Opioids and the FDA

OxyContin approved (oxycodone that allowed dosing every 12 hours instead of every 4-6 hours)

Actiq (fentanyl) approved; 1st pain medicine approved to treat cancer breakthrough pain with additional safety measure

Reports of overdose and death from prescription pain drugs, especially OxyContin, began to rise sharply.

OxyContin label was changed to add and strengthen warnings about the drug’s potential for misuse and abuse.

FDA issued a Warning Letter to OxyContin’s manufacturer for misleading advertisements.

FDA Amendments Act granted FDA authority to require for certain drugs specified safety measures known as Risk Evaluation and Mitigation Strategies (REMS).

FDA begins to hold public meetings to discuss abuse. With help, the FDA launches two initiatives. They helped ensure safe use and reduce preventable harm. FDA begins to work on educating the public on how to safely dispose of opioids. FDA partnered with U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) to launch an initiative to help ensure the safe use of the opioid methadone. FDA launched the Safe Use Initiative to reduce preventable harm by medications, including opioids.

FDA implemented the ER/LA opioids REMS program, which includes voluntary training for prescribers.

FDA assists industries to develop abuse-deterrent opioids.

FDA holds a public hearing to obtain info on opioids and chronic pain. FDA writes prescribers a letter to ensure they have enough training and knowledge about the opioids they prescribe and that they are helping to curb the crisis.

FDA responded to a petition and the original formulation of Opana ER (oxymorphone hydrochloride) Extended-Release Tablets was not withdrawn from the market for reasons of safety or effectiveness. As a result, generic versions of the original formulation can continue to be approved and marketed.

FDA approved Evzio (naloxone hydrochloride injection) for the emergency treatment of opioid overdose.

FDA approved Narcan nasal spray, the first FDA approved nasal spray version of naloxone hydrochloride, a life-saving medication that can temporarily stop or reverse the effects of an opioid overdose, including an overdose from heroin.

FDA leaders, in response to the opioid abuse epidemic, called for a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief. FDA released five postmarketing (PMR) requirements announced on September 13, 2013, and replaced them with 11 PMRs (10 postmarketing studies and one clinical trial) because the 10 postmarketing observational studies and one

FDA requires a new boxed warning about the serious risks of misuse and abuse, which can lead to addiction, overdose and death. The FDA also requires several additional safety labeling changes across all prescription opioid products to include additional information on the risk of these medications.

FDA requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market based on its concern that the benefits of the drug may no longer outweigh its risks.

FDA held a public meeting, Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities, to discuss ways to improve the analysis and interpretation of existing data, as well as to discuss opportunities and challenges for collecting and/or linking additional data to improve national surveillance and research capabilities in this area.

FDA held a Pediatric Advisory Committee meeting to discuss the use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients. The discussion included current practice for the treatment of cough in children and benefit-risk considerations regarding the use of prescription opioid products in pediatric patients.

FDA advised that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS). The combined use of these drugs increases the risk of serious side effects; however, the harm caused by untreated opioid addiction can outweigh these risks. Careful medication management by health care professionals can reduce these risks.

FDA approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe opioid use disorder in adult patients who have initiated treatment with a transmucosal (absorbed through mucus membrane) buprenorphine- containing product. It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days.

FDA hosted a public workshop addressing abuse, misuse, or inappropriate access of prescription opioid drug products; ways in which FDA could encourage the development and assessment of packaging, storage, and disposal options for opioids that have the potential to enhance opioid safety.

FDA Commissioner, Scott Gottlieb, M.D., announced the 2018 Strategic Policy Roadmap. Part of the Roadmap is reducing misuse and abuse of opioid drugs. FDA announced that it is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone. Additional safety measures also added.

FDA and the Federal Trade Commission posted joint warning letters to the marketers and distributors of 12 opioid cessation products, for illegally marketing unapproved products with claims about their ability to help in the treatment of opioid addiction and withdrawal.

FDA held a public hearing, “Opioid Policy Steering Committee: Prescribing Intervention- Exploring a Strategy for Implementation” FDA announced limits to packaging for anti- diarrhea medicine Loperamide (Imodium) to encourage safe use. FDA posted the revised Blueprint, “Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain,” which broadens the current Blueprint to include information on pain management, including the principles o

Through a cooperative agreement with the FDA, the Duke-Margolis Center hosted a public workshop.

FDA held a meeting of the Psychopharmacologic Drugs Advisory Committee to discuss the new drug application for lofexidine hydrochloride, submitted by US WorldMeds, LLC, for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment.

