Knowledge Type: Drugline

The Therapeutic Goods Administration (TGA) has issued a medicines safety update regarding the administration of respiratory syncytial virus (RSV) prevention products. These products include the two vaccines, Arexvy® and Abrysvo®, and the monoclonal antibody nirsevimab (Beyfortus®).

As of 13 June 2025, the TGA has received 84 medication error reports involving the administration of these products outside their approved indications. While most cases did not result in adverse events, concerns remain about the level of protection provided to patients when these products are used incorrectly.

The TGA acknowledges that the introduction of three RSV preventative medicines, each with different indications, within a short timeframe may be contributing to these errors. To help reduce the risk of further incidents, the TGA recommends the following strategies:

• Education on the differences between RSV prevention products;
• Use of both generic and brand names when prescribing these products;
• Improving storage practices to better differentiate between adult and paediatric vaccines;
• Following recommended checking protocols; and
• Implementation of local risk mitigation strategies.

A summary of the approved indications for these three products is shown in Table 1.

Table 1. Summary of RSV preventative therapies

Medication	Population for administration			Dose frequency	Immunity provided
	≤ 24 months	Pregnant women	≥ 60 years
Arexvy®	No	No	Yes*	Once	Active
Abrysvo®	No	Yes	Yes	Once	Active
Nirsevimab	Yes	No	No	Once	Passive

* Arexvy® is also approved for use in patients 50-59 years old who are at higher risk for RSV disease

The Pharmaceutical Benefits Scheme (PBS) listing for Trikafta^® (elexacaftor + tezacaftor + ivacaftor) has recently been expanded. Patients with cystic fibrosis are now eligible for subsidised therapy if they have at least one mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that is considered responsive to Trikafta^®. This update broadens access to this medication, including for patients with rarer mutations.

Trikafta^® is a CFTR modulator therapy with three active ingredients. Elexacaftor and tezacaftor are CFTR correctors and help stabilise defective CFTR protein. Ivacaftor is a CFTR potentiator that enhances the transport of sodium and chloride ions across cell membranes. Triple corrector–potentiator combinations, such as Trikafta^®, have demonstrated greater efficacy than dual combination therapies.

All three components are metabolised by CYP3A enzymes, therefore, there are several significant drug interactions. To be eligible for PBS subsidy, the patient must not be receiving a strong CYP3A inducer such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, or St. John’s wort.

Trikafta^® is presented as tablets that should be swallowed whole or granules that may be mixed with soft food or liquid. Absorption is improved when doses are taken with a fat-containing meal or snack.

Edaravone was recently added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of amyotrophic lateral sclerosis (ALS).

Oxidative stress is thought to be a key factor in the progression of ALS, causing damage to motor neurons. While the exact mechanism of action of edaravone in ALS is not currently known, it acts as a free radical scavenger which may minimise this damage.

Edaravone is administered as an intravenous infusion over 60 minutes. There is an initial induction period of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent cycles involve daily dosing for 10 days out of 14-day periods, followed by a 14-day drug-free period.

Studies on the efficacy of edaravone have yielded conflicting results, with genetic differences potentially playing a role. Randomised controlled trials suggest that the following factors increase the likelihood of a favourable response to edaravone:

• Forced vital capacity (FVC) of at least 80% before treatment;
• Score at least 2 points or better on each item of the ALS Functional Rating Scale – Revised (ALSFRS-R), i.e. functionality retained in most activities of daily living; and
• Initiating edaravone within two years of symptom onset.

These factors are reflected in the clinical criteria of the PBS approval.

Dexrazoxane is used to reduce the incidence and severity of doxorubicin-associated cardiomyopathy. The Therapeutic Goods Administration (TGA) has recently approved its use for women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300mg/m² and require continuing doxorubicin therapy to maintain tumour control.

Chronic cardiotoxicity is a dose-dependent adverse effect associated with anthracycline therapy. It may present with reduced left ventricular ejection fraction (LVEF) or congestive heart failure (CHF). This cardiotoxicity can be severe and represents the cumulative dose-limiting toxicity for anthracyclines.

Several mechanisms have been proposed to explain this cardiotoxicity. One involves the iron-mediated generation of free radicals, which leads to oxidative stress in cardiac muscle. Dexrazoxane, a structural analogue of ethylenediaminetetraacetic acid (EDTA), acts as a metal ion chelator. It may prevent the formation of iron-anthracycline complexes and reactive oxygen species. Additionally, dexrazoxane inhibits DNA topoisomerase IIβ, and some evidence suggests that reducing cardiac levels of this enzyme may contribute to its cardioprotective effects.

Studies conducted in patients with breast cancer showed a reduced risk of heart failure (risk ratio: 0.22; 95% CI 0.11-0.43) and no significant difference in oncologic outcomes. Most adverse effects occurred at similar rates in both treatment and control groups. However, some studies conducted in paediatric populations have found a higher risk of secondary malignant neoplasms. It should also be noted that dexrazoxane does not protect against non-cardiac toxicities.

