Treatment safety and tolerability were consistent with findings reported in pivotal trials, with non-severe diarrhea continuing to be the most common side effect noted, its researchers wrote.
Their study, “Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Global Pharmacovigilance Data,” was published in the journal Advances in Therapy.
Clinical trial data that supported the U.S. approval of Ofev in 2014 — particularly from the INPULSIS trials (NCT01335464 and NCT01335477) — showed the therapy lowered by nearly half the rate of lung function decline, as measured by forced vital capacity (FVC), over 52 weeks compared with a placebo. An open-label extension study, called INPULSIS-ON (NCT01619085), showed continued safety up to 68.3 months (more than 5.5 years).
Side effects in these trials were mostly gastrointestinal and reported as manageable, with diarrhea being one of the more common.
Clinical trials, however, tend to exclude patients with severe disease and those who have certain comorbidities, or other simultaneous disorders.
Boehringer Ingelheim, Ofev’s maker, maintains a global pharmacovigilance program to track reports of adverse events related to their products. Company scientists, together with other researchers, used this database — based on product sales — to characterize Ofev’s safety and tolerability over four years of real-life clinical use.
Between Oct. 15, 2014, and Oct. 15, 2018, the team found 60,107 patient-years worth of Ofev use. Patient-years is a parameter thats sums up the total follow-up years of all included patients in a specific study; for example, if 100 patients are followed for two years, there are 200 patient-years of follow-up.
Diarrhea was the most frequently observed event — 301.6 events per 1,000 patient-years — with 97% of these cases reported to be non-serious. About 34% of these people reported more than one episode of diarrhea, and the median time to onset of a first episode was 60 days after starting treatment.
Other adverse events of interest included elevated levels of liver enzymes and bilirubin, a bile pigment whose levels reflect liver health. These events both occurred at a rate of 31.5 per 1000 patient-years, which the team noted was lower than that reported in the INPULSIS trials (162 events).
Similar to diarrhea, the median time to onset of elevated liver enzyme or bilirubin levels was 60 days.
Because changes to the liver can be treatment related, “it is recommended that liver function tests … be conducted prior to the initiation of treatment, at regular intervals during the first 3 months of treatment, and periodically thereafter,” the study noted.
Bleeding was also reported, at a rate of 36.8 events per 1000 patient-years, which was also lower than the 118 events reported in the Ofev trials. About 81% of these bleeding events were considered non-serious. The median time to bleeding onset was 68 days.
Bleeding was most frequently reported in respiratory (31.7% of events) and lower gastrointestinal (24.2%) tracts, and most often in the form of nosebleeds (25%), bruising (14.4%), blood in the stool (11.6%), and rectal bleeding (7.2%).
Approximately 28% of these patients were taking bleeding-related medications, and serious bleeding events were more common among this group.
Major cardiac events, which are frequent comorbidities in IPF, occurred at a rate of 13.4 events per 1000 patient-years, compared to the rate of 39 events reported in the INPULSIS trials.
The median age at a major cardiac event was 75, and nearly 70% of patients reporting such events were male.
High blood pressure, drug hypersensitivity, and coronary artery disease most often accompanied a major cardiac event.
Heart attacks were reported at a rate of 4.3 events per 1000 patient-years, as compared to 17 events in the INPULSIS trials.
Ruptured bowels, a condition known as gastrointestinal perforation, occurred at a rate of one event per 1000 patient-years. The median age of onset for this event was 75, and 61% of those who experienced it were male.
Overall, no new safety concerns were observed in this study, with the most frequently reported event remaining diarrhea.
“On the basis of pharmacovigilance data collected over 4 years, the safety profile of nintedanib [Ofev] in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed,” the team concluded.
But, these researchers added, “observational studies conducted in clinical practice suggest that patients with more advanced disease are more likely to discontinue nintedanib because of adverse events … Proactive counselling … and appropriate management through dose adjustment and symptom relief are crucial to optimize adherence” and therapy benefits.
“Importantly,” they continued, “the dose adjustments used to manage adverse events … have been shown not to reduce the efficacy of nintedanib in reducing FVC decline.”
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