A US Food and Drug Administration (FDA) advisory committee voted overwhelming against recommending approval of an abuse-deterrent formulation of an extended-release (ER) oxycodone hydrochloride product. The drug releases a unique blue dye when crushed or chewed.
The joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) noted concerns that the sponsor (Intellipharmaceuticals Corp) provided only category 1 physical-manipulation and chemical-extraction studies, not category 2 or 3 oral and intranasal human abuse-potential studies.
The 2015 FDA guidance for industry recommends the submission of studies in all three categories.
These guidelines are "very clear" and need to be followed, said meeting chair Raeford Brown Jr, MD, professor of anesthesiology and pediatrics, College of Medicine, University of Kentucky, Lexington.
"The committee feels uncomfortable in providing a signal that it's all right to present incomplete data and expect a positive outcome," said Dr Brown.
The proposed treatment indication is for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period. The product is available in seven doses: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg.
The company was requesting abuse deterrent labeling only for the IV route of abuse, which it said is the most dangerous route.
Stains Hands, Face
In addition to the lack of studies on the potential for abuse, committee members were concerned that their questions about the blue dye were not sufficiently addressed by the sponsor.
The dye, which is released when manipulated, stains the hands, face, and tongue -- and is difficult to remove. In addition, the viscous product turns into a gel upon contact with water, making it difficult to put into a syringe.
"We need long-term studies to tell us what the effect [of the blue dye] will be. Will it turn people blue. and will the gel be a problem when it hits the gastrointestinal system?" asked Suzanne Robotti, consumer representative and executive director of DES Action USA and founder and president of the MedShadow Foundation, New York City.
"We don't know that it is even effective or, if abused, if the blue dye will show up on people's skin. And we have no studies to prove it can't be washed off with soap or with vinegar or with makeup remover," said Robotti.
Some committee members worried that the product could become more of an attraction than a deterrent and wondered if it might become something of a status symbol among young people.
"I can see Smurf parties and blue lollipops suddenly becoming very popular," said Melinda Campopiano, MD, senior medical advisory, Center for Substance Abuse Treatment at the Substance Abuse and Mental Health Services Administration.
Prepubescent Safety Concerns
Or drug users may come under the impression that the blue color is a sign of purity, noted committee members.
"Does the presence of color actually reduce its use or have a perverse impact on increasing the perception of purity, and therefore increase its use?" asked Steven Meisel, PharmD, system director of patient safety, Fairview Health Services, Minneapolis, Minnesota.
The color itself may draw children to the product. "I'm concerned about accidental pediatric exposure," said Dr Campopiano. "It's a colorful and attractive product, so if someone cuts or mashes it and reveals the inside color, a child might come by and put it in their mouth."
There was some discussion of whether the blue dye in the product is the same as that in the sports drink Gatorade, and how much of the dye would be safe to ingest.
Many committee members reminded others that addiction is a mental illness and that "shaming" people in an effort to reduce abuse is not helpful.
"That's wrong on so many different levels," said Dr Brown.
Because the company proposed that under certain circumstances, patients as young as 11 years would have access to the product, some committee members expressed safety concerns and called for further study among a prepubescent population.
The proposed product has a combination of chemical barriers and aversion techniques. In addition to the blue dye, it contains the nasal irritant sodium lauryl sulfate, a polyethylene oxide (PEO) gelling agent, and other proprietary excipients.
Many panel members said these excipients should be evaluated as independent drug products.
"The committee believes that we should have all the toxicity data, long-term and short-term, that we would expect from an individual drug," said Dr Brown. "The excipients themselves have not been studied vis-a-vis toxicity."
On the minds of many committee members were recent events surrounding reformulated Opana ER (extended-release oxymorphone). This drug has been associated with cases of thrombotic microangiopathy, possibly due to IV injection of PEO. In July of this year, as reported by Medscape Medical News, Opana ER was voluntarily withdrawn from the market.
In a series of presentations, company representatives discussed studies comparing the proposed product with OxyContin (Purdue Pharma).
Single-dose pharmacokinetic studies compared the bioavailability of the highest and lowest proposed strengths of ER oxycodone tablets with OcyContin under fasting and fed conditions.
