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.
The product information for Cardizem® (diltiazem) has recently been updated to include the potential for an interaction with direct-acting oral anticoagulants (DOACs). Diltiazem is a moderate inhibitor of cytochrome P450 3A4 and a weak inhibitor of the P‐glycoprotein efflux transporter. It is thought that diltiazem may potentiate the bleeding risk of DOACs.
The DOAC class of medications includes:
- Dabigatran etexilate (a substrate for P-glycoprotein);
- Apixaban (metabolised by CYP3A4 and a substrate of P-glycoprotein); and
- Rivaroxaban (metabolised by CYP3A4 and a substrate of P-glycoprotein).
The impact of these potential drug interactions was investigated in a study of patients with atrial fibrillation who were initiated on one of the above DOACs. At the time of initiation, 15% of patients were taking diltiazem and a further 5% were started on diltiazem during the study. The concomitant use of diltiazem plus a DOAC was associated with a higher risk of any bleeding-related hospitalisation (adjusted hazard ratio 1.56, 95% CI: 1.15–2.12) and major bleeding (adjusted hazard ratio 1.84, 95% CI: 1.18–2.85). This increased risk occurred in patients with and without renal impairment. However, findings were inconsistent for dabigatran which was only taken by around 12% of the cohort. The authors concluded that diltiazem should only be used with a DOAC when the benefit outweighs the risk and the patient is closely monitored for signs of bleeding.
A larger and more recent study looking at only apixaban and rivaroxaban had similar findings. This study found that patients taking a DOAC with diltiazem had a higher risk of serious bleeding compared to patients taking a DOAC with metoprolol. The risk was noted to be particularly high in patients receiving diltiazem doses greater than 120mg per day.
Icosapent ethyl is now listed on the Pharmaceutical Benefits Scheme (PBS) for patients with established atherosclerotic cardiovascular disease with hypertriglyceridaemia. To be eligible for PBS-subsidy, treatment must be in conjunction with lifestyle modification and a statin (unless contraindicated or not tolerated).
Icosapent ethyl is a stable and highly purified ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). Following oral administration, icosapent ethyl is de-esterified to release EPA, the active metabolite. While the mechanism of action is not completely understood, icosapent ethyl produces reduced triglyceride levels, antiplatelet effects, anti-inflammatory effects, reduced blood pressure, and stabilisation of atherosclerotic plaques.
The effectiveness of icosapent ethyl was evaluated in the REDUCE-IT trial. This trial included over 8,000 statin-treated patients who had established cardiovascular disease or diabetes and other risk factors. Patients were randomly assigned to receive icosapent ethyl (2g twice daily) or placebo. The primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation, or unstable angina) occurred in 17.2% of the icosapent ethyl group compared to 22.0% of placebo.
Overall, the rates of adverse events did not differ significantly between the two groups. However, the rate of atrial fibrillation was higher in the icosapent ethyl group (5.3% vs 3.9%). The manufacturer recommends monitoring for clinical evidence of atrial fibrillation or flutter. Caution is required in patients with a known hypersensitivity to fish or shellfish, as icosapent ethyl is derived from fish oil.
The Pharmaceutical Benefits Scheme (PBS) listing for cabozantinib has been expanded to include non-clear cell renal cell carcinoma (RCC). Cabozantinib is now PBS subsidised for stage IV RCC (clear cell and non-clear cell) in addition to locally advanced or metastatic differentiated thyroid cancer. Cabozantinib is also indicated for the treatment of hepatocellular carcinoma in adults previously treated with sorafenib. However, this is currently not a PBS-subsidised indication.
Non-clear cell RCC is a less common subtype of RCC, accounting for around 20% of cases. Expansion of the PBS listing to include non-clear cell subtypes is significant as there were previously no targeted therapies available on the PBS for this subset of patients. While evidence is limited in this group, the clinical benefit of cabozantinib appears to be similar to that seen in patients with clear cell RCC.
Cabozantinib inhibits multiple receptor tyrosine kinases associated with tumour growth, angiogenesis, drug resistance, and metastatic progression. The tablets should be swallowed whole and taken on an empty stomach. Common adverse effects include fatigue, diarrhoea, palmar-plantar erythrodysesthesia syndrome, and dry mouth. Fistulas have been reported in some studies, with persistent or recurrent diarrhoea noted as a potential risk factor. Patients should be advised to contact their doctor if they experience severe diarrhoea.
