The FDA’s REMS Program for Opioid Analgesics
The FDA’s REMS Program for Opioid Analgesics
In July the FDA issued its Risk Evaluation and Mitigation Strategy (REMS) program for extended-release and long-acting (ER/LA) opioid analgesics, which has been in preparation for the past 3 years.
The requirement for the FDA to develop REMS became law in 2007 and since then these strategies have been issued for several drugs. REMS focus on drugs that present special risks that the FDA does not feel are sufficiently addressed by the standard prescribing information.
There is already in place a REMS that addresses one group of opioid analgesics—the transmucosal immediate-release fentanyl (TIRF) products. These drugs are only FDA-approved for the management of breakthrough cancer-related pain in patients already receiving strong opioids. Physicians who prescribe these medications must be registered and have completed an educational program and post-test.
The new ER/LA REMS covers the following medications:
• ER oral forms of:
- hydromorphone (Exalgo)
- morphine (MS Contin, Avinza, Kadian, Oramorph, Embeda (which is still FDA-approved but has been taken off the market), and generic formulations
- oxycodone (OxyContin)
- oxymorphone (Opana ER and generics)
- tapentadol (Nucynta ER)
• transdermal fentanyl (Duragesic and generics)
• transdermal buprenorphine (Butrans)
• methadone (Dolophine and generics)
Except for methadone, a long-acting opioid, all of the agents listed are immediate-release (IR) opioids that have been formulated into LA/ER products.
Although the REMS is supposed to cover all the LA/ER opioid analgesics available in the United States, the FDA failed to include the other pharmacologically LA opioid analgesic levorphanol (Levo-Dromoran). (I informed the FDA of this oversight last year during the public comment period on the proposed REMS but received no response.)
What are the requirements for physicians under the new REMS? Essentially none. Unlike the REMS for TIRFs, participation in the REMS for ER/LA opioid analgesics is completely voluntary for physicians who are only “strongly encouraged” to do the following:
• Participate in training programs on the use of the LA/ER medications;
• Counsel patients on the safe use and the risks of these medications;
• Emphasize to patients the importance of reading the medication guides that pharmacists will be required to dispense whenever filling a prescription for these medications;
• And, consider the use of patient-provider agreements and other unspecified tools for risk assessment regarding potential abuse of these medications.
The educational component of the program will be provided free of charge to prescribers and will be paid for by the manufacturers of the medications. The education will be required to follow the current restrictions on all CME programs.
Short-acting Agents Left Out?
Although the new ER/LA REMS indicates that one of its purposes is to improve the management of pain, it is clear that the major reason for its existence is concern about the misuse and abuse of prescription opioids. This makes the decision to only address the ER/LA opioid analgesics and not the immediate-release/short-acting (IR/SA) opioids an odd one.
Earlier proposals for REMS addressed both types of opioid formulations. Prescriptions for ER/LA opioids are only a small minority of total number of outpatient opioid prescriptions written in the US. According to the FDA, in 2009 the ratio of outpatient prescriptions for IR/SA opioids to those for ER/LA opioids was 10:1.1 IR hydrocodone (the opioid in Vicodin), which is one of the most commonly prescribed and, as a result, one of the most frequently abused of all the opioids, is not one of the drugs covered by the REMS—although the recently approved ER form of it is.2
Also, with the introduction of a number of abuse-deterrent/tamper resistant ER/LA opioids, including the current formulations of OxyContin and Opana ER, we may be seeing a reduction in the abuse of these products. A recent study found that since the introduction of abuse-deterrent OxyContin there has been a significant reduction in its use by drug abusers but, unfortunately, there has also been a corresponding increase in their use of other prescription opioids and heroin.3
Will the REMS result in a significant improvement in how physicians’ prescribe the listed opioids and result in a reduction of their abuse and misuse, and better management of pain? I wish I could be more optimistic, but I doubt that it will.
Who will be trained?
For the group of health care professionals who prescribe these drugs primarily for illegitimate reasons and apparently care little about the people to whom they are providing them or the negative impact on society in general, the program will obviously do little to inhibit their activity.
The health care professionals who believe they are prescribing these opioids for legitimate medical reasons and consider themselves to be doing so appropriately may see little reason for additional training. Thus, without the mandatory educational requirement carried by the TIRF REMS, I wonder if most of those who opt for the training will already be knowledgeable about prescribing the ER/LA opioids and will do so simply to make sure they have the most up-to-date information.
Regarding the patient education aspects of the program: probably the same complaint about physicians not taking sufficient time to discuss the proper use and the associated risks could be made about most medications, both prescription and over-the-counter. Is it realistic to expect this to change by simply encouraging physicians to do better?
I recommend that you review the specifics of the REMS if you prescribe or are considering prescribing any of the ER/LA opioid analgesics. The REMS provides a useful overview of the medications covered and issues of concern regarding their use.
Finally, as to the other tools the REMS suggests physicians use to monitor the risk for abuse and misuse of opioids: there is little research demonstrating that the use any of these actually reduces the risk of problems.
1. United States Food and Drug Administration. Outpatient Prescription Opioid Utilization in the U.S., Years 2000 –2009. Presentation given July 22, 2010.
2. Centers for Disease Control and Prevention. Emergency department visits involving nonmedical use of selected opioid prescription drugs—United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.
3.Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of OxyContin. N Engl J Med. 2012;367:187-189.