PTI's Remoxy: US FDA Panel To Weigh Intranasal Abuse Deterrence Against Oral Abuse Potential

Agency reviewers see lower potential for intranasal abuse with Pain Therapeutics' extended-release opioid compared to immediate-release oxycodone, but an increased abuse potential when Remoxy is chewed compared to swallowing the drug intact.

The US FDA will ask its external experts whether the decreased likelihood of intranasal abuse with Pain Therapeutics Inc.’s long-acting opioid Remoxy ER (oxycodone extended-release) is outweighed by public health concerns about the drug’s potential for oral abuse.

The agency’s Anesthetic and Analgesic Drug Products Advisory Committee, along with the Drug Safety and Risk Management Advisory Committee, meets June 26 to give their verdict on the approvability of Pain Therapeutics (PTI’s) Remoxy and whether the data support abuse-deterrent labeling. The product has had a 10-year regulatory journey, including three complete response letters.

Reviews contained in FDA’s meeting briefing document suggest Remoxy demonstrated a lower potential for intranasal abuse compared to immediate-release oxycodone in a human intranasal abuse liability study.

FDA's seeking of comment on oral abuse deterrence even though PTI is not seeking deterrence labeling for this route of abuse suggests that the agency may be considering including negative study results in labeling.

However, results from a human oral abuse liability study suggested that chewing Remoxy, instead of swallowing it intact as intended, created drug-liking effects almost on par with oral consumption of crushed oxycodone immediate-release tablets.

Questions For The Committee

In draft questions, the agency asks the committee to discuss whether PTI has demonstrated that Remoxy ER has properties that can be expected to deter abuse by the oral, nasal and intravenous routes, and whether data are sufficient to support inclusion of language regarding abuse-deterrent properties for each of the three routes.

That the agency seeks comment on oral abuse deterrence even though PTI is not seeking deterrence labeling for this route of abuse suggests FDA may be considering including negative study results in labeling. The agency took this approach with KemPharm Inc.'s Apadaz (benzhydrocodone/acetaminophen), an immediate-release product with labeling that contains negative results from in vitro testing and human abuse potential studies.

FDA’s third discussion question to the committee notes that PTI is requesting approval as an analgesic with properties expected to deter abuse by the intravenous and intranasal routes. “Discuss whether you have any concerns regarding the impact of Remoxy ER on public health,” the draft questions state. “Take into consideration its potential effect on abuse of extended-release oxycodone as well as potential consequences of administration of this product by unintended routes.”

The agency poses a single voting question: “Based on the data presented and the discussions about the data, do the efficacy, safety and risk-benefit profile of Remoxy ER support the approval of this application?”

10 Products With Abuse-Deterrent Labeling

Remoxy ER has a sticky, high viscosity, hydrophobic gel formulation that is intended to make the drug difficult to cut, divide or draw up into a syringe.

PTI is seeking to make Remoxy the 11th opioid analgesic labeled with abuse-deterrent properties as described in an April 2015 final guidance. The new drug application (NDA) has an Aug. 7 user fee goal date.

Other single-ingredient, extended-release oxycodone products approved with abuse-deterrent labeling are Purdue Pharma LP’s OxyContin and Collegium Pharmaceutical Inc.'s Xtampza ER.

The NDA for Pfizer's Troxyca, one of 10 products with abuse-deterrent labeling, was withdrawn May 2.

Collegium recently petitioned FDA requesting that it not approve any NDA for extended-release oxycodone unless it contains abuse-deterrent labeling based on laboratory manipulation and extraction studies, pharmacokinetic studies and clinical abuse potential studies, and that it also demonstrates abuse deterrence at least equivalent to approved extended-release oxycodone products for all routes of abuse. (Also see "Collegium Targets Remoxy ER Through Citizen Petition Process – Again" - Pink Sheet, 10 Apr, 2018.)

Two multi-ingredient, extended-release formulations that contain oxycodone also have been approved with abuse-deterrent labeling claims: Purdue’s Targiniq (oxycodone/naloxone) and Pfizer Inc.’s Troxyca ER (oxycodone/naltrexone). However, these products have not been marketed, and the Troxyca NDA was withdrawn on May 2, FDA’s briefing document states.

Daiichi Sankyo Co. Ltd./Inspirion Delivery Sciences LLC’s Roxybond (oxycodone immediate-release) is the only immediate-release opioid approved with abuse-deterrent labeling language.

