The Food and Drug Administration will require boxed warnings on the risks of abuse, misuse, addiction, overdose, and death for all immediate-release opioids.

The decision is part of the latest wave of efforts by federal officials to combat the ballooning opioid epidemic. It comes a week after the Centers for Disease Control and Prevention issued guidelines recommending nonopioid analgesia for noncancer pain, and 3 years after FDA required boxed warnings for all extended-release opioids, Dr. Douglas Throckmorton, deputy director of regulatory programs at the FDA Center for Drug Evaluation and Research, said during a news conference March 22.

The FDA has faced criticism for doing too little, too late to curtail opioid-related deaths, which have surpassed motor vehicle accidents as the leading cause of injury-related fatality in the United States. The agency initially limited its boxed warning to extended-release opioids because they contain more drug per tablet, are more attractive to substance abusers, and have a longer temporal risk of potentially fatal respiratory depression, Dr. Throckmorton said.

“This change will remind prescribers that immediate-release opioids are also powerful drugs with important safety concerns,” he said. “We will continue to monitor the situation, and as we need to do more, we will.”

The new boxed warning requirement affects 87 innovator products and 141 generic immediate-release opioids, whereas the 2013 decision involved just 8 long-acting products. The FDA notified manufacturers of its decision today and expects to finish reviewing label updates by the end of 2016, officials said.

In addition, all prescription opioids will be required to include warnings about potentially harmful drug interactions; serotonin syndrome; adrenal insufficiency and other endocrine problems; and neonatal opioid withdrawal syndrome, FDA Commissioner Dr. Robert Califf said during the press conference. While some pregnant women with chronic pain may need to stay on opioids, providers should be prepared to treat withdrawal syndrome in newborns, Dr. Throckmorton added.

The American Congress of Obstetricians and Gynecologists responded to the CDC guidelines and FDA announcement by advising women who are already taking opioids to consider staying on them during pregnancy. Neonatal opioid withdrawal is treatable and has not been clearly linked to long-term problems, while withdrawal during pregnancy can cause fetal demise, according to an ACOG statement.

Dr. Califf emphasized that the FDA does not intend to stop physicians from prescribing opioids to patients with serious pain.

Most physicians do not read labels, but label changes trigger discussions, which lead to formulary changes and updates to electronic prescription monitoring programs, he added. “That really starts with a label from the FDA. I can assure you the label will have an impact.”

The FDA will convene an advisory committee meeting on May 3 to May 4 to discuss the impact of boxed warnings for extended-release opioids and approvals of abuse-deterrent formulations, Dr. Throckmorton said. Advisers also will discuss whether to add immediate-release opioids to the existing Risk Evaluation and Mitigation Strategies (REMS) for extended-release formulations.

“The totality of these actions is what’s going to be needed for change,” Dr. Throckmorton said. “The labeling is an important part, but its not the only thing that’s going to be necessary.”


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