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

Naloxone – FDA hosts meeting to discuss expanded use of overdose medicine

By: Peter Lurie, M.D., M.P.H.

At the FDA, we’re proud of our work supporting the development of important and innovative medical products that address the critical needs of patients. Sometimes this means wholly new molecules to treat previously untreatable diseases; other times it simply requires the combination of more user-friendly formulations and enhanced efforts to get the drug to patients. The potentially life-saving drug naloxone, which can reverse opioid overdoses, is a poster child for the latter situation. The drug, which literally dislodges opioid drugs such as heroin or oxycodone from their receptors, thus reversing overdoses in minutes, has increasingly been administered outside of conventional medical settings by community and family members, as well as by first responders such as police and fire departments.

Dr. Peter LurieA little over three years ago, FDA partnered with other HHS agencies and laid out the pathway for the development and marketing of naloxone. It was the first public meeting on naloxone sponsored by the Federal government. A key development since that first meeting was FDA’s approval of Evzio, a prescription naloxone hydrochloride injection that can be used by family members or caregivers to treat a person known or suspected to have had an opioid overdose. Evzio rapidly delivers a single dose of the drug via a hand-held auto-injector. Now work is underway to administer naloxone through the nose.

According to a survey just published in CDC’s medical journal, there also has been enormous growth in the number of programs in which naloxone kits, primarily for delivering naloxone through the nose, and the associated training have been provided to laypersons. That survey reveals that since 2010 there has been a 243% increase in the number of local sites providing naloxone, a 183% increase in the number of laypersons provided naloxone kits, and a 160% increase in the number of overdose reversals reported.

This week FDA is hosting a two-day public meeting, co-sponsored by the National Institutes of Health’s National Institute on Drug Abuse, the Centers for Disease Control and Prevention, the Substance Abuse and Mental Health Services Administration, and the Health Resources and Services Administration. It brings together members of the community-based organizations that first pioneered lay administration of naloxone, medical professionals, policy-makers, public health officials, first responders, product developers, researchers and, of course, patients and their families, to explore and discuss issues surrounding the use of naloxone. The group will address a wide range of topics from a review of current naloxone use in clinical and non-clinical settings to questions of access, state law, over-the-counter status, training and evaluation of effectiveness.

The meeting builds on the good work already done to examine “second generation” questions: growth and sustainability. Discussions will include ways to further involve police and fire departments, expand the range of new products, and address issues of cost, logistics, and supply.

Science doesn’t stand still. But, as this week’s meeting on Exploring Naloxone Uptake and Use demonstrates, neither does the FDA. We will continue to explore every opportunity to apply the best regulatory science to the technology of today in support of our work to protect and promote the health of all Americans.

Peter Lurie, M.D., M.P.H., is associate FDA commissioner for public health strategy and analysis.

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

A reminder of the promise and limitations of abuse-deterrent properties

By: Douglas C. Throckmorton

The ongoing growing amount of drug abuse in our nation, particularly with prescription pain relievers known as opioids, has prompted a lot of talk about the potential of opioids with “abuse-deterrent” properties to help combat this public health problem. But care must be taken in putting  too much promise into abuse-deterrent technology at this time because the science is still relatively new and evolving.

Douglas C. Throckmorton, M.D.While the FDA strongly supports the development of products with effective abuse-deterrent properties and believes they can make a real difference, abuse-deterrent properties do not make an opioid impossible to abuse, and do not prevent overdose and death – they only makes certain kinds of abuse more difficult or less rewarding.

Current abuse-deterrent technologies tend to focus on making the drug either harder to crush, which makes them harder to snort or inject; harder to extract, which means the opioid cannot be easily separated from the other ingredients in the drug for purposes of abuse; more difficult to abuse orally, which is the most common form of opioid abuse; or  less attractive for abuse (e.g., the drug may contain an ingredient that counteracts the action of the opioid, making the drug less “likeable” or even unpleasant).

