Knowledge Type: Drugline

A new presentation of paliperidone is now available on the Pharmaceutical Benefits Scheme (PBS). Invega Hafyera^® is a six-monthly injection indicated for the maintenance treatment of adults with schizophrenia. Patients may be eligible for PBS supply once stabilised on the monthly paliperidone injection (Invega Sustenna®) for at least four consecutive months, or the three-monthly injection (Invega Trinza®) for at least one cycle.

A recent study compared the safety and efficacy of six-monthly and three-monthly paliperidone. The efficacy of the six-month formulation was found to be non-inferior to the three-month formulation in clinically stable patients with schizophrenia. In addition, no new safety concerns were identified for the six-monthly formulation.

Long-acting antipsychotic injections are associated with improved adherence and more stable plasma levels. The reduced dosing frequency may also be more convenient for patients. Invega Hafyera® currently offers the longest dosing interval, which may particularly benefit patients with serious adherence issues and those living in isolated areas. Long-acting antipsychotics available on the PBS are shown in the table below.

Product	Active ingredient	Strengths	Usual dosing interval
Abilify Maintena®	Aripiprazole monohydrate	300mg 400mg	Monthly
Fluanxol® Depot	Flupentixol decanoate	20mg	Every 2-4 weeks
Fluanxol® Concentrated Depot	Flupentixol decanoate	100mg	Every 2-4 weeks
Haldol® Decanoate	Haloperidol decanoate	50mg 150mg	Monthly
Zyprexa Relprevv®	Olanzapine pamoate monohydrate	210mg 300mg 405mg	Every 2-4 weeks
Invega Sustenna®	paliperidone palmitate	25mg 50mg 75mg 100mg 150mg	Monthly
Invega Trinza®	paliperidone palmitate	175mg 263mg 350mg 525mg	Every 3 months
Invega Hafyera®	paliperidone palmitate	700mg 1000mg	Every 6 months
Risperdal Consta®	Risperidone	25mg 37.5mg 50mg	Every 2 weeks
Clopixol® Depot	zuclopenthixol decanoate	200mg	Every 2-4 weeks

Anifrolumab has recently been approved by the Therapeutic Goods Administration (TGA). It is indicated as an add-on to standard therapy for adult patients with moderate to severe active systemic lupus erythematosus (SLE). This chronic autoimmune disease produces inflammation, tissue damage, and pain. While SLE is complex and associated with many immunologic abnormalities, upregulation of type I interferon is thought to be a major pathogenic factor.

Anifrolumab is a monoclonal antibody that binds with high affinity and specificity to the type I interferon receptor (IFNAR1). Binding of anifrolumab to this receptor inhibits type I interferon signalling, thereby blocking its biological activity.

In the TULIP-2 trial, BICLA (British Isles Lupus Assessment Group–based Composite Lupus Assessment) response was used to measure improvement in disease activity. In the anifrolumab group, 47.8% had a BICLA response compared to 31.5% in the placebo group. Anifrolumab therapy was also associated with a reduction in glucocorticoid dose and greater improvement in the severity of skin disease compared to placebo.

Anifrolumab is administered as an intravenous infusion, typically every four weeks. Infusion-related reactions may occur involving headache, nausea, vomiting, fatigue, or dizziness. These reactions are typically mild or moderate in intensity. Anifrolumab also increases the risk of respiratory infections and herpes zoster. Therefore, caution is required in patients with chronic infection, a history of recurrent infection, or known risk factors for infection.

Anifrolumab is not currently subsidised on the Pharmaceutical Benefits Scheme (PBS). However, a submission is under consideration by the Pharmaceutical Benefits Advisory Committee.

The indications for lenvatinib have been extended. It is now indicated, in combination with pembrolizumab, for the first-line treatment of adults with advanced renal cell carcinoma.

