (RCTs) are the backbone of evidence-based medicine; however, strict inclusion criteria within RCTs can limit the generalisability of results (e.g., the study cohort was almost entirely restricted to participants with better ECOG PS than what would be observed in the general population).

6. What are the next steps?

Future research should examine the association between clinician interpreted ECOG PS and patient-reported outcomes in early breast cancer, other breast cancer subtypes, and in real-world populations, which are more likely to have broader distributions of ECOG PS and PROs scores.

HPS Pharmacies is delighted to share the following study overview written by Natansh Modi, a pharmacist at HPS Pharmacies St Andrew’s. The study, conducted by Natansh and her colleagues looked at side effects in breast cancer patients treated with abemaciclib. Click here to read the published study.

1. What was the main purpose of your study?

The study aimed to develop clinical prediction models that allows for personalised predictions of diarrhoea and neutropenia following abemaciclib initiation.

2. What was the rationale behind the study? Why is it important to do research on this topic?

Abemaciclib is a novel cyclin-dependent kinase (CDK) 4/6 reversible inhibitor that is used in the treatment of hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Current guidelines support the use of abemaciclib as a first-line therapy either in combination with a non-steroidal aromatase inhibitor (NSAI) or fulvestrant in patients with HR+/HER2-ABC. Safety data emerging from the clinical trials have identified diarrhoea and neutropenia (characterised by low neutrophil count) as key side effects associated with abemaciclib use.

The regulatory approval and existing literature present limited information about risk factors associated with developing diarrhoea and neutropenia in patients initiating abemaciclib. Valid prediction models can enable clinicians to understand patients needing increased monitoring or pre-emptive strategies to manage toxicities – ultimately allowing patients to remain on beneficial treatments for longer.

3. What was the key finding of your study?

The study identified that advanced age (70 years and above) was associated with an increased risk of abemaciclib induced grade ≥ 3 diarrhoea.

The study used large, pooled data to develop and present the first clinical prediction tool of abemaciclib induced grade ≥3 neutropenia in patients with HR+/HER2- ABC. The tool defined the risk of grade ≥3 neutropenia, which ranged from 5% to 64% according to patient race (Asian vs non-Asian), Eastern Cooperative Oncology Group performance status (ECOGPS) (1+ vs 0) and pre-treatment white blood cell count (<4.0 vs 4.0–4.99 vs 5.0–6.5 vs ≥ 6.5 × 10⁹/L).

4. What are the implications of your findings for patient care?

Effective communication of personalised and well-validated predictions of an individual’s expected adverse outcomes can improve shared decision making, empower patients, and enable patients and clinicians to make better decisions regarding strategies to mitigate adverse outcomes.

5. What are the key limitations of your study?

Randomised control trials (RCTs) are the backbone of evidence-based medicine, however, strict inclusion criteria within RCTs can limit the generalisability of results.

6. What are the next steps?

With advances in large electronic health record platforms, future opportunities to externally validate the presented tool within observational datasets of patients using abemaciclib in routine clinical care should occur – in the future, this may also include evaluating the tools appropriateness for abemaciclib’s use as a neo-adjuvant treatment.

Opioids are high-risk medicines that are associated with significant harm or death when misused. A report commissioned by the Australian Institute of Health and Welfare (AIHW) highlights the harms caused by opioids. It shows that there are three drug-induced deaths involving opioids and almost 150 hospitalisations involving opioid harm each day in Australia.

There has been a raft of changes implemented to address these issues. This includes scheduling changes for codeine, increased restrictions for opioids supplied on the Pharmaceutical Benefits Scheme (PBS), and the progressive rollout of real-time prescription monitoring by the states and territories. However, the inappropriate use of opioids continues to be a problem in Australia

The World Health Organization (WHO) launched the third Global Patient Safety Challenge in 2017 with the theme of ‘medication without harm’. One of the priority actions identified in the Australian response was to develop a national guideline for the peri-surgical management of high-risk medicines such as opioids.

Opioid Analgesic Stewardship in Acute Pain Clinical Care Standard

The Australian Commission on Safety and Quality in Health Care (the Commission) has recently published the first national Opioid Analgesic Stewardship in Acute Pain Clinical Care Standard (acute care edition).

Opioid analgesic stewardship can be defined as coordinated interventions to optimise the use of opioid analgesics. The benefits of an opioid analgesic stewardship program are many. They include improved patient safety, improved patient satisfaction regarding pain management, reduced inappropriate opioid use, and reduced potential for opioid-related harm. This may result in reduced healthcare and economic costs associated with the inappropriate use of opioids.

