March 28, 2018
A US Food and Drug Administration (FDA) advisory committee has recommended approval of lofexidine hydrochloride, a nonopioid, for the mitigation of symptoms in the setting of abrupt opioid withdrawal.
If the FDA follows the panel's advice — as it usually does — lofexidine, an α2-adrenergic agonist, would join clonidine (multiple brands) in the withdrawal toolbox. Clonidine has been used off label as a nonopioid for the management of withdrawal symptoms, but it's not clear how often it is employed. Most cases of opioid withdrawal are treated with opioid therapies such as methadone or buprenorphine in conjunction with gradual tapering.
The Psychopharmacologic Drugs Advisory Committee voted 11-1 that lofexidine be marketed as Lucemyra (US WorldMeds). It was found to be both safe and effective in reducing symptoms such as diarrhea, nausea, vomiting, anxiety, and an overall feeling of sickness that often keeps patients from successfully withdrawing from opioids.
"This is an extraordinarily difficult cluster of symptoms to treat, and I felt that the differences shown were clinically meaningful," said Felipe A. Jain, MD, assistant clinical professor of psychiatry, University of California, San Francisco.
The advisory panel member who voted against approval — consumer representative Kim O. Witczak — said she believed the company had not shown enough evidence of efficacy, especially in helping people completely withdraw over the long term.
In addition to approval for the management of symptoms, US WorldMeds was seeking approval to claim that lofexidine facilitates completion of abrupt opioid discontinuation treatment.
Witczak also said she was concerned about safety signals, including an increase in the incidence of bradycardia, hypotension, and syncope associated with lofexidine in studies.
She said, "I'm concerned with the marketing aspect" and how issues of safety and effectiveness "get communicated to the public."
Safety was also on the minds of other panelists, who said they did not believe the 3.2-mg daily dose being proposed by US WorldMeds should be approved. In one of the company's pivotal studies, patients who received that dose experienced slightly greater relief, but there was also a higher incidence of cardiovascular side effects.
The company has also proposed selling a 2.4-mg daily dose, which most advisory committee members said was more appropriate.
New Life for an Old Drug?
Lofexidine is an old drug — it's been marketed in the United Kingdom as BritLofex since 1992 — but it has never been available in the United States. In the United Kingdom, the recommended dose is 2.4 mg/day; the typical treatment duration is 7 days.
In its two pivotal trials, US WorldMeds tested different doses and durations of use.
In study 3002, patients with opioid use disorder and physical dependence on heroin or short-acting opioids were randomly assigned to receive placebo or lofexidine 3.2 mg daily for 5 days. In study 3003-1, a similar patient population was randomly assigned to receive placebo, lofexidine 3.2 mg daily, or lofexidine 2.4 mg daily for 7 days.
Patients were recruited at academic research units, community treatment centers, or private research centers through advertisements or because they had arrived seeking treatment. All were treated in bed-based care settings. Enrollees had to be actively withdrawing, as defined by an Objective Opiate Withdrawal Scale score of 2 or greater, just prior to randomization.
Patients could not be experiencing a psychological or medical condition that prevented study participation. In addition, patients were excluded if they used any of a wide range of medications, including many psychiatric drugs.
The company enrolled 264 patients in study 3002 and 602 patients in study 3003-1. Efficacy was evaluated using the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop), which asks patients to rate 10 symptoms as to degree. Symptoms could be rated none, mild, moderate, or severe. The maximum possible score is 30, which would mean a rating of severe for every symptom.
Both FDA and USWorldMeds agreed that patients who took lofexidine in the 3002 study experienced a significant 2-point-lower score on the SOWS-Gossop in comparison with patients who took placebo. The difference was less pronounced in study 3003-1 — there was only a 0.3 difference, according to the FDA.
But overall, the odds of completing withdrawal were significantly higher in both studies for patients taking lofexidine.
High Dropout Rate
The odds were better even though large numbers of patients did not complete withdrawal.
In study 3002, 49% of lofexidine patients completed the 5-day treatment regimen and were discharged on day 6 or later, compared to 33% of patients who received placebo. For the second pivotal trial, 41% of patients who received lofexidine 2.4 mg and 40% of those taking 3.2 mg completed 7 days of treatment, compared to 28% of those taking a placebo.
The missing data were initially of concern, said FDA reviewers, but ultimately, they said that sensitivity analyses supported the primary efficacy findings.
Discontinuations were highest among patients taking the 3.2-mg dose. In the pivotal 3003-1 study, 5% of patients taking that dose discontinued because of bradycardia, and 3% discontinued because of hypotension, orthostatic hypotension, and insomnia (3% for each disorder).
The FDA also said that lofexidine prolongs the QTc interval — a problem that advisory committee members said should be monitored should the drug be approved and marketed.
The FDA is due to make a decision on lofexidine by May 26.
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