Statement from FDA Commissioner Scott Gottlieb, M.D., on new steps to strengthen agency's safety requirements aimed at mitigating risks associated with transmucosal immediate-release fentanyl products

SILVER SPRING, Md., March 27, 2019 /PRNewswire/ -- As the FDA continues to forcefully confront the opioid crisis, rationalizing prescribing practices and ensuring safe and appropriate use of these powerful medications remains a cornerstone of our efforts. More appropriate prescribing can reduce the rate of new addiction and mitigate the serious, and sometimes deadly, risks associated with opioids.

To confront this crisis, we continue to use all facets of our regulatory authority. This includes requiring Risk Evaluation and Mitigation Strategy (REMS) programs to ensure the benefits of a medication outweigh its risks. In the context of opioids, these REMS programs and related requirements can in part help us strike a balance between reducing the rate of new addiction by decreasing exposure to opioids and rationalizing prescribing, while still enabling appropriate access to those patients who have a legitimate medical need for these medicines.

Last fall, for example, we approved the Opioid Analgesics REMS, which we expanded to include immediate-release opioid analgesics intended for use in an outpatient setting. Among other things, this broadened the REMS training to cover information about acute and chronic pain management, safe use of opioids, and other non-opioid or non-drug treatments.

While the Opioid Analgesics REMS program covers most prescription opioids, other classes of opioid products like the transmucosal immediate-release fentanyl (TIRF) medicines have their own REMS program to mitigate the serious risks specific to those medications. TIRF medicines are a class of products indicated to manage breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines to treat around-the-clock pain. Breakthrough pain comes on suddenly for short periods of time and is not alleviated by a patient's normal pain management plan.

TIRF medicines can fill an important medical need for a small and carefully selected group of patients who are opioid-tolerant. But these products also have significant risks associated with their use. That is why the FDA has had a REMS in place since 2011 to ensure the benefits of TIRF products outweigh their risks.

The REMS was intended to ensure that TIRF products are prescribed only to appropriate patients. The REMS also included measures that were designed to: limit use to opioid-tolerant patients; avoid inappropriate conversion between TIRF medicines; reduce accidental exposure; and educate prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose.

We know there are questions in the community about whether the REMS program is appropriately designed to mitigate the risks of TIRF products. As part of our ongoing commitment to the safe use of these products, the FDA held a public joint advisory committee meeting in August 2018 to seek the committees' feedback on any possible modifications to the TIRF REMS goals and requirements. We also sought input on the adequacy of the evaluations conducted in the REMS assessments to determine whether the TIRF REMS goals are being met.

Today we are announcing new steps to strengthen the TIRF REMS to better ensure the safe use of these products.

It's important to underscore that outpatient utilization of TIRF products has substantially declined in recent years. In 2012 – the first full year the REMS was implemented – an estimated 14,400 patients received TIRF prescriptions dispensed from U.S. outpatient retail pharmacies. By 2017, utilization declined to an estimated 4,700 patients who received TIRF dispensed prescriptions, and TIRF products accounted for only 0.02 percent of all opioid analgesic prescriptions dispensed from U.S. outpatient retail pharmacies. Despite the decline in the use of these medicines, the historical data on the prescribing of TIRF products indicates that prescribing behavior is not consistent with the strict labeling. To the extent that some of these prescribing practices still persist, even as prescriptions declined sharply, that causes the FDA concern.

Specifically, while many of the operational and functional compliance aspects of the REMS appeared to be working, the program wasn't fully achieving its intended public health purpose. Based on data submitted to the FDA in REMS assessments, while prescribers consistently appear to be knowledgeable about the risks and the safe use of TIRF medicines, an estimated 35 to 55 percent of patients treated with a TIRF medicine were not opioid-tolerant and many received a TIRF prescription for an unapproved use to treat other types of pain. The prescribing of these medicines for non-FDA approved uses to non-opioid-tolerant patients tells us that there may be a disconnect between prescriber knowledge and prescribing behavior. While physicians can prescribe a drug "off-label" when they believe it is medically appropriate for a particular patient, physicians should take heed of the narrow, approved indication of these products and the agency's strongest warning, called a contraindication, on labeling stating it should not be used in opioid non-tolerant patients. While all opioids pose serious risks, these are not your typical opioids and should be prescribed by providers with extra care and attention. 

It's clear more needs to be done to better ensure the safe use of these medicines, mitigate their risks, and assure appropriate prescribing. Today we're taking important new steps to help improve the safety of TIRF medicines under the TIRF REMS.

We're moving forward to modify the TIRF REMS to ensure the benefits of the drugs continue to outweigh the risks. We are issuing letters to the manufacturers of these nine products notifying them of the following required changes to the REMS, including:

• Requiring that prescribers document a patient's opioid tolerance concurrently with each prescription of a TIRF medicine for outpatient use. 
• Requiring inpatient pharmacies to develop internal policies and procedures to verify opioid tolerance in patients who require TIRF medicines while hospitalized.
• Requiring that a TIRF medicine be dispensed for outpatient use with evidence or other documentation of safe use conditions, including concurrent documentation of opioid tolerance.
• Requiring the development of a new patient registry to monitor for serious adverse events including overdose (both fatal and non-fatal).

These changes are significant. They're intended to drive more judicious prescribing and better patient awareness of the serious risks of these medications.

For example, TIRF medicines are contraindicated in opioid non-tolerant patients due to the risk of respiratory depression and death, which may occur in these patients. The current TIRF REMS requires only that prescribers attest to their understanding that patients must be opioid tolerant before using a TIRF medicine; it currently does not include a requirement that prescribers document that a patient is opioid tolerant before prescribing a TIRF medicine. Although outcomes of use in patients who are not opioid-tolerant are lacking, the agency is concerned about serious adverse events that could occur if TIRF medicines are used in patients that are not opioid-tolerant.

That's why we're now requiring verification of opioid tolerance with each prescription written and dispensed to provide greater assurance that only opioid tolerant patients are treated with a TIRF medicine in order to lower the risks for adverse events, including overdose and death. This is in addition to the patient-prescriber agreement form (PPAF) that patients initiating therapy with a TIRF medicine for outpatient use are required to sign with the prescriber, acknowledging their understanding of the risks, safe use, safe storage, and disposal of their TIRF medicine.

Finally, the FDA has acknowledged the challenges with the available data sources and limitations of spontaneous reporting of adverse events for such a small patient population. To further address these challenges, the agency is requiring that a patient registry be added to the REMS to monitor patients for serious adverse events including overdose (both fatal and non-fatal). By adding a patient registry to the TIRF REMS, we'll be better able to evaluate adverse events and the safe use of TIRF medicines.

Today's action is the first step in the process to update the REMS over the next year. We're committed to finalizing these meaningful modifications to the TIRF REMS program as quickly as possible. We may also take other new actions.

This matter is a high priority. We'll continue to take steps to ensure the TIRF REMS program is achieving its goal of assuring safe use and mitigating the risks of misuse, abuse, addiction, overdose and accidental exposure associated with these medicines. At the same time, we must also make sure that patients suffering from significant pain, in this case, adults with breakthrough cancer pain, have access to appropriate medications and aren't unduly burdened in getting the treatment they need.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

For more information:
Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA's continued, careful oversight of the REMS associated with transmucosal immediate-release fentanyl products Transmucosal Immediate-Release Fentanyl (TIRF) Products

Transmucosal Immediate-Release Fentanyl (TIRF) Medicines

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SOURCE U.S. Food and Drug Administration

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