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.
The Therapeutic Goods Administration (TGA) has issued a safety advisory regarding an association between liver injury and medicines containing turmeric or curcumin. The TGA has received 18 reports of liver problems in people taking products containing turmeric or curcumin, including one fatality.
Following a safety investigation, the TGA concludes that the current evidence demonstrates a rare risk of liver injury from taking medicinal products containing curcumin. Factors that potentially increase the risk of liver injury include high curcumin doses, products with enhanced absorption, and pre-existing liver problems. As a precautionary measure, the TGA advises that curcumin-containing medicines should be avoided by people with a history of liver problems.
Evidence suggests that the incidence of liver injury related to herbal and dietary supplements is increasing in Australia. As complementary medicines are typically considered safe, patients may not always think it relevant to inform their healthcare professional that they are taking them. Utilising the principles of the best possible medication history ensures that these types of products are not missed when a patient presents to hospital.
Eptinezumab has been added to the Pharmaceutical Benefits Scheme (PBS) for the preventive treatment of chronic migraine in adults. To qualify for PBS subsidy, patients must average 15 or more headache days per month (with at least eight days of migraine) for at least six months before initiating treatment.
Eptinezumab is a calcitonin gene-related peptide (CGRP) antagonist. Elevated CGRP levels have been associated with migraine, with this neuropeptide implicated in pain modulation. The safety and efficacy of eptinezumab were evaluated in the PROMISE-2 trial. Adults with chronic migraine were randomly assigned to receive eptinezumab 100mg, eptinezumab 300mg, or placebo on day 0 and week 12. Patients in the eptinezumab group achieved a significant reduction in monthly migraine days compared to placebo, with benefits becoming apparent on the first day after initiation of therapy. These results were supported by the longer-term open-label PREVAIL trial. Favourable safety and efficacy profiles were maintained over the two-year trial period. However, this trial used a 300mg dose, which is not subsidised on the PBS.
Other CGRP antagonists available include galcanezumab, fremanezumab, and erenumab. Due to their large molecular size, all of these medicines must be administered parenterally. Galcanezumab and fremanezumab are also available on the PBS.
A new indication has been added to the product information for baricitinib. In addition to rheumatoid arthritis and atopic dermatitis, baricitinib is now also approved for the treatment of severe alopecia areata. This therapy may be considered for adult patients for whom other therapies are either ineffective or inappropriate.
Alopecia areata is a complex autoimmune condition that can cause hair loss of the scalp, eyebrows, and eyelashes. Many of the cytokines involved in the pathogenesis of this disorder depend upon Janus kinases (JAKs) for intracellular signalling. The BRAVE-AA trials investigated the safety and efficacy of baricitinib, a JAK inhibitor, for this condition.
Patients with a Severity of Alopecia Tool (SALT) score of at least 50 (where 0 = no scalp hair loss and 100 = complete scalp hair loss) were randomly assigned to receive baricitinib 2mg daily, baricitinib 4mg daily, or placebo. The primary outcome was a SALT score of 20 or less at week 36. In the BRAVE-AA2 trial, the primary outcome was reached in 35.9% of patients in the baricitinib 4mg group, 19.4% in the baricitinib 2mg group, and 3.3% in the placebo group.
Adverse effects more commonly reported in the baricitinib groups include acne, elevated creatine kinase levels, and increased low- and high-density lipoprotein cholesterol levels. Baricitinib is not currently subsidised on the Pharmaceutical Benefits Scheme (PBS) for treating alopecia areata.
The tablet presentation of acalabrutinib has recently been added to the Pharmaceutical Benefits Scheme (PBS). Acalabrutinib is also available in a capsule and is PBS-subsidised for the treatment of relapsed or refractory chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL).
There are some significant differences between the tablet and capsule presentations. The tablets are smaller and film-coated, which may make them easier for patients to swallow. In addition, the tablets may be co-administered with gastric acid-reducing agents.
The bioavailability of acalabrutinib capsules is pH-dependent, with solubility reducing with increasing pH. Co-administration of acalabrutinib capsules with 40mg omeprazole reduced the area under the curve (AUC) by 43%. Therefore, acalabrutinib capsules are not recommended to be co-administered with proton pump inhibitors. If a gastric acid-reducing agent is required, it is recommended to use an antacid or H2 receptor antagonist and separate the dosing by at least two hours.
In contrast, the tablet presentation contains the maleate salt of acalabrutinib, which exhibits pH-independent release. The ELEVATE-PLUS study demonstrates that the tablet and capsule formulations have almost identical bioavailability. This study also suggests that proton pump inhibitors do not have a clinically relevant impact on acalabrutinib tablets. Administration of acalabrutinib tablets with rabeprazole resulted in an approximately 24% lower maximum concentration (Cmax) and a 14% higher AUC, which is not considered clinically significant.
