From 1 December 2020, rivaroxaban 2.5mg tablets are available on the Pharmaceutical Benefits Scheme (PBS) for chronic stable atherosclerotic disease. The PBS criteria requires that rivaroxaban 2.5mg be used in combination with aspirin in high-risk patients with coronary artery disease or peripheral artery disease.
Evidence to support the use of rivaroxaban 2.5mg in this patient group comes from the COMPASS trial. Participants with stable atherosclerotic vascular disease were randomly assigned to receive rivaroxaban 2.5mg twice daily plus aspirin 100mg daily, rivaroxaban 5mg daily, or aspirin 100mg daily. The primary efficacy outcome was the composite of cardiovascular death, stroke, or myocardial infarction. This occurred in 4.1% of the rivaroxaban plus aspirin group, 4.9% of the rivaroxaban alone group, and 5.4% of the aspirin alone group.
There was no significant difference in the rate of intracranial or fatal bleeding events between groups. However, major bleeding events were more common in the rivaroxaban plus aspirin group (3.1% compared to 1.9% in the aspirin alone group). The study was stopped after a mean follow-up of 23 months due to the superiority of rivaroxaban plus aspirin.
The Therapeutic Goods Administration (TGA) has investigated metformin-containing medicines for potential contamination with N-nitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen and can be found in low levels in a variety of foods, some drinking water, and air pollution. It has also recently been detected in some ranitidine and angiotensin II antagonist medicines.
Testing of a selection of immediate-release and modified-release metformin products found that around 30% of batches contained NDMA at levels that modestly exceeded the acceptable limit. While one batch was found to have higher levels, limited stock of this product was supplied to the Australian market.
A risk analysis was conducted that included consideration of commonly prescribed doses. The TGA concludes that the risk is very low for patients taking metformin from batches that modestly exceed the NDMA limit. The limits set for NDMA are conservative and calculated so that an individual’s excess cancer risk would not exceed 1:100,000 if they received the maximum daily dose of that medicine for 70 years.
Metformin is an important treatment for type 2 diabetes. The TGA advises that the risks of untreated diabetes greatly outweigh the risks posed by the low levels of NDMA detected in these products. Patients are strongly recommended to continue taking their medication as prescribed. The TGA is currently working with manufacturers and sponsors to improve processes and ensure that metformin products supplied in Australia meet the TGA’s high standards for quality.
From 1 November 2020, siponimod became available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of relapsing-remitting multiple sclerosis. Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. It acts as a functional antagonist at S1P1 receptors to inhibit the release of lymphocytes from the lymph nodes. This may reduce lymphocyte migration to the central nervous system and minimise central inflammation.
A large double-blind clinical trial demonstrates that siponimod reduces disability progression and has a similar safety profile to fingolimod. The primary endpoint of time to onset of confirmed disability progression (CDP) at three months was significantly delayed, with a relative risk reduction of 21% (CDP events occurred in 26% of siponimod patients, compared to 32% of the placebo group). Adverse events most commonly reported during this trial include elevated liver enzymes, bradycardia at initiation, macular oedema, hypertension, varicella-zoster virus reactivation, and convulsions.
Siponimod is extensively metabolised by the cytochrome P450 system, primarily by CYP2C9. Patients should be tested for their CYP2C9 metabolising enzyme status before commencing treatment. Dose reductions are required for patients with CYP2C9*1*3 or CYP2C9*2*3 genotypes, while use is contraindicated in patients with a CYP2C9*3*3 genotype as substantially higher plasma levels will occur.
Apomorphine was added to the Pharmaceutical Benefits Scheme (PBS) General Schedule on 1 October 2020. Apomorphine is indicated for the treatment of Parkinson disease in patients who have experienced severely disabling motor fluctuations that are refractory to conventional therapy.
Apomorphine is a short-acting dopamine agonist with similar efficacy to levodopa, but with a shorter onset and duration of effect. Apomorphine freely crosses the blood-brain barrier, achieving a concentration in the brain up to eight times greater than the plasma. Intermittent dosing provides rapid and effective relief of “off” periods. However, a continuous subcutaneous infusion may be considered for patients whose overall control remains inadequate or for patients who require many injections throughout the day. A recent double-blind trial found that continuous apomorphine infusion reduced daily “off” time by 2.47 hours at week 12, compared to 0.58 hours in the placebo group.
Gastrointestinal adverse effects, such as nausea and vomiting, are commonly reported. Pre-treatment with domperidone, a peripherally acting dopamine antagonist, should begin at least 48 to 72 hours before apomorphine therapy is initiated. Tolerance to gastrointestinal adverse effects develops rapidly, and the domperidone dose can be gradually reduced over several weeks to the lowest effective dose.
The Pharmaceutical Benefits Scheme (PBS) listing for aflibercept was expanded on 1 October 2020. Aflibercept is now subsidised for the treatment of subfoveal choroidal neovascularisation, in addition to macular oedema secondary to diabetes or retinal vein occlusion.
Aflibercept binds vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) to prevent their interaction with VEGF receptors. Excessive activation of VEGF receptors is associated with pathologic angiogenesis and increased vascular permeability. Interruption of these pathways by aflibercept can slow vision loss by reducing vascular leakage and neovascularisation.
Aflibercept is administered by ophthalmologists as an intravitreal injection. Following administration, patients must be monitored for increased intraocular pressure. Patients should also be advised to seek immediate medical advice if they experience any symptoms indicative of endophthalmitis such as eye pain or redness, photophobia, or blurred vision.
