Saturday, September 26, 2009

New Opioid, Exalgo, on Slippery Slope of REMS

[ADDENDUM: Exalgo was FDA-approved for marketing on March 1, 2010 with a risk evaluation and mitigation strategy (REMS) program that requires education for healthcare providers and a patient medication guide. However, the previously proposed program requiring the registration of prescribers and patients was not part of the REMS. -- SBL]

On September 23, 2009 an FDA expert panel endorsed manufacturer plans to introduce Exalgo™, a new extended-release formulation of hydromorphone. Final FDA approval of the analgesic, possibly in November, would include a REMS (Risk Evaluation and Mitigation Strategy) program that may portend the future of regulatory burdens on opioids and have serious negative consequences for both healthcare providers and patients.

Developed by Neuromed (Vancouver, BC) and licensed to Covidien (St. Louis, MO) for United States distribution, Exalgo is a once-daily formulation of hydromorphone intended for the treatment of moderate to severe pain. Currently, only an immediate-release hydromorphone (eg, Dilaudid® and others), dosed every 4 to 6 hours, is available as an oral formulation in the U.S. The new extended-release version uses a novel bilayer tablet system, the OROS® Push-Pull™ technology, to release hydromorphone at a relatively constant rate during a 24-hour period. As with all other opioids, the primary risks of Exalgo are overdose, abuse, and diversion, which can be associated with inappropriate prescribing, dispensing, use, and handling. Therefore, to help win FDA approval, Neuromed proposes a REMS program called the “Exalgo Alliance (The Alliance for Responsible Exalgo Prescribing and Use),” which is a controlled access program including the following elements [also see Neuromed Briefing Material]:

  • Exalgo will be available exclusively through the Alliance program and practitioners can only prescribe the product after they have demonstrated their understanding of the drug’s risks and enrolled in the program.

  • Exalgo can only be used to treat patients who are enrolled in the Alliance program and have signed an agreement with their prescriber acknowledging that they understand the risks and will adhere to responsible drug use and handling.

  • The product can only be dispensed by pharmacies and in other healthcare settings that have demonstrated an understanding of Exalgo risks and are enrolled in the Alliance program.

  • Wholesalers and distributors must agree to sell Exalgo only to enrolled pharmacies and healthcare settings.

  • Pharmacists must verify that both the prescriber and the patient presenting a prescription are enrolled in the Exalgo Alliance and that they are adhering to program requirements, including safe-use conditions being followed by the patient.
Upon FDA approval of Exalgo, implementation of the REMS and program monitoring will be handled by Covidien. Details of enrollment procedures (including education) and the various paperwork that may be required on a continuing basis are unspecified at this time. However, it is clear that Exalgo will incur a considerable burden of time and effort throughout the distribution chain, involving prescribers, distributors, dispensers, and patients — and, no doubt, this would entail added expense.

Commentary: According to a Reuters news report, the FDA’s experts largely agreed that Exalgo could be beneficial and was more convenient but they said the manufacturer needed to closely watch how the drug was used. According to panel chairman, Jeffrey Kirsch, MD, the panel felt Exalgo was "…very prone to crushing and other methods of abuse. On the spectrum of abuse, I think it's toward the top." Yet, the FDA Briefing Material for the meeting [available here] provides no data indicating exceptional abuse liability for hydromorphone. For example, one of the FDA’s citations in their briefing document refers to a clinical study conducted in only 9 subjects that found hydromorphone was no different in abuse potential than hydrocodone or oxycodone [Walsh et al. 2008].

The FDA briefing also mentioned the government’s DAWN report as a data source [SAMHSA 2008]; however, the most recent data, for 2006, indicates hydromorphone products accounted for less than 1% of nonmedical use of all pharmaceuticals, less than 3% of such cases involving opioid agents, and it was implicated in less than 1% of all drug-related suicide attempts. Data provided by the manufacturer covering 12 clinical trials specifically of Exalgo indicated there were only 44 cases of *possible* misuse/abuse among 2811 patients treated [see Neuromed briefing material, p 82]. Furthermore, according to FDA data in its briefing document, hydromorphone has not been a frequently prescribed analgesic; in 2008 there were 1.9 million prescriptions dispensed for IR-hydromorphone but this represented merely 1% of the total market for all IR-opioid analgesics. And, the total market for extended-release opioids was small; less than 9% of the overall opioid-analgesic market. So, looking at all available data, one must question why a new extended-release version of hydromorphone would merit such an extensive and restrictive REMS program.

Last July we expressed concerns about the highly restrictive and costly REMS program associated with Onsolis®, a new, rapid-acting, buccal-soluble fentanyl product for acute breakthrough pain [see blogpost 7/17/09]. At the time, the FDA claimed that this was an exceptional case and not typical of what might be required for extended-release opioid analgesics. Now, along comes the REMS for Exalgo, specifically described as a “controlled access” program and seeming to impose onerous obstacles remarkably similar to many of those for Onsolis. And, all of this appears like an “end run” that circumvents and undermines efforts by opioid manufacturers and other groups who have been working for many weeks under an FDA mandate to develop a rational class-wide REMS covering all extended-release and long-acting opioids.

Some very serious and disturbing questions need answers: Is the restrictive Exalgo REMS a harbinger of what lies ahead for all opioid analgesics? Will there eventually be separate REMS programs for every opioid analgesic, each with its own registration requirements and prescribing procedures? How will healthcare providers cope with this? How many patients with chronic pain might ultimately suffer from reduced access to opioid analgesics as a result?

