Phase 3 Studies Support Stand-Alone Hydrocodone Formulation

September 27, 2012 (Phoenix, Arizona) — A novel single-entity, extended-release formulation of hydrocodone (Zohydro, Zogenix) is moving closer to possibly becoming the first drug of its kind on the US market to offer long-lasting stand-alone opioid pain management without being combined with a nonopioid analgesic, new research suggests.

Hydrocodone is currently available only in combination with nonopioid analgesics, such as acetaminophen, which prevents clinicians from titrating doses to therapeutic levels because of the risks for liver toxicity.

The new drug, hydrocodone bitartrate (HC-ER), would be the first to allow clinicians to manage moderate-to-severe manage pain without that concern, according to the investigators. Manufacturer Zogenix filed a new drug application for the product in May 2012, and the drug is under review by the US Food and Drug Administration.

The phase 3 trial results were presented here at the American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting.

Pivotal Trial

Phase 3 clinical trials included a pivotal double-blind, placebo-controlled trial of HC-ER in which opioid-experienced patients with moderate to severe chronic low back pain were assigned to a conversion/titration phase for up to 6 weeks, followed by a 12-week placebo-controlled, randomized treatment phase.

In the conversion phase, patients underwent titration to a stabilized dose of 20 to 100 mg twice daily. The groups of 151 patients each then received the stabilized HC-ER dose or placebo. Each day patients in both groups were permitted up to 2 tablets of hydrocodone bitartrate 5 mg/acetaminophen 500 mg.

The study's primary efficacy endpoint was a mean change in average pain intensity score from baseline to day 85 using a 0 to 10 numeric rating scale. A secondary endpoint was treatment response, defined as treatment phase completion with 30% or greater average improvement in pain intensity score from screening to day 85.

At the end of the 12-week treatment phase, the HC-ER group showed a significantly lower mean (± standard deviation) change in average pain intensity score than the placebo group (0.48 ± 1.56 vs 0.96 ± 1.55; P = .008).

The percentage of responders in the HC-ER group was significantly higher than that in the placebo group (68% vs 31%; P < .001), and mean increases in pain intensity score from baseline were significantly less with HC-ER than with placebo for worst pain (0.42 ± 1.76 vs 1.03 ± 1.79; P = .002) and least pain (0.50 ± 1.43 vs 0.98 ± 1.47; P = 0.004).

Patients in the HC-ER group meanwhile had a lower mean total daily use of the rescue medication use during the treatment phase versus placebo (6.0 ± 3.4 vs 7.5 ± 3.9 mg), and they were also less likely to discontinue treatment compared with patients receiving placebo (P ≤ .001).

The adverse events were similar to those seen with other opioids.

Open-Label Study

A second multicenter, open-label study evaluating the drug for long-term safety and efficacy enrolled 638 patients. Among them, 424 (66%) completed the conversion/titration phase, which lasted up to 6 weeks, and 285 of those 424 (67%) completed the treatment phase, which lasted up to 48 weeks.

The results showed a safety profile consistent with that of other opioids; the most common adverse events were constipation (53 of 424; 13%) and back pain (47 of 424; 11%).

The most frequent adverse events that led to study discontinuation in the conversion/titration phase were nausea (10 of 638; 2%), somnolence (9 of 638; 1%), insomnia (7 of 638; 1%), lethargy (7 of 638; 1%), and headache (7 of 638; 1%).

In the conversion phase, the most frequent adverse events that led to discontinuation were constipation, upper abdominal pain, and cognitive disorder. Four patients died during the study, but all deaths were considered unrelated or unlikely to be related to HC-ER.

The study showed no trends in terms of laboratory measures or vital signs.

A disability and satisfaction study of the same cohort showed similar positive results. Patients' mean Oswestry Disability Index score at screening was 41.2% ± 14.9%, within the lower limit for severe disability ( > 40% to 60%).

The mean score improved to 31.0% ± 14.5% at baseline and was maintained at week 48 (n = 285) or until the study termination (34.1% ± 17.3%). The score was near the midlevel of moderate disability ( > 20% to 40%).

The percentage of patients who reported being "very much" or "completely" satisfied with their treatment, according to the Subject Global Assessment of Medication, increased from just 20.5% at screening to 82.3% at baseline and 72.7% at the study's end.

"HC-ER appeared to reduce disability and increase overall satisfaction in subjects with chronic pain who require around-the-clock opioid therapy," the authors write.

Schedule II Drug

According to coauthor Srinivas R. Nalamachu, MD, Zohydro is classified as a Drug Enforcement Agency Schedule II drug product, meaning it would carry stricter prescription and dispensing rules compared with the currently available hydrocodone combination products, which are typically Schedule III.

"When hydrocodone is sold as a single entity, it will be a Schedule II, so it will be a little less convenient, but the fact is that the world has changed since the original hydrocodone, with issues," Dr. Nalamachu said.

The trade-off will be the ability to manage pain more consistently, Dr. Nalamachu noted.

"Right now you can get relief for 4 or maybe 6 hours, and some patients really have anxiety in worrying when the next pain will emerge before they can take their next pill," he said. "But with the controlled release you get pain control around the clock, without the ups and downs of pain."

Other pharmaceutical companies that are also developing extended-release, stand-alone hydrocodone products include Purdue Pharma, Cephalon, and Egalet.

Pain management specialist Forest Tennant, MD, director of the Veract Intractable Pain Clinic in West Covina, California, said clinicians have long desired an extended-release opioid formulation that can be provided to patients without the concern for liver toxicity associated with acetaminophen.

"Hydrocodone is such a good compound, as is morphine, and the party line for the past 10 years among doctors has been that we need single-day dosages of these opioid drugs, so there has been a big push by physicians to make those drugs available," he told Medscape Medical News.

"The issue of acetaminophen is always a concern, so the push has been for a pure, extended-release formulation and several companies are working to respond to that demand."

The studies were sponsored by Zogenix. Dr. Nalamachu disclosed that he has been a clinical investigator for Zogenix and is a consultant for the company. Dr. Tennant has disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting. Abstracts 27, 28 and 29. Presented September 21, 2012.