Cabozantinib is metabolised by cytochrome P450 3A4. Administration with strong inhibitors of this enzyme (e.g. ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase the risk of toxicity. Conversely, chronic combination with inducers (e.g. phenytoin, carbamazepine, rifampicin, phenobarbital, St. John’s Wort) may reduce efficacy.
The Pharmaceutical Benefits Scheme (PBS) listing for trastuzumab deruxtecan has recently been expanded to include human epidermal growth factor receptor 2 (HER2)-low unresectable or metastatic breast cancer.
Breast cancer patients have historically been classified as HER2-positive or HER2-negative. Up to 20% of breast cancers are classified as HER2-positive, and these patients can be treated with HER2-targeted therapies, such as trastuzumab deruxtecan. While HER2-negative cancers are not treated with these therapies, more than half of breast cancers have low levels of HER2 expression and may still be targetable with trastuzumab deruxtecan.
The DESTINY-Breast04 study was conducted in patients with previously treated HER2-low metastatic breast cancer. Patients were randomly assigned to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The median progression-free survival (PFS) was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group; overall survival was 23.4 months and 16.8 months, respectively. The majority of patients (88.7%) had hormone receptor-positive disease. In this cohort, the median PFS was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group; overall survival was 23.9 months and 17.5 months, respectively.
The safety profile of trastuzumab deruxtecan in this population was consistent with that seen in previous studies. Interstitial lung disease, pneumonitis, reduced left ventricular ejection fraction, and neutropenia have been associated with trastuzumab deruxtecan. Patients should have their complete blood count monitored and counselled to seek medical advice if they experience any new or worsening respiratory or cardiovascular symptoms.
The Therapeutic Goods Administration (TGA) has issued a safety update for azithromycin. New warnings have been added to the azithromycin product information and consumer medicine information documents regarding a transient increased risk of cardiovascular death.
These warnings were added following a review by the Advisory Committee on Medicines. One large observational study included in the review compared azithromycin and amoxicillin. This study found that azithromycin was associated with a significantly higher hazard of cardiovascular death (hazard ratio 1.82: 95% CI: 1.23-2.67) within five days of use.
The TGA advises that the risk of cardiovascular death associated with azithromycin is rare. Based on the available information, it is also not possible to establish or exclude causality. However, due to the seriousness of the event, a screening ECG should be considered for patients with a high risk of prolonged QT.
Azithromycin is available in oral preparations for the treatment of infections such as respiratory tract infections, uncomplicated skin and skin structure infections, acute streptococcal pharyngitis/tonsillitis, and Chlamydia trachomatis. The parenteral formulation is indicated for the treatment of community-acquired pneumonia.
An oromucosal formulation of midazolam is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of generalised convulsive status epilepticus.
Zyamis® pre-filled syringes are ready to use and are presented in four strengths, as shown in Table 1. Approximately half of the prescribed dose should be administered to each buccal cavity over two to three seconds. If access to each side is difficult, the entire dose may be administered to one buccal cavity over a period of four to five seconds. It is recommended that carers only administer one midazolam dose as the use of a second dose increases the risk of adverse effects, such as respiratory depression. Emergency assistance should be sought if the seizure continues.
A randomised, controlled trial compared the safety and efficacy of oromucosal midazolam and intravenous diazepam for seizure control in children. The study authors found no significant difference in the proportion of patients achieving seizure control or the mean time required to control convulsive episodes. However, apnoea occurred in around 7% of the intravenous diazepam group but was not observed in the oromucosal midazolam group. Potential adverse effects associated with midazolam include sedation, nausea, and vomiting.
Ready-to-use midazolam syringes may address some of the safety concerns associated with the off-label use of midazolam ampoules in this population. Zyamis® is much simpler to use, an important consideration for parents and carers in emergency situations. The risk of incorrect dosing may be reduced, along with the risk of drug loss or abuse.
Carers must be educated on how to administer this medication safely. Administration instructions can be found in the consumer medicines information (CMI), and training videos are available on the Zyamis® website.