Presented by Beatrice Setnik, PhD, vice president of medical and scientific affairs for INC Research Early Phase and adjunct professor, Department of Pharmacology and Toxicology, University of Toronto, Canada, these studies demonstrated that ER oxycodone is bioequivalent to OxyContin under both conditions.
Results of another pharmacokinetic study supported the safety and efficacy of ER oxycodone at all dosage strengths.
Edward Cone, PhD, principal scientist at Pinney Associates and adjunct professor at Johns Hopkins School of Medicine, Baltimore, Maryland, presented results of category 1 abuse-deterrent studies.
These studies evaluated ER oxycodone and OxyContin using usual volumes and methods employed to render the product capable of injection, such as grinding, extracting, heating, and using a filter to syringe. Results indicated that ER oxycodone has superior abuse-deterrent properties for the IV route.
Essentially, ER oxycodone turns into a viscous material that is difficult to put into a syringe under many tested conditions.
Methods or recipes to overcome gelling properties found on drug abuser websites yielded appreciable amounts of injectable oxycodone from OxyContin, but little to none from ER oxycodone.
The research also showed that consuming alcohol does not lead to "dose dumping," whereby more of the drug is released with alcohol.
In addition, experiments using several different solvents showed that the solvents did not eliminate the blue dye, said Dr Cone.
Panel member, Jeffrey Galinkin, MD, professor of anesthesiology and pediatrics, University of Colorado, Denver, said he wanted to see studies of long-term exposure, "since none of the studies I saw went past 3 days."
Such studies, he said, might indicate whether the product affects nail beds, as well as other factors that could affect resuscitation in cases of overdose.
The committee also heard from experts about the continuing epidemic of opioid diversion, abuse, and deaths. According to Richard Dart, MD, director of the Rocky Mountain Poison and Drug Center and professor of emergency medicine at the University of Colorado School of Medicine, 15% to 20% of deaths reported to the RADARS System poison center involve injections.
The risk for death or major adverse events is 2.6 times greater when the IV route is involved. In 2015, 6% of HIV diagnoses and 10% of AIDS cases were attributed to IV drug use, said Dr Dart, who noted that other risks of IV injection include hepatitis C infection, endocarditis, and blood clots.
Jennie Wong, PharmD, research officer, Division of Epidemiology II, Center for Drug Evaluation and Research, told the meeting that outpatient utilization of ER oxycodone decreased by 23% from 2012 to 2016.
Surveys she cited showed that family physicians, general practitioners, and internal medicine specialists constitute the biggest group of prescribers of ER oxycodone. The most common reason for prescribing these drugs is pain related to disease of the musculoskeletal system and connective tissue.
Not Ready for Prime Time
At the end of the day-long meeting, the committee voted 4 to 19 that the applicant demonstrated that the product has properties that can be expected to deter IV abuse. Those voting "yes" said they were strictly addressing the question as written and that the product does have properties that can be expected to deter abuse.
Many of those voting against commented that it would be inappropriate to consider labeling this product as having abuse-deterrent properties for a single route of abuse and that doing so might create confusion.
There was unanimous agreement that there were insufficient data to support inclusion of language regarding abuse-deterrent properties in the product's label for the IV route of administration.
Only Scott Novak, PhD, senior development epidemiologist, RTI International, Research Triangle Park, North Carolina, voted in favor of approving this drug.
"It comes down to the equivalence to OxyContin," said Dr Novak. "I don't think that the drug is going to be any more effective, but I also don't think it's going to be any less effective."
Many panel members reiterated the need for category 2 and 3 studies and noted that there are alternative products on the market. These include 10 opioid analgesics labeled with abuse-deterrent properties, nine of which are extended-release products, and one of which is an immediate-release product.
The consensus of committee members was that this product "isn't ready for prime time," as one member put it.
"All of us endorse the concept of providing efficacious products that assist in the safe treatment of pain, but I cannot endorse products that are not adequately tested or that we can predict could be toxic when they come to the market," said Dr Brown.
Source: FDA live webcast of joint meeting of the AADPAC and DSaRM FDA advisory committees, presented July 26, 2017.
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Cite this: FDA Committee Nixes Opioid With Blue Dye Deterrent - Medscape - Jul 27, 2017.