A phase 3 trial investigated the efficacy of this therapy in patients with advanced renal cell carcinoma and no previous systemic therapy. Patients were randomly assigned to receive lenvatinib (20mg daily) plus pembrolizumab (200mg every three weeks), lenvatinib (18mg daily) plus everolimus (5mg daily), or sunitinib (50mg daily, alternating four weeks on and two weeks off treatment). Median progression-free survival was longer in the lenvatinib groups (23.9 months when combined with pembrolizumab and 14.7 months with everolimus) compared to the sunitinib group (9.2 months). Overall survival was also longer for lenvatinib plus pembrolizumab, but was not longer for lenvatinib plus everolimus compared to sunitinib.

Adverse events most commonly reported in the lenvatinib plus pembrolizumab group include diarrhoea (61.4%), hypertension (55.4%), hypothyroidism (47.2%), and reduced appetite (40.3%). Grade 3 or higher adverse events occurred in 82.4% of patients, with hypertension and diarrhoea most common. The product information provides recommendations for the management of adverse reactions, including dose modification and treatment discontinuation.

Lenvatinib is not currently subsidised on the Pharmaceutical Benefits Scheme (PBS) for the treatment of renal cell carcinoma.

The Australian Commission on Safety and Quality in Health Care has launched Australia’s first standard of care for sepsis. Sepsis is a life-threatening condition that requires rapid treatment to reduce the risk of death and ongoing morbidity. The Sepsis Clinical Care Standard aims to ensure that patients presenting with signs and symptoms of sepsis are recognised early and receive best-practice care.

The standard consists of seven quality statements:

1. Could it be sepsis?
2. Time-critical management
3. Management of antimicrobial therapy
4. Multidisciplinary coordination of care in hospital
5. Patient and carer education and information
6. Transitions of care and clinical communication
7. Care after hospital and survivorship

The first three statements focus on early recognition and rapid treatment. When signs of infection-related organ dysfunction are present, patients should receive appropriate antimicrobial therapy within 60 minutes. This therapy should be managed in accordance with the Antimicrobial Stewardship Clinical Care Standard. The next three statements concern the patient journey through the hospital. These points aim to ensure that hospitals are providing coordinated, patient-centred care. Lastly, there is a focus on care following discharge. Coordinated care after leaving hospital can improve patient outcomes and reduce rehospitalisation.

The Sepsis Clinical Care Standard is just one part of the National Sepsis Program. Further details on this program, as well as supplementary resources, can be found on the Commission’s website.

A new contraindication has been added to the product information of Klacid® (clarithromycin). This product is now contraindicated in patients with hypomagnesaemia.

Clarithromycin is a macrolide antibiotic indicated for the treatment and prevention of various infections caused by susceptible microbes. Like other macrolides, clarithromycin can prolong the QT interval and lead to cardiac arrhythmia and torsades de pointes. This risk is increased in the presence of electrolyte disturbances such as hypomagnesaemia.

Hypomagnesaemia is common in patients who are hospitalised, particularly those who are critically ill. Potential causes of hypomagnesaemia are poor oral intake, gastrointestinal or renal losses, and medications. Medications associated with reduced magnesium levels include diuretics, aminoglycoside antibiotics (e.g. amikacin, gentamicin, tobramycin), cisplatin, amphotericin B, ciclosporin, foscarnet, pentamidine, and proton pump inhibitors (e.g. omeprazole, rabeprazole).

Other risk factors for ventricular arrhythmias that should be considered before administering clarithromycin include:

• Hypokalaemia;
• Pre-existing cardiovascular conditions (e.g. coronary artery disease, severe cardiac insufficiency, conduction disturbances, clinically relevant bradycardia);
• Congenital or documented acquired QT prolongation;
• History of ventricular arrhythmia; and
• Other medications associated with QT prolongation.

The Therapeutic Goods Administration (TGA) has released a safety advisory regarding clozapine and the potential for severe gastrointestinal side effects. Additional warnings have been added to the product information (PI) and consumer medicine information (CMI) that expand on previous advice concerning this issue.

