August 2020 Volume 43 Number 4 AN INDEPENDENT REVIEW nps.org.au/australian-prescriber CONTENTS EDITORIALS Immunosuppression for 106 COVID-19: repurposing medicines in a pandemic S Shivakumar, OC Smibert, JA Trubiano, AG Frauman, DFL Liew What is hypertension? 108 G Gabb ARTICLES Deprescribing in older people 114 M Liacos, AT Page, C Etherton-Beer Management of proteinuria: 121 blockade of the renin– angiotensin–aldosterone system A Athavale, DM Roberts Chronic leukaemias in 126 the community E Wenlong Li, D Yeung, S Fuller LETTERS TO THE EDITOR 110 NEW DRUGS 131 Brigatinib for non-small cell lung cancer Brolucizumab for macular degeneration Galcanezumab for migraine Semaglutide for type 2 diabetes VOLUME 43 : NUMBER 4 : AUGUST 2020 EDITORIAL Immunosuppression for COVID-19: repurposing medicines in a pandemic Senthuran Shivakumar It might seem paradoxical to suggest Interleukin-6 and interleukin-1 driven pathways have a Clinical pharmacology immunosuppression could play a role in managing central role in cytokine release syndrome associated registrar, Department of COVID-19. The seemingly logical therapeutic option with COVID-19 and in other previously recognised Clinical Pharmacology and Therapeutics1 for this disease would be an antiviral. Unfortunately, cytokine release syndromes. Therapies targeting Olivia C Smibert repurposing antiviral therapies has proven these pathways include tocilizumab (an interleukin-6 Infectious diseases physician, disappointing so far, and evidence to support their receptor antagonist) and anakinra (an interleukin-1 COVID Unit, Department of routine use in COVID-19 is currently lacking.1-4 receptor antagonist). These are both registered by the Infectious Diseases1 While the current standard of care for most people Therapeutic Goods Administration (TGA) for cytokine Doctoral candidate, release syndrome-like autoimmune conditions such Sir Peter MacCallum with COVID-19 is supportive, a subset of patients Department of Oncology2 become severely unwell with a potentially life- as systemic juvenile idiopathic arthritis. Anakinra has Doctoral candidate3 threatening hyperinflammatory state called cytokine previously been used in the treatment of macrophage Jason A Trubiano release syndrome.5 This clinical state is difficult to activation syndrome, a cytokine release syndrome Infectious diseases predict in advance. When it occurs it is characterised associated with autoimmune conditions.11 Tocilizumab physician, Head of COVID by rapidly worsening multiorgan dysfunction is registered for the management of cytokine release Unit, Department of including respiratory failure and a clinically distinctive syndrome secondary to CAR T-cell therapy. The Infectious Diseases1 possibility of adopting these immunosuppressive Clinical associate professor, coagulopathy involving immunothrombosis of the Department of Medicine2 pulmonary vasculature.6 Antigens presented by therapies in COVID-19 is supported by early evidence 12 Postdoctoral fellow3 infected cells activate both the innate and adaptive from observational studies. However, these Albert G Frauman immune systems. The uncontrolled upregulation of drugs need the same caution as any off-label and Professor and Head, immune cells leads to a surge of proinflammatory experimental prescribing in COVID-19 until they are Department of Clinical cytokines including interleukin-6 and interleukin-1. validated in clinical trials.13-15 Pharmacology and This in turn increases vascular permeability and Therapeutics1 Not all immunosuppressive drugs hold the same inflammatory cell recruitment into lung parenchyma Professor of Clinical promise. While systemic corticosteroids are Pharmacology and causing acute lung injury and subsequent respiratory effective immunosuppressants, previous and Therapeutics2 failure. As a myriad of proinflammatory molecules current outbreaks suggest that their broader David FL Liew and inflammatory markers are involved in both physiological effects lead to uncertain benefit and Rheumatologist and Clinical the typical immune response to infection and this potential harm.16-18 Accordingly, they are avoided pharmacologist, Department hyperinflammatory and hypercoagulable state, the of Rheumatology, and in routine care unless for a recognised indication. Department of Clinical key drivers of inflammation and mortality in severe Colchicine has also generated interest due to its Pharmacology and COVID-19 are contentious. As such, the benefit of effect on the inflammasome-mediated interleukin-1 1 Therapeutics treating this hyperinflammatory state has not yet beta pathway which is part of the innate immune Doctoral candidate, been completely established in COVID-19. response. However, its use in COVID-19 remains Department of Medicine2 In patients with severe COVID-19, there is significant unproven.19 Baricitinib, a Janus kinase inhibitor used 1 Austin Health mortality in the second week of disease,7,8 despite for rheumatoid arthritis, was identified through a 2 University of Melbourne many studies describing a progressive fall in viral machine-learning exercise as potentially reducing 3 National Centre for count.9,10 This may partially explain the lack of success viral entry into cells in COVID-19, but currently has no Infections in Cancer, Peter 20 MacCallum Cancer Centre with antivirals. In this situation, immune-driven established use in cytokine release syndrome. Melbourne damage, such as cytokine release syndrome, may be Some important distinctions exist between the what is driving mortality. Therefore early recognition rational repurposing of immunosuppression in Keywords and prompt initiation of immunosuppression may COVID-19 and other widely discussed experimental COVID-19, benefit these patients. therapies.21 Tocilizumab is already part of the immunosuppression, evidence-based management of CAR T-cell- interleukin-1, interleukin-6, Cytokine release syndrome is a known phenomenon, pandemic, tocilizumab and pathophysiologically similar syndromes exist induced cytokine release syndrome,6,22 a condition in autoimmune diseases such as systemic juvenile that shares pathological similarities. In contrast, First published 17 June 2020 idiopathic arthritis and adult onset Still’s disease. It proposed antiviral strategies that include chloroquine, Aust Prescr 2020;43:106–7 is also encountered as a complication of chimeric hydroxychloroquine, and ivermectin are reliant on https://doi.org/10.18773/ antigen receptor T-cell (CAR T-cell) therapy used for novel mechanisms of action and low-quality evidence, austprescr.2020.037 haematological malignancies. while raising significant safety concerns.23,24 106 Full text free online at nps.org.au/australian-prescriber © 2020 NPS MedicineWise VOLUME 43 : NUMBER 4 : AUGUST 2020 EDITORIAL COVID-19 poses a multifaceted threat requiring drug and therapeutic committees.21 Decision making a multimodal and stratified treatment approach, should also include patients and their families.25 As possibly transitioning from virus-targeted approaches it is not yet standard of care, reporting safety and in the early state of disease to immunomodulation in efficacy outcomes as part of clinical trials is highly late-onset immune-mediated disease. The example of desirable. With such measures, repurposed medicines interleukin-6 and interleukin-1 inhibition demonstrates can be appropriately recruited into the pandemic fight that a cohesive and considered approach towards off- without defying sensible prescribing.21,25 label prescribing in COVID-19 is needed. This should be used in consultation with relevant subspecialties and Conflict of interest: none declared REFERENCES 1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review 14. Coombes I, Markwell A, Kubler P, Redmond AM, McGurk G, of treatment effects. PLoS Med 2006;3:e343. https://doi.org/ Roberts JA. Principles of ethical prescribing for self and 10.1371/journal.pmed.0030343 others: hydoxychloroquine in the COVID-19 pandemic. 2. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. 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