New Medication for Hot Flushes

The neurokinin-3 receptor antagonist, fezolinetant, is now available for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. This is the first non-hormonal medication approved for this indication.

The physiology of VMS is not fully understood. However, signalling via the kisspeptin/neurokinin B/dynorphin (KNDy) neurons is thought to be involved. These neurons innervate the thermoregulatory centre of the hypothalamus and are normally inhibited by estrogen and stimulated by neurokinin B. As estrogen levels decline during menopause, neurokinin B signalling increases activity at the thermoregulatory centre, which can lead to VMS. Fezolinetant blocks neurokinin B signalling, thereby normalising KNDy neuronal activity and reducing VMS.

The SKYLIGHT 2 trial investigated the efficacy of fezolinetant in reducing the frequency and severity of VMS. At week 12, the mean change in VMS frequency was -51.60% for fezolinetant 30mg, 55.16% for fezolinetant 45mg, and -33.60% for placebo. The reduction in VMS frequency compared to placebo was statistically significant in both fezolinetant dose groups at all time points between weeks 1 and 12. While there are currently no head-to-head studies comparing fezolinetant with estrogen, a recent meta-analysis suggests that its efficacy may be similar to that of hormonal therapies and greater than that of available non-hormonal therapies.

Fezolinetant is supplied as an oral tablet for daily administration. Serious treatment-emergent adverse effects were infrequently reported in clinical trials. Some elevations in liver enzymes occurred. These were generally asymptomatic and returned to baseline with continuing treatment or discontinuation. Fezolinetant is a substrate of CYP1A2, and the concomitant use of moderate or strong CYP1A2 inducers is contraindicated.

Fezolinetant may be an appropriate alternative for the treatment of VMS in women who cannot take hormonal therapies or for whom estrogen therapies are not effective.

Inclisiran on the PBS

Inclisiran was recently added to the Pharmaceutical Benefits Scheme (PBS) as a third-line option for non-familial hypercholesterolaemia and familial heterozygous hypercholesterolaemia.

Inclisiran is a first-in-class therapy known as a small interfering ribonucleic acid (siRNA). This medication reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme involved in LDL receptor regulation. The reduced level of circulating PCSK9 leads to increased LDL receptor recycling and expression on the surface of hepatocytes, increasing the uptake of LDL. Studies demonstrate that inclisiran lowers LDL levels by around 50% compared to placebo.

A potential advantage of inclisiran is the favourable dosing schedule. The first two doses are given three months apart, and maintenance doses are every six months. This may be particularly advantageous for patients with poor adherence to regular therapy. Inclisiran is administered as a subcutaneous injection, with each dose intended to be given by a healthcare professional. Inclisiran appears to be well-tolerated, with clinical trials generally reporting similar adverse events between placebo and inclisiran groups. The exception was injection site reactions, which occurred in 8.2% of inclisiran-treated patients and 1.8% of the placebo group in pivotal trials.

Expanded PBS Listing for Dapagliflozin

The Pharmaceutical Benefits Scheme (PBS) listing for dapagliflozin has recently been expanded. It is now subsidised for the treatment of heart failure independent of left ventricular ejection fraction (LVEF).

When used for the management of heart failure, dapagliflozin was previously only subsidised for patients with reduced ejection fraction. This was supported by the DAPA-HF trial, which found benefits in patients with an LVEF of <40%. The DELIVER study built on this by investigating the efficacy of dapagliflozin in patients with an LVEF > 40%. Patients were randomly assigned to receive dapagliflozin 10mg daily or placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure or cardiovascular death. With a median follow-up of 2.3 years, the primary outcome occurred in 16.4% of the dapagliflozin group and 19.5% of the placebo group (hazard ratio: 0.82, 95% CI: 0.73-0.92, P<0.001).

Common adverse effects include genital infections (such as vulvovaginal candidiasis and balanitis), polyuria, dysuria, urinary tract infection, and dyslipidaemia. This class of medications is rarely reported to cause euglycaemic ketoacidosis in patients with diabetes, particularly in association with stressors such as surgery or acute illness. To reduce this risk, the Australian Diabetes Society recommends withholding dapagliflozin for at least three days for most surgical procedures in patients with diabetes. The current evidence suggests that the risk of dapagliflozin causing ketoacidosis in patients without diabetes is unlikely.

