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.
The product information for Flagyl® (metronidazole) has recently been updated to include a warning regarding posterior reversible encephalopathy syndrome (PRES). This rare neurological condition has a variable presentation. Symptoms may include visual disturbances, seizures, headaches, and altered consciousness. Life-threatening complications, such as status epilepticus or cerebral haemorrhage, can occur.
There are many potential causes of this syndrome, including autoimmune disorders, eclampsia, and some medications. A recent review of antibiotic-associated PRES found that metronidazole was one of the most frequently implicated agents. While metronidazole-induced encephalopathy (MIE) has previously been described in the literature, few cases presenting as PRES have been reported. Prompt diagnosis is crucial as outcomes are generally good when appropriate treatment is started early. The Flagyl® product information now advises radiologic imaging for any patient who presents with symptoms suggestive of PRES.
Metronidazole is a commonly used antibiotic that is generally well tolerated. However, it is associated with rare and potentially serious neurotoxicity. In the past ten years, the Therapeutic Goods Administration (TGA) has received 74 reports of nervous system disorders in association with metronidazole and three reports of encephalopathy.
Selpercatinib has been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). This is a targeted therapy for patients with RET (rearranged during transfection) fusion-positive disease.
While NSCLC is the most common type of lung cancer, RET fusions are only found in 1-2% of cases. Data suggests that RET fusions may be more likely to occur in patients who are female, younger than 60 years, non-smokers, or of Asian background.
Selpercatinib is a highly selective inhibitor of the RET receptor tyrosine kinase. Under normal conditions, RET plays an important role in the development of a variety of tissues. However, genetic alterations are associated with uncontrolled cellular proliferation and the development of cancer.
A recent randomised clinical trial compared the efficacy of selpercatinib with platinum-based chemotherapy (with or without pembrolizumab) in advanced RET fusion-positive NSCLC. Median progression-free survival was 24.8 months for selpercatinib (95% CI: 16.9 to not estimable) and 11.2 months for control (95% CI: 8.8 to 16.8).
Selpercatinib is usually administered twice daily without regard to food. However, patients who are also taking a proton pump inhibitor should take their selpercatinib dose with food. Metabolism is primarily via CYP3A4. Selpercatinib dose reduction may be required if co-administered with a strong CYP3A4 inhibitor (e.g. itraconazole, voriconazole, ritonavir, saquinavir, posaconazole). The concomitant use of strong inducers of CYP3A4 (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John’s Wort) is not recommended.
The Therapeutic Goods Administration (TGA) has issued a new safety alert for montelukast. A boxed warning highlighting possible neuropsychiatric adverse events is being added to all montelukast product information and consumer medicine information documents.
The TGA previously released an alert regarding this issue in 2018. A further investigation was undertaken in 2024 after international regulators strengthened their warnings. While this most recent review did not uncover any new risks, the Australian Advisory Committee on Medicines recommended enhanced warnings to address consumer concerns and better align with international practice.
Montelukast is a leukotriene antagonist that is indicated in the management of chronic asthma and seasonal allergic rhinitis. Neuropsychiatric events have been reported in all age groups taking montelukast. The most common of these reactions are aggression, anxiety, suicidal ideation, depression, and sleep disturbances. While reactions are typically mild, the TGA has received seven reports of completed suicide in association with montelukast over the past ten years.
It is important to note that causality has not been established for montelukast. However, the TGA advises healthcare professionals to inform patients and their carers of the possibility of neuropsychiatric reactions and to seek immediate medical advice if they occur.
The TGA encourages the reporting of all suspected adverse events.
A longer-acting formulation of risperidone has recently been added to the Pharmaceutical Benefits Scheme (PBS). Risvan® is a modified-release injection that is indicated for the treatment of schizophrenia in adults for whom oral risperidone has been effective and well-tolerated.
Risvan® is intended for monthly administration. Risvan® should be initiated around 24 hours after the last oral risperidone dose or two weeks after the last fortnightly injection. Risvan® is available in two strengths: 75mg and 100mg. To maintain a similar steady-state exposure, patients previously receiving 3mg oral risperidone daily or the 37.5mg fortnightly injection can be initiated on Risvan® 75mg. The 100mg Risvan® injection is recommended for patients who have previously taken 4mg orally per day or the 50mg fortnightly injection. Supplemental oral risperidone doses are not recommended during therapy with Risvan®.
Risvan® is supplied as a pre-filled powder syringe that must be reconstituted immediately before use with the accompanying pre-filled diluent syringe. The product information should be referred to for detailed reconstitution instructions. Incorrect preparation can lead to a higher initial peak of risperidone (and potentially signs of overdose) followed by lower plasma levels (and poorer efficacy) over the rest of the dosing period.
A comparison of oral and injectable risperidone products can be seen in Table 1.
Table 1. Overview of risperidone preparations
| |
Oral |
Risperdal Consta® |
Risvan® |
| Type |
Immediate release |
Modified release
|
| Strengths |
0.5mg, 1mg, 2mg, 3mg, 4mg tabs
1mg/ml liquid |
25mg
37.5mg
50mg |
75mg
100mg |
| Administration |
Oral |
Intramuscular
(gluteal or deltoid)
|
| Usual dosing frequency |
Daily to twice daily |
Every two weeks |
Every 28 days |
| Approved indications |
Schizophrenia (+ related psychoses)
Behaviour disorders
Acute mania (bipolar 1)
Behavioural symptoms of dementia (≤ 12 weeks) |
Schizophrenia (+ related psychoses)
Bipolar 1 disorder |
Schizophrenia |
A new combination product has recently been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of type 2 diabetes.
