July 24, 2012
FDA and Extended-Release/Long-Acting Opioids
In our June 28, 2011 Patient Safety Tip of the Week “Long-Acting and Extended-Release Opioid Dangers” we discussed potential dangers of a number of long-acting or extended-release opioids, including fentanyl patches. Then in our September 13, 2011 Patient Safety Tip of the Week “Do You Use Fentanyl Transdermal Patches Safely?” we provided numerous recommendations to improve the safety of fentanyl patches. We stressed the importance of appropriate disposal of such patches because of potential dangers to children and pets.
Now, as one piece of a multi-pronged approach by the government to reduce misuse, abuse and addiction with opioids, the FDA has recently announced a new REMS (Risk Evaluation and Mitigation Strategy) program for extended-release and long-acting opioids (FDA 2012a). The FDA has mandated that the manufacturers of these agents fund educational programs for providers who prescribe these drugs. The educational programs, however, must be based on a “blueprint” established by the FDA. That blueprint also includes educational materials for patients, including not only safe and appropriate use of these agents but also proper disposal techniques (see our May 2012 What’s New in the Patient Safety World column“Another Fentanyl Patch Warning from FDA”).
The materials in the FDA “blueprint” are actually very good. They educate providers and prescribers on abuse potential, tools for screening for addiction, understanding the difference between “opioid-naïve” and “opioid-tolerant” patients, acute vs. chronic pain, titration strategies, potency differences between various products, establishing goals and monitoring effects, and how to counsel patients on use and disposal of opioid products. The document is over 40 pages long but reading it is well worth your while.
These drugs are intended for use in management of chronic pain and in patients who are opioid-tolerant. Yet more and more we are seeing them being used (inappropriately) in patients with acute pain and those who are opioid-naïve. We also see them being prescribed in patients at high risk for respiratory depression, such as those with COPD or sleep apnea. The advice here is important not just to those providers who prescribe these agents but is relevant for anyone who works in an emergency department or hospital or other healthcare facility. We’ve seen cases where application of a new transdermal patch without removal of the old one leads to unintentional overdoses and cases where patients intentionally overdosed on long-acting preparations and did not develop respiratory depression until almost 24 hours later. So a thorough understanding of multiple aspects of these agents and preparations is critical.
The FDA “blueprint” does a good job of discussing abuse/addiction potential and provides tables for each drug preparation that give dosing information, equipotency information relative to morphine, specific instructions and special warnings specific to each drug. It discusses nuances such as which drugs are metabolized via the various cytochrome systems that may lead to drug-drug interactions and which may predispose to the long-QT interval syndrome (torsades de pointes) and which may predispose to the serotonin syndrome or other relatively rare conditions.
The “blueprint” also stresses the importance of educating not only patients who will be using these agents but also their caregivers and families. It is extremely important that the latter understand safe and secure storage and disposal of such agents to reduce the risk that children or pets may inadvertently be exposed to these dangerous agents.
The FDA also just announced it will be forcing companies to remove unapproved oxycodone products from the market (FDA 2012b). Many of these products came onto the market prior to certain FDA regulatory requirements. Currently, the law requires that new drugs be shown to be safe, effective, adequately labeled, and of appropriate manufacturing quality prior to being approved by FDA for marketing in the United States. In an attempt to address this issue, the FDA’s Unapproved Drugs Initiative, which began in 2006, has been systematically targeting marketed unapproved drugs and removing them from the market.
There are FDA-approved versions of these drug products on the market that contain the same active ingredient, strength(s), and dosage forms as the unapproved products. All of the manufacturers of the approved versions of these products have given FDA assurances that they can adequately supply the market.
And talk about good timing! There was just a great article in the New England Journal of Medicine (Boyer 2012) on management of opioid analgesic overdoses. It highlights the pathophysiology, clinical manifestations, management, and special considerations. It points out that tolerance to the respiratory depression from opioids develops more slowly than tolerance to the analgesic effects. This narrows the therapeutic window and, paradoxically, patients with long-standing opioid therapy may be at greater risk for respiratory depression. It highlights, as we have in several columns, that 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. Other clinical pearls are the necessity to totally unclothe the patient so a thorough search for fentanyl patches can be done and to always consider the possibility of coexisting acetaminophen overdose since so many opioid preparations are mixtures of acetaminophen plus the opioid. Good article, great timing!
And we think you’ll learn a lot from our prior articles pertaining to long-acting and/or extended release preparations of opioids:
June 28, 2011 “Long-Acting and Extended-Release Opioid Dangers”
September 13, 2011 “Do You Use Fentanyl Transdermal Patches Safely?”
May 2012 “Another Fentanyl Patch Warning from FDA”
FDA. Extended-Release (ER) And Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). July 9, 2012
FDA. FDA prompts companies to remove certain unapproved oxycodone products from market. July 5, 2012
Boyer E. Management of Opioid Analgesic Overdose. N Engl J Med 2012; 367: 146-155