The recommended dose ratio of dexrazoxane to doxorubicin of 10:1. Dexrazoxane is administered as an intravenous infusion over 15 minutes. Doxorubicin administration should occur within 30 minutes after the dexrazoxane infusion is completed.

A new longer-acting formulation of aripiprazole, Abilify Asimtufii®, is now listed on the Pharmaceutical Benefits Scheme (PBS). This injection is administered once every two months and is indicated for the maintenance treatment of schizophrenia and the prevention of manic and mixed episodes in bipolar I disorder.

Currently, PBS subsidy for Abilify Asimtufii® is limited to patients with schizophrenia who have already been stabilised on once-monthly aripiprazole (i.e. Abilify Maintena®). Eligible patients can transition to Abilify Asimtufii® when their next monthly Abilify Maintena® dose is due.

A 32-week open-label study compared the safety and tolerability of aripiprazole two-monthly injection with that of the monthly formulation. Key findings include:

• A similar incidence of treatment-emergent adverse events in each group
• Weight gain and injection-site pain were the most commonly reported adverse events
• Injection-site pain was more frequent in the two-monthly group (18.2% vs 9.0%)
• Plasma concentrations of aripiprazole were comparable in the two groups
• No new safety concerns were identified.

Compared to oral therapy, long-acting injectable antipsychotics are associated with improved adherence and more stable plasma levels. They may offer many clinical benefits, including a reduced risk of relapse and hospitalisation, and an improved quality of life.

A comparison of aripiprazole formulations is shown in Table 1.

Table 1. Comparison of aripiprazole formulations

Product	Presentation	Strengths	Usual dosing interval
Abilify®	Tablets	2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg	Daily
Abilify Maintena®	Vials	300mg 400mg	Monthly
Abilify Asimtufii®	Pre-filled syringes	720mg/2.4mL 960mg/3.2mL	Every 2 months

From 1 May 2025, esketamine nasal spray became available on the Pharmaceutical Benefits Scheme (PBS) for treatment-resistant major depression.

Intravenous and subcutaneously administered ketamine has been used off-label for this purpose. Ketamine is thought to exert its effect in depression primarily via antagonism of the N-methyl-D-aspartate (NMDA) receptor. Ketamine is a racemic mixture, containing equal parts of the S-enantiomer and R-enantiomer. Studies demonstrate that esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor.

Short-term studies demonstrate that esketamine plus a newly initiated oral antidepressant provides clinically meaningful improvement in depressive symptoms compared to an antidepressant plus placebo nasal spray. In some cases, symptom reduction was apparent at 24 hours after the first dose and continued throughout the four-week trials. Long-term studies demonstrate that patients in stable remission who continued with esketamine plus an oral antidepressant were 51% less likely to relapse compared to patients who continued the oral antidepressant but were switched to the placebo nasal spray.

Esketamine must be prescribed by a psychiatrist and be started in combination with a newly initiated oral antidepressant. Esketamine nasal spray can be self-administered, but this must always occur under the direct supervision of a healthcare professional at an accredited treatment centre. Supervised administration reduces the risk of abuse, misuse, and diversion. It also allows appropriate monitoring for adverse effects, such as elevated blood pressure, sedation, and dissociation.

Esketamine is presented in a single-use device that delivers 28 mg of esketamine in two actuations. One spray is administered into each nostril, and patients should then rest in a semi-reclined position for five minutes. If more than one device is required, a five-minute rest should be taken between each device to facilitate absorption.

The Australian Technical Advisory Group on Immunisation (ATAGI) has published advice on seasonal influenza vaccines for 2025. Annual vaccination is recommended for all people six months of age and older, and is particularly important for those at increased risk of severe illness. Protection from an influenza vaccine is expected to last throughout the year. However, optimal protection occurs in the three to four months after vaccination.

The National Immunisation Program (NIP) provides free influenza vaccines to the following high-risk groups:

• Children aged six months to less than five years;
• All adults aged 65 years or older; and
• The following populations of people aged 5 years up to 65 years due to an increased risk of severe influenza
  • All Aboriginal and Torres Strait Islander people
  • People with certain medical conditions (e.g. certain cardiac, respiratory, neurological, immunocompromising, metabolic, renal, and haematological conditions; and children aged 5-10 years on long-term aspirin therapy)
  • Pregnant women (at any stage during pregnancy).

People 65 years of age and older are at higher risk of developing severe influenza. However, the effectiveness of influenza vaccines is reduced in this age group. Two higher-immunogenicity influenza vaccines are available and are preferred over standard vaccines in this population. Fluad® Quad contains an adjuvant to increase immunogenicity, while Fluzone® High-Dose Quad is a higher strength, containing 240mcg influenza virus haemagglutinin in 0.7mL (compared to 60mcg in 0.5mL for the standard dose vaccines). Both of these vaccines are equally preferred for people 65 years of age and older, although only the adjuvanted vaccine is funded on the NIP in this age group.

