Incidence of adverse events associated with roflumilast use in patients with COPD: a population-based cohort study

Dr Chan, Esther Wai Yin   (Principal Investigator (PI))

Dr Lam Chi Leung David   (Co-Investigator)

Professor Wong Ian Chi Kei   (Co-Investigator)

Dr Suh In Hye   (Co-Investigator)

14

2019-06-01

2020-07-31

66570

Incidence of adverse events associated with roflumilast use in patients with COPD: a population-based cohort study

adverse events, COPD, medication safety, mental health, neuropsychiatric events, roflumilast

Epidemiology

201811159185

Seed Fund for PI Research – Basic Research

2018

Completed

In Hong Kong, COPD was ranked the sixth leading cause of mortality in 2015.(1) While inhaled bronchodilators and corticosteroids remain mainstays in the treatment of stable COPD, additional pharmacotherapy is often required to address exacerbations in severe COPD. Roflumilast is a potent and highly selective phosphodiesterase-4 (PDE4) inhibitor, which acts by reducing neutrophilic airway inflammation and exhibits an anti-inflammatory response.(2) After treatment with roflumilast demonstrated significant improvements in lung function and reductions of acute exacerbations of COPD in randomised controlled trials (RCTs), roflumilast was approved by the U.S. Food and Drug Administration (FDA) in 2011 as a treatment to reduce the risk of acute exacerbations in patients with severe COPD. (3-5) Compared with placebo, there was a 17% reduction in moderate to severe exacerbations, as well as improvements in lung function regardless of age and smoking status.(4) Specifically, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend roflumilast as the drug of choice for this indication.(6) Roflumilast was registered in Hong Kong in 2011 and has since been available in the Hospital Authority. Despite a good efficacy profile, the rate of roflumilast treatment discontinuation was noted to be significantly higher in RCTs when compared with placebo.(7) The risk of adverse events and serious adverse events was also observed to be high.(7) Although the overall mortality in patients with stable COPD was comparable (risk ratio [RR]=0.90; 95% confidence interval [CI]=0.63 to 1.29; p=0.56) for roflumilast versus placebo groups, the withdrawal rate was higher in the roflumilast group due to various adverse events (RR=1.62; 95%CI=1.44 to 1.82; p<0.00001).(8) Gastrointestinal adverse events, weight loss, headaches, anorexia, and insomnia were the major reasons for subject withdrawal from roflumilast treatment.(9) Notably, evidence of suicidal ideation and suicide attempts in those treated with roflumilast during clinical trials raised concerns and led to the FDA advising prescribers to be cautious with the use of roflumilast in patients with a history of depression.(4, 7) Dose-dependent neuropsychiatric events with roflumilast such as depression, anxiety, insomnia, nervousness, confusion, suicidal ideation, and suicide attempts were reported in the safety analysis by the FDA, which included data on adverse events reported in the RCTs.(10) The FDA analysis compared roflumilast 500mcg (n=5,677), roflumilast 250mcg (n=797), and placebo (n=5,491).(10) The risk of neuropsychiatric events was twice as high at the recommended therapeutic dose of roflumilast 500 mcg compared with placebo (insomnia: 3.0% in roflumilast group vs. 1.1% in placebo group; anxiety: 1.4% vs. 0.8%; depression: 1.4% vs. 0.8%; suicidal ideation/suicide attempts: 1.21% vs. 0.82%, respectively).(10) These adverse events were also more common in the higher dose roflumilast (500mcg) group (5.9%) compared to the lower dose (250mcg) group (3.3%).(10) There were five suicide-related cases (3 completed suicides and 2 suicide attempts) in the treatment groups but none in the placebo group.(10) None of the three completed suicides had a prior history of depression.(10) However, as two of the patients had discontinued roflumilast treatment a few days before the suicidal events, roflumilast was ruled out as a definitive cause.(10) There is limited evidence of the effectiveness and safety of roflumilast in real-life clinical practice, especially in Asian populations. Moreover, the results from the real-life studies are not consistent with the RCTs with respect to the rate of discontinuation and occurrence of adverse events.(9, 11-13) An observational study conducted in Spain found that the incidence of adverse events was much higher (66.9%) in practice.(12) Another study in Spain found that the addition of roflumilast to the triple therapy of long-acting muscarinic antagonists, long-acting beta-2 agonists, and inhaled corticosteroids in 55 patients with severe COPD also resulted in a higher percentage of treatment discontinuations (50.9%) after 1 year of therapy, despite improvements in the clinical status of the patients.(13) Addressing these limitations, an observational study in real-life clinical practice will fill the knowledge gaps surrounding the incidence of adverse events associated with roflumilast use, specifically in the Hong Kong population. Our goal is to assess the association between the use of roflumilast in patients with COPD and associated incidence of adverse events and discontinuations in Hong Kong. Specifically, the objectives of this project are as follows: 1. To determine the characteristics and incidence of known adverse events in roflumilast users compared to non-roflumilast users. 2. To identify patient-related risk factors among roflumilast users that may be related to the development of adverse events, especially neuropsychiatric events 3. To characterise the duration of therapy, median duration of therapy and patterns of discontinuation with roflumilast use and possible association with adverse events.