The availability of acalabrutinib tablets may overcome some of the dosing issues associated with acalabrutinib capsules and remove the need for staggering the doses of gastric acid-lowering therapies.
| |
Acalabrutinib tablet |
Acalabrutinib capsule |
| Presentation |
Film-coated tablet |
Hard gelatin capsule |
| Active ingredient |
Acalabrutinib maleate monohydrate |
Acalabrutinib (free base) |
| Proton pump inhibitors |
May be co-administered |
Avoid co-administration |
| Other gastric acid-lowering agents |
May be co-administered |
Separate doses by at least 2 hours |
The Topamax® (topiramate) product information has recently been updated. When used for migraine prophylaxis, this medicine is now contraindicated in pregnancy and in women of childbearing potential unless a highly effective method of contraception is used.
Topiramate belongs to category D in the Australian categorisation system for prescribing medicines in pregnancy. Studies suggest that topiramate significantly increases the risk of overall major congenital malformations, foetal loss, prenatal growth retardation, and cleft lip/palate. However, some evidence suggests that the risks associated with topiramate may be disproportionately higher when used for the treatment of epilepsy compared to other indications.
If migraine prophylaxis is required during pregnancy, a beta blocker or tricyclic antidepressant is considered safer.
The Pharmaceutical Benefits Scheme (PBS) listings for pembrolizumab and lenvatinib have been expanded. These agents are now listed for use in combination to treat advanced, metastatic, or recurrent endometrial carcinoma.
The safety and efficacy of this therapy was investigated in the KEYNOTE-775 trial. Patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen were randomly assigned to receive pembrolizumab plus lenvatinib or chemotherapy of the physician’s choice (doxorubicin or paclitaxel). Compared to the chemotherapy group, patients in the lenvatinib plus pembrolizumab group had significantly longer progression-free survival (7.2 months vs 3.8 months) and overall survival (18.3 months vs 11.4 months). The most common adverse effects experienced by patients in the pembrolizumab plus lenvatinib group included hypertension (64.0%), hypothyroidism (57.4%), diarrhoea (54.2%), and nausea (49.5%).
Lenvatinib is a tyrosine kinase inhibitor, and pembrolizumab is a monoclonal antibody. The usual doses for endometrial cancer are lenvatinib 20mg orally daily with pembrolizumab 200mg every three weeks or 400mg every six weeks administered as an intravenous infusion.
The Pharmaceutical Benefits Scheme (PBS) listing for apalutamide has been expanded to include metastatic castration-sensitive prostate cancer. Apalutamide is an androgen receptor inhibitor. It can reduce tumour volume by decreasing tumour cell proliferation and increasing apoptosis.
The efficacy of apalutamide in patients with metastatic castration-sensitive prostate cancer was investigated in the TITAN trial. In this double-blind study, patients were randomised to receive apalutamide or a placebo, in addition to androgen deprivation therapy. Radiographic progression-free survival at 24 months was significantly longer in the apalutamide group compared to placebo (68.2% vs 47.5%). Overall survival was also significantly longer in the apalutamide group (82.4% vs 73.5%) at 24 months. The side effect profile was similar in the two groups, although apalutamide was associated with a higher incidence of rash, hypothyroidism, and ischaemic heart disease.
Apalutamide may induce the drug metabolising enzymes, UDP-glucuronosyl transferase (UGT). These enzymes also metabolise thyroid hormones, which may increase the risk of hypothyroidism. Patients already prescribed thyroid replacement therapy may require dose adjustment. Apalutamide can also cause drug interactions due to its effect on other drug metabolising enzymes. It is a strong inducer of CYP2C19 and CYP3A4, a weak inducer of CYP2C9, and is predominantly metabolised by CYP2C8 and CYP3A4.
The usual apalutamide dose is 240mg orally daily. It should be given in conjunction with a gonadotropin-releasing hormone (GnRH) analogue unless the patient has had a bilateral orchiectomy.
The Therapeutic Goods Administration (TGA) has published a Medicines Safety Update for the Janus kinase (JAK) inhibitors, tofacitinib, baricitinib and upadacitinib. This update relates to the findings of the ORAL Surveillance study, a large, post-authorisation, safety end-point trial of patients with active rheumatoid arthritis taking tofacitinib or a tumour necrosis factor (TNF) inhibitor. As baricitinib and upadacitinib have a similar mechanism of action to tofacitinib, the TGA considers that the findings of this study are also relevant to these agents.
To be enrolled in the ORAL Surveillance study, participants had to be 50 years of age or older with at least one cardiovascular risk factor. During a median follow-up of four years, the incidence of major adverse cardiovascular events was 3.4% in patients taking tofacitinib, compared to 2.5% for those treated with a TNF inhibitor. The incidence of cancers (excluding nonmelanoma skin cancer) was 4.2% in the tofacitinib group and 2.9% in the TNF inhibitor group. Subgroup analyses found that these differences were more pronounced in patients 65 years of age or older. The incidence of thromboembolic events, serious infections, and death due to any cause was also higher for tofacitinib compared to TNF inhibitors.
The TGA recommends periodic skin examinations and regular re-evaluation of thrombosis risk for patients taking tofacitinib, baricitinib, or upadacitinib. A new boxed warning has also been added to the product information documents for these medicines advising consideration of alternative therapies for patients who are 65 years of age or older or have cardiovascular or malignancy risk factors.