FDA is hosting a public meeting on Patient- Focused Drug Development for Opioid Use Disorder (OUD), in collaboration with National Institute of Drug Abuse (NIDA). In addition to NIDA, FDA is also working closely with patient advocacy and community organizations to encourage participation from individuals with OUD. This meeting aligns with FDA’s ongoing work aimed at reducing the impact of opioid abuse and addiction.

FDA issued the draft guidance, “Opioid Dependence: Developing Buprenorphine Depot Products for Treatment”

FDA approved Lucemyra (lofexidine hydrochloride), the first non-opioid treatment for the mitigation of withdrawal symptoms associated with abrupt discontinuation of opioids.

FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for buprenorphine sublingual spray, submitted by INSYS Development Company, Inc., for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic isappropriate.

FDA launched an innovation challenge to spur development of medical devices ‒ including digital health and diagnostics ‒ that target pain, addiction and diversion.

FDA sent safety labeling change notification letters to drug companies with approved opioid analgesic products intended for use in an outpatient setting, which require the companies to include new safety information regarding the Opioid Analgesic REMS in the Boxed Warning and Warnings and Precautions sections of prescribing information due to a general lack of awareness of the REMS among all opioid analgesic prescribers.

FDA took action against 53 websites marketing unapproved opioids as part of a comprehensive effort to target illegal online sales.

FDA approved the first generic versions of Suboxone sublingual film.

FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for oxycodone extended-release capsules, submitted by Pain Therapeutics, with the proposed indication of the management of pain severe enough to require daily, around-the- clock, long-term opioid treatment and for which alternative treatment options are inadequate. The product is intended to have abuse-deterrent

FDA convened internet stakeholders, government entities, academic researchers, and advocacy groups at a one-day Online Opioid Summit to discuss ways to collaboratively take stronger action in combatting the opioid crisis by reducing the availability of illicit opioids online.

FDA hosted a public meeting on Patient-Focused Drug Development for chronic pain to hearing patients’ perspectives on chronic pain, views on treatment approaches, and challenges or barriers to accessing treatments for chronic pain.

FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss results from assessments of the transmucosal immediate-release fentanyl (TIRF) medicines’ risk evaluation and mitigation strategy (REMS), approved in December 2011. The TIRF REMS requires that healthcare providers who prescribe TIRF medicines for outpatient use are specially certified, that pharmacies that dispense TIRF medicines for i

FDA issued the draft guidance for industry, “Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Medication-Assisted Treatment,” which is intended to assist sponsors in developing drugs for medication-assisted treatment of opioid use disorder (OUD) and addresses the clinical endpoints acceptable to demonstrate effectiveness of such drugs.

FDA held a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for Hydexor (proposed tradename), a fixed-dose combination oral tablet, submitted by Charleston Laboratories, Inc., 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

FDA sent safety labeling change notification letters to drug companies with approved opioid analgesic products intended for use in an outpatient setting, which require the companies to include new safety information regarding the Opioid Analgesic REMS in the Boxed Warning and Warnings and Precautions sections of prescribing information due to a general lack of awareness of the REMS among all opioid analgesic prescribers.

FDA issued a final guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.” This guidance recommends studies, including comparative in vitro and pharmacokinetic studies, that the potential abbreviated new drug application (ANDA) applicant should conduct and submit to FDA in an ANDA to demonstrate that a generic solid oral opioid drug product is no less abuse-deterrent than its reference listed drug with respect to all potential routes of

FDA sent letters to IR opioid analgesic manufacturers informing them that their products that are intended to be used in the outpatient setting will be subject to the same REMS requirements as the ER/LA opioid analgesics.

The National Academies of Science, Engineering, and Medicine release the consensus report, commissioned by the FDA, which outline the state of the science regarding prescription opioid abuse and misuse, as well as the evolving role that opioids play in pain management.

The JAMA Viewpoint article by Dr. Scott Gottlieb and Dr. Janet Woodcock entitled, “Marshaling FDA Benefit-Risk Expertise to Address the Current Opioid Abuse Epidemic," was published. Following the FDA’s request, Endo announced that it would voluntarily remove reformulated Opana ER from the market.

FDA released the "FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain" ,which broadens the current Blueprint to include information on pain management, including the principles of acute and chronic pain management; non-pharmacologic treatments for pain; and pharmacologic treatments for pain (both non-opioid analgesic and opioid analgesic).

FDA held a public meeting, Training Health Care Providers on Pain Management and Safe Use of Opioid Analgesics – Exploring the Path Forward, to obtain input on issues and challenges associated with Federal efforts to support training on pain management and the safe prescribing, dispensing, and patient use of opioids (safe use of opioids) for health care providers.

