The Pharmaceutical Benefits Scheme (PBS) introduced some changes to adalimumab listings on 1 April 2021. Four biosimilar brands have been ‘a-flagged’ with the originator brand, and a new reduced volume formulation of Humira® has been added.
The new Humira® product contains the same active ingredient but is formulated without the citrate buffer. Studies demonstrate that citrate buffers are associated with more pain on injection than histidine buffers or isotonic saline. Minimising the pain of subcutaneous injections offers obvious patient benefits as well as potentially improving compliance. This is important as Humira® is indicated for many chronic conditions, such as rheumatoid arthritis and Crohn’s disease.
Two randomised, single-blind studies compared the tolerability of the two Humira® formulations in patients with rheumatoid arthritis. The pooled results demonstrate a 54% mean reduction in pain immediately after injection for the citrate-free formulation. The study was not able to identify which factor in the new presentation was most significant (i.e. the formulation, reduced volume, or needle size).
The original Humira® formulations are now designated ‘Supply Only’ and may only be dispensed on the PBS using prescriptions written prior to 1 April 2021. AbbVie advises that the original Humira® formulation will eventually be discontinued.
From 1 April 2021, short-course packs of immediate-release oxycodone (5mg x 10 capsules) are available on the Pharmaceutical Benefits Scheme (PBS). The criteria for this restricted benefit is the short-term management of acute severe pain where non-opioid analgesics are inappropriate.
This PBS listing supports the recommendations of the Therapeutic Goods Administration (TGA) to improve the safety of opioid use. Studies suggest that up to 71% of opioid doses prescribed to surgical patients are not used, and the majority of unused doses are not disposed of or stored correctly. These practices increase the risk of opioid misuse and diversion.
This new PBS listing may provide a more appropriate option for patients with acute severe pain, e.g., following surgery or injury. However, the larger pack sizes (20 capsules) are still available on the PBS for patients who need them. Further information on opioid reforms is available on the TGA website. A collection of pain management tools and resources is also available to help guide clinical decision-making.
Ozanimod was added to the Pharmaceutical Benefits Scheme (PBS) on 1 March 2021 for relapsing-remitting multiple sclerosis. Ozanimod is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits lymphocyte release from lymph nodes. This reduces lymphocyte migration into the central nervous system, which may prevent nerve inflammation and damage. Other medicines in this class that are listed on the PBS are fingolimod and siponimod.
There are five subtypes of the S1PR (S1PR1-5), with ozanimod showing a high affinity for S1PR1 and S1PR5. Fingolimod is the least specific of the three agents, which is thought to be partly responsible for some of its adverse effects. A six-hour observation period is recommended for all patients after the first fingolimod dose. This is not routinely required on the initiation of ozanimod or siponimod.
There is a lack of head-to-head clinical trials comparing S1PR modulators. However, ozanimod’s efficacy was demonstrated in the SUNBEAM trial that used interferon beta-1a (30mcg weekly) as an active comparator. In this trial, the annualised relapse rate was 0.18 for patients taking ozanimod 920mcg daily, compared to 0.35 for interferon. The mean number of relapses in the year before treatment was 1.3 for all groups. The incidence of serious adverse events was low and similar across the treatment groups.
Ozanimod is initiated with a dose titration regimen to minimise bradycardia. Ozanimod has many potential drug interactions due to extensive metabolism by multiple enzyme systems, including cytochrome P450 and monoamine oxidase. Coadministration with rifampicin and monoamine oxidase inhibitors is not recommended.
Dupilumab was added to the Pharmaceutical Benefits Scheme (PBS) on 1 March 2021. Dupilumab is indicated for the treatment of moderate to severe atopic dermatitis and asthma in people aged 12 years of age and older. However, it is currently only PBS-subsidised for the treatment of chronic severe atopic dermatitis.
Dupilumab is a human monoclonal antibody that acts as an antagonist at the interleukin-4 (IL-4) receptor alpha subunit shared by IL-4 and IL-13 receptors. This results in inhibition of signalling via IL-4 and IL-13, key cytokines involved in atopic disease.