Clozapine is an antipsychotic indicated for the management of treatment-resistant schizophrenia. It is considered a potent anticholinergic agent, which is thought to be largely responsible for its gastrointestinal adverse effects.

Clozapine-induced gastrointestinal hypomotility can lead to severe complications such as intestinal obstruction, faecal impaction, megacolon, paralytic ileus, and intestinal ischaemia or infarction. The degree of gastrointestinal hypomotility does not always correspond with subjective symptoms of constipation. Therefore, patients should be advised to seek immediate medical advice if they develop constipation or any other signs of reduced gastrointestinal motility. This includes reduced frequency of bowel movements; difficulty passing stool; nausea or vomiting; stomach pains or spasms; or abdominal bloating, tenderness or swelling.

To minimise patient risk, the TGA recommends healthcare professionals:

• Carefully monitor clozapine patients for gastrointestinal effects;
• Promptly manage patients who present with evidence of constipation or gastrointestinal hypomotility;
• Use clozapine with caution in patients with constipation or a history of constipation; and
• Avoid concomitant use of clozapine with other anticholinergic medications.

From 1 May 2022, sacituzumab govitecan is available on the Pharmaceutical Benefits Scheme (PBS) for unresectable locally advanced or metastatic triple-negative breast cancer. The PBS listing requires patients to have progressive disease following at least two prior systemic therapies, with at least one of them in the locally advanced or metastatic setting.

Sacituzumab govitecan is an antibody-drug conjugate (ADC). The antibody binds to Trop-2 (trophoblast cell-surface antigen-2) which is highly expressed in many cancers, including breast cancer. A hydrolysable linker joins this antibody to the cytotoxic drug, SN-38. The SN-38 molecule is a topoisomerase I inhibitor and the active metabolite of irinotecan. Following intravenous administration, the ADC binds to Trop-2 on the tumour cell surface which allows for targeted delivery of SN-38. The cytotoxic effect of SN-38 is achieved through DNA damage which leads to apoptosis and cell death.

The ASCENT trial compared sacituzumab govitecan with single-agent chemotherapy (physician’s choice of eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary endpoint of median progression-free survival was 5.6 months with sacituzumab govitecan and 1.7 months with chemotherapy. The median overall survival was also greater (12.1 months versus 6.7 months), as was the objective response rate (35% versus 5%). The most common adverse events in the sacituzumab govitecan group were neutropenia (63%), diarrhoea (59%), and nausea (57%). Treatment discontinuation due to adverse events occurred in 5% of patients in each group.

Pre-medication is recommended prior to each dose to prevent infusion reactions and chemotherapy-induced nausea and vomiting.

The Pharmaceutical Benefits Scheme (PBS) listing has recently been expanded for nintedanib. Nintedanib was previously subsidised for the treatment of idiopathic pulmonary fibrosis; it is now covered for other types of progressive fibrosing interstitial lung disease (PFILD). PFILD is an umbrella term for a diverse range of interstitial lung diseases characterised by accelerated respiratory failure, frequent exacerbations, and early mortality.

Nintedanib is a tyrosine kinase inhibitor that can slow disease progression in PFILD. It blocks vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and β) and fibroblast growth factor receptors (FGFR 1-3). This produces antifibrotic and anti-inflammatory effects that lead to inhibition of key processes involved in pulmonary fibrosis.

The INBUILD trial investigated the safety and efficacy of nintedanib in PFILD. The annual rate of decline in forced vital capacity (a measure of disease progression) was significantly lower in the nintedanib group compared to placebo (-80.8mL vs -187.8mL). However, changes in health-related quality of life (measured by the K-BILD questionnaire) were low over the 52-week study period. Some of the more commonly reported adverse effects included diarrhoea (66.9%), nausea (28.9%), vomiting (18.4%), and reduced appetite (14.5%).

