FDA Supports Greater Access to Naloxone to Help Reduce Opioid Overdose Deaths

By: Karen Mahoney, M.D.

Overdose deaths involving prescription opioids such as oxycodone, hydrocodone and morphine and illicit opioids such as heroin and illegally produced fentanyl have more than tripled since 1999 – with about 28,000 people dying in 2014 alone.

Many of these tragedies could have been avoided if the people experiencing the overdose had immediately received the prescription drug naloxone, a life-saving medication that can stop or reverse the effects of an opioid overdose.

Naloxone is still a prescription in all 50 states and the District of Columbia, though many have or are taking steps to make naloxone more accessible. Consistent with our opioid action plan announced earlier this year, the FDA is exploring options to make naloxone more available to treat opioid overdose. One option to do this is identifying ways to assist manufacturers in submitting an application to the FDA for an over-the-counter (OTC) version of a naloxone product.

That’s why the FDA is working on innovative ways to help facilitate the process of helping manufacturers pursue approval of an OTC naloxone product, including helping to develop the package label that would be required for such a product. This is an important step to help increase access to and the use of this life-saving drug.

Although the two currently available prescription naloxone products intended for use in the community — an auto-injector product for self-injection, and a nasal spray formulation – have instructions for use, they do not have the consumer-friendly Drug Facts Label (DFL), which is required for OTC drug products. Before submitting a new drug application or supplement for an OTC drug product, companies develop this DFL and conduct the required studies to show that consumers can follow the DFL to understand how to use the product without the help of a healthcare professional.

To help facilitate the development of OTC naloxone, the FDA has created a model DFL and an accompanying simple pictogram that could be placed next to the DFL to visually correspond to the label directions. This model DFL and pictogram are intended to provide consumers with the information they would need to understand how to safely use naloxone, including when it is appropriate to purchase naloxone and how to use it in an emergency opioid overdose situation. Since it is a model label, information that is highly specific to a particular product would not be included.

The FDA has also arranged for label comprehension testing of the model DFL. This testing is now being conducted and we expect that the results will yield important information about consumer understanding of the model naloxone DFL. Using this information, naloxone manufacturers may then be able to focus their final label comprehension testing on how well consumers understand product-specific information, such as instructions for the device that delivers naloxone that has not been already tested on the model DFL.

Creating a model DFL and arranging for label comprehension testing are among the ways that the FDA is working to fulfill our commitment to enhanced naloxone access, where possible, in our opioids action plan. We will continue to work with interested manufacturers and developers to further explore the best uses of naloxone for the emergency treatment of known or suspected opioid overdoses until emergency medical help arrives.

FDA’s opioid action plan is part of the comprehensive Opioid Initiative launched by the U.S. Department of Health and Human Services (HHS) in March 2015. The Initiative focuses on high-impact strategies to 1) improve opioid prescribing, 2) expand access to medication-assisted treatment for opioid use disorders, and 3) increase the use of naloxone to reverse opioid overdoses.

Karen Mahoney, M.D., is FDA’s Deputy Director, Division of Nonprescription Drug Products, at the Center for Drug Evaluation and Research

Additional progress on reducing the abuse of opioid pain relievers

By: Janet Woodcock, M.D.

FDA’s approval today of the extended-release opioid pain medicine Hysingla ER (hydrocodone bitartrate) marks additional progress in the fight against the ongoing misuse and abuse of prescription opioids. Hysingla ER’s approval provides prescribers with another option for managing pain severe enough to require daily, around-the-clock, long term opioid treatment in patients for whom alternative treatment options are inadequate, while potentially reducing hydrocodone abuse.

Janet WoodcockIn pre-approval testing, Hysingla ER exhibited properties that we expect will reduce the likelihood users could abuse the drug by chewing the tablet and ingesting it orally, or crushing it into powder for snorting or injecting. This is important because immediate-release combination products containing hydrocodone are among the most frequently abused opioid products. Hysingla ER is the fourth prescription opioid approved with product labeling that is consistent with the FDA’s 2013 guidance on abuse-deterrent opioids. The drug’s abuse-deterrent properties are expected to reduce – but not totally prevent – abuse by these routes.

While Hysingla ER has the same active ingredient (hydrocodone) as Zohydro ER, the only other approved extended-release hydrocodone product, there are important differences between the two. Hysingla ER has approved abuse-deterrent labeling, while Zohydro ER does not. Also, Zohydro ER is taken every 12 hours, and so comes in lower dosage strengths than Hysingla ER, which is taken every 24 hours. FDA has not yet determined whether Hysingla ER will prove to be safer than Zohydro ER.

It’s important to address some potential misperceptions about these extended-release hydrocodone products.

First, it would be misleading to suggest these products are stronger than other opioids on the market. Both Zohydro ER and Hysingla ER contain larger amounts of hydrocodone compared to immediate-release hydrocodone combination products because they need to be taken much less frequently. The range of tablet strengths for Hysingla ER is comparable to the strengths of existing approved extended-release opioids. The highest tablet strength of Hysingla ER, 120 mg, is comparable in potency to the currently marketed highest tablet and capsule strengths of extended-release morphine and hydromorphone products which, like Hysingla ER, are taken once daily.

