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Focus on Regulation

FDA Notifies Applicants of Intent to Require Sweeping Changes to Labeling for IR Opioid Analgesics and Entire Class of Prescription Opioids

FDA has announced its intent to require new class-wide labeling requirements for immediate-release (IR) opioid pain medications including new black and other safety warnings.  The enhanced warnings are intended “to inform prescribers and patients of additional risks related to opioid use.”  FDA, News Release (March 22, 2016) (hereinafter, “News Release”).  FDA further announced its intent to impose labeling changes to better address safety risks for all prescription opioid drugs.  Id.

FDA clarified “[p]rescription opioids are divided into two main categories – IR products, usually intended for use every four to six hours; and extended-release/long-acting (ER/LA) products, which are primarily intended to be taken once or twice a day, depending on the individual product and patient.”  Id.  In 2013, FDA imposed labeling requirements for ER/LA opioids, similar to those announced yesterday for IR opioid analgesics.  See FDA, Letter to Application Holders re: Labeling Supplement and PMR Required (2013).  In 2014, a Citizen Petition  was filed challenging FDA’s decision to require labeling revisions and postmarket study requirements for extended-release and long acting opioid analgesic products but not immediate-release products.  Simultaneous with its press-release, FDA partially granted and denied that petition. See FDA, Citizen Petition Response, Doc. No. FDA-2014-P-0205 (Mar. 22, 2016) (hereinafter, “CP Response”).

FDA stated in the petition response that the purpose of the new safety labeling changes is two-fold: (1) to more effectively communicate the serious risks of misuse, abuse, neonatal opioid withdrawal syndrome (NOWS), addiction, overdose, and death associated with the use of IR opioids; and (2) to more clearly describe the population in which IR opioids should be used in light of these serious risks – thus encouraging better prescribing, monitoring, and patient counseling practices involving these drugs.  Id. at 2.

FDA’s press release states for all IR opioid analgesics, i.e. oxycodone, hydrocodone, and oxymorphone, FDA is requiring a new boxed warning about the serious risks of misuse, abuse, addiction, overdose and death.  The new boxed warning provides that IR opioids “expose[] patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.”  CP Response at 7.  It also urges prescribers to “[a]ssess each patient’s risk” before prescribing and to “monitor all patients regularly for the development of these behaviors or conditions.”  Id.  The black box warning will also include a precaution that “chronic maternal use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening if not recognized and treated using protocols developed by neonatology experts” and that “NOWS may occur in a newborn exposed to opioid drugs for a prolonged period while in utero.”  News Release at 1.

FDA also notified application holders of its intent to update the indication for IR opioid analgesics “to clarify they should be reserved for pain severe enough to require opioid treatment and for which alternative treatment options (e.g., non-opioid analgesics or opioid combination products, as appropriate) are inadequate or not tolerated.”  Id.  The new language would identify specific examples of alternative treatment options, namely “opioid/non-opioid combination products” or “non-opioid analgesics.”  CP Response at 8.  FDA clarified that the new indication for IR opioid analgesics will parallel but not exactly duplicate the language from the ER/LA opioid analgesic indication and may be modified to fit the individual product, as appropriate.  CP Response at 7.

Further, FDA notified application holders of the need to change the dosing information for IR opioid analgesics to provide “clearer instructions regarding patient monitoring and drug administration, including initial dosage, dosage changes during therapy and a warning not to abruptly stop treatment in a physically dependent patient.”  News Release at 1.

FDA’s labeling changes extend beyond IR opioid analgesics.  In its press release, FDA stated its intent to require changes to labeling for all opioids (including ER/LA opioids).  In an accompanying Safety Announcement, FDA warned of several additional safety issues for these drugs. Specifically, FDA announced:

  • Opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity.
  • Taking opioids may lead to a rare, but serious condition in which the adrenal glands do not produce adequate amounts of the hormone cortisol. Cortisol helps the body respond to stress.
  • Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as reduced interest in sex, impotence, or infertility.


The Safety Announcement reports that the agency analyzed data from the FDA Adverse Event Reporting System (FAERS) and medical literature in reaching its conclusions about the existence of these risks.  Id.  FDA further found that some opioids’ labeling already address these risks and thus clarified where changes are necessary.  FDA said:

  • Cases of serotonin syndrome in the FAERS database were reported more frequently with the opioids fentanyl and methadone used at the recommended doses. Therefore, FDA is requiring a new statement in the Warnings and Precautions section to be added to these drug labels. Some opioids, including tramadol, tapentadol, and meperidine, already have warnings about serotonin syndrome. Cases were also reported with other opioids, so the labels of all these drugs will be updated to include information about serotonin syndrome in the Drug Interactions and Adverse Reactions sections.
  • FDA is requiring a new statement about adrenal insufficiency to be added to the Warnings and Precautions section of all opioid labels.
  • Although FDA reviewed published studies that assessed levels of sex hormones in patients taking opioids chronically, the studies had limitations that make it difficult to determine whether the symptoms were caused by the opioids or other factors. The labels of some opioids already describe this possible risk, and FDA is now adding consistent information to the Adverse Reactions section of all opioid labels.


FDA also noted that it is aware of, and carefully reviewing, available scientific information about potentially serious outcomes related to interactions between benzodiazepines and opioids” and “will take necessary actions” once that review is complete.”  News Release at 1.

Application holders have 30 days to either submit a supplement proposing changes to their drugs’ approved labeling or notify FDA that they do not believe a labeling change is warranted and explain why that is their view.  See CP Response at 4 (citing 21 USC 355(o)(4)(B)).

FDA Commissioner Robert Califf, M.D., stated FDA’s “actions are one of the largest undertakings for informing prescribers of risks across opioid products, and one of many steps the FDA intends to take this year as part of our comprehensive action plan to reverse [the prescription drug abuse] epidemic.”  News Release at 1.  Similarly, CDER Director Janet Woodcock, M.D., said “The broad set of actions  . . .  is reflective of the FDA’s efforts to improve informed prescribing of opioids across the board . . . . We have been and will continue to evaluate all new data to ensure that labels of opioid drugs contain appropriate prescribing information about the benefits and risks of prescription opioids.”  Id.  CDER Deputy Director of Regulatory Programs, Douglas Throckmorton, M.D., stated “We know that there is persistent abuse, addiction, overdose mortality and risk of NOWS associated with IR opioid products . . . . Today, we have taken an important next step in clarifying and making more prominent the known risks of IR opioid medications.”  Id.