FDA held an expert roundtable for healthcare professionals to discuss their experiences with the use of cough suppressants in children (<18 years of age), particularly opioid containing antitussive products, as well as the data available to support recommendations made by various professional societies regarding the treatment of cough in children.

FDA announced the restricted the use of codeine and tramadol medicines in children. On April 20, the FDA approved RoxyBond (oxycodone hydrochloride), an opioid analgesic indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. RoxyBond is the first immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s 2015 Guidance for Industry: Abuse- Deterrent Opio

FDA approved Arymo ER (morphine sulfate extended-release tablets), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Arymo ER is the eighth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Arymo ER is formu

FDA approved Vantrela ER (hydrocodone bitartrate extended-release tablets), an extended- release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long- term opioid treatment for which alternative treatment options are inadequate. Vantrela ER is the ninth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. The ph

FDA approved several safety labeling changes (SLCs) about the serious risks of prescription opioid analgesics and opioids approved for medication assisted treatment (MAT) of opioid addiction including class-wide SLCs for immediate-release (IR) opioid pain medications, SLCs for methadone and buprenorphine products, and class-wide SLCs about the serious risks associated with the combined use of certain opioid medications with benzodiazepines or other central nervous system (CNS) depressants.

FDA held a public meeting, Pre-Market Evaluation of Abuse-Deterrent Properties of Opioid Drug Products, to discuss scientific and technical issues relating to formulation development and pre- market evaluation of opioid drug products with abuse-deterrent properties.

FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management to discuss naloxone products intended for use in the community, specifically the most appropriate dose or doses of naloxone to reverse the effects of life-threatening opioid overdose in all ages.

FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee to discuss the appropriate development plans for establishing the safety and efficacy of prescription opioid analgesics for pediatric patients.

FDA announced required class-wide changes to drug labeling to help inform health care providers and patients of the serious risks associated with the combined use of certain opioid medications and a class of central nervous system depressant drugs called benzodiazepines. Among the changes, the FDA is requiring boxed warnings and Medication Guides.

FDA approved Troxyca ER (oxycodone hydrochloride and naltrexone hydrochloride extended-release capsules), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate.

FDA announced required safety labeling changes for methadone and buprenorphine products when used by pregnant women for medication- assisted treatment (MAT) of opioid use disorder to ensure providers have complete information about the benefits and risks of these products. FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence.

FDA convened a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss results from assessments of the extended-release and long- acting (ER/LA) Opioid Analgesics Risk Evaluation and Mitigation Strategies (REMS)

FDA approved Xtampza ER (oxycodone), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the- clock, long-term opioid treatment for which alternative treatment options are inadequate.

FDA issued a draft guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.”

The FDA convened the Science Board to hear about and discuss a range of pressing issues related to the current opioid epidemic,

The FDA announced that during the April 12th meeting of the Pediatric Advisory Committee (PAC) they will present a framework of current plans for a 2-day joint meeting of the PAC, the Anesthetic and Analgesic Drug Products Advisory Committee, and the Drug Safety and Risk Management Advisory Committees.

FDA approved MorphaBond (morphine sulfate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the- clock, long-term opioid treatment for which alternative treatment options are inadequate.

FDA approved OxyContin for certain pediatric patients for pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

FDA issued a final guidance to assist industry in developing opioid drug products with potentially abuse-deterrent properties. Guidance for Industry: Abuse-Deterrent Opioids”.

FDA approved a modified formulation of Zohydro ER (hydrocodone bitartrate extended-release capsules). The FDA has not approved an abuse- deterrent labeling claim for Zohydro ER.

FDA approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

FDA finalized the proposed class-wide safety labeling changes for all extended-release and long-acting (ER/LA) opioid analgesics, and responded to two citizen petitions regarding labeling for neonatal opioid withdrawal syndrome (NOWS).

FDA approved revisions to the ER/LA Opioid Analgesics REMS to incorporate information from the ER/LA opioid analgesic safety labeling changes.

FDA approved Targiniq ER, an extended-release pain reliever that contains a combination of oxycodone and naloxone.

FDA approved new labeling for Embeda (morphine sulfate and naltrexone hydrochloride), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the- clock, long-term opioid treatment and for which alternative treatment options are inadequate.

FDA issued Statement on Proposed Hydrocodone Reclassification from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research.

FDA announced a set of significant measures to enhance the safe and appropriate use of extended-release and long-acting (ER/LA) opioids.

FDA approved REMS for transmucosal immediate-release fentanyl (TIRF) products, such as Actiq.

FDA approved a new formulation of OxyContin.

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