Assessing Adverse Drug Reactions Reported for New Respiratory Medications in the FDA Adverse Event Reporting System Database

Discussion

In this retrospective pharmacovigilance study, 25 recently approved CLRD medications were reviewed using FAERS data. Of these medications, 4 were chosen for analysis: UMEC, UMEC/VI, roflumilast, and FF/VI. To our knowledge, this is the first comprehensive evaluation of post-marketing surveillance of new CLRD products. Our results suggest that COPD medications (ie, UMEC, UMEC/VI, and roflumilast) have a post-marketing safety profile similar to that reported in their clinical studies, whereas FF/VI seemed to have novel ADRs not fully captured in its product labeling. There were some gender and age differences with adverse event reports found in our data. These patient safety findings are important for respiratory therapists, as patient care team members, to understand and contribute to possible ADR detection on hospital admission or during in-patient care, thus leading to early management when possible.

Of the total reporters in our data, 70% were consumers. The large percentage of consumer reporters likely stems from the nature of respiratory disease medication administration, as most are self-administered at home without direct oversight from a health care professional. The FAERS database is therefore a valuable resource for obtaining patient-centered reports for CLRD treatments.

Both UMEC inhaler powder and UMEC/VI inhaler powder received approval in 2013 for patients with COPD. Because both medications include UMEC in their ingredients, their safety profiles are prone to be very similar. A 52-week, double-blind, placebo-controlled, parallel-group safety trial of 563 subjects was conducted to compare safety and tolerability of UMEC and UMEC/VI. Various types of infection were observed to be the most common ADRs in both groups, followed by headache, back pain, and hypertension.¹⁶ This similarity is also present in our data (see the supplemental materials http://www.rcjournal.com). Excluding medication administration errors, the most reported ADRs for both UMEC and UMEC/VI were dyspnea, cough, pain, and asthenic condition. Because many of these are patient-reported ADRs, it is possible that reports of infections are unlikely while the symptoms of various infections are provided. It is interesting, however, to see that UMEC had a higher reporting odds ratio of pain than UMEC/VI in our findings (Table 2). This is contrary to the EMAX trial (Early Maximization of bronchodilation for improving COPD stability) that was conducted for 24 weeks to compare the efficacy and safety of UMEC and UMEC/VI.¹⁷ In the published trial, about 2% and 1% of subjects in UMEC/VI group reported pain in extremity and the neck, respectively. However, < 1% of the reports in UMEC group were for pain.¹⁷ It is difficult to conclude that the clinical study yielded false safety outcomes because there is an innate bias in the FAERS data that comes with the nature of voluntary reporting. However, the higher risk of patients on UMEC feeling pain in this real-world data may raise an important awareness for clinicians when they make patient-specific decisions on determining the ideal COPD treatment. Further post-marketing surveillance should be continued to strengthen and establish actual pain rates in both medications.

Roflumilast is an oral tablet indicated for a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and history of exacerbations.¹⁸ A post hoc, pooled analysis of 2 pre-marketing clinical studies of roflumilast revealed that the most common ADRs reported in the roflumilast group were diarrhea (12.1%), nausea (6%), and weight loss (7.5%).¹⁹ The roflumilast package insert also suggests that diarrhea and nausea were the 2 most common ADRs that led to discontinuation in all clinical trials conducted during drug development.¹⁹ A retrospective real-world study was conducted for 3 y post-marketing in subjects using roflumilast. Although limited with a small sample size of 83, the findings indicate that weight loss (10.8%) was the most common ADR, followed by loss of appetite (10.8%) and nausea (8.4%).²⁰ These findings in pre-marketing and post-marketing studies align with our post-marketing findings using FAERS data. The supplemental materials indicate that diarrhea (7.1%), nausea and vomiting symptoms (5.5%), pain (5.0%), and weight loss (4.7%) were the 4 most reported ADRs for roflumilast. Because our findings with patient-reported data from FAERS resemble the safety profile of roflumilast extracted from various clinical studies, it is important to closely monitor and consider patients’ tolerance of roflumilast.

FF/VI inhalation powder was approved by the FDA in 2013 for maintenance treatment of COPD or asthma in patients > 18 y old.¹³ FF/VI is a combination product of a corticosteroid (FF) and a long-acting β₂-adrenergic agonist (VI), just like the preexisting medications BUD/FORM and FP/SAL. BUD/FORM and FP/SAL were approved by the FDA in 2006 and 2000, respectively, therefore many clinicians are familiar with patient responses to these medications. Their safety profile is also being updated actively post-marketing. For example, in 2017, the FDA removed the boxed warning for serious asthma-related outcomes from the BUD/FORM drug label after sufficient evidence was evaluated post-marketing.²¹ On the contrary, FF/VI has not established a strong safety profile post-marketing because it is relatively new in the market. The primary aim for comparing FAERS data between FF/VI and the 2 preexisting medications is to raise awareness to possible adverse events that require monitoring.

The supplemental materials show that BUD/FORM had > 6 times the total number of ADRs reported than FF/VI (47,947 vs 7,154, respectively) but had far lower reporting odds ratios for 4 ADRs listed in Table 3: cough, dysphonia, pain, and dizziness. Interestingly, dizziness is listed in the drug product label for BUD/FORM under post-marketing experience as an ADR, but it is not mentioned as an ADR in the drug product label of FF/VI.¹² Similarly, Table 4 shows that FP/SAL also yielded far lower reporting odds ratios for dyspnea, cough, pain, and dizziness than FF/VI. Dyspnea and dizziness are listed under post-marketing experience of FP/SAL; however, these adverse events are not addressed in the drug product label of FF/VI.¹³ These competitor findings suggest that patients taking FF/VI experience certain adverse events not commonly observed in its pre-approval clinical trials as they were not mentioned as potential adverse events in its drug label.

The primary goal of treatment for both asthma and COPD is to improve the patient’s quality of life because there is no definitive cure for either disease. To accomplish this, it is important to personalize medication regimens to maximize patient symptom relief while minimizing adverse events. Therefore, it is crucial to continually update medication safety profile as more data are available to be able to make an ideal treatment decision.