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.
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.
