From 1 February 2024, Opdualag® will be available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of advanced melanoma. Opdualag® is a combination of two immune checkpoint inhibitors, nivolumab and relatlimab.
Nivolumab inhibits the programmed death 1 (PD‑1) receptor from binding to its ligands (PD‑L1 and PD‑L2). This reduces PD-1 pathway-mediated immune inhibition and can restore anti-tumour immune responses. Relatlimab blocks lymphocyte-activation gene 3 (LAG-3). Inhibition of this cell-surface molecule promotes T-cell proliferation and cytokine secretion. Studies suggest that inhibiting these two pathways offers synergistic anti-tumour activity.
A recent trial comparing nivolumab with nivolumab plus relatlimab in a fixed-dose combination found that median progression-free survival was 10.1 months (95% CI: 6.4-15.7) in the combination group compared with 4.6 months (95% CI: 3.4-5.6) in the nivolumab group. Patients receiving the combination therapy experienced more adverse events of any grade (97.2% vs 94.4%) and more adverse events of grade 3 or higher (40.3% vs 33.4%). Serious adverse events in the nivolumab plus relatlimab group include hepatitis, adrenal insufficiency, diarrhoea or colitis, fatigue, and renal dysfunction.
The usual recommended dose is 480 mg nivolumab and 160 mg relatlimab (i.e. two vials). This is administered as a 30-minute intravenous infusion once every four weeks until disease progression or unacceptable toxicity.
The Pharmaceutical Benefits Scheme (PBS) listing for lumacaftor plus ivacaftor (Orkambi®) has recently been expanded to include patients from one year of age. This medicine is indicated for the treatment of cystic fibrosis in patients who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
One of the functions of the CFTR protein is regulation of the flow of chloride ions across the membranes of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The F508del mutation leads to a reduction in the quantity and functionality of CFTR at the cell surface, resulting in the production of abnormally thick and sticky mucous. In the respiratory tract, accumulation of this dehydrated mucous leads to chronic infection, inflammation, and irreversible lung damage.
It is hoped that initiating treatment in younger patients may slow the progression of organ damage. Rayment et al. (2022) conducted a phase 3 study of lumacaftor plus ivacaftor in one-year-old children with cystic fibrosis. The chloride concentration of sweat was measured as this is a clinical indicator of CFTR function and disease severity. Sweat chloride concentration reduced following four weeks of treatment, which was sustained for the 24-week treatment period (mean reduction of 29.1 mmol/L). While this study did have a small sample size, the observed safety profile was consistent with that seen in larger studies conducted in adolescents and adults. In these larger trials, the most commonly reported adverse effects include dyspnoea, diarrhoea, and nausea.
Orkambi® is available as tablets and granules. The tablets should be swallowed whole, while the granules may be mixed with one teaspoon of age-appropriate soft food or liquid. For optimal absorption, doses should be administered just before or just after the ingestion of fat-containing food.
Enfortumab vedotin has recently been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of locally advanced or metastatic urothelial cancer that has progressed despite therapy. Urothelial cancer begins in the urothelial cells, a specialised type of epithelial cell that line the urinary tract. Around 80-90% of bladder cancers are urothelial carcinomas.
Enfortumab vedotin is an antibody-drug conjugate (ADC). It comprises a Nectin-4 targeted monoclonal antibody that is bound to monomethyl auristatin E (MMAE), the cytotoxic payload. Nectin-4 is a cell adhesion molecule that is highly expressed on the surface of urothelial cancer cells. Once the ADC binds to Nectin-4, it is internalised, and the MMAE is released to disrupt the microtubule network within the cell. This leads to cell cycle arrest and apoptosis.
Study EV-301 investigated the efficacy of enfortumab vedotin in locally advanced or metastatic urothelial carcinoma. Patients who had received prior platinum-containing chemotherapy and had disease progression with a PD-1 or PD-L1 inhibitor were randomly assigned to receive enfortumab vedotin or investigator-chosen therapy (standard docetaxel, paclitaxel, or vinflunine). The primary endpoint of overall survival was longer in the enfortumab vedotin group, with a median of 12.88 months (95% CI: 10.58-15.21) compared to 8.97 months (95% CI: 8.05-10.74) in the chemotherapy group.
Enfortumab vedotin is administered as an intravenous infusion on days 1, 8, and 15 of a 28-day cycle and continued until disease progression or unacceptable toxicity. Severe cutaneous reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Permanent discontinuation is required if a patient develops these reactions, any Grade 4 skin reaction, recurrent Grade 3 skin reaction, or severe pneumonitis/interstitial lung disease or peripheral neuropathy. Doses may need to be withheld or reduced in the case of hyperglycaemia or less severe forms of the aforementioned adverse effects.