This new clinical care standard addresses the priority actions identified for the Global Patient Safety Challenge and aims to support the appropriate use of opioid analgesics for acute pain. The standard is relevant to the care of people of all ages with acute pain where opioids may be considered or prescribed. It does not relate to the management of opioid use disorders, chronic non-cancer pain, cancer pain, palliative care, or pain in labour and delivery. While it does apply to acute pain in the emergency department and following surgery, it does not apply to patients presenting with acute major trauma in categories 1, 2 or 3 of the Australasian Triage Scale.

The standard focuses on the following key areas of care that have the greatest need for quality improvement:

1. Patient information and shared decision making;
2. Acute pain assessment;
3. Risk-benefit analysis;
4. Pathways of care;
5. Appropriate opioid analgesic prescribing;
6. Monitoring and management of opioid analgesic adverse effects;
7. Documentation;
8. Review of therapy; and
9. Transfer of care.

Consideration of alternatives to opioids is encouraged in the emergency department and following surgery. Opioid-sparing strategies may include the use of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and non-pharmacological options such as physiotherapy, exercise, splinting, and heat packs. Where opioids are required, a cessation plan is important.

When the prescriber considers it appropriate to initiate an opioid in an opioid-naïve patient with acute pain, the standard makes the following recommendations:

• Use an immediate-release preparation;
• Use the lowest appropriate dose;
• Limit the duration; and
• Prescribe in line with best practice guidelines.

Modified-release opioids

Modified-release opioids should generally be avoided in acute pain as they cannot be safely or rapidly titrated. The Australian and New Zealand College of Anaesthetists (ANZCA) previously issued a position statement advising against the use of modified-release opioids in this setting. This document advises that the inappropriate use of modified-release opioids in acute pain is associated with a significant risk of respiratory depression, which may result in severe adverse events or death. This recommendation is in line with the indications approved by the Therapeutic Goods Administration (TGA) for modified-release opioids.

Review

Limiting the duration of opioid use is vital. Studies demonstrate that the duration of the first opioid prescription is more strongly related to misuse in the postoperative period than the dosage prescribed. Therefore, documentation of the intended therapy duration and plans for review and referral are vital.

Opioid dose reduction should begin as soon as possible. Following major surgery or trauma, dose reduction can often begin within one or two days as pain intensity quickly reduces for most patients. The standard also advises that opioid analgesics should generally be ceased before non-opioid analgesics.

These recommendations aim to minimise adverse effects and also reduce the incidence of persistent postoperative opioid analgesic use.

Persistent postoperative opioid analgesic use

Persistent postoperative opioid analgesic use (PPOU) can be defined as the continued use of opioids prescribed for postoperative pain for longer than 90 days after surgery. Australian studies have found rates of PPOU, from 3.9% to 10.5% overall. However, analysis suggests that this may be largely affected by surgery type, with a prevalence of 23.6% following spinal surgery and 13.7% after orthopaedic surgery observed in one study. Preoperative anxiety has also been identified as an independent risk factor for persistent opioid use.

Summary

It is known that the initiation of opioids for the management of acute pain can lead to chronic use in some cases. Identifying risk factors associated with PPOU and implementing the recommendations contained in the clinical care standard may minimise the risk of acute use transitioning into chronic use. The clinical care standard should be referred to for details on how to implement these quality standards into practice.

Further reading

The opioid hub on the TGA website contains current information on regulatory changes. The Therapeutic Guidelines: Pain and Analgesia and Acute Pain Management: Scientific Evidence (5th edition) may be referred to for guidance on current best practice. The PROSPECT (PROcedure-SPECific postoperative pain managemenT) initiative provides procedure-specific evidence-based recommendations for the treatment of postoperative pain.

From 1 April 2022, a new treatment for cystic fibrosis was listed on the Pharmaceutical Benefits Scheme (PBS). Trikafta® (elexacaftor, tezacaftor + ivacaftor) is an authority required item supplied under the Section 100 Highly Specialised Drugs program.

Trikafta® is indicated for the treatment of cystic fibrosis in patients 12 years of age and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This is the most common cystic fibrosis mutation and involves the removal of a single amino acid from the CFTR protein.

Mutations of the CFTR gene can affect the production, structure, or stability of the CFTR protein. This protein acts as an ion channel across the membranes of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. It helps regulate the flow of chloride ions, which contributes to the maintenance of water in tissues. While there are many types of mutations that can affect disease severity, the common feature of cystic fibrosis is the production of mucous that is abnormally thick and sticky. This has effects throughout the body, including the respiratory, digestive, and reproductive systems. In the lungs, accumulation of this dehydrated mucous leads to chronic infection, inflammation, and fibrosis.

