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Questions and Answers: FDA approves a Risk Evaluation and Mitigation Strategy (REMS) for Extended-Release and Long-Acting (ER/LA) Opioid Analgesics
[7/9/2012; updated 3/1/2013]
On July 9, 2012, the U.S. Food and Drug Administration (FDA) approved a risk management program, known as a Risk Evaluation and Mitigation Strategy (REMS), for a class of potent pain medicines called extended-release and long-acting (ER/LA) opioid analgesics. The REMS was developed by FDA and there are more than 20 companies and more than 30 products (NDAs and ANDAs) affected by the REMS. This new REMS will require ER/LA opioid analgesic companies to make available training for health care professionals who prescribe ER/LA opioid analgesics on proper prescribing practices and also to distribute educational materials to prescribers and patients on the safe use of these powerful pain medications.
The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require companies to develop and implement a REMS when necessary to ensure that the benefits of a drug or biological product outweigh its risks. The new ER/LA opioid analgesic REMS advances the Agency’s goal of improving the safe use of ER/LA opioid analgesics while ensuring continued access to these medications for patients who need them. The new ER/LA opioid analgesics REMS is also part of the national prescription drug abuse plan (PDF - 306KB) announced by the Obama Administration in 2011 to combat prescription drug misuse and abuse.
Q1. What are extended-release and long-acting (ER/LA) prescription opioid analgesics?
A. ER/LA prescription opioid analgesics are potent pain-relieving medicines used primarily for the management of persistent moderate pain to severe pain requiring around-the-clock opioid analgesics for an extended period of time.
A. Opioids are widely prescribed and carry a risk of abuse, misuse and death. In 2009, there were nearly 425,000 emergency department visits involving non-medical use of opioid analgesics. According to estimates from the Centers for Disease Control and Prevention, 15,597 Americans died from overdoses involving opioid pain relievers in 2009. In 2010, there were 16,651 deaths involving an opioid medication.
A. A REMS is a risk management plan that goes beyond requirements in the drug prescribing information to manage serious risks associated with a drug. Under the Food and Drug Administration Amendments Act of 2007, FDA has the authority to require a manufacturer to develop a REMS when further measures are needed to ensure that the drug’s benefits outweigh its risks.
A. All ER/LA opioid analgesics will be required to have a REMS. The innovator products are listed below:
|1||Avinza||Morphine sulfate extended-release capsules||Pfizer|
|2||Butrans||Buprenorphine transdermal system||Purdue Pharma|
|3||Dolophine||Methadone hydrochloride tablets||Roxane|
|4||Duragesic||Fentanyl transdermal system||Janssen Pharmaceuticals|
|5||**Embeda||Morphine sulfate and naltrexone extended-release capsules||Pfizer|
|6||Exalgo||Hydromorphone hydrochloride extended-release tablets||Mallinckrodt|
|7||Kadian||Morphine sulfate extended-release capsules||Actavis|
|8||MS Contin||Morphine sulfate controlled-release tablets||Purdue Pharma|
|9||Nucynta ER||Tapentadol extended-release oral tablets||Janssen Pharmaceuticals|
|10||Opana ER||Oxymorphone hydrochloride extended-release tablets||Endo Pharmaceuticals|
|11||OxyContin||Oxycodone hydrochloride controlled-release tablets||Purdue Pharma|
|12||*Palladone||Hydromorphone hydrochloride extended-release capsules||Purdue Pharma|
*No longer being marketed, but is still approved.
**Not currently available or marketed due to a voluntary recall, but is still approved.
Generic versions of the ER/LA opioid analgesics listed above are also required to have a REMS.
See also: List of Opioid Products Required to have a REMS (PDF - 22KB).
A. FDA is requiring a REMS for ER/LA opioid analgesics because FDA has concluded that there is a disproportionate safety problem associated with these products that must be addressed. ER/LA prescription opioid analgesics can provide effective pain management when used as directed; however, there are serious risks associated with patients being prescribed these drugs who should not take them, and with improper use (whether accidental or intentional).
Prescription opioids are available as either immediate-release (IR) or ER products. Immediate-release (IR) opioid analgesics work for shorter periods of time. ER opioid analgesics are designed to provide a longer period of drug release so that they can be taken less frequently. Examples of opioid analgesics formulated as IR and ER products include hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. Long-acting (LA) opioid analgesics, such as methadone, have a longer period of action because of the inherent characteristics of the drug substance, which stays longer in the body, and not because of special design features of the finished product.
The amount of opioid analgesic contained in an ER tablet can be much more than the amount of opioid analgesic contained in an IR tablet because ER tablets are designed to release the opioid analgesic over a longer period of time. Improper use of any opioid can result in serious side effects, including overdose and death, and this risk is magnified with ER/LA opioid analgesics.
A REMS focused on prescriber education is intended to reduce the potential for serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while ensuring that patients with legitimate need for these drugs continue to have access to them.
A. This announcement will alert health care professionals and patients about the importance of proper prescribing and the safe and proper use of ER/LA opioid analgesic medications, and will explain the responsibility that manufacturers of these products have to make educational materials available for prescribers and patients. The first continuing education activities under the REMS are available to prescribers as of March 1, 2013, with others to follow.
All prescribers are encouraged to thoroughly discuss the risks and benefits of these products with their patients. A patient counseling document approved with the REMS is available to assist the prescriber in these discussions.
Patients who are currently taking ER/LA opioid analgesics should continue to take their medications as directed. Patients who have concerns about the medications they are taking should consult with their health care professional.
