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Background Analysis: US FDA Advisory Committees to Review HYDEXOR by Charleston Laboratories – FEB 14, 2018 (AADPAC/DSRM)


The US FDA has scheduled a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSRM) for Wednesday, February 14, 2018. The Committees will discuss a new drug application for HYDEXOR (proposed trade name), a fixed-dose combination oral tablet, submitted by Charleston Laboratories, Inc. (Charleston) that contains hydrocodone, acetaminophen, and promethazine, for the short-term management of acute pain severe enough to require an opioid analgesic while preventing and reducing opioid-induced nausea and vomiting (OINV).

Indication Background

Description of Indication

Acute pain occurs as a sensation to alert individuals to possible bodily injury. The pain is typically sudden and sharp in nature and can be caused by many types of bodily injury (e.g., joint sprains and broken bones, dental problems, burns or cuts, and childbirth). Acute pain usually disappears when the underlying cause of pain has been treated or has healed. Unrelieved acute pain, however, can lead to chronic pain.

Severe acute pain that cannot be managed with non-opioid analgesics is sometimes managed with opioid analgesics. Many patients who take an opioid analgesic experience side effects of nausea and vomiting, among other side effects. Charleston has designed HYDEXOR to be an opioid-containing analgesic that is combined with ingredients to prevent and reduce opioid-induced nausea and vomiting (OINV).

Product Background

Description of Product

HYDEXOR is a bi-layered tablet containing 7.5 mg of hydrocodone and 325 mg of acetaminophen with 12.5 mg of immediate-release promethazine. While each individual component has been FDA-approved as an active ingredient for single-entity products, no fixed-dose product combining these specific ingredients in a single product has been approved.

Description of Drug Classes


Acetaminophen is an antipyretic and non-opioid analgesic agent.


Promethazine is an antihistamine and antiemetic agent.


Hydrocodone is an opioid analgesic agent.

Special FDA Considerations for Opioid Analgesics

The US is facing an epidemic of overprescribing, misuse and abuse of opioid drugs. The drug class includes the active ingredients fentanyl, oxymorphone, hydromorphone, morphine, hydrocodone, and oxycodone. Opioids work by reducing the perception of pain through binding to opioid receptors, which are found in the brain, spinal cord, gastrointestinal tract, and other organs in the body. Because opioids affect regions of the brain that are involved in reward mechanisms, many people experience a euphoric response. Abusers may take higher or more frequent opioid doses than prescribed or tamper with opioid products in order to administer them in ways that were not intended (e.g., manipulating an oral opioid for injection or to snort it) in an attempt to increase the euphoric affect, which is referred to as dose-dumping. Such misuse and abuse can lead to fatal respiratory depression. The US Centers for Disease Control and Prevention (CDC) has reported that, in 2015, drug overdoses accounted for 52,404 US deaths, including 33,091 (63.1%) that involved an opioid.

In response to the epidemic, in February 2016, the FDA announced its Opioid Action Plan. Among the key components, the Agency said it will encourage the development of opioids with abuse-deterrent properties (ADP). Formulations with ADP target the known or expected routes of abuse, such as dissolving for injection or crushing for snorting, with the aim of making these routes of abuse more difficult. Since the science of abuse deterrence is relatively new, the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. It is no surprise, in light of the increased pace of scientific development of ADP technology and related drugs, that the FDA has frequently sought the joint input of the AADPAC-DSRM in related regulatory decisions. A lack of understanding about the real-world impact of these products has also been a frequent topic of discussion at advisory committee meetings.

The Opioid Action Plan also states that all new drug applications (NDAs) for an opioid product that does not have ADP must be reviewed by an FDA advisory committee.

The FDA announcement for this upcoming meeting states that the Committees will discuss the HYDEXOR NDA and also will be asked to discuss the abuse potential of this non-abuse-deterrent product and whether it should be approved.

Another key FDA response to the opioid epidemic occurred in September 2017. At this time, the FDA announced that manufacturers of immediate-release (IR) opioid products will be required to offer training to healthcare professionals about the appropriate use of opioid drug products. Such training was formerly only required for manufacturers of extended-release and long-acting opioid (ER/LA) opioid products. Extending this requirement to IR opioid products has been a topic of discussion in the medical community and at FDA advisory committees since FDA set the requirement for ER/LA opioid products in July 2012. The training is required under an FDA-mandated program called Risk Evaluation and Mitigation Strategies (REMS).

Charleston noted in their announcement of the HYDEXOR NDA that “Charleston Laboratories endeavors to create a new class of opioid analgesics supported by responsible labeling and dispensing strategies that will aid in efforts to minimize abuse and misuse.”

Clinical Trials of Proposed Indication

Charleston has reported that the HYDEXOR NDA is based primarily on two randomized-controlled clinical trials, one in patients with pain after bunionectomy surgery (N=552, ClinicalTrials.gov ID: NCT02462811) and a second in patients with pain after molar removal surgery (N=460, ClinicalTrials.gov ID: NCT01780428). The company has also completed an open-label clinical trial in patients with flares of osteoarthritis of the knee or hip (N=178, ClinicalTrials.gov ID: NCT02462850) and a human abuse liability study (N=34, ClinicalTrials.gov ID: NCT02712554).

Detailed results of the data provided in the NDA, including the outcomes from the aforementioned trials, will be presented in FDA and Company briefing materials, which the FDA will post ahead of the meeting. These data will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

Unknown – PDUFA date

October 17, 2017 – Charleston announced the resubmission of NDA 209257

August 13, 2017 - Charleston reacquired all US rights to develop and commercialize HYDEXOR from Daiichi Sankyo Co., Ltd. and its US subsidiary, Daiichi Sankyo, Inc., ending a 3-year collaboration between the companies.

February 3, 2017 - Charleston Laboratories, Inc. and Daiichi Sankyo, Inc. confirmed their receipt of a Complete Response Letter (CRL) from the FDA in response to the initial NDA for HYDEXOR, which was then referred to as CL-108. No details were provided. This initial NDA had been accepted by the FDA on June 13, 2016.

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US development of HYDEXOR.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Charleston Laboratories, Inc. Drug Name: hydrocodone, acetaminophen, and promethazine Drug Class: analgesic, opioid analgesic, anti-emetic Indication: acute pain

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.