CFTR modulators

The three medications contained in Trikafta® are known as CFTR modulators. There are two main types of CFTR modulators: correctors and potentiators. Correctors help stabilise the defective CFTR protein, allowing it to form the correct three-dimensional shape. This increases CFTR availability by reducing the premature degradation of defective CFTR. On the other hand, potentiators restore channel activity. There is also a third type of modulator currently undergoing clinical trials. These are known as CFTR amplifiers and act to increase the amount of CFTR protein produced.

Trikafta®

Elexacaftor and tezacaftor are CFTR correctors. These two agents bind to different sites on the CFTR protein and have demonstrated additive effects. Ivacaftor is a CFTR potentiator that increases the open probability of the CFTR channel gate. This enhances the transport of chloride ions across cell membranes.

The VX17-445-102 Study investigated the safety and efficacy of Trikafta® over 24 weeks. This double-blind, placebo-controlled trial had a primary endpoint of absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week four. Treatment with elexacaftor, tezacaftor, and ivacaftor resulted in a significant improvement in this endpoint, with a mean treatment difference of 13.8 points compared to placebo. This improvement was sustained throughout the trial, with a mean treatment difference of 14.3 points seen at week 24. The annualised rate of pulmonary exacerbations was 63% lower in the treatment group compared to placebo. The majority of patients reported at least one adverse effect (93% of the treatment group and 96% of the placebo group). Adverse effects were typically mild or moderate and led to discontinuation in only 1% of patients in the treatment group (one case of rash and one case of portal hypertension in a patient with pre-existing cirrhosis).

Administration:

Trikafta® is supplied as a composite pack. The tablets marked as the morning dose contain 100mg of elexacaftor, 50mg of tezacaftor and 75mg of ivacaftor; the evening dose tablets contain only 150mg of ivacaftor.

The usual recommended dose is two tablets in the morning and one tablet in the evening. The tablets should be swallowed whole with a fat-containing meal or snack. Dose adjustments may be required in the event of moderate hepatic impairment or co-administration with strong or moderate CYP3A inhibitors.

Interactions:

Trikafta® has several significant interactions, and patients should be encouraged to check with their healthcare professional before starting any new medication.

Elexacaftor, tezacaftor and ivacaftor are metabolised by CYP3A. Co-administration with strong inducers of CYP3A (e.g. rifampicin, carbamazepine, St John’s wort) is not recommended as efficacy may be significantly reduced. Conversely, exposure is increased when co-administered with inhibitors of CYP3A. The product information provides recommendations for reduced doses when Trikafta® is co-administered with strong or moderate inhibitors of CYP3A (e.g. clarithromycin, erythromycin, verapamil, fluconazole).

Food and drinks containing grapefruit should be avoided during treatment as they may increase the exposure to elexacaftor, tezacaftor and ivacaftor.

Adverse effects:

Common adverse effects associated with Trikafta® include increased creatinine kinase, increased blood pressure, and rash. Non-congenital cataracts have been reported in children and adolescents taking ivacaftor-containing regimens. Although causality has not been confirmed, the product information recommends baseline and follow-up ophthalmological examinations in paediatric patients initiated with Trikafta®.

Being a new medication, Trikafta® is included in the Black Triangle Scheme; practitioners and patients are encouraged to report suspected adverse events to the Therapeutic Goods Administration (TGA).

Other CFTR modulators:

Other CFTR modulator therapies available for the management of cystic fibrosis include:

• Ivacaftor (Kalydeco®);
• Lumacaftor + ivacaftor (Orkambi®); and
• Tezacaftor + ivacaftor (Symdeko®).

The choice of agent is dependent upon the CFTR mutation present.

The Australian Technical Advisory Group on Immunisation (ATAGI) has published advice on the use of seasonal influenza vaccines for 2022.

Some of the key points include:

• Annual vaccination is recommended for all people six months of age and older to prevent influenza and its complications;
• Influenza vaccines can be administered on the same day as any COVID-19 vaccine;
• A 2022 influenza vaccine is recommended even if a 2021 influenza vaccine was administered in late 2021 or early 2022; and
• Adults 65 years of age and older are recommended to receive Fluad® Quad or Fluzone® High Dose Quadrivalent.

Vaccine choice:

Eight influenza vaccines are available in Australia this year, all of which are quadrivalent. The choice of vaccine type is primarily influenced by the patient’s age and availability on the National Immunisation Program (NIP).

Cell-based

Flucelvax® is the only cell-based influenza vaccine available. It is produced using mammalian cell culture instead of hens’ eggs. This cell-based production method may produce a closer vaccine match by avoiding egg-adapted mutations. This may improve vaccine effectiveness, although some clinical studies demonstrate that these differences may be small. Flucelvax® is available on the private market; it is not funded on the NIP.

