FDA To Require Risk Evaluation and Mitigation Strategies for Opioids

Susan Jeffrey

February 10, 2009

February 10, 2009 — The US Food and Drug Administration (FDA) announced that it has contacted the manufacturers of opioid pain medications, including fentanyl, morphine, and oxycodone, requiring them to have a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of these drugs outweigh the risks.

Letters went out February 6 to 16 manufacturers of 24 brand-name and generic products with either approved new drug applications (NDAs) or approved abbreviated NDAs, most of them extended-release products or transdermal systems.

In a press briefing, John Jenkins, MD, director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research (CDER), and Bob Rappoport, MD, director of the Division of Anesthesia, Analgesia, and Rheumatology Products at CDER, discussed the perceived need for these new requirements.

"Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients," Dr. Jenkins told reporters. "At the same time, opioid drugs have serious risks when used improperly."

The FDA, drug manufacturers, and others have taken steps to prevent misuse, abuse, and accidental overdose of these drugs, including warning labels, risk-management plans, and direct communications to prescribers and patients, he said. "Despite these efforts, the rates of misuse and abuse and of overdosage of opioids have risen over the past decade."

The drugs are widely used; data from 2007 indicate that some 21 million prescriptions for these 24 drugs were given to about 3.7 million patients. Although it is hard to get exact numbers for the adverse events associated with these drugs, Dr. Jenkins added, "I think it's clear there are hundreds of deaths reported each year for these products related to misuse, which can be intentional or unintentional."

Dr. Rappoport added that data released from a survey conducted by the Substance Abuse and Mental Health Services Administration showed that in 2007, 5.2 million people, aged 12 years or older, reported using prescription pain relievers nonmedically in the previous month. "Of particular concern is that the number seems to be increasing in certain age categories," he added. "Use among adults aged 26 or older increased from 1.3% to 1.6%, so this is an ongoing problem, and it's getting worse."

The authority for the FDA to require REMS comes from FDA Amendments Act of 2007 (FDAAA).

"Over the years, a variety of plans have been put in place to improve the safe use of these drugs, but I think when we got the new authority under FDAAA, we went back and revisited what we could do," Dr. Jenkins said. "Once we got the interpretation that the new authority would be applicable here, we started working through what type of program we [thought] would be useful and how we would go about implementing it.

"We recognize this is going to be a relatively massive new program," Dr. Jenkins added. The 21 million prescriptions is "orders of magnitude" greater than any other program now in place. "It's likely that legitimate patients will see new procedures that will be in place for obtaining these products, but we hope to make those procedures not so intrusive that it impacts their ability to receive the products while still meeting the second goal of having an impact on safe use."

Nothing is expected to change in the short term, though, they noted. The FDA will meet with the companies marketing the affected opioids drugs on March 3 to discuss REMS development. It also plans to meet with other stakeholders, including other federal agencies, nongovernment groups, and patient and consumer advocates. It is also planning a public meeting, slated for late spring or early summer, to allow broader public input.

The drugs affected by the new requirements are outlined below. For more information, visit the FDA's website.

Brand Name Opioid Products

Generic Name Trade Name Applicant/Sponsors
Fentanyl Duragesic extended-release transdermal system Ortho-McNeil-Janssen
Hydromorphone Palladone extended-release capsules* Purdue Pharma
Methadone Dolophine tablets Roxanne
Morphine Avinza extended-release capsules King Pharms
Morphine Kadian extended-release capsules Actavis
Morphine MS Contin extended-release tablets Purdue Pharma
Morphine Oramorph extended-release tablets Xanodyne Pharms
Oxycodone OxyContin extended-release tablets Purdue Pharma
Oxymorphone Opana extended-release tablets Endo Pharma
size="1">*No longer being marketed, but still approved

Generic Opioid Products

Generic Name Drug Name Applicant/Sponsors
Fentanyl Fentanyl extended-release transdermal system Actavis
Fentanyl Fentanyl extended-release transdermal system Lavipharm Labs
Fentanyl Fentanyl extended-release transdermal system Mylan Technologies
Fentanyl Fentanyl extended-release transdermal system Teva Pharms
Fentanyl Fentanyl extended-release transdermal system Watson
Methadone Methadose tablets Mallinckrodt
Methadone Methadone HCL tablets Mallinckrodt
Methadone Methadone HCL tablets Sandoz
Morphine Morphine sulfate extended-release tablets Endo
Morphine Morphine sulfate extended-release tablets KV Pharmaceuticals
Morphine Morphine sulfate extended-release tablets Mallinckrodt
Morphine Morphine sulfate extended-release tablets Watson Labs
Oxycodone Oxycodone extended-release tablets Mallinckrodt
Oxycodone Oxycodone extended-release tablets* Impax Labs
Oxycodone Oxycodone extended-release tablets* Teva
size="1">*Discontinued products


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