Despite concerns that a proposed new drug would push a more effective and less expensive treatment off the table, the FDA Psychopharmacologic Drugs Advisory Committee recommended in April that the FDA approve lofexidine to treat opioid withdrawal symptoms.

The FDA will consider the Advisory Committee's nonbinding recommendation in its review of the NDA for Lucemyra. The agency has set a Prescription Drug User Fee Act (PDUFA) target action date in the second quarter of 2018. If the FDA gives it the go-ahead, lofexidine would be the first nonopioid drug approved by the FDA to treat opioid withdrawal.

FDA staff have some concerns about the drug, however, and presented those concerns to the Psychopharmacologic Drugs Advisory Committee on April 2.

Concerns include the quality of the data, whether there is enough of it, and whether it is clinically significant.

Economic questions have arisen among physician readers of the news story posted by MedPage Today,1 even though those concerns are not raised in the main article, which focuses on the FDA staff concerns about efficacy and the quality of the data. The economic concerns are whether lofexidine is any more effective than clonidine. Both are [alpha]-2 adrenergic agonists. Clonidine is already prescribed off-label to treat opioid withdrawal symptoms.

The concerns raised by the staff about lofexidine, which was submitted by its manufacturer, US WorldMeds (Lexington, Kentucky), include:

* Lofexidine's base of evidence consists of 2 inpatient studies of patients who abruptly stopped short-acting opioids, and may not be clinically meaningful and effective;

* The data are described as "very limited" beyond 5 days of dosing;

* The drug trials focused only on short-term use in patients quitting opioids abruptly, and therefore do not provide enough data about its use in tapering opioids; and

* The trials reported cardiovascular side effects, including bradycardia and hypotension.

Economic Impact and Access

Among the physician readers who commented, the concern is that lofexidine, if it is approved for treating withdrawal, could supersede the off-label prescribing of the much less-expensive clonidine for treating withdrawal. They question whether lofexidine will be safer and more effective than clonidine to the point of justifying its greater cost.

One reader commented that she has used clonidine for years to detox opioid-dependent patients "without any untoward effects. This is a very safe detox drug and the minimal side effects from hypotension [are] corrected by increasing the fluid intake of the individual."

Another reader commented: "A great story on how to use the regulatory structure and the law to enable pharma to make obscene profits. The questions that are not pertinent to approval, but should be: Does pre-clinical evidence indicate the mechanism of action is the same as clonidine? If so, the pertinent questions to approval are: Is there any evidence it is superior, or safer, or in any other way offers a benefit that clonidine does not?"

The commenter also noted that there is "far more real world data on risks, benefits, and side effects of clonidine than [lofexidine]. Yet if this is approved, it will be the only alpha-2 agonist approved for use in opiate withdrawal. The price of this patented drug will be orders of magnitude higher than clonidine. The net effect is that access to any alpha-2 agonist in opiate withdrawal will be reduced."

Yet, another who had been prescribing clonidine wrote, "I am wondering if lofexidine has an increased efficacy to warrant the cost? If it is used by the British NHS then I would hope it has a generic dose available at a reasonable cost."

Marketed as Lucemyra, lofexidine is an oral tablet. Like clonidine, it is a selective alpha 2-adrenergic receptor agonist that reduces the release of norepinephrine. In clinical trials, lofexidine significantly reduced the severity of withdrawal symptoms compared to placebo as reported by patients experiencing opioid withdrawal. According to US WorldMeds, clinical trials with lofexidine showed that patients who were treated with it while they underwent opioid withdrawal reported the drug significantly reduced the severity of withdrawal symptoms compared with placebo.

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