Andexanet alfa has provisional approval for the reversal of anticoagulation in adult patients who experience life-threatening or uncontrolled bleeding with a direct factor Xa inhibitor (apixaban or rivaroxaban).
Andexanet alfa is a recombinant form of the human factor Xa protein. While its primary mechanism of action is to bind and sequester factor Xa inhibitors, it also inhibits the activity of tissue factor pathway inhibitor (TFPI). Andexanet alfa has no anticoagulant effect of its own, as the protein has been modified to remove the enzymatic activity of factor Xa.
Andexanet alfa is administered as an initial intravenous bolus followed by an intravenous infusion. The recommended dose depends upon the dose of apixaban or rivaroxaban and the time since the last dose of the anticoagulant. It is not recommended to use andexanet alfa if more than 18 hours have passed since the last dose of apixaban or rivaroxaban.
The single-arm ANNEXA-4 trial investigated the efficacy of andexanet alfa in patients with acute major bleeding within 18 hours of receiving a factor Xa inhibitor. The co-primary outcomes were change in anti-factor Xa activity and the proportion of patients with good or excellent haemostatic efficacy 12 hours after the completion of the infusion. In patients who had received apixaban or rivaroxaban, andexanet alfa resulted in a 92% reduction in anti-factor Xa activity at the end of the bolus administration. Good or excellent haemostatic efficacy at 12 hours was achieved in 82% of patients (80% in patients presenting with intracranial bleeding and 85% for gastrointestinal bleeding).
Following the reversal of factor Xa inhibitor therapy, patients are at risk of thromboembolic events associated with their underlying disease state. Therefore, consideration should be given to restarting anticoagulant therapy as soon as is appropriate.
Trastuzumab deruxtecan has been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer. Around 15-20% of all breast cancers are HER2 positive, with this subtype traditionally associated with poorer patient outcomes.
Trastuzumab deruxtecan is an antibody-drug conjugate (ADC). The antibody portion selectively targets the extracellular domain of the HER2 protein, and deruxtecan is a topoisomerase inhibitor. Once the ADC binds to HER2 on the tumour cell, it is internalised and undergoes enzymatic cleavage. This causes the topoisomerase I inhibitor to be released, which leads to DNA damage and apoptosis. The cytotoxic portion of the ADC has high membrane permeability, allowing it to also act against neighbouring cells. This “bystander effect” is beneficial as not all cells in HER2-positive breast cancer overproduce HER2.
Trastuzumab deruxtecan is not interchangeable with trastuzumab (Herzuma®) or trastuzumab emtansine (Kadcyla®). The DESTINY-Breast03 trial compared the efficacy and safety of trastuzumab deruxtecan with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. In the trastuzumab deruxtecan group, 75.8% of patients were alive without disease progression at 12 months, compared to 34.1% in the trastuzumab emtansine group. The overall incidence of drug-related adverse effects was higher in the trastuzumab deruxtecan group (98.1% versus 86.6%). The incidence of interstitial lung disease was also higher in the trastuzumab deruxtecan group (10.5%) compared to the trastuzumab emtansine group (1.9%). Patients should be monitored for signs and symptoms of this condition and advised to immediately report cough, dyspnoea, fever, or new or worsening respiratory symptoms.
The Therapeutic Goods Administration (TGA) has published a safety alert regarding the use of high doses of baclofen. This alert has been issued following recent coronial inquiries into two deaths.
Baclofen is a skeletal muscle relaxant indicated for chronic spasticity of spinal or cerebral origin. The usual oral dose range for these patients is 30-75mg daily (given in three divided doses). However, baclofen is sometimes prescribed off-label for the management of alcohol-use disorder. There is no universally accepted dosing recommendation in this setting, and higher doses are often used.
Baclofen is a structural analogue of gamma-aminobutyric acid (GABA) and can cause significant depression of the central nervous system (CNS). The TGA advises health professionals to be aware of the risk of intentional and unintentional overdose in patients taking baclofen for alcohol-use disorder. Symptoms of overdose may include reduced consciousness, respiratory depression, hyporeflexia, convulsions, and cardiac arrhythmias. Deterioration is more likely if combined with other CNS depressants.
Azacitidine tablets are now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of acute myeloid leukaemia (AML) following intensive induction chemotherapy.
The safety and efficacy of azacitidine tablets in this setting was evaluated in the pivotal QUAZAR AML-001 trial. In this double-blind study, patients with AML in first remission were randomised to receive oral azacitidine or placebo. Oral azacitidine was associated with a significantly longer overall survival compared to placebo (24.7 months versus 14.8 months). This favourable effect was noted in patients with both measurable residual disease (MRD)-positive and MRD-negative status at baseline.