Cephalosporin-induced Neurotoxicity

The product information documents of many cephalosporin products have recently been updated to include warnings of neurotoxicity. Cephalosporins are broad-spectrum beta-lactam antibiotics that are commonly used to treat a range of infections. Neurotoxicity has been reported with their use and may present as encephalopathy, seizures, or myoclonus.

Risk factors for developing neurotoxicity during cephalosporin treatment include:

  • Older age;
  • Renal impairment (especially if doses are not adjusted appropriately);
  • Underlying central nervous system disorders; and
  • Intravenous administration.

The onset of neurotoxicity is typically one to ten days after initiating the antibiotic, with resolution reported to occur two to seven days after discontinuation. Symptoms of cephalosporin-induced neurotoxicity have the potential to be incorrectly attributed to another neurological condition or metabolic abnormality, particularly in hospitalised patients. Therefore, a high degree of suspicion is required in order to recognise this adverse event in a timely manner.

Tebentafusp for Uveal Melanoma

Tebentafusp is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of advanced uveal melanoma. Uveal melanoma is a rare cancer originating from melanocytes in the choroid, iris, or ciliary body of the eye. Around half of all people diagnosed with uveal melanoma will develop metastatic disease, primarily of the liver.

Tebentafusp belongs to a new medication class called immune-mobilising monoclonal T-cell receptors against cancer (ImmTACs). It is a bispecific fusion protein containing a T-cell receptor and antibody fragment. The T-cell receptor is specific for a peptide that is preferentially expressed in melanoma cells, and the antibody fragment is specific for the CD3 receptor. While the T-cell receptor recognises its target protein, the antibody fragment allows the recruitment and activation of CD3+ T-cells. In vitro studies demonstrate that when tebentafusp binds to these targets, it results in direct lysis of the tumour cells following the release of inflammatory cytokines and cytolytic proteins.

An open-label phase 3 trial compared the efficacy of tebentafusp with control (investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine). At one year, the estimated overall survival was 73% in the tebentafusp group and 59% in the control group. The estimated median duration of overall survival was 21.7 months for tebentafusp and 16.0 months for control. A recently published three-year analysis demonstrates the long-term benefits of tebentafusp. At a minimum follow-up of 36 months, median overall survival was higher in the tebentafusp group than in the control (21.6 months vs 16.9 months).

Tebentafusp is administered as a weekly intravenous infusion. The most common treatment-related events observed in clinical trials were cytokine-mediated and skin-related events, such as rash, pyrexia, and pruritus. The product information contains a black box warning on cytokine release syndrome (CRS). Although this was reported in 89% of clinical trial patients, only 1% had grade 3 CRS, and no patients developed grade 4 or 5. This adverse event typically occurs within a few hours of the first three doses, and the manufacturer recommends additional monitoring for these initial infusions.

Subcutaneous Natalizumab on the PBS



The subcutaneous form of natalizumab is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of relapsing-remitting multiple sclerosis. Natalizumab is a monoclonal antibody that binds to α4 integrins on leucocytes. This inhibits their migration into the central nervous system, which is thought to reduce central inflammation and demyelination. Previously only available as an intravenous infusion, the introduction of a subcutaneous form has potential advantages for some patients.

The usual natalizumab dose is 300mg every four weeks. The vials for intravenous use contain 300mg and should be diluted in 100 mL of 0.9% sodium chloride and infused over one hour. The pre-filled syringes for subcutaneous use contain 150mg each and are administered as two consecutive injections (given not more than 30 minutes apart). While the subcutaneous form still requires administration by a healthcare professional, it may be given in a wider range of clinical settings. This may be particularly convenient for patients who live remotely.

The DELIVER study compared the pharmacokinetics and pharmacodynamics of natalizumab administered by different routes. Following two weeks of continuous dosing, the serum concentration and trough serum concentration were similar in patients receiving natalizumab via the intravenous or subcutaneous route. All pharmacodynamic parameters appeared similar in each group.

Natalizumab is generally well tolerated. Common adverse events include headache, fatigue, and mild infections (e.g. respiratory and urinary tract infections). Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that can cause death or severe disability. Patients should be closely monitored for early signs and symptoms of PML during treatment and for around six months after stopping.

Melanoma Therapy Added to the PBS

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.

Expanded PBS Listing for Orkambi®

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 on the PBS

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.

Reversing the Anticoagulant Effects of Factor Xa Inhibitors

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.