Only a transient decline in prescriptions for transmucosal immediate-release fentanyl (TIRF) medicines occurred after the FDA ordered a restricted distribution program, an analysis of Medicare Part D beneficiaries found.
But the Risk Evaluation and Mitigation Strategy (REMS) program was associated with a lasting decline in TIRF prescriptions for patients not previously tolerant of opioids, according to William Fleischman, MD, MHS, of Hackensack Meridian Health in New Jersey, and colleagues, writing online in .
"The TIRF REMS program, as well as other opioid REMS programs, is intended to improve opioid prescribing, but we don't know whether they are effective," Fleischman told 鶹ý. "Studying the impact of these programs is critical to help us understand what works and what doesn't."
"There has not been a detailed, granular analysis of what happened to opioid prescribing following TIRF REMS implementation," he added.
Transmucosal immediate-release fentanyl drugs are potent rapid-acting opioids approved to manage . The drugs are limited to opioid-tolerant patients due to fentanyl's ability to cause life-threatening respiratory depression in patients who are not already taking opioids.
In March 2012, the FDA implemented a REMS to oversee TIRF drugs. In August 2018, FDA advisors questioned the REMS program, raising concerns about whether the drugs were being prescribed to patients for whom they were not intended -- including people who were not opioid-tolerant -- and whether cancer patients who needed the drugs could get them.
In this analysis, researchers looked at TIRF prescriptions to Medicare Part D beneficiaries nationwide from 2010 to 2014 using an interrupted time series analysis. Over that period, there were 99,601 TIRF prescriptions written by 8,619 clinicians to 10,472 patients.
Most patients (67%) did not have a diagnosis of cancer. Before the REMS program was implemented, TIRF prescribing decreased by 1.0% per month. Implementing the REMS was associated with a 26.7% level decline in TIRF prescribing, which was followed by 2.0% monthly increases. This trend change was driven by prescribing increases that began approximately a year after the REMS was in effect.
By the end of the study period in 2015, total TIRF prescription rates were about 25% higher than when the REMS was implemented.
"Notably, the increase in prescribing coincided with a marked increase in filled prescriptions for Subsys, a fentanyl sublingual spray that became the most commonly prescribed TIRF during this period," Fleischman and co-authors wrote. "There have been reports that the Subsys manufacturer used aggressive, possibly illegal, strategies to increase drug sales and made efforts to guide prescribers and patients through the REMS program requirements" -- a reference to , former executives of which are related to Subsys.
"These efforts may have attenuated the prescribing decrease associated with TIRF-REMS implementation," Fleischmann and colleagues suggested.
There were no significant changes associated with REMS implementation in the level or trend of the percentage of prescriptions for patients without cancer, but a sensitivity analysis using a broader cancer definition found implementation was associated with a 7.2% level decrease in the percentage of TIRF prescriptions for non-cancer patients. The REMS implementation also was associated with a 22.5% relative level decline in prescribing to patients not previously tolerant of opioids, followed by 1.98% monthly decreases.
"While the REMS was associated with modest reductions in TIRF use among those without opioid tolerance, such use should never occur, given the risks involved and the presence of so many safer and similarly effective alternatives," said G. Caleb Alexander, MD, MS, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, who was not involved in the study.
"TIRFs are not your typical product, and unfortunately, there is abundant evidence that the restricted distribution system that the FDA and manufacturers used to ensure their safe use failed to do so," Alexander told 鶹ý. "While the REMS may have decreased some types of inappropriate TIRF use among Medicare patients, other analyses, including some commissioned by opioid makers at the request of the FDA, have showed unacceptably high rates of off-label use of TIRFs."
These findings are specific to the Medicare Part D population (although patients receiving prescriptions in the study were younger than 65; their mean age was 56) and include only prescriptions Medicare paid for, the researchers noted. Policy or clinical practice changes, like the increasing use of prescription drug monitoring programs, may have affected the results. Demographic shifts among Part D enrollees also could have affected prescribing.
This past week, the FDA announced that will require a patient's opioid tolerance to be documented with each TIRF prescription, both inpatient and outpatient.
Disclosures
At the time of writing, Fleischman was an employee of the Centers for Medicare & Medicaid Services (CMS). Other researchers reported relationships with the FDA, the CMS, the Agency for Healthcare Research and Quality, the National Heart, Lung, and Blood Institute, the National Science Foundation, the Patient Centered Outcomes Research Institute, the Department of Health and Human Services, Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, and the Laura and John Arnold Foundation.
Primary Source
JAMA Network Open
Fleischman W, et al "Association of a Risk Valuation and Mitigation Strategy Program With Transmucosal Fentanyl Prescribing" JAMA Network Open 2019; DOI:10.1001/jamanetworkopen.2019.1340.