The potential adverse health consequences of prescription opioid analgesics are well documented and include abuse, addiction, and death due to overdose.1–3 In 2007, the US Congress passed the Food and Drug Administration Amendments Act (FDAAA), which authorized the Food and Drug Administration (FDA) to require that drug manufacturers implement a Risk Evaluation and Mitigation Strategy (REMS) for pharmaceuticals with known or suspected risks of abuse and overdose, although REMS were not required for short-acting opioids (eg, combination oxycodone/acetaminophen).4–7 FDAAA required that the REMS for each drug be designed with the purpose of evaluating and mitigating the risks of adverse events. This editorial briefly describes the development of a shared REMS for transmucosal immediate-release fentanyl (TIRF) products from individual REMS (with examples from a previous, separate program for sublingual TIRF tablets [Abstral®]), implementation of the shared REMS, and remaining challenges.
The goals of the TIRF REMS, which is required by the FDA, are to ensure patient access to important medications and to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” In 2009, the FDA released a draft “Guidance for Industry” describing the requirements for how a REMS should attempt to achieve these goals.9 Although problems with opioid analgesics range from accidental medical misuse (eg, through treatment noncompliance) to intentional illegal use, the new REMS policies for opioids focus primarily on safe and appropriate medical use. The FDAAA and the 2009 Guidance recommended “Elements to Assure Safe Use” (ETASU); this document refers to a variety of methods to promote safe medication access. However, a REMS program that imposes undue restrictions on appropriate opioid treatment could negatively affect the adequate care of all patients who may need these medications.10 The law therefore also obligates the FDA to ensure, via periodic evaluations, that REMS requirements do not limit medication access or create an undue burden on the healthcare system.
A separate REMS for sublingual TIRF tablets, which received final approval from the US FDA in January 2011, served as one model for the shared REMS that has now been implemented for all TIRF products. These sublingual fentanyl tablets are a Schedule II controlled substance with an abuse liability similar to that of other legal or illicit opioid agonists.12 They are approved only for the management of breakthrough pain in patients, 18 years of age and older, who are already receiving and are tolerant to opioid therapy for underlying persistent cancer pain. The stated goals of the REMS for the sublingual TIRF tablets, identical to those of the current shared TIRF REMS Access program (hereafter referred to as TIRF REMS), were to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” As with the shared TIRF REMS, the goals of the sublingual TIRF tablets REMS were to be achieved by the following actions:
- Prescribing and dispensing only to appropriate patients, which includes use only in patients with cancer who are opioid tolerant.
- Preventing inappropriate conversion between fentanyl products.
- Preventing accidental exposure to children and others for whom it was not prescribed (ie, reducing the incidence of adverse events associated with accidental exposures and use by nontolerant individuals).
- Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose.
Although an ETASU plan can suggest various methods to address these issues, the available strategies are open to some criticism. For example, a REMS program may limit opioid distribution to certain healthcare settings, specially certified registrant pharmacies, or patients listed in a registry.14 However, although opioid-associated misuse, abuse, addiction, and mortality have increased contemporaneously with prescribing, the exact relationship between medical and nonmedical prescription opioid use remains unclear.15 Training can be required, but there is limited evidence for the efficacy of educational efforts. The components of the TIRF REMS that attempt to modify illegal behavior by patients represent an extension of FDA authority that has not been seen previously. The complexity of nonmedical use of prescription opioids, coupled with the unproven and unknown effects of a REMS, have led to skepticism that there is sufficient understanding of how to develop an effective and safe REMS.5 Although the FDA is mandating these mitigation strategies now in an attempt to reduce adverse events related to the use of prescription opioids, close attention to their intended and unintended consequences is warranted in the future.