Sidapvia™ 10/100 tablets contain dapagliflozin 10mg and sitagliptin 100mg. Dapagliflozin is a sodium-glucose co-transporter (SGLT2) inhibitor, and sitagliptin is a dipeptidyl peptidase‑4 (DPP‑4) inhibitor. The recommended dose of Sidapvia™ is one tablet taken once a day without regard to meals.
To be eligible for PBS subsidy, patients must meet the following criteria:
- Therapy must be in combination with metformin;
- Condition must be inadequately controlled with dual therapy of metformin plus either a DPP-4 inhibitor or SGLT2 inhibitor; and
- Therapy must not be in combination with PBS-subsidised treatment that includes a glucagon-like peptide‑1 (GLP-1) analogue, another SGLT2 inhibitor, or another DPP-4 inhibitor.
It has been reported that suboptimal adherence to prescribed therapies affects almost half of all people with diabetes. Initiation of this combination tablet has the potential to improve compliance by reducing the pill burden. This may lead to better clinical outcomes by improving glycaemic control and reducing the risk of diabetes-related complications.
From 1 December 2024, the Pharmaceutical Benefits Scheme (PBS) criteria were expanded for dapagliflozin. Dapagliflozin is now subsidised for the treatment of type 2 diabetes in patients who either have cardiovascular disease, a high risk of a cardiovascular event, or who identify as Aboriginal or Torres Strait Islander. There is no longer a requirement for patients to have a specific unmet glycaemic target for dapagliflozin to be added to therapy. However, the criteria still require treatment to be in combination with metformin (unless contraindicated or intolerant). This change further aligns PBS criteria with the recommendations of the Australian Evidence-Based Clinical Guidelines for Diabetes.
Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor. Inhibition of this enzyme in the kidneys prevents the reabsorption of glucose from the glomerular filtrate, improving overall glycaemic control. Other beneficial effects may include a slight reduction in blood pressure, modest weight loss, and preservation of renal function.
The results of a large network meta-analysis, available in the Australian guidelines, found that SGLT-2 inhibitors are associated with lower odds of:
- Hospitalisation for heart failure compared to placebo, sulfonylureas, gliptins, or glucagon-like peptide-1 (GLP-1) analogues when added to background therapy;
- Cardiovascular mortality compared to placebo, gliptins, and sulfonylureas; and
- Major adverse cardiovascular events compared to placebo or GLP-1 analogues added to background therapy.
Dienogest is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of endometriosis. It is estimated that one in seven Australian women have this condition, which can cause pain, impair fertility, and affect overall quality of life.
Dienogest is a progestogen and has an inhibitory effect on endometrial cell proliferation. When taken continuously, dienogest produces atrophy of endometriotic lesions. A meta-analysis evaluating the efficacy of dienogest following surgery suggests that dienogest is more effective than placebo in reducing disease and pain recurrence. Dienogest was also found to be as effective and better tolerated than gonadotrophin-releasing hormone (GnRH) agonists.
Dienogest is usually prescribed at a dose of 2mg each day. Most women taking dienogest will experience changes in their menstrual bleeding pattern. Other common adverse effects include headache, breast discomfort, depressed mood, and acne. As dienogest suppresses estradiol production, concerns about its effects on bone health exist. Studies demonstrate a reduction in bone mineral density over the first 12 months of dienogest therapy, although the clinical significance of this is not clear. Risk factors for osteoporosis should be taken into account when considering the risks and benefits of dienogest therapy.
The Therapeutic Goods Administration (TGA) has issued a safety alert for oral promethazine hydrochloride. The product information (PI) and consumer medicine information (CMI) documents for Phenergan® have been updated to state that it must not be given to children under six years of age. Sponsors of all other brands of promethazine will also be required to update their PI, CMI, and product labelling accordingly.
This alert strengthens previous advice to not give first-generation oral sedating antihistamines to children under six for the relief of cold and flu symptoms or to children under two years for any indication. A review of safety data supports a causal association between promethazine and safety concerns in children under six years. Psychiatric and central nervous system adverse effects in this population may include hyperactivity, aggression, and hallucination. In children under two, there are reports of respiratory depression resulting in death.
This safety alert applies to all oral promethazine products. These products can be purchased without a prescription, and there will likely be a significant time lag before all labelling is updated. Healthcare professionals should be alert to this issue and counsel parents and carers who may intend to give promethazine to a child. Advice on alternative products, such as non-sedating antihistamines or non-pharmacological therapies, may be provided where appropriate.
This updated advice does not currently apply to the injectable form of promethazine, although this product is prescription-only.
The Pharmaceutical Benefits Scheme (PBS) listing for romosozumab has been expanded to the treatment of severe established osteoporosis as a first-line therapy.
Romosozumab is a monoclonal antibody that inhibits sclerostin, an osteocyte-derived protein that can suppress bone formation. Remosozumab therapy increases bone formation as well as reducing bone resorption. This dual action results in increased bone mass and improved bone structure and strength.
The ARCH study found that 12 months of romosozumab treatment followed by alendronate was superior to alendronate alone in reducing fracture risk in postmenopausal women at high risk. The BRIDGE study demonstrated efficacy in men, with romosozumab associated with increased bone mineral density (BMD) at the hip and spine compared to placebo.
The usual dose of romosozumab is 210mg subcutaneously once a month for 12 doses. Patients should begin antiresorptive therapy (e.g., bisphosphonate or denosumab) once the romosozumab course is complete to preserve bone mass. Hypocalcaemia is an uncommon adverse event but may be more likely in patients with severe renal impairment. Adequate intake of calcium and vitamin D is important. Some studies suggest that romosozumab is associated with an increased risk of major cardiovascular adverse events. While additional real-world data is required, a recent meta-analysis did not find a significant increase in risk compared to placebo. Previous myocardial infarction or stroke are listed as contraindications in the product information.
