FDA will require that patients receive a medication guide when prescribed immediate-release opioids, which may be a precursor to adding the products to the existing Risk Evaluation and Mitigation Strategy (REMS) for the extended-release version of the pain products.

The additional information is intended to help patients have better discussions with providers about whether opioids should be used to treat their pain, FDA said in a March 22 announcement that also included the addition of several boxed warnings and drug interactions to the labels for immediate-release (IR) opioid product labels (see table at bottom of article).

Whether IR opioids will be subject to the same risk management plan as long-acting products may depend on upcoming discussions. Douglas Throckmorton, Center for Drug Evaluation and Research deputy center director for regulatory programs said "broadening that REMS to include the IR opioids" will be discussed at an upcoming advisory committee meeting.

"The question of whether or not to have a REMS, … in this case like the REMS that we have for the extended-release, long-acting opioids, will be on the table when we have that advisory committee," Throckmorton said during a conference call on the changes.

FDA has scheduled its Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees to meet May 3-4 to talk about potential REMS revisions. Mandatory prescriber education is a likely discussion topic; the REMS for the long-acting opioids now includes voluntary prescriber education ([A#14160311004]).

What More Does FDA Need To Do?

When FDA calls a press conference, the objective is never only communicating with sponsors, patients or physicians, even if that's the announced audience. It's the public and policymakers that FDA wants to persuade when it speaks to the press, and implicit in each of the agency's answers – as it is for anyone who calls a press conference anywhere – is actually a question: "Have we alleviated your concerns?"

Concerns regarding opioids have been with FDA for a while; in July 2015 a number of members of Congress sent a letter to FDA asking why a black-box warning had not been added to the IR opioid label ([A#14150709004]) and the questions became more acute after several Senators also held up FDA Commissioner Robert Califf's confirmation due to FDA's opioid policies ([A#14160222005]).

The labeling changes are part of FDA's opioid action plan, issued to break Califf out of his senatorial purgatory, which promises the agency will conduct additional advisory committee meetings for new opioid products, update the REMS, and continue encouraging development of abuse-deterrent formulations ([A#14160204003]).

In the Hamburg era, the agency got plenty of criticism for its opioid policies as well, but FDA was able to advance its dual priorities of product safety and patient access by touting its anti-abuse measures while trying to more quietly approve new entrants into the category ([A#14140403005]).

Califf probably isn't going to have that luxury, and he's already shown he intends to be hands-on when addressing the risks of the products ([A#14160302005]). He's also admitted that the agency should have handled the review of Zogenix Inc.'s hydrocodone Zohydro ER better ([A#00160307013]).

The commissioner made another admission at the press conference: doctors may not read labels, but it still is an important tool. That's a safety conundrum that FDA faces even for products that aren't addictive political hot potatoes, but most of the agency's product initiatives don't merit White House-level attention, as was evidenced by a same-day briefing from National Drug Control Policy Director Michael Botticelli.

The fact that labeling changes alone probably won't be enough to change prescriber behavior is likely why officials are already telegraphing the discussion of mandatory education for doctors, but even still the new opioid labels stop short of what many critics have wanted in terms of explicit limits on duration and dosage.

Indeed, the guidelines issued by the CDC last week were much more detailed in terms of how opioids should be prescribed ([A#14160315007]) which suggests that despite its new assertive stance, the agency remains fundamentally uncomfortable with limiting access to opioids.

And that signals that FDA is unlikely to use any of its more restrictive REMS tools for the products, which means it will be up to education efforts – and ultimately state prescription drug monitoring programs – to stop abusive prescribing.

Limiting The Indication

The indication for IR opioids will be adjusted to encourage their use as second-line therapy. The products should be used for "pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate," according to the sample labeling language. Currently, immediate-release hydrocodone's label states that it should be used for relief of moderate to moderately severe pain.

The dosing section of the IR opioid label will change to give "clearer instructions regarding patient monitoring and drug administration," according to an FDA statement on the labeling changes.

Sharon Hertz, director of the Division of Anesthesia, Analgesia and Addiction Products in CDER's Office of New Drugs, said during the conference call that the changes will vary depending on the individual product.

FDA wants to give doctors more help determining the initial dose and changing the dose over time, Hertz said. The existing hydrocodone label includes a table with potential doses based on body weight and age. Sample new language includes comments on conversion from other opioids, including extended-release opioids, as well as advice on titration and maintenance of therapy and discontinuation instructions.

The actual black box warning language will be submitted by each sponsor based on FDA requirements. But the changes should make the immediate-release opioid warnings more closely resemble those of the long-acting and extended-release products.Purdue Pharma LPhad asked for that change, and FDA response to the citizen petition says the safety labeling changes "are similar, but not identical," to the changes made to the long-acting and extended-release opioid label several years ago Also see "Opioid Indication Change Could Draw Legal Challenge From Physicians Group Seeking More Restrictions" - Pink Sheet, 11 September, 2013..

Sample labeling language indicates that the warning could state the product "exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing … and monitor all patients regularly for the development of these behaviors or conditions."

It is nearly identical to the language used in the label for Purdue's extended-release opioid OxyContin (oxycodone).

The new immediate-release boxed warning also will highlight the risk of neonatal opioid withdrawal syndrome (NOWS) with maternal use of opioids during pregnancy.

Extended Release Warnings Strengthened Too

FDA also issued a safety alert the same day indicating that the immediate and extended-release opioid labels will include new information about a potentially harmful interaction with other medications and other adverse events.

The agency said it is requiring opioid labels to note that use with antidepressants and migraine medicines can cause high levels of serotonin to build up in the brain and cause toxicity.

It will be added to the Drug Interactions and Adverse Reactions sections.

Opioids' potential to cause adrenal glands to produce inadequate amounts of cortisol, a rare but serious condition, will be included in the Warnings and Precautions section.

And the risk of decreased sex hormone levels and symptoms such as reduced interest in sex, impotence or infertility associated with long-term opioid use will be added to the Adverse Reactions section.

More Than 200 Products Need Label Changes

The labeling changes likely will take several months – possibly to the end of the year – to implement since 87 innovator and 141 generic products are affected. Hertz said the agency sent the letter mandating the labeling changes to sponsors on March 22. After the agency completes its review of the supplementary applications and approves the new language, the revised labels will be posted on FDA's website and eventually will be made available in print.

Immediate Release Opioids

Boxed warning on risk of misuse, abuse, addiction, overdose and death

Boxed warning on risk of neonatal opioid withdrawal syndrome from chronic use during pregnancy

Indication update stating that immediate-release opioids should be reserved for pain severe enough to require opioid treatment and for which alternative treatments are inadequate or not tolerated.

More dosing instructions added to give prescribers more guidance on patient monitoring and drug administration, including the initial dose, dosing changes and a warning not to abruptly stop use in a physically dependent patient.

Medication guide on opioid use required to be given to patients

Note: Similar provisions already are included in the long-acting, extended-release opioid label and REMS

Immediate and Extended-release Opioids

Information about potential for serotonin syndrome if taken along with an antidepressant and migraine medicine added to Drug Interactions and Adverse Reactions sections

Potential for developing rare condition where the body produces inadequate cortisol amounts added to Warnings and Precautions Section

Risk of decreased sex hormone levels, including reduced interest in sex, impotence or infertility, associated with long-term opioid use added to Adverse Reactions section

[Editor's note: This story has been updated to clarify that black box warning language will be submitted by the sponsor based on FDA requirements.]

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