The usual recommended dose is 300mg orally once daily for 14 days, followed by a 14-day treatment-free period. During the first two treatment cycles, an antiemetic is given 30 minutes before each azacitidine dose. In the event of disease relapse (5-15% blasts in the peripheral blood or bone marrow), treatment may be extended to 21 days of each 28-day cycle. However, treatment should be discontinued if disease progression occurs (blasts exceed 15% in either the peripheral blood or bone marrow).
The availability of an oral formulation improves convenience for patients and avoids injection site reactions which are common with the injectable formulation. Azacitidine tablets cannot be used interchangeably with azacitidine injection as there are significant differences in exposure and the dosing schedule. The mean oral bioavailability of azacitidine tablets relative to subcutaneous administration is around 11%. However, there is high interpatient variability. Food has a minimal effect on exposure and azacitidine tablets may be administered either with or without food.
The Pharmaceutical Benefits Scheme (PBS) listing for enzalutamide has recently been expanded. Enzalutamide is an oral inhibitor of androgen receptor signalling. It is now subsidised for the treatment of metastatic hormone-sensitive prostate cancer, in addition to castration-resistant metastatic and non-metastatic prostate cancer.
The ARCHES trial investigated the safety and efficacy of enzalutamide in the treatment of metastatic hormone-sensitive prostate cancer. Patients were randomised to receive enzalutamide (160mg daily) or placebo, with both groups also receiving androgen deprivation therapy (ADT). Patients in the enzalutamide group had a 61% reduced risk of radiographic disease progression or death compared to the placebo group. The ENZAMET trial further supports the efficacy of enzalutamide in this patient group. In this trial, patients were randomised to receive ADT plus either enzalutamide or standard care with a nonsteroidal antiandrogen (e.g. bicalutamide, nilutamide, or flutamide). After a median follow-up of 68 months, the median overall survival was not reached. However, the five-year overall survival was significantly higher in the enzalutamide group (67% versus 57%).
The safety of enzalutamide in the ARCHES trial was consistent with the findings of earlier studies conducted in castration-resistant prostate cancer. Adverse effects of grade 3 or higher were slightly more common in the placebo group (25.6% versus 24.3%). The most common adverse effects reported in the active group included hot flushes, fatigue, and musculoskeletal events. No unexpected adverse events were reported.
The darolutamide product information has recently been updated to include information about hepatotoxicity.
Darolutamide is a non-steroidal androgen receptor antagonist used in the treatment of prostate cancer. In the ARAMIS trial involving 1508 men with nonmetastatic, castration-resistant prostate cancer, darolutamide was associated with some changes in liver enzymes. Elevated serum aspartate aminotransferase (AST) occurred more commonly in the darolutamide group compared to placebo (23% versus 14%); serum bilirubin was also more frequently raised in the darolutamide group (16% versus 7%). However, elevations in AST and bilirubin were typically mild to moderate. Increases in alanine aminotransferase (ALT) levels were uncommon.
Cases of idiosyncratic drug-induced liver injury (DILI) with increases in ALT or AST of ≥ grade 3, including cases accompanied with bilirubin two or more times the upper limit of normal, have been reported during therapy with darolutamide. The onset ranged from around one month up to a year after starting darolutamide and were reversible following discontinuation. The manufacturer recommends permanent discontinuation of darolutamide if liver function test results suggestive of idiosyncratic DILI occur.
Patiromer is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of chronic hyperkalaemia. Criteria to qualify for PBS-subsidised treatment include:
- Stage 3-4 chronic kidney disease;
- Condition not adequately controlled by a low potassium diet;
- At least two episodes of hyperkalaemia (serum potassium ≥ 6.0 mmol/L) within the 12 months before initiating patiromer; and
- Patient must be receiving a renin-angiotensin-aldosterone system inhibitor (unless unable to tolerate).
Patiromer is a non-absorbable polymer that binds potassium in the lumen of the gastrointestinal tract. This increases the faecal excretion of potassium, thereby lowering serum levels. Patiromer is not recommended as the sole treatment of hyperkalaemia in patients with ECG changes, as the onset of effect is around four to seven hours.
Patiromer may bind some co-administered oral drugs, which could reduce their absorption. The product information lists medications that are not affected by this interaction. It is recommended that the administration of all other oral medications be separated from patiromer by at least three hours. As patiromer is not absorbed, drug interactions are expected to be confined to the gastrointestinal tract.
The incidence of adverse events was similar for patiromer and placebo groups in clinical trials. Caution is required in patients at risk of hypercalcaemia as patiromer contains calcium as part of the counterion complex, which is partially released. Magnesium levels should be monitored for at least one month after starting therapy as reductions in serum magnesium may occur.
Polystyrene sulfonate resins are another option to increase faecal potassium excretion. However, there is a lack of randomised data to support their use in the treatment of chronic hyperkalaemia, and they are also associated with serious gastrointestinal adverse effects. These factors, combined with the poor palatability of polystyrene sulfonate resins, may make patiromer a more attractive option in some cases.