Nintedanib is a substrate of P-glycoprotein. Co-administration with potent inhibitors of P-glycoprotein (e.g. ketoconazole, erythromycin) may increase nintedanib exposure, while potent inducers (e.g. rifampicin, carbamazepine, phenytoin, St. John’s Wort) may reduce exposure. Nintedanib capsules should be swallowed whole, preferably with food.

From 1 May 2022, Paxlovid™ will be available on the Pharmaceutical Benefits Scheme (PBS). This will be the second oral agent PBS-listed for the treatment of COVID-19. Paxlovid™ is provisionally approved for the treatment of COVID-19 in adults who do not require initiation of supplemental oxygen but are at increased risk of progression to hospitalisation or death.

Paxlovid™ contains nirmatrelvir co-packaged with ritonavir. Nirmatrlevir inhibits the main protease of the SARS-CoV-2 virus, an enzyme with a key role in viral replication. To increase plasma levels of this antiviral, it is taken with ritonavir, a strong inhibitor of cytochrome P450 3A4. The recommended dose is two nirmatrelvir tablets and one ritonavir tablet taken together every 12 hours for five days. Therapy should be initiated as soon as possible after a diagnosis of COVID-19 and within five days of symptom onset.

The efficacy of nirmatrelvir and ritonavir was investigated in the EPIC-HR Study. An interim analysis of patients treated within three days of symptom onset showed a reduction in the incidence of COVID-19-related hospitalisation compared to placebo. At day 28, the incidence of hospitalisation was 0.77% in the nirmatrelvir and ritonavir group and 7.01% in the placebo group. There were no deaths in the treatment group and seven in the placebo group.

Paxlovid™ has many clinically significant drug interactions due to its effect on cytochrome P450. It is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated levels are associated with serious reactions. It is also contraindicated with potent CYP3A inducers where significantly reduced levels of nirmatrelvir or ritonavir may lead to loss of efficacy and resistance. A summary of contraindicated medicines is shown in Table 1. Refer to the product information for complete details.

Table 1. Medications contraindicated with Paxlovid™

Medicine Class	Contraindicated Medicines
α1-antagonists	Alfuzosin
Antianginal	Ranolazine
Antiarrhythmics	Amiodarone, flecainide
Anticancer	Apalutamide, neratinib, venetoclax
Anti-gout	Colchicine
Antipsychotic	Lurasidone, clozapine
Ergot derivatives	Ergometrine
HMG-CoA reductase inhibitors	Simvastatin
NSAIDs	Piroxicam
Opioids	Pethidine
PDE5 inhibitors	Avanafil, sildenafil, vardenafil, tadalafil
Benzodiazepines	Diazepam
Anticonvulsants	Carbamazepine, phenobarbital, phenytoin
Antimicrobials	Rifampicin
Complementary medicines	St. John’s Wort

The COVID-19 Clinical Evidence Taskforce publishes recommendations on a range of COVID-19 therapies. The relative effectiveness of these therapies is currently unclear. 

The triple-therapy inhaler, Trelegy®, is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of severe asthma.

Trelegy® contains a corticosteroid (fluticasone furoate), a long-acting muscarinic antagonist (umeclidinium), and a long-acting beta₂ agonist (vilanterol). There are two strengths of Trelegy® available. The higher strength inhaler (200mcg/62.5mcg/25mcg) is only PBS listed for asthma, while the lower strength product (100mcg/62.5mcg/25mcg) is only PBS listed for the treatment of chronic obstructive pulmonary disease (COPD).

The CAPTAIN trial assessed the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/V) compared with FF/V in patients with inadequately controlled asthma. This study demonstrated improved lung function, symptoms and asthma control on FF/UMEC/V compared to FF/V. This adds to the growing evidence showing the clinical benefits of adding a long-acting muscarinic antagonist for patients who are not well-controlled on medium to high doses of an inhaled corticosteroid with a long-acting beta₂ agonist.