Teva's Opioid Vantrela: Conflicting Data On Oral Abuse Deterrence

Human abuse liking study, in vitro data paint different pictures of potential for hydrocodone extended-release product to deter oral abuse, FDA says ahead of advisory committee review; agency finds support for abuse-deterrent claims for intranasal, intravenous use.

An FDA advisory committee review of Teva Pharmaceutical Industries Ltd.'s long-acting opioid Vantrela ER (hydrocodone extended-release) sets the stage for debate as to whether in vitro or clinical data are more persuasive in assessing a product's abuse-deterrent capabilities pre-approval.

At a June 7 meeting, FDA will ask its Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees whether Vantrela may deter oral abuse in the face of apparently conflicting in vitro and clinical data.

Vantrela is "designed to maintain an ER profile even when reduced to a fine powder through both common and advanced manipulation techniques," Teva said.

The panelists will vote on whether Vantrela should be approved, and whether it should be labeled as an abuse-deterrent product by the intranasal, intravenous and oral routes of abuse.

In FDA's briefing document released late in the day June 3, the agency said in vitro and clinical data suggest Vantrela has properties that deter abuse by intravenous and intranasal methods. A human abuse liking study also showed that Vantrela has properties that deter oral abuse, FDA staff said.

However, FDA's review of in vitro data on oral abuse came to a different conclusion. "The superiority of Vantrela ER tablets over [hydrocodone] ER capsules for abuse-deterrence by oral route of administration or solvent extraction following physical manipulation has not been established at this time," the agency said.

Labeling for deterrence against all three routes of abuse could prove helpful for Teva to keep pace with Purdue Pharma LP's Hysingla ER, the only other long-acting hydrocodone product with abuse-deterrent labeling (see sidebar).

Opioids Action Plan Leads To AdComm

Teva Branded R&D Inc. is seeking Vantrela's approval for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. If approved, it would be available in five dosage strengths ranging from 15-90 mg of hydrocodone bitartrate. The drug is dosed twice a day without regard to food.

Vantrela is formulated with proprietary abuse-deterrent technology from Teva affiliate CIMA Labs Inc. It consists of three complementary formulation layers designed to release drug substance over a 12-hour period when administered orally as instructed and to retain its extended-release properties when manipulated, Teva's briefing document states.

"The CIMA ADT formulation does not rely on tablet hardness as a physical barrier to deter abuse," Teva said. "Accordingly, Vantrela ER tablets are not exceptionally hard and are not intended to be physically difficult to manipulate. They are, however, designed to maintain an ER profile even when reduced to a fine powder through both common and advanced manipulation techniques."

The rolling NDA submission for the product, also known as CEP-33237, was completed in December 2014, making the product's original user fee date October 2015 (Also see "Another Day, Another Opioid Advisory Committee" - Pink Sheet, 16 Mar, 2016.).

The Vantrela NDA appears to have gotten caught up in the agency's opioids action plan, which calls for expanded use of advisory committee reviews for such products. Specifically, the plan states that FDA will convene advisory committees before approving new opioid products that lack abuse-deterrent properties and for abuse-deterrent formulations that raise novel issues (Also see "FDA's Opioid Action Plan Could Clear Califf Nomination Roadblock" - Pink Sheet, 4 Feb, 2016.).

The agency's action plan helped clear the way for Senate confirmation of Robert Califf as commissioner after his nomination got bogged down in opioid-related regulatory issues, including the agency's approval standards for such products (Also see "Califf Nomination Suffers 'Pile On': What Can FDA Do To Break Logjam?" - Pink Sheet, 1 Feb, 2016.).

During a two-day meeting in May, the same two advisory committees reviewed the Risk Evaluation and Mitigation Strategy for the extended-release/long-acting opioids and concluded that prescriber education under the program should be mandatory, rather than voluntary (Also see "Opioid REMS Prescriber Education Should Be Mandatory, FDA Panel Says" - Pink Sheet, 4 May, 2016.).

The REMS meeting was followed by a single-day advisory committee review of KemPharm Inc.'s Apadaz (benzhydrocodone/acetaminophen). The panel recommended approval of the immediate-release product but did not support abuse-deterrent labeling claims (Also see "KemPharm's Opioid Apadaz Will Likely Miss Out On Abuse Deterrence Claim" - Pink Sheet, 5 May, 2016.).