> Briefing Information for the September 23, 2009 Joint Meeting of the Anesthetic Life Support Drugs Advisory Committee with the Drug Safety and Risk Management Advisory Committee Meeting Announcement. FDA Briefing Material —
PDF available here. Neuromed Briefing Material — PDF available here.
> SAMHSA (Substance Abuse and Mental Health Services Administration), Office of Applied Studies. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-30, DHHS Publication No. (SMA) 08-4339, Rockville, MD, 2008 [
report available here].
> Walsh SL, Nuzzo PA, Lofwall MR, Holtman Jr JR. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend. 2008;98(3):191-202 [see


sulley said...

Onsolis and possibly Exalgo getting approval with their own proprietary opioid REMS is the beginning of a mudslide which could result in the FDA losing interest in developing a unified, comprehensive opioid REMS because the drug manufacturers bring them to the approval table already figured out, making things very easy for the FDA to leave them untouched (or slightly modified). This then ignores the possibility that prescribers, distributors, pharmacists, and patients may have to jump through the hoops of multiple drug company's proprietary REMS which at an absolute minimum would delay availability of a drug to the patient.

What about the cost of each drug's own REMS implementation and administration costs (which will increase the drug's cost outrageously)? How is a patient on multiple opioids supposed to keep each drug's REMS clear to make sure they can continue to get their medication without interruption? Of primary importance, what about the prescribers, who may use all of these different manufacturer's opioid drugs (since pain management, when it is most effective, is an individualized process) and then have to keep strict track of all of the company's different REMS requirements? If they fail to keep up with a change in a single detail of just one of a dozen or more different companies REMS' requirements, it could result in their patient's prescription not being filled at the pharmacy (if the patient could even afford it anyways)? What does the patient do then? Let me metion one thing again, the cost of this to the insurance companies (if they pay for any of these drugs at all because of the high cost of the administrative components of each different REMS) and ultimately the patients when they can't pay for the drug and suffer because of it? This is as bad as a mudslide or a wildfire at its onset -- uncontrollable, unmanageable, and unrelenting in its human costs which is the pain that results in lives being stopped in their tracks or never even given a chance to get started. It's an atrocity that cannot be allowed to happen.

The FDA can and should be approving opioids as they are made produced and determined safe, however until a unified, comprehensive opioid REMS is developed, their release should be delayed. It would put those drug companies with such drugs waiting for a release approval in a position to help support the already combined efforts of other opioid manufacturers and interested groups in forulating an opioid REMS which would be universal. Neither Onsolis (with fentanyl having mutilple delivery routes already available) nor Exalgo (with hydromorphone having less than a 1% share of the opioid prescriptions dispensed in 2008) are earth-shattering enough to warrant an exception to this rule -- plain and simple.

The FDA needs to place the emphasis (and their time) in supporting the opioid manufacturers and interested groups already working to develop a unified, comprehensive opioid REMS that the FDA is comfortable with. That's where the focus should be right now -- not in developing stop-gap REMS for manufacturers that want their products on the market now so they can begin to recoup their R&D costs quickly, especially when the products are not revolutionary.

This is an idea that ultimately helps the patients (and protects those who might be able to abuse or misuse the drugs by diversion, etc.) by placing the efforts of the drug manufacturers, interested groups, and the FDA on one goal -- creating a unified, comprehensive, and reasonable opioid REMS for both short and long acting opioids. The FDA should not be spending time examining every different company's REMS that is brought to them to see if it would work and provide safety. Their focus should be on a universal opioid REMS. It's as simple as that!

Anonymous said...

I don't understand this comment here:

-> According to panel chairman, Jeffrey Kirsch, MD, the panel felt Exalgo was "…very prone to crushing and other methods of abuse. On the spectrum of abuse, I think it's toward the top."

According to drug users online, Jurnista (exactly the same as exalgo) is unbreakable! This is coming from guys who are trying to abuse this stuff.

SB. Leavitt, MA, PhD said...

In reference to above comment… we didn’t understand the FDA panel's concerns either, since there was nothing in the background data to suggest any exceptional abuse potential for Exalgo, via crushing or otherwise. Jurnista isn’t marketed in the U.S. and, while it appears to use the same technology as Exalgo, perhaps it is somehow different (ie, crushproof?).

The FDA is expected to make a final go or no-go decision on Exalgo next week (March 1, 2010). However, with such a restrictive REMS blanketing the product we wonder if it would even be prescribed very often. -- SBL

Anonymous said...

I have recently been prescribed Exalgo for long-term chronic pain. To answer the question about "crushablilty" : I accidently dropped one on the floor and then rolled over it with my very heavy desk chair (heavy enough to pulverize any other pill I've ever come across). Aside from some bruising to "paint" (the thin orange coating on which the pill's information is printed), there appeared to be no damage whatsoever to pill's casing. Before flushing the pill, I scraped off the thin orange coating and noticed that one half of the pill is white, while the other half is a dark grey. There appears to be a very tiny hole in the middle of the white half (size of a pinprick), which may be how the medication is released? Also, the pill casing is not dissolved through digestion: it appears whole when passed as stool.

Perhaps someone here should examine a tablet and revise this page based on first-hand observations.

Anonymous said...


Anonymous said...

I have been taking this medicine for 1 month and haven't seen a huge relief in pain. I was taking oxycontin 30mg and was not getting any relief at all. This Med is new and is supposed to be the safest and strongest out there. I am not very impressed with it at all. I wish there was something out there that would help me......