10-Year Regulatory Saga

Remoxy has had a long, difficult regulatory journey in the US that has coincided with the growing opioid public health crisis and FDA’s increasing attention to the potential unintended consequences and adverse public health impacts from the approval of new opioid products, even those with properties aimed at deterring abuse. (Also see "Remoxy's Woes Stoke Criticism Of FDA's Review Of Abuse-Deterrent Opioids" - Pink Sheet, 30 Sep, 2016.)

The drug has been the subject of three complete response letters since its initial submission in June 2008.

The first two complete response letters in December 2008 and June 2011 largely addressed commercial manufacturing and non-clinical data, PTI’s briefing document states. However, the third complete response letter issued in September 2016 cited the need for a human intranasal abuse liability study and additional laboratory-based in vitro manipulation and extraction studies.

The company originally sought abuse-deterrent claims for four routes of abuse: injection, inhalation, snorting and chewing. However, the third complete response letter ruled out the possibility of obtaining a claim for deterring abuse by the oral method, according to the company. (Also see "Pain Therapeutics Confident It Has US Approval Pathway Set For Remoxy ER" - Pink Sheet, 21 Mar, 2017.)

“The sponsor is requesting regulatory approval of Remoxy ER as an analgesic with properties that can be expected to meaningfully deter the injection, snorting and smoking routes of abuse,” PTI’s briefing document states. “Sponsor does not seek a label claim for oral abuse.”

FDA’s briefing document does not address any data relative to abuse deterrence through smoking, although a draft agenda indicates an agency pharmacologist will discuss results of an in vitro smoking study during the advisory committee meeting.

The briefing document also does not discuss PTI’s data specific to deterrence by the intravenous route of abuse, but it does suggest a potential safety concern.

“Based on feedback from prior advisory committee meetings, the agency is now requesting that applicants address the safety of excipients when administered by unintended routes, that is abused by the IV or nasal route,” Division of Anesthesia, Analgesia and Addiction Products Director Sharon Hertz said in a May 21 memo. “You will hear a presentation by FDA on this issue that discusses … the safety of excipients and how this relates to unintended routes of abuse.”

FDA previously suggested that high molecular weight polyethylene oxide, an excipient in Endo Pharmaceuticals Inc.’s Opana ER (oxymorphone extended-release), was a potential cause of thrombotic thrombocytopenic purpura associated with the drug’s intravenous abuse. Endo ultimately withdrew the drug after FDA concluded that its risks, including IV abuse potential, outweighed its benefits. (Also see "Curtain Falls On Opana ER As Endo Agrees To US FDA Withdrawal Request" - Pink Sheet, 6 Jul, 2017.)

Questions about the safety of a blue dye excipient intended to deter abuse of Intellipharmaceutics International Inc.’s Rexista (oxycodone extended-release) led to a negative FDA advisory committee recommendation in July 2017. (Also see "What's Missing In Intellipharmaceutics' Opioid Filing? FDA Panel Offers List" - Pink Sheet, 30 Jul, 2017.) The application went on to receive a complete response letter.

Chewing On Oral Abuse Concerns

The agency’s briefing document reviews results from an intranasal abuse potential study and an oral abuse potential study.

Pharmacokinetic results demonstrated that intranasal administration of Remoxy, with or without manipulation, may result in significantly lower plasma oxycodone concentrations compared to intranasal administration of crushed, immediate-release oxycodone, the agency said.

In the intranasal study, Remoxy was associated with statistically significantly lower scores than immediate-release oxycodone on visual analog scales that measured drug effect liking, drug high, desire to take the drug again, and overall drug liking. Remoxy also was shown to be more difficult to administer intranasally than immediate-release oxycodone powder.

The peak serum concentration of crushed Remoxy is approximately 25% lower than crushed, immediate-release oxycodone, but roughly approximately twice that of intact Remoxy.

However, the oral abuse study suggested concerns about the abuse potential of Remoxy when chewed.

The peak serum concentration (Cmax) of crushed Remoxy is approximately 25% lower than immediate-release oxycodone taken orally after crushing. However, Cmax after chewing and swallowing Remoxy was approximately twice that of intact Remoxy, FDA reviews show.

“The earlier Tmax and the high relative bioavailability compared to intact product indicate that the proposed product may not deter oral abuse by chewing,” FDA Clinical Pharmacology Reviewer Srikanth Nallani and Clinical Reviewer Lisa Wiltrout say in a May 21 memorandum.

Chewed Remoxy was not statistically significantly different from immediate-release oxycodone on the visual analog scales for drug effect liking, take drug again and overall drug liking in the oral human abuse liability study, FDA said.