WASHINGTON -- FDA staff expressed numerous concerns about the safety and efficacy of lofexidine, a novel non-opioid drug intended to treat symptoms of opioid withdrawal, in briefing documents prepared for an advisory committee meeting on Tuesday.
Among them: the drug's trials focused only on short-term use in patients quitting opioids abruptly, raising questions as to whether it would be of any use in other, arguably more common situations including opioid taper.
And the review pointed up several adverse cardiovascular effects seen in the trials, including bradycardia and hypotension.
If approved, lofexidine -- developed by with a proposed trade name of Lucemyra -- would become the first non-opioid medication approved to treat opioid withdrawal and the first drug approved to help patients successfully terminate their opioid discontinuation treatment.
The is scheduled to vote on two overarching questions:
- Whether "the data provide substantial evidence of effectiveness" for relieving opioid withdrawal symptoms
- Whether the drug should be approved for this purpose in the context of abrupt opioid discontinuation
The committee is also being asked to discuss the drug's potential to help patients withdraw completely from opioid dependence, according to the FDA's .
Other topics the committee is schedule to address:
- Dosing recommendations
- Whether the available safety data regarding the medication is substantial enough "to support use between 7 and 14 consecutive days"
- Issues to be addressed in post-marketing studies
is an alpha-2 adrenergic agonist -- similar to clonidine, which FDA staff noted is often used off-label for opioid withdrawal symptoms -- slated to be part of a long-term treatment plan when patients stop using opioids.
The new medication's evidence base is limited to two "brief" inpatient studies of OUD patients who suddenly stopped using short-acting opioids, according to the FDA staff review.
US WorldMeds said the studies demonstrate the drug's ability to reduce opioid withdrawal symptoms in this situation, and that the drug "increases the likelihood that the course of withdrawal treatment will be completed, and the patient will reach a state of no longer being physically dependent."
"But," the FDA briefing document noted, "how can we interpret the information on symptomatic relief to determine whether the effect is not just statistically significant, but clinically significant? How do we know if the drug has made enough difference to be clinically meaningful?"
Moreover, the document emphasized that the company's studies did not directly demonstrate that the symptomatic relief "translates to improvement in completion of detoxification."
The study data are "very limited" beyond five days of dosing and does not detail the effects of administering the smaller dosages studied in other, older medical literature.
In addition, FDA staff noted that dropout rates in the two studies were very high -- well over half by day 7 in the lofexidine groups, although discontinuations were even more common in the placebo groups.
Concerning side effects and adverse events, lofexidine "causes clinically significant hypotension, bradycardia, and orthostatic hypotension in a dose-dependent fashion," according to the briefing document's safety summary.
The United Kingdom approved lofexidine in the mid-1980's to relieve symptoms "in patients undergoing opiate detoxification," with patients in the 1990's typically taking doses between 1.6-2.2 mg for a median of 10 days.
The FDA committee is chaired by Rajesh Narendran, MD, a University of Pittsburgh psychiatrist. The FDA is not obliged to follow its advisory committees' recommendations but it usually does.