Labeling Changes; Postmarket Studies Announced for Certain Opioid Analgesics

The FDA has announced class-wide safety labeling changes and postmarket study requirements for extended-release (ER) and long-acting (LA) opioid analgesics. The changes will require a new boxed warning on the effects of neonatal opioid withdrawal syndrome (NOWS) and, when final, will include new language to help health care professionals tailor their prescribing decisions based on a patient’s individual needs. These changes have been communicated to consumers via the agency’s “For Consumers” page.

FDA Commissioner’s View

On September 10, 2013, FDA Commissioner, Margaret A. Hamburg, M.D., stated that “[t]hese medications, which include drugs such as morphine, oxycodone, and fentanyl, can improve the quality of life for many people who must live every day with pain. But ER/LA opioids often also contain a large amount of the active ingredient, sometimes in sufficient quantity to be lethal, and they are a prime target of drug abusers.” Hamburg indicated that, due to these concerns, the FDA looked more closely at the product labeling (package insert) to determine whether this information should be revised. According to Hamburg, the FDA concluded “that if we improved what the labeling says about proper patient selection and the risks from these drugs, we might be able to reduce the frequency of bad outcomes.”

Updated Indication

The updated indication for the opioids will: (1) state that they are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate; (2) clarify that because of the risks of addiction, abuse, and misuse, even at recommended doses, and because of the greater risks of overdose and death, these drugs should be reserved for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain; and (3) clarify that they are not indicated for as-needed pain relief.

Postmarket Studies

The FDA will also require the manufacturers of ER/LA opioids to conduct further studies and clinical trials to further assess the known serious risks of misuse, abuse, increased sensitivity to pain (hyperalgesia), addiction, overdose, and death.


A new boxed warning must caution that chronic maternal use of these products during pregnancy can result in NOWS, which may be life-threatening and require management according to protocols developed by neonatology experts. According to the FDA, possible symptoms of NOWS include poor feeding, rapid breathing, trembling, and excessive or high-pitched crying.

Notice to New Drug Applicants

As a result of these new requirements, ER/LA opioid analgesic application holders will need to make changes to their drug labeling sections in their package inserts, including Dosage and Administration, Warnings and Precautions, Drug Interactions, Use in Specific Populations, Patient Counseling Information, and the Medication Guide. The FDA will send a letter to application holders setting forth their labeling supplement and postmarket reporting requirements.

REMS Modifications

Once the safety labeling changes are finalized by the FDA, modifications will also be made to the ER/LA Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS) to reflect the changes. Originally approved July 9, 2012, the ER/LA Opioid Analgesics REMS requires companies to make available to health care professionals educational programs on how to safely prescribe ER/LA opioid analgesics and to provide Medication Guides and patient counseling documents containing information on the safe use, storage, and disposal of ER/LA opioids. Questions and Answers regarding REMS for ER/LA Opioid Analgesics are available on the FDA website.

Citizen Petitions

In addition to the safety labeling changes and postmarket study requirements, the FDA has issued responses to two related citizen petitions: (1) Physicians for Responsible Opioid Prescribing (FDA-2012-P-0818-0793) and (2) Kirk Van Rooyan and Barbara Van Rooyan (FDA-2005-P-0325-0014).