On June 8, the day after the Vantrela meeting, the committees will weigh approval and potential abuse-deterrent claims for Pfizer Inc.'s Troxyca (oxycodone/naltrexone extended-release) (see related story, (Also see "Pfizer’s Troxyca ER Opioid Combo Faces Intravenous Abuse Concerns" - Pink Sheet, 6 Jun, 2016.)).

In Vitro Data Tell One Story On Oral Abuse Potential …

Teva conducted in vitro and clinical studies to support abuse-deterrent labeling claims for Vantrela. The drug was tested against hydrocodone bitartate active pharmaceutical ingredient powder, AbbVie Inc.'s Vicoprofen, an immediate-release combination of hydrocodone and ibuprofen, and Pernix Therapeutics Holdings Inc.'s Zohydro ER (hydrocodone extended-release) once it became commercially available.

In their analysis of laboratory-based in vitro manipulation studies, FDA reviewers Venkateswara Pavuluri and Julia Pinto said that overall Vantrela "has superior abuse-deterrent properties when compared to immediate-release combination HC/ibuprofen, and has comparable or better resistance to manipulation than HC ER Capsules, depending on the mode of abuse."

"Vantrela ER tablets demonstrated better resistance for abuse by inhalation and injection routes, but in vitro data submitted by the sponsor is not sufficient to establish any significant abuse-deterrence by oral route or its superiority over the comparator extended-release, single-entity hydrocodone product," the reviewers said.

The in vitro studies show that Vantrela ER was susceptible to simple solvent and complex liquid/liquid extractions comparable to Zohydro capsules, "more so upon physical manipulation, for separation of drug substance and/or preparation of concoctions by methodical abusers."

… But Drug Liking Study Tells Another

However, data from an oral human abuse potential study point to a different conclusion.

The single-dose, randomized, double-blind, placebo-controlled, crossover study evaluated the oral abuse potential, safety, tolerability and pharmacokinetics of Vantrela (intact and crushed) compared to hydrocodone bitartrate powder and placebo in healthy, nondependent recreational opioid users. Subjective measures of assessment included drug liking, taking drug again, drug value, good drug effects and bad drug effects.

The peak plasma concentration (cMax) for crushed Vantrela was less than half that of hydrocodone bitartrate powder but more than that of intact Vantrela.

Intact Vantrela produced responses on positive and negative subjective measures that were not statistically different from placebo, said Katherine Bonson, a pharmacologist on the agency's Controlled Substance Staff.

"The hydrocodone bitartrate powder immediate-release condition produced responses on the subjective measures that were statistically greater than placebo," Bonson said. "Crushed Vantrela produced responses on the same subjective measures that were statistically significantly greater than the responses on these measures that were produced by intact Vantrela and placebo, but statistically significantly less than the responses produced by hydrocodone bitartrate powder."

"These results suggest that Vantrela has abuse-deterrent properties when it is physically manipulated and ingested orally for abuse purposes," the review states.

A separate human abuse potential study also suggested that Vantrela has abuse-deterrent properties when it is physically manipulated for intranasal abuse.

In the intranasal study, administration of finely milled Vantrela produced responses that were statistically significantly less than those produced by hydrocodone powder and finely milled Zohydro. "In contrast, oral administration of intact Vantrela produced responses on these measures that were comparable to placebo, similar to the results in the oral administration human abuse potential study," FDA's review states.

Small Slice Of ER/LA Opioids Market

There are currently two extended-release hydrocodone products on the market – Hysingla, approved in November 2014, and Zohydro, approved in October 2013.

Hysingla labeling states that in vitro data demonstrate physical and chemical properties that are expected to deter intranasal and intravenous abuse. Furthermore, data from clinical abuse potential studies, along with support from in vitro data, also indicate that Hysingla has physicochemical properties expected to reduce intranasal abuse and oral abuse when chewed. The drug is approved for once-daily dosing.

Zohydro lacks abuse-deterrent labeling. Its approval came against an advisory committee's recommendation and sparked a backlash among lawmakers and others who thought FDA was not taking concerns about opioid abuse seriously enough. During a March congressional hearing, Califf said the agency should have conducted another committee meeting to consider the proposed post-marketing plan for Zohydro before approval (Also see "FDA's Opioid Regret? Skipping Another Zohydro Meeting, Califf Says" - Pink Sheet, 2 Mar, 2016.).

Collectively, Hysingla and Zohydro represent a small fraction of the US ER/LA opioids market. FDA's briefing document cites IMS Health data from outpatient retail pharmacies showing that the hydrocodone extended-release products accounted for less than 1% of prescriptions dispensed for ER/LA opioids in 2015.