Egg-based

The other influenza vaccines are cultivated in embryonated hens’ eggs. Whilst these vaccines may contain traces of ovalbumin (<1mcg per vaccine dose), they are considered safe for egg-allergic individuals. The Australasian Society of Clinical Immunology and Allergy (ASCIA) provides detailed information on vaccination in individuals with egg allergy. They recommend that egg-based influenza vaccines may be administered as a single dose followed by the usual 15-minute observation period. Split dosing and allergy testing prior to vaccination are not recommended. This advice is supported by a recent review of 28 studies, including over 4,000 individuals with egg allergy, 656 of whom had a history of egg anaphylaxis. No severe reactions were reported after influenza vaccination in this review.

Older adults

There are two brands specifically indicated for use in older adults:

1. Fluzone® High-Dose is indicated for use in adults 60 years of age and older. This vaccine contains 60mcg of influenza virus haemagglutinin for each of the four strains. In comparison, standard-dose vaccines contain 15mcg of haemagglutinin for each strain. Fluzone® High-Dose is not funded on the NIP.
2. Fluad® Quad is available on the NIP for adults 65 years of age and older. This formulation contains the standard 15mcg of haemagglutinin for each strain, but also contains an adjuvant to increase its immunogenicity.

ATAGI advises that adjuvanted influenza vaccines may provide greater protection against influenza disease-related outcomes, particularly critical outcomes such as hospitalisation. However, the incidence of non-serious local adverse events is slightly higher for adjuvanted influenza vaccines.

Children

There are four brands available for children from six months of age:

• Fluquadri®;
• Fluarix® Tetra;
• Influvac® Tetra; and
• Vaxigrip® Tetra.

Flucelvax® Quad may be used in children from two years of age and Afluria® Quad is for children from five years of age.

Funded vaccines:

Influenza vaccines are available for free on the National Immunisation Program (NIP) for all children aged six months to five years and all adults aged 65 years and older. Other specific populations with an increased risk of influenza complications (e.g. pregnant women, Aboriginal and Torres Strait Islander people, and people with certain medical conditions) may also receive influenza vaccination under the NIP.

The medical conditions that confer eligibility for funded vaccination are those associated with an increased risk of influenza disease complications, including:

• Certain cardiac diseases (e.g. congestive heart failure);
• Certain chronic respiratory conditions (e.g. severe asthma, cystic fibrosis, chronic obstructive pulmonary disease);
• Certain chronic neurological conditions (e.g. seizure disorders, neuromuscular disorders);
• Immunocompromising conditions (e.g. immunocompromise due to disease or treatment, asplenia, splenic dysfunction, HIV infection);
• Diabetes (type 1 or 2)
• Chronic metabolic disorders;
• Chronic renal failure;
• Haemoglobinopathies;
• Children aged 5-10 years who are taking long-term aspirin therapy (due to an increased risk of Reye syndrome following influenza infection).

Full details on NIP eligibility can be obtained from the Department of Health.

The Australian Immunisation Handbook also strongly recommends influenza vaccines for additional populations that would not be eligible under the NIP. This includes:

• People with
  • Chronic liver disease
  • Down syndrome
  • Obesity (BMI ≥ 30kg/m²)
  • Harmful use of alcohol
• Occupational groups
  • Healthcare workers
  • Staff and residents of aged care and long-term residential facilities
  • Essential services providers
• People who are travelling during influenza season.

Interactions:

ATAGI advise that influenza vaccines may be administered on the same day as COVID-19 vaccines. The safety of administering multiple adjuvanted vaccines on the same day has not been studied. Therefore, it would be preferable for patients receiving the adjuvanted Fluad® Quad to separate the administration of Shingrix® by a few days. However, ATAGI advises that co-administration of these two vaccines is acceptable if necessary.

Summary

A summary of approved influenza vaccines is shown in Table 1. The individual product information should be reviewed for further details.

Table 1. Overview of 2022 influenza vaccines

	Vaxigrip® Tetra	Fluarix® Tetra	Afluria® Quad	FluQuadri®	Influvac® Tetra	Flucelvax® Quad	Fluad® Quad	Fluzone® HighDose Quad
Type	Egg	Egg	Egg	Egg	Egg	Cell	Egg	Egg
Registered age group	≥ 6 months	≥ 6 months	≥ 5 years	≥ 6 months	≥ 6 months	≥ 2 years	≥ 65 years	≥ 60 years
Funded on NIP	Yes	Yes	Yes	Yes*	No	No	Yes	No
Dose	0.5mL	0.5mL	0.5mL	0.5mL	0.5mL	0.5mL	0.5mL	0.7mL

*Primarily available on the private market, but will be available on the NIP as a backup.