Table 1. Dosing recommendations for oromucosal midazolam
| Strength |
Age range |
Weight range |
PBS listed |
| 2.5 mg/0.25mL |
> 6 months to < 1 year |
7 to < 12 kg |
No |
| 5 mg/0.5mL |
1 to < 5 years |
12 to < 21 kg |
Yes |
| 7.5 mg/0.75mL |
5 to < 10 years |
21 to < 29 kg |
Yes |
| 10 mg/1mL |
≥ 10 years |
≥ 29 kg |
Yes |
The combination product, Vyxeos® (daunorubicin and cytarabine), is now listed on the Pharmaceutical Benefits Scheme (PBS). It is indicated for the treatment of acute myeloid leukaemia (AML), specifically newly diagnosed therapy-related AML and AML with myelodysplasia-related changes.
Vyxeos® is a liposomal formulation containing daunorubicin and cytarabine in a 1:5 molar ratio. This formulation provides an extended duration of effect compared to conventional daunorubicin and cytarabine. In a Phase 3 study, Vyxeos® was associated with improved clinical outcomes. The median overall survival was 9.56 months for Vyxeos® compared to 5.95 months for conventional therapy, and the overall remission rate was 47.7% compared to 33.3%. The incidence and severity of adverse effects were similar for each group.
Vyxeos® should be used with caution in patients with Wilson’s disease or other disorders of copper metabolism. Copper gluconate is added to this formulation to ensure stable encapsulation of daunorubicin within the liposome. The International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) recommends a permitted daily exposure (PDE) of 340 micrograms for parenterally administered copper. While each Vyxeos® vial contains 14mg of elemental copper, the number of lifetime doses is limited and pharmacokinetic data indicates that the copper is released slowly from the liposomes. Therapy should be discontinued in patients who exhibit signs or symptoms of acute copper toxicity.
Vyxeos® is not interchangeable with other daunorubicin and cytarabine products. The product information should be consulted for the recommended dosing schedule.
Anifrolumab has recently been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of systemic lupus erythematosus (SLE). To be eligible for PBS subsidy, patients must be receiving hydroxychloroquine, an immunosuppressant, and a corticosteroid unless contraindicated or intolerant.
Anifrolumab is a monoclonal antibody that binds with high affinity and specificity to the type I interferon receptor (IFNAR1). This inhibits type I interferon signalling, thereby blocking its biological activity. While SLE is complex and associated with many immunologic abnormalities, upregulation of type I interferon is thought to be a major pathogenic factor. In the phase 3 TULIP trials, anifrolumab was associated with improved overall disease severity, reduced glucocorticoid use, and a greater improvement in the severity of skin disease compared to placebo.
Anifrolumab is administered intravenously, typically as a 30-minute infusion every four weeks. The infusion rate may be reduced if infusion-related reactions occur. These reactions are typically mild or moderate in intensity and may include headache, nausea, vomiting, fatigue, or dizziness. In the case of a serious infusion-related or hypersensitivity reaction, immediate interruption of the infusion is required. Other potential adverse reactions include an increased risk of respiratory infections and herpes zoster. Treatment should not be initiated in patients with active infection, and caution is required in patients with chronic infection, recurrent infection, or known risk factors for infection.
A novel therapy for the treatment of acne vulgaris is now available. Clascoterone is a topical androgen receptor inhibitor indicated for use in people aged 12 years and older.
Androgens stimulate sebum production and play an important role in the pathogenesis of acne. Systemic antiandrogen therapies such as spironolactone and cyproterone have been successfully used in the management of acne. However, these medications can only be used for the treatment of acne in females.
Topical clascoterone has limited systemic antiandrogenic effects and can be used by males and females. The safety and efficacy of clascoterone were demonstrated in two Phase 3 trials. Clascoterone cream was significantly more effective than the vehicle cream, with 18.4% and 20.3% of patients in the active groups achieving treatment success at week 12, compared to 9.0% and 6.5% in the respective placebo groups.
Clascoterone cream is recommended to be applied twice a day as a thin uniform layer to clean dry skin. Studies demonstrate that the safety profile of clascoterone cream is similar to that of the vehicle, and adverse effects are infrequent and mild in nature. Long-term studies have not found any systemic antiandrogenic effects in males. However, to minimise systemic absorption, occlusive dressings should not be applied to the treated area.