The safety and efficacy of dupilumab in atopic dermatitis were evaluated in three pivotal placebo-controlled clinical trials. The proportion of subjects with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and an improvement of at least two points was significantly higher in the dupilumab groups in all three studies. This outcome occurred in 38% of patients in the SOLO 1 trial and 36% of patients in the SOLO 2 trial who received dupilumab every second week, compared to 10% and 8% in the placebo groups, respectively.
Dupilumab is presented as a single-use pre-filled syringe for subcutaneous injection. It is intended for long-term use and can be combined with topical therapy, if required. The most commonly reported adverse reactions include injection site reactions, herpes simplex virus infection, conjunctivitis, and blepharitis.
From 1 March 2021, Atectura® is available on the Pharmaceutical Benefits Scheme (PBS) for the maintenance treatment of asthma in people 12 years of age and older. Atectura® contains the long-acting beta2– agonist (LABA), indacaterol, plus the corticosteroid, mometasone. It is presented as a capsule, the contents of which must be inhaled using the Breezhaler® device supplied in the carton.
The Australian Asthma Handbook advises that, for adult patients already taking an inhaled corticosteroid, the addition of a LABA reduces the risk of exacerbations compared with increasing the corticosteroid dose. The results of the PALLADIUM study support this advice. In this study, medium and high doses of mometasone plus indacaterol demonstrated superior improvements in forced expiratory volume in one second (FEV1) compared to higher doses of mometasone. In addition, high-dose mometasone plus indacaterol was shown to be non-inferior to high-dose fluticasone propionate plus salmeterol in improving FEV1.
Atectura® is available in three mometasone strengths, with each presentation containing 125mcg of indacaterol. Dysphonia and candidiasis were among the most frequent adverse events reported in clinical trials; patients should be advised to rinse their mouth with water after each dose.
The product information for metronidazole intravenous infusion (Pfizer) has recently been updated to include new contraindications. The contraindications now include disulfiram therapy in the previous two weeks, and consumption of alcohol or products containing propylene glycol.
Interactions with disulfiram and alcohol have long been associated with metronidazole, although the incidence is uncertain and the severity varied. Psychotic reactions and confusion have been reported when disulfiram is administered with metronidazole. Disulfiram-like reactions have been described when metronidazole is combined with alcohol or propylene glycol. These reactions may include tachycardia, flushing, or vomiting.
The updated product information recommends that alcohol and products containing propylene glycol be discontinued during metronidazole therapy and for at least three days after the last metronidazole dose. Avoiding these agents requires some care as alcohol and propylene glycol are excipients in many medications.
Medications containing ethanol and propylene glycol include:
- Diazepam for injection;
- Phenobarbital (phenobarbitone) injection;
- Phenytoin injection;
- Glyceryl trinitrate injection;
- Digoxin (Lanoxin® Paediatric Elixir, Lanoxin® Paediatric Injection, Lanoxin® Adult Injection); and
- Lopinavir + ritonavir (Kaletra®) oral solution.
Medicines that may contain ethanol include:
- Ranitidine oral liquid;
- Furosemide oral solution;
- Trimethoprim + sulfamethoxazole oral liquid; and
- Iron liquids (e.g. Maltofer® Syrup)
The approved product information should be reviewed to determine if a medicine contains ethanol or propylene glycol.
Ripretinib is a switch-control tyrosine kinase inhibitor recently approved by the Therapeutic Goods Administration (TGA). It is indicated for the treatment of advanced gastrointestinal stromal tumours (GIST) in adults who have previously been treated with imatinib and at least two other kinase inhibitors. This approval addresses a previously unmet clinical need as there are no other approved therapies for patients with advanced or unresectable GIST who experience disease progression following treatment with imatinib, sunitinib, and regorafenib.
Ripretinib inhibits KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) kinase activity. Most GISTs have activating mutations in these kinases that may cause dysregulated cell growth. Ripretinib can transform the kinase into an inactive conformation which prevents downstream signalling and cell proliferation. It is also active against a broad spectrum of KIT and PDGFRA mutations.