Table 1 shows the influenza vaccines and their registered age groups for the 2025 season.

Table 1. 2025 influenza vaccines by age group

Age group	Vaxigrip Tetra	Flucelvax Quad	FluQuadri	Afluria Quad	Influvac Tetra	Fluad Quad	Fluzone High-Dose
6 months to <5 years	Yes^	Yes	Yes^	No	Yes	No	No
5 to <60 years	Yes*	Yes*	Yes	Yes	Yes	No	No
60 to < 65 years	Yes*	Yes*	Yes	Yes	Yes	No	Yes
≥ 65 years	Yes	Yes	Yes	Yes	Yes	Yes^	Yes

^ Available under the NIP

* Available under the NIP only for the populations listed as being at an increased risk of severe influenza

The Therapeutic Guidelines: Antibiotic has recently had a major update. One of the more significant changes relates to the empirical antibiotic treatment of acute cystitis. The updated recommendations are shown in Table 1.

Table 1. Empiric antibiotic therapy recommendations from the Therapeutic Guidelines

	1st line	2nd line	3rd line
Non-pregnant adult females*	Nitrofurantoin	Fosfomycin	Trimethoprim
During pregnancy	Nitrofurantoin	Cefalexin	Fosfomycin
Adult males*	Nitrofurantoin	Trimethoprim
Children who can swallow tablets/capsules	Nitrofurantoin	Trimethoprim
Children who cannot swallow tablets/capsules	Cefalexin	Trimethoprim +/- sulfamethoxazole

* Cefalexin is considered an alternative option if the other recommended agents cannot be used for empirical therapy.

Trimethoprim is no longer recommended as a first-line agent due to rising rates of resistance among Escherichia coli. The most recent AURA report (Australian report on antimicrobial use and resistance in human health) states that 22.6% of urinary E. coli isolates were resistant to trimethoprim in 2021. In contrast, only 0.9% were resistant to nitrofurantoin.

Nitrofurantoin is now the first-line agent in most cases. The typical adult dose is 100 mg six-hourly for five days in women and seven days in men. Doses should be administered with food or milk to reduce nausea and vomiting.

Fosfomycin is now the second-line choice for non-pregnant adult females. It is administered orally as a 3 g single dose. Fosfomycin is available in single-dose sachets that are mixed with water immediately before use. Doses should be taken on an empty stomach, preferably before bedtime and after emptying the bladder. At this time, fosfomycin is not subsidised on the Pharmaceutical Benefits Scheme (PBS).

For a full list of new and updated topics, please refer to the summary provided by the Therapeutic Guidelines.

From 1 May 2025, Ryeqo® will be available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of endometriosis. Each Ryeqo® tablet contains relugolix (40mg), estradiol (1mg), and norethisterone acetate (0.5 mg).

Relugolix is a gonadotrophin-releasing hormone (GnRH) receptor antagonist. Inhibition of this receptor reduces the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. This, in turn, leads to a reduction in ovarian estrogen and progesterone production.

As endometriosis is an estrogen-dependent condition, relugolix can significantly improve symptoms. However, reduced estrogen is also associated with significant adverse effects such as hot flushes and reduced bone mineral density (BMD). Estradiol is included in the formulation in a low dose to minimise hypoestrogenic effects; norethisterone is added to protect the endometrium from the effects of unopposed estrogen.

The SPIRIT trials assessed the efficacy of Ryeqo® in premenopausal women with endometriosis-associated pain ranging from moderate to very severe. Ryeqo® was associated with a significant improvement compared to placebo, with benefits seen as early as eight weeks for dysmenorrhea and twelve weeks for non-menstrual pelvic pain. The SPIRIT open-label extension study demonstrated that these benefits are maintained with continued treatment of 104 weeks.

Relugolix may offer some advantages over GnRH agonists in the management of endometriosis: it is orally administered, does not trigger an initial disease flare-up, and can be used long-term. Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and annually thereafter. The decision to continue treatment should be dependent upon stable DXA results.

Osilodrostat has been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of endogenous Cushing’s syndrome. This is a rare condition caused by glucocorticoid overproduction, often due to a pituitary tumour. Excess cortisol is associated with significant morbidity and mortality, largely related to cardiovascular disease and infections.

Osilodrostat inhibits 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), enzymes responsible for the final step of cortisol and aldosterone production in the adrenal gland. Cortisol levels must be regularly monitored throughout therapy. Adverse effects related to low cortisol levels can occur, including dizziness, nausea, vomiting, fatigue, and reduced appetite. Accumulation of adrenal steroid precursors and increased testosterone levels can also occur. In female patients, elevated testosterone may be associated with hirsutism or acne.

The dose of osilodrostat is adjusted according to individual response and tolerability. The usual initial dose is 2mg twice daily. However, a lower starting dose of 1mg twice daily is recommended for patients of Asian descent as this population demonstrates higher relative bioavailability.