Lorlatinib was recently added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of metastatic non-small cell lung cancer (NSCLC). To be eligible for subsidised therapy, patients must have evidence of an anaplastic lymphoma kinase (ALK) gene rearrangement and have experienced disease progression following treatment with an ALK inhibitor other than crizotinib.
Lorlatinib is a tyrosine kinase inhibitor with activity against ALK and the structurally similar protein, c-ros oncogene 1 (ROS1) kinase. Inhibition of these kinases impairs signalling pathways involved in cell proliferation and survival in lung and other cancers. ALK inhibitors, such as crizotinib, alectinib, and ceritinib, have improved the prognosis for ALK-positive tumours. However, relapse and disease progression are common due to acquired resistance.
Lorlatinib is a third-generation ALK inhibitor that overcomes some of the resistance mechanisms of other agents in this class. It also demonstrates improved penetration of the blood-brain barrier compared to crizotinib, which provides better intracranial disease control.
In a Phase I/II study, the most commonly reported adverse events included hypercholesterolaemia, hypertriglyceridaemia, oedema, peripheral neuropathy, cognitive effects, and diarrhoea. Serious adverse events were reported in just over a third of the cohort, and 2.7% of patients permanently discontinued lorlatinib due to treatment-related adverse events.
From 18th September 2020, all products containing bufexamac will be removed from the Australian Register of Therapeutic Goods (ARTG). This action follows an investigation by the Therapeutic Goods Administration (TGA), which concluded that the risk-benefit ratio of bufexamac is not favourable.
Bufexamac is a non-steroidal anti-inflammatory drug (NSAID) and is a well-documented cause of allergic contact dermatitis. Reactions range from localised irritation to widespread polymorphic eruptions, with some patients requiring hospitalisation. The risk of developing a reaction to bufexamac is high, particularly in atopic individuals. Bufexamac has, therefore, been withdrawn in many countries where it was once approved for the treatment of dermatitis. In Australia, bufexamac was only found in combination with a topical anaesthetic and antiseptic for the first aid treatment of minor skin complaints such as abrasions and stings.
In addition to the risk of allergic reactions, the TGA declares that there is insufficient evidence to support the efficacy of bufexamac. While bufexamac will no longer be sold in Australia, a range of alternative first aid creams remain available.
On September 1, acalabrutinib was listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). Acalabrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK), an important enzyme in oncogenic signalling. Inhibition of BTK ultimately leads to reduced proliferation and survival of malignant B-cells.
The efficacy of acalabrutinib in the treatment of CLL was assessed in two randomised Phase III clinical trials. In the ASCEND trial, patients received acalabrutinib monotherapy or physician’s choice (rituximab plus idelalisib or bendamustine) with a median follow-up of 16.1 months. The median progression-free survival (PFS) was not reached in the acalabrutinib group, compared to 16.5 months for the control group. In the ELEVATE-TN trial, patients received acalabrutinib monotherapy, acalabrutinib with obinutuzumab, or obinutuzumab with chlorambucil. After a median follow-up of 28.3 months, the median PFS was not reached for patients taking acalabrutinib, compared to 22.6 months for the control group.
The most common adverse events reported during these clinical trials include anaemia, neutropenia, thrombocytopenia, upper respiratory tract infection, and diarrhoea. Bleeding events, such as bruising and petechiae, are very common; major haemorrhage was reported in 3.6% of patients. To minimise the risk of bleeding, physicians may consider withholding therapy in the three to seven days before and after surgery.
Evidence suggests that hydrochlorothiazide is associated with an increased risk of carcinoma in sun-exposed tissues. It is theorised that this may be due to the photosensitising properties of hydrochlorothiazide.
A recent Australian study demonstrated that hydrochlorothiazide use was associated with a 2.6-fold greater risk of lip cancer and a 20% increased risk of cutaneous melanoma. The risk also appeared to be dose-related, as patients with high hydrochlorothiazide use (defined as a cumulative dose of ≥ 25,000mg) demonstrated a 4.7-fold higher odds of lip cancer. This echoes the findings of two Danish case-control studies that showed an increased risk of squamous cell carcinoma and basal cell carcinoma with hydrochlorothiazide use. This increased risk was not observed for furosemide, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II antagonists.
Hydrochlorothiazide is a thiazide diuretic indicated for the treatment of hypertension and oedema. It is available as a single ingredient tablet and is also formulated with other antihypertensive agents in a range of fixed-dose combination products. Patients taking hydrochlorothiazide should be advised to regularly check their skin and lips and promptly report any new or changed skin lesions or moles to their doctor. Patients should also limit their sun exposure and practice sun safety.
The Therapeutic Goods Administration (TGA) has issued a safety advisory regarding the use of Zostavax® in people with compromised immune function. Zostavax® is a live, attenuated varicella-zoster vaccine indicated for the prevention of herpes zoster in people aged 50 years and older. This vaccine is contraindicated in people with primary and acquired immunodeficiency states as well as those receiving immunosuppressive therapy. However, the product information emphasises that it is not contraindicated in people receiving topical or inhaled corticosteroids, low-dose systemic corticosteroids, or corticosteroid replacement therapy.
The TGA warning follows a new report of death due to disseminated varicella-zoster virus (Oka vaccine strain) infection. This patient was taking hydroxychloroquine and low-dose prednisolone when they received the zoster vaccine, in line with clinical recommendations. The TGA reminds healthcare professionals that this potentially life-threatening condition can occur in patients on low-dose immunosuppressive therapy and highlights the importance of a risk-based assessment prior to Zostavax® administration.
The Australian Immunisation Handbook can be referred to for further information regarding zoster vaccine use in people taking immunosuppressive therapy and the value of serological testing.
