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