A. The central component of the ER/LA opioid analgesics REMS is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants). Under the REMS, sponsors of ER/LA opioid analgesics are making education programs available to all DEA registered prescribers, including prescribers of ER/LA opioid analgesics. As expected, sponsors are meeting this obligation by providing educational grants to accredited CE providers who are offering training to prescribers at no or nominal cost. These CE activities cover the content and messages of a blueprint developed by FDA for this purpose (see: FDA Blueprint for Prescriber Education (PDF - 104KB)).
Prescriber education includes drug information on ER/LA opioid analgesics; information on assessing patients for treatment with these drugs; initiating therapy, modifying dosing, and discontinuing use of ER/LA opioid analgesics; managing therapy and monitoring patients; and counseling patients and caregivers about the safe use of these drugs. Additionally, prescribers will learn how to recognize evidence of and potential for opioid misuse, abuse, and addiction.
The ER/LA opioid analgesics REMS also includes a patient counseling document for prescribers to give to patients, helping prescribers to properly counsel patients on their responsibilities for using these medicines safely. Patients will receive from their pharmacist an updated one-page Medication Guide along with their prescription that contains consumer-friendly information on the safe use and disposal of ER/LA opioid analgesics. Included in the guide are instructions for patients to consult their health care professional before changing doses, signs of potential overdose and emergency contact instructions, and advice on safe storage to prevent accidental exposure to family members.
A. There are approximately 320,000 prescribers of ER/LA opioid analgesics in the United States, and FDA expects companies to train 25% of these prescribers at the end of the first year following implementation of the program, 50% after two years, and 60% of them within four years of the start of training. The first continuing education activities under the REMS are available to prescribers as of March 1, 2013, with others to follow.
A. At this time, the ER/LA opioid analgesics REMS training program will not include a mandatory requirement linked to allowing health care professionals to prescribe ER/LA opioid analgesics. Such a requirement would require the establishment of a new system for registering prescribers of ER/LA opioid analgesics that would duplicate the existing Drug Enforcement Administration (DEA) registration system. This would be potentially burdensome. Instead, FDA supports a mandatory training program on responsible opioid prescribing practices that would be linked to Drug Enforcement Administration registration. Such a program was proposed in the Administration’s comprehensive plan to address the epidemic of prescription drug abuse in April 2011. At present, FDA intends to exercise its authority to require mandatory elements for manufacturers and voluntary elements for prescribers—all of which are important and necessary steps to help curb the misuse and abuse of ER/LA opioid analgesics, without being overly burdensome.
A. Follow-up surveys will be conducted to assess prescriber understanding of the important safety information and assess whether the REMS is adversely affecting patient access to necessary pain medications. Companies are offering additional funding to CE providers as an incentive to identify and track prescribers who take the REMS-compliant training and to perform follow-up surveys to assess the amount of information retained.
As part of the REMS, companies will report periodically on actions taken to implement the REMS, including, for training provided by CE providers, the number of grants awarded to CE providers, the number of prescribers trained, and other relevant information.
If FDA determines that the REMS is not meeting its goals, the Agency will re-evaluate the program.
A. FDA understands how important it is for patients to get their pain treated and does not expect that this action will affect patient access to their pain medicines. As part of the opioid REMS, FDA will monitor patient access to pain medicines and will continue to talk with the community of pain patients and prescribers to ensure that patients get proper pain management.
A. Yes. In 2009, FDA held several public meetings with various stakeholder groups to hear perspectives regarding the need for access to adequate options for pain management and about concerns associated with abuse and misuse of prescription opioids. FDA also obtained their feedback regarding the development of a REMS for opioids. Stakeholder groups that participated at the meetings included patient advocacy organizations, organizations representing prescribers, pharmacy organizations, insurance providers, and other government agencies. In addition, FDA solicited written comments through a public docket. See: summary of comments (PDF - 6MB).
On July 22 and 23, 2010, FDA held a joint meeting of its Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss FDA’s proposal for a class-wide REMS for ER/LA opioid analgesics (for complete background information discussed at this meeting, see: July 22-23, 2010 AC meeting).
The Advisory Committee members agreed that education of prescribers should be a central component of the REMS program. The Committee members suggested that this education requirement be mandatory and linked to the existing system of prescriber registration with the DEA.
A majority of the Advisory Committee members also recommended FDA require a REMS for all opioids, not just ER/LA opioid analgesics. FDA has decided not to require the REMS for all opioids. The agency concluded that there is a disproportionate safety problem associated with the ER/LA opioid analgesics and will incorporate a step-wise approach to focus first on educating prescribers of ER/LA opioid analgesics.
FDA also held meetings with manufacturers of certain opioid analgesic products in 2009 and 2011 to discuss the process for designing and implementing a REMS, without placing an unreasonable burden on the health care system.
For complete background information about these meetings, see: 2009 Meeting Materials, Anesthetic and Analgesic Drug Products Advisory Committee and 2011 Meeting Materials, Anesthetic and Analgesic Drug Products Advisory Committee.
A. FDA developed core messages to be communicated to prescribers in the FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics (FDA Blueprint), published a notice of availability of the Blueprint in the Federal Register and solicited public comments, and considered the public comments when finalizing the FDA Blueprint. The final FDA Blueprint contains the core educational messages.
For information about the request for public comments, see the November 7, 2011 Federal Register Notice (PDF - 150KB). To view the public comments, see the Docket Folder Summary for the November 7, 2011 Federal Register Notice.
A. FDA understands how important it is to assure that ER/LA opioid analgesics are stored safely and securely and that they are disposed of properly when they are no longer needed. Educational messages about storage and disposal of ER/LA opioid analgesics are included in the final FDA Blueprint. For information on how to safely dispose of unused medicines, please visit the FDA's Safe Disposal of Medicines web page.
A. A list of all REMS-compliant CE activities that are supported by independent educational grants from the ER/LA opioid analgesic companies to accredited CE providers are posted at www.ER-LA-opioidREMS.com.