The efficacy of ripretinib is supported by the INVICTUS study. This randomised, double-blind trial investigated ripretinib as a fourth-line agent in patients with advanced GIST. The median progression-free survival was 6.3 months in the ripretinib group, compared to 1.0 months in the placebo group. The most common adverse effects associated with ripretinib were alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysaesthesia syndrome, and diarrhoea.
From 1 January 2021, apremilast is available on the Pharmaceutical Benefits Scheme (PBS). Apremilast is PBS listed for the treatment of severe chronic plaque psoriasis that has a significant effect on quality of life. Patients must be unable to take methotrexate or have achieved an inadequate response following at least six weeks of methotrexate therapy.
Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Inhibition of PDE4 increases cyclic adenosine monophosphate (cAMP), an important regulator of innate and adaptive immune functions. The result is reduced production of inflammatory cytokines such as interleukin (IL)-17, IL-23, and tumour necrosis factor-alpha (TNF-α), and an increase in anti-inflammatory mediators such as IL-10.
The safety and efficacy of apremilast were studied in the ESTEEM-2 trial. Significantly more patients in the apremilast group achieved ≥75% improvement in their Psoriasis Area and Severity Index (PASI) score compared to placebo (28.8% versus 5.8%). The mean change in PASI score was -50.9% for apremilast compared to -15.8% for placebo. The most commonly reported adverse events were diarrhoea and nausea. The apremilast dosing schedule includes an initial titration period which is intended to minimise gastrointestinal adverse effects.
Dapagliflozin has recently been approved for the treatment of symptomatic heart failure. Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor originally only indicated for the management of type 2 diabetes mellitus.
Initial safety trials of dapagliflozin suggested a reduced cardiovascular risk, which was further investigated in the DAPA-HF Trial. In this trial, patients with heart failure and an ejection fraction of ≤40% were randomly assigned to receive dapagliflozin 10mg daily or placebo, in addition to standard therapy. The primary outcome, a composite of worsening heart failure or cardiovascular death, occurred in 16.3% of the dapagliflozin group compared to 21.2% of the placebo group. There was no significant difference between the two groups in the incidence of adverse effects related to volume depletion, renal dysfunction, or hypoglycaemia. Interestingly, the cardiovascular benefits of dapagliflozin were observed regardless of diabetes status.
For the treatment of heart failure, dapagliflozin should be administered in conjunction with individualised standard of care therapy. Dapagliflozin is currently only subsidised on the Pharmaceutical Benefits Scheme (PBS) for the treatment of type 2 diabetes mellitus.
A new fixed-dose combination inhaler has been added to the Pharmaceutical Benefits Scheme (PBS). Fostair® contains the corticosteroid, beclometasone and the long-acting beta2 agonist, formoterol. It is PBS-subsidised for adults who have previously had frequent episodes of asthma while receiving treatment with oral corticosteroids or optimal doses of inhaled corticosteroids. Fostair® is also approved for the symptomatic treatment of severe chronic obstructive pulmonary disease (COPD), although this is not currently a PBS-subsidised indication.
Fostair® contains beclometasone and formoterol with an extra-fine particle size distribution. A study conducted in patients with moderate to severe asthma demonstrated that Fostair® is more effective at improving lung function than a double equipotent dosage of non-extra-fine beclometasone. In more severe asthma, studies demonstrated that Fostair® is as effective in improving lung function as the two individual components administered separately and superior to non-extra-fine beclometasone alone.
There are two approved treatment approaches for asthma: maintenance therapy and maintenance and reliever therapy. Patients taking Fostair® as maintenance therapy should have a separate rapid-acting bronchodilator to use when required for acute symptoms. For maintenance and reliever therapy, Fostair® is used both regularly for maintenance treatment and as needed in response to asthma symptoms. However, Fostair® is not PBS-subsidised for maintenance and reliever therapy.
