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.
Yonsa Mpred™ is now listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of castration-resistant metastatic prostate cancer. Yonsa Mpred™ is supplied as a composite pack containing abiraterone acetate 125mg tablets and methylprednisolone 4mg tablets.
Abiraterone is an inhibitor of cytochrome P450 C17 (CYP17), an enzyme involved in the synthesis of testosterone and other androgens. Studies demonstrate that blocking this enzyme can produce tumour responses in patients who no longer respond to standard hormonal therapies.
Abiraterone also reduces cortisol levels, which leads to a compensatory increase in adrenocorticotropic hormone (ACTH) release. This can result in increased production of adrenal mineralocorticoids, with adverse effects such as hypertension, oedema, and hypokalaemia. The addition of the glucocorticoid, methylprednisolone, suppresses ACTH drive and reduces the incidence and severity of mineralocorticoid excess.
This is the second abiraterone preparation available on the PBS. Zytiga® (abiraterone acetate) tablets exhibit large variations in absorption depending on the fat content of meals. Therefore, these tablets must be taken on an empty stomach. In comparison, the abiraterone in Yonsa Mpred™ was developed to have a smaller particle size, improving bioavailability and allowing tablets to be taken without regard to food. The dosing of these two products is also different. A small study demonstrated therapeutic equivalence between 500mg of fine particle abiraterone acetate (i.e. Yonsa Mpred™) and 1000mg of originator abiraterone acetate based on testosterone suppression.
The Australian Technical Advisory Group on Immunisation (ATAGI) has published advice on seasonal influenza vaccines for 2023. Annual vaccination is recommended for all people six months of age and over and is particularly important for those most at risk.
The National Immunisation Program (NIP) provides free influenza vaccines to the following high-risk groups:
- Children aged six months to less than five years;
- All Aboriginal and Torres Strait Islander people aged six months and over;
- People aged six months and over with certain medical conditions that increase their chance of severe influenza and complications (e.g. certain cardiac, respiratory, neurological, immunocompromising, metabolic, renal, and haematological conditions; and children aged 5-10 years who are taking long-term aspirin therapy);
- Pregnant women (at any stage during pregnancy); and
- People aged 65 years and over.
Table 1 shows the influenza vaccines registered for use in 2023 by age group.
Table 1. 2023 influenza vaccines by age group
| Age group |
Registered influenza vaccines |
| From six months |
Vaxigrip® Tetra |
| Fluarix® Tetra |
| FluQuadri® |
| Influvac® Tetra |
| ≥ 2 years |
Flucelvax® Quad |
| ≥ 5 years |
Afluria® Quad |
| ≥ 60 years |
Fluzone® HighDose Quad |
| ≥ 65 years |
Fluad® Quad |
People 65 years of age and older are at higher risk of developing severe influenza. However, the effectiveness of influenza vaccines is reduced in this age group. Two higher-immunogenicity influenza vaccines are available and are preferred over standard vaccines in this population. Fluad® Quad contains an adjuvant to increase immunogenicity, and Fluzone® HighDose Quad is a higher dose vaccine, containing 240mcg influenza virus haemagglutinin in 0.7mL (compared to 60mcg in 0.5mL for the standard dose vaccines).
There is a lack of data on the co-administration of Fluad® Quad with the adjuvanted shingles vaccine (Shingrix®). While they may be given on the same day, separating the administration by a few days is preferable. ATAGI advises that influenza vaccines can be administered on the same day as any COVID-19 vaccine.
Protection from an influenza vaccine is expected to last for the entire influenza season. However, optimal protection occurs in the three to four months after vaccination. The peak season throughout most of Australia is June to September.
The Pharmaceutical Benefits Scheme (PBS) listing for ruxolitinib has been expanded. The listing now includes acute or chronic graft-versus-host disease (GvHD) in patients with an inadequate response to corticosteroids.
Ruxolitinib is an inhibitor of the Janus Associated Kinases (JAKs), JAK1 and JAK2. Inhibition of these enzymes disrupts cytokine and growth factor signalling pathways involved in the pathogenesis of GvHD. The REACH 2 and REACH 3 studies investigated the safety and efficacy of ruxolitinib compared to control (investigator’s choice of commonly used therapies) in glucocorticoid-refractory GvHD.
The REACH 2 trial was undertaken in patients with acute GvHD. At day 28, the overall response was 62% in the ruxolitinib group compared to 39% in the control group. The REACH 3 trial was conducted in patients with chronic GvHD. At week 24, the overall response was 49.7% in the ruxolitinib group and 25.6% in the control group.
Ruxolitinib is an oral medication with a usual starting dose of 10mg twice daily in chronic GvHD and 5-10mg twice daily in acute GvHD. The dose may require adjustment according to patient response and toxicity or due to interacting drugs. Ruxolitinib is metabolised by CYP3A4 and CYP2C9; the manufacturer recommends halving the dose when administered with dual moderate inhibitors of these enzymes, such as fluconazole ≤ 200mg daily (higher doses of fluconazole should be avoided).
The Therapeutic Goods Administration (TGA) has issued a Medicines Safety Update on the use of pregabalin during pregnancy. The pregnancy risk category for pregabalin has changed from Category B3 to Category D, and product information documents are being updated to strengthen the advice against prescribing pregabalin during pregnancy.
This update is based on the findings of an observational study investigating the safety of pregabalin in the first trimester of pregnancy. Data were obtained from population-based registries in Denmark, Finland, Norway, and Sweden. The incidence of major congenital malformations, birth outcomes, and selected neurodevelopmental outcomes was evaluated for babies exposed to pregabalin in utero. These outcomes were compared to babies exposed to lamotrigine (chosen as an alternative antiepileptic drug), duloxetine (alternative for neuropathic pain and generalised anxiety disorder), and none of these medicines.
The data showed a higher prevalence of major congenital malformations in babies exposed to pregabalin compared with those not exposed to pregabalin or any other antiepileptic drug (crude percentage 5.9% versus 4.1%). However, the adjusted prevalence ratio in the final meta-analysis was not statistically significant (1.13 [95% CI 0.97-1.31]).
The study authors note that their results do not provide strong evidence of human teratogenicity, although a small increased risk cannot be ruled out. The TGA advises that pregabalin should only be prescribed to pregnant women if the benefits clearly outweigh the potential risks.
