Abuse-Deterrent Hydrocodone ER Safe, Effective in Back Pain

Pauline Anderson

October 04, 2016

SAN ANTONIO — As an abuse-deterrent version of hydrocodone extended-release (ER) moves closer to market, the company developing the product (Vantrela ER, Teva Pharmaceutical Industries) has released additional data.

A 6-month extension of a phase 3 randomized study shows that the drug provided adequate pain relief, had acceptable adverse events (AEs), and didn't have a high rate of diversion.

The new data were presented here at the American Academy of Pain Management (AAPM) 2016 Annual Meeting. The society has recently changed its name to the Academy of Integrative Pain Management.

A formulation of hydrocodone bitartrate, the product incorporates an abuse-deterrent technology called CIMA. The product has three separate layers that help resist drug extraction via the most common routes.

The company's pivotal 12-week, double-blind, phase 3 study included 370 patients who had a 3-month or longer history of moderate to severe lower back pain. Patients were randomly assigned to abuse-deterrent hydrocodone ER (30 to 90 mg every 12 hours) or placebo.

That study showed that hydrocodone ER was significantly more effective than placebo in alleviating chronic low back pain requiring treatment with opioids. The safety profile was consistent with the known safety profile of hydrocodone and other opioid analgesics.

Patients in that study had the opportunity to be included in this extension study. It enrolled 182 patients who received at least one dose of study drug and were included in the safety analysis. This included 78 patients who had received placebo in the previous study.

The mean age of enrolled patients was 52.1 years, and 69% of patients were white.

Patients who had been receiving hydrocodone ER continued their identified analgesic dose unless adjustments were needed. Those receiving placebo underwent dose titration/adjustment to an analgesic dose (30 to 90 mg every 12 hours).

Of the 182 patients, 170 achieved a successful analgesic dose of hydrocodone ER (so they reached an adequate level of analgesia without undesirable safety concerns) and were included in the 22-week open-label extension phase. Of these, 136 completed the study.

"There was a small number of patients who were unable to identify an analgesic dose — that's not unexpected," said Richard Malamut, MD, vice president of global clinical development and therapeutic area and head of pain, Teva Pharmaceuticals USA.

Still Safe

The extension study provided important additional safety information. "We wanted to take the opportunity to gain more information on these patients for an additional 6 months," commented Dr Malamut.

AEs were reported in 36% of patients during the dose titration/adjustment phase and 52% during open-label treatment.

The most common AEs during open-label treatment were constipation (7%) and nausea (6%). Most AEs were mild to moderate.

One severe AE of neurosensory deafness was considered treatment related. Because hearing loss may be a risk of hydrocodone drugs, all patients had undergone pure tone audiometry, said Dr Malamut.

Researchers defined stable pain relief as an average pain intensity score of 4 or less, a worst pain intensity score of 6 or less over the preceding 24 hours, and use of rescue medication at 20% or less of the daily hydrocodone ER dose for 3 consecutive days while on the same dose of study drug.

This extension study found that most patients maintained their analgesic benefit. Only about 4% of patients increased (and the same percentage decreased) their dose during open-label treatment.

The most common stable dose was 30 mg every 12 hours among patients who were opioid naive before the previous study and 90 mg every 12 hours for those who were opioid experienced.

As for diversion, the researchers found that 3% reported diversion and 3% reported medication "loss."

The rate of diversion is determined through pill counts and patient explanation of missing pills. Although this method is "unfortunately subjective," patients appear to be forthcoming with relevant information, said Dr Malamut. "You would have thought patients wouldn't volunteer such a thing, but they do."

Across the company's entire program for its abuse-deterrent formulation — and that of other companies too — the rate of drug diversion is more like 1%, "which is pretty low," said Dr Malamut.

At a June joint meeting of the US Food and Drug Administration (FDA) Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee, members voted to approve Vantrela ER and recommended that labeling for the oral, intranasal, and intravenous versions of the drug reflect its abuse-deterrent properties.

"We have demonstrated that when abusers crush our product, they don't get the euphoria they're after; the drug is not liked and the pharmacokinetics, the amount released, is not increased, so they don't get that spike," said Dr Malaut. "Likewise, when abusers crush our product into a powder and snort it, they don't get the high."

And in vitro studies demonstrated "that our product, when crushed and put into various solutions, was not 'syringeable;' you have difficulty getting it into a form where you can inject it."

Another "key deterrent" of the product, added Dr Malamut, is that excessive amounts of the drug are not released when dissolved in alcohol.

The company has submitted a new drug application for the product.

Long Wait

Asked to comment on this new research, Bob Twillman, PhD, executive director, Academy of Integrative Pain Management, said it's very welcome.

"Clinicians have been waiting for an abuse-deterrent ER hydrocodone product for some time."

The previously marketed non–abuse-deterrent ER hydrocodone product (Zohydro ER, Zogenix) was "very controversial" because it could relatively easily be crushed and then snorted or injected, and some US states, "notably Massachusetts," even went so far as to try to ban it, said Dr Twillman.

(The FDA has since approved an abuse-deterrent version of the single entity hydrocodone, Zohydro Extended Release Capsules, CII).

"We need an ER hydrocodone option and it's good to see that we may now have an abuse-deterrent version that works."

The new results are "encouraging" and suggest that "this particular product can be used safely and effectively to treat chronic pain, and it gives prescribers one more tool for their pain care toolbox," said Dr Twillman.

The study was sponsored by Teva Branded Pharmaceutical Products R & D Inc. Dr Malamut is an employee of Teva Pharmaceuticals Inc. Dr Twillman has disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 2016 Annual Meeting. Poster 11. Presented September 23, 2016.

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