What’s New in the Patient Safety World

February 2017

FDA Approves Even More Long-Acting Opioids

 

 

The FDA has just approved another long-acting opioid (FDA 2017). So we’ll take this opportunity to repeat our warnings and concerns about the use of such drugs. For quite some time now we have highlighted the dangers of long-acting and/or extended-release opioids (see our Patient Safety Tips of the Week for June 28, 2011 “Long-Acting and Extended-Release Opioid Dangers”, July 24, 2012 “FDA and Extended-Release/Long-Acting Opioids” and February 24, 2015 “More Risks with Long-Acting Opioids”).

 

The newly approved drug, Arymo ER, is an extended-release tablet formulation of morphine sulfate, designed with properties intended to deter abuse based on its physicochemical properties. The proposed indication is the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. It is unique in that it is formulated to give it physicochemical properties expected to make abuse by injection difficult. Apparently the manufacturer had hoped to be allowed to claim the drug deters abuse by snorting or chewing it but the FDA approval did not allow that claim.

 

One of the elements of the FDA Opioids Action Plan is to expand access to abuse-deterrent formulations to discourage abuse. That is essentially developing formulations that abusers cannot manipulate and use the opioid for intravenous, intranasal, or oral abuse.

 

But our concerns about the safety of long-acting or extended-release opioid formulations extend well beyond the issue of manipulating the product for abuse. Such preparations have other dangers (well described in our Patient Safety Tips of the Week for June 28, 2011 “Long-Acting and Extended-Release Opioid Dangers”, July 24, 2012 “FDA and Extended-Release/Long-Acting Opioids” and February 24, 2015 “More Risks with Long-Acting Opioids”).

 

First and foremost is that these long-acting and extended-release opioid formulations are not intended for use as first-line agents in opioid-naοve patients. The newer opiate formulations are either more potent or designed to produce a longer peak action, two characteristics that lead to some of the greatest dangers. These have been designed to be used in patients who are opioid-tolerant and have pain of a chronic nature that has not been controlled with more conventional opiates. They were not intended to be used for treatment of acute pain nor to be used as first line agents in patients with pain. But in practice they are often being (mis)used in that way.

 

A second significant factor related to the association between long-acting opioids and overdoses is dosage equipotency. The amount of morphine equivalents in these preparations is typically higher than that found in most short-acting formulations and many prescribers are not appreciative of this. Of course, the issue of dose is not unique to the long-acting opioids. We’ve highlighted the same problem with HYDROmorphone in our September 21, 2010 Patient Safety Tip of the Week “Dilaudid Dangers” and the other columns on HYDROmorphone safety issues listed below. It is also problematic that when switching from short-acting opioids to long-acting or extended-release opioids it is very common to see misunderstandings of the relative potencies of the various opiate preparations.

 

We’ve also seen patients develop delayed-onset coma after attempting suicide. If the specific formulation they took is unknown, they may be evaluated in an ER prior to admission to a behavioral health unit, at which time they lack clinical signs of opioid intoxication and may have very low toxicology levels. They are given “medical clearance” and admitted to the behavioral health unit. Overnight they get further release of the opioid into their bloodstream and the following morning they may be comatose.

 

Another important issue for these long-acting and extended release opioids is the phenomenon of re-narcotization. The effect of the reversal agent naloxone may wear off long before the effect of the opioid wears off, raising the danger of recurrence of respiratory depression.

 

We’ve also seen rare cases in which patients on these long-acting opioid formulations have developed acute opioid withdrawal symptoms following naloxone injections.

 

Note that long-acting opioid formulations (particularly those in transdermal patches) are also now frequent causes of accidental overdoses, including those for whom they were not prescribed such as children and pets (see our September 13, 2011  Patient Safety Tip of the Week “Do You Use Fentanyl Transdermal Patches Safely?” and our May 2012 What’s New in the Patient Safety World column “Another Fentanyl Patch Warning from FDA”).

 

So even though we appreciate the FDA’s vision of abuse-proof formulations, we are concerned about the ever increasing availability of long-acting or extended-release opioid formulations. Ironically, the following quote from the FDA briefing document (FDA 2016) for the advisory committee meeting that evaluated the new opioid formulation says a lot about the siloed nature of our healthcare system: “There has been much discussion at recent advisory committee meetings about whether any new extended-release opioid analgesics are necessary or should be approved. As long as a product meets the regulatory standards for approval, whether or not there is need for a new version of an opioid is not a criterion for not approving the product.”

 

And as if that were not enough, as we went to post this column we received word the FDA (FDA 2017b) has just approved yet another extended-release opioid formulation: Vantrela ER (hydrocodone bitartrate)! FDA documents (FDA 2017c) note that “the physical and chemical properties of Vantrela ER are expected to make intravenous (injection) abuse difficult and are expected to reduce, but not eliminate, abuse by nasal and oral routes. However, abuse of Vantrela ER by these routes is still possible.”

 

 

Our prior articles pertaining to long-acting and/or extended release preparations of opioids:

 

 

Our prior columns on patient safety issues related to Dilaudid/HYDROmorphone:

 

 

References:

 

 

FDA (US Food & Drug Administration). Impact of Exclusivity on Approval of Arymo ER. FDA 2017; January 9, 2017

http://www.fda.gov/Drugs/DrugSafety/ucm535708.htm

 

 

FDA (US Food & Drug Administration). Fact Sheet – FDA Opioids Action Plan. Accessed January 23, 2017

http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm484714.htm

 

 

FDA (US Food & Drug Administration). FDA Briefing Document. Joint Meeting of Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee. August 4, 2016

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM514378.pdf

 

 

FDA (US Food & Drug Administration). Approval letter for Vantrela ER (hydrocodone bitartrate) extended-release tablets. January 19, 2017

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/207975Orig1s000ltr.pdf

 

 

FDA (US Food & Drug Administration). Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse. January 17, 2017

http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm338566.htm

 

 

 

 

 

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