New Asthma Indication for Triple-Ingredient Inhaler May Increase Orosystemic Complications

Recently, the Food and Drug Administration (FDA) approved the supplemental New Drug Application for Trelegy Ellipta® for the maintenance treatment of asthma in patients aged 18 years and older. This new indication is in addition to Trelegy Ellipta®’s previous indication for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adults.

This new indication, and resulting increased market demand, for Trelegy Ellipta® is of importance to dentistry since its ingredients have dental implications and adverse effects which, due to the fixed combination in this one product, may be additive and synergistic.

Trelegy Ellipta® is a first-in-class triple ingredient oral inhaler. It combines fluticasone furoate, a corticosteroid with anti-inflammatory and immunosuppressive properties, umeclidinium, a long-acting muscarinic antagonist which causes bronchodilation and improves airflow, and vilanterol, a long-acting selective beta2-adrenergic agonist which relaxes bronchial smooth muscle and causes bronchodilation to help keep airways open.

The FDA’s approval was based on data from the double-blind, active-controlled CAPTAIN study that evaluated the efficacy and safety of Trelegy Ellipta® in 2436 adults with inadequately controlled asthma despite treatment with a combined inhaled corticosteroid/long acting beta2 agonist. Results of the study showed a statistically significant improvement in forced expiratory volume with Trelegy Ellipta® as compared with fluticasone furoate/vilanterol alone.

Corticosteroids, like fluticasone furoate, used by oral inhalation have immunosuppressive effects which increase the risk of localized oropharyngeal infections with Candida albicans or Aspergillus niger. These infections may require treatment with topical antifungal agents, such as nystatin or clotrimazole or systemic antifungal agents, such as fluconazole. Topical antifungal therapy is often difficult to maintain due to patient non-compliance and systemic antifungal therapy with fluconazole may result in significant drug interactions. In addition, treatment of oropharyngeal fungal infections may also include discontinuance of the corticosteroid inhaler, which may result in exacerbations of asthma or COPD. Prolonged use of corticosteroids may also prolong or exacerbate viral infections or limit response to vaccines.

Long acting muscarinic antagonists (LAMAs), like umeclidinium, especially in combination with long-acting beta2 adrenergic agonists (LABAs), like vilanterol, have been associated with an increased risk of cardiovascular disease (CVD) in patients with COPD. Two potential mechanisms for this increased risk have been proposed: LABAs and LAMAs are believed to cause overactivation of the sympathetic autonomic system (resulting in tachycardia and palpitations), and LABA and LAMA use in COPD patients has been shown to increase inflammatory cytokine levels which could lead to an increased risk of CVD. Also, LAMAs have frequently been implicated in hyposalivation and xerostomia, however, no reports of xerostomia have yet occurred with umeclidinium.

Interestingly, Trelegy Ellipta® is supplied as a dry powder for inhalation and, as with other inhaled medications, may result in paradoxical bronchospasm.  Also, patients should be advised to rinse their mouths with water without swallowing after each use and to keep short-acting beta-2 agonists available for the management of acute episodes or exacerbations.

FDA approves Trelegy Ellipta® as the first once-daily single inhaler triple therapy for the treatment of both asthma and COPD in the US. Accessed September 20, 2020.

Wang M, Liou J, Lin CW, et al. Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease: A Nested Case-Control Study. JAMA Intern Med. 2018;178(2):229–238. doi:10.1001/jamainternmed.2017.7720.

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