Second, we do not expect these drugs to increase the number of patients treated with opioids. FDA is monitoring the use of all opioid products carefully and has been monitoring Zohydro ER prescribing since it was approved. In July 2014, Zohydro ER’s sixth month of marketing, there were 3,588 outpatient retail prescriptions dispensed. This represents 0.23% of the 1.6 million extended release, long acting (ER/LA) opioid analgesic prescriptions and only 0.02% of the nearly 18 million prescriptions dispensed for all opioid analgesics during the same month.

As with all extended release opioid medicines, FDA will carefully monitor and assess the use of Hysingla ER over time, and we are requiring the manufacturer to conduct studies to measure the effects of the abuse-deterrent features on abuse in the community.

Third, FDA has heard concerns about whether there is a need for additional prescription opioids. Given what we know about the needs of doctors and patients for additional choices of medicines, we believe having an additional choice of pain medicine like Hysingla ER, the first once daily hydrocodone product, is beneficial overall when treating patients in pain.

This latest approval also marks an important reminder of the limitations of today’s abuse-deterrent formulations. The reality is that opioids with abuse-deterrent properties can still be abused. Currently available abuse-deterrent technologies are important and offer a step in the right direction, but the science in this area is still evolving.

Prescription opioids with abuse-deterrent properties will not completely fix the prescription opioid abuse problem, but they can be part of a comprehensive approach to combat the epidemic. And the development of abuse-deterrent opioids is only one of many elements of FDA’s overall approach, which includes provider and patient education, close monitoring of approved opioids, and review and approval of drugs to treat addiction and prevent overdose. We will continue to work hard to address the serious problem of opioid abuse while providing needed pain medicines for patients.

Janet Woodcock, M.D., is Director of FDA’s Center for Drug Evaluation and Research

Re-scheduling prescription hydrocodone combination drug products: An important step toward controlling misuse and abuse

By: Douglas C. Throckmorton, M.D.

Hydrocodone is the most prescribed opioid in the United States, including 137 million prescriptions in 2013. While it is useful in the treatment of pain, it has also contributed significantly to the very serious problem of opioid misuse and abuse in the United States. With the aim of curbing this misuse and abuse, new prescribing requirements go into effect today for hydrocodone combination products, which include products such as Anexsia, Lorcet, Vicodin, and some cough suppressants that contain both hydrocodone and another active ingredient, such as acetaminophen.

Douglas C. Throckmorton, M.D.Under a final rule issued by the U.S. Drug Enforcement Administration (DEA), hydrocodone combination products are now in a more restrictive category of controlled substances, along with other opioid drugs for pain like morphine and oxycodone.  After a scientific review, FDA made the recommendation that DEA take this step in December 2013. We concluded that hydrocodone combination products meet the criteria for control under Schedule II of the Controlled Substances Act, and we believe DEA’s new rule will help limit the risks of these potentially addictive but important pain-relieving products.

Here are some of the key changes that will occur with the reclassification of hydrocodone from a Schedule III drug to a Schedule II drug:

  • If a patient needs additional medication, the prescriber must issue a new prescription. Phone–in refills for these products are no longer allowed.
  • In emergencies, small supplies can be authorized until a new prescription can be provided for the patient.
  • Patients will still have access to reasonable quantities of medication, generally up to a 30-day supply.

After DEA requested a scientific and medical recommendation from FDA regarding a change of schedule for hydrocodone combination products in 2009, FDA considered the eight statutorily required factors related to the abuse potential of hydrocodone. These included such questions as the products’ actual or relative potential for abuse, their liability to cause psychic or physiological dependence, and dangers they might pose to public health. After a thorough analysis of the available information, including a public Advisory Committee meeting to solicit input from outside experts and patients (the committee recommended upscheduling by a vote of 19 to 10), HHS recommended to DEA that hydrocodone combination products be reclassified into Schedule II.

We also recommended two other actions we believe are critical to maximizing the benefits to the public health of rescheduling hydrocodone:

  • Include rescheduling in a broad-based set of actions targeting abuse prevention. In particular, HHS identified a need to work with prescribers and patients to make certain that patients are prescribed the right number of doses of hydrocodone for a patient’s need to avoid unused hydrocodone being available for abuse.
  • Continue to monitor the use and abuse of hydrocodone combination products carefully to assess the impact of rescheduling on public health. Based on the results of this monitoring, we may need to take additional actions to support the appropriate use of hydrocodone combination products while reducing their tragic abuse.

FDA understands that it is crucial to achieve a goal of balancing the risk of abuse and misuse with the need to maintain access to these important medications that provide needed relief to people in pain. Rescheduling hydrocodone combination products is one important action in support of this goal.

Douglas C. Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research