This week, FDA approved a new prescription opioid tablet called Targiniq ER, which contains a combination of the opioid pain medicine oxycodone and a drug called naloxone, an opioid antagonist. Naloxone can block the euphoric effects of opioid medicines and is used most often to treat an overdose. The science behind this particular abuse-deterrent formulation works like this: If the Targiniq ER tablet is taken as directed (i.e., swallowed according to its approved use), the naloxone will not interfere with the oxycodone. If, however, the tablets are crushed into a powder and snorted or injected, the naloxone inside the tablet will be absorbed and block the desired effect from the oxycodone.

Targiniq ER joins OxyContin (oxycodone) as the second drug FDA has approved with labeling describing the product’s abuse-deterrent properties consistent with FDA’s 2013 draft guidance for industry Abuse-Deterrent Opioids –Evaluation and Labeling which states that for claims to be made, they must be based on robust, compelling, and accurate data and analysis, and the description of the abuse-deterrent properties or potential to reduce abuse must be clearly and fairly communicated.

OxyContin gets its abuse-deterrent properties differently than Targiniq, by including ingredients that make the tablet hard to crush or dissolve. Efforts to pulverize the tablets into a powder result in a chemical reaction that makes the crushed tablet into a gooey gel that makes it more difficult to be inhaled or injected the way drug abusers would like.  While Targiniq and OxyContin use different abuse-deterrent technologies, they serve the same purpose: they are expected to help deter the often lethal practice of snorting or injecting prescription drugs.

In the context of this important and evolving area of science, FDA is very encouraged to see another drug with proven abuse-deterrent properties come to the market. We do need to remember that “abuse-deterrent” is not the same as “abuse-proof” and even abuse-deterrent formulations can be abused and people who take them can overdose and die.  For example, someone who wants to “get high” from prescription opioids can still swallow more than the prescribed amount, and this simple but common form of abuse can result in overdose and death.

Currently available products with abuse-deterrent properties are an important step in the right direction, but there is much more work to be done. The technologies involved in abuse deterrence and methods for evaluating whether those technologies actually deter abuse are rapidly evolving. To address this rapid change, FDA is working with many drug makers to advance the science of abuse deterrence and to help them navigate the regulatory path to market as quickly as possible. While FDA strongly supports a transition to opioids with abuse-deterrent properties, we do not believe it is feasible or in the interest of public health at this time to require all opioid products to have such properties.

To help support the safe use of all opioid products, FDA is working in many other ways to help prescribers and patients make the best possible choices about how to use these powerful drugs. Our goal is to find the balance between appropriate access to opioids for patients with pain and the need to reduce the tragedies of their abuse and misuse.

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

Opioid Auto-Injector Can Help Prevent Overdose Deaths

By: Dr. Douglas C. Throckmorton

The Food and Drug Administration has today made an important advance in helping to save lives when overdoses from drugs known as opioids occur: the approval of a drug that can actually reverse that overdose.

Douglas C. Throckmorton, M.D.Opioids include legal prescription drugs, such as OxyContin (oxycodone) and Vicodin (hydrocodone with acetaminophen), used to treat pain, as well as illegal street drugs, such as heroin. In 2010, overdoses of prescription opioids were linked to 16,651 deaths and heroin was linked to 3,036 deaths in the United States.

Whether opioids are used by patients as prescribed by their health care professional or are misused or abused, these drugs have one important thing in common: They can all cause rapid and fatal overdose.

FDA, along with other organizations, has been working diligently on ways to address this major public health issue. That’s why FDA has approved a drug-device combination product that delivers the medication known as naloxone, which is the standard treatment for a drug overdose. This product is potentially easier to use than existing technology and thus could save lives.

Overcoming an Obstacle

Naloxone reverses the effects of opioids. Most significantly, it reverses the severely slowed breathing that can lead to death during an overdose. When naloxone works, the results can be dramatic: Comatose patients can wake up in minutes.

Over the years, emergency health care professionals and others with special training have saved thousands of lives by giving injections of naloxone to people suffering from opioid overdoses. Although effective, this requires expertise – to be able to draw the naloxone up from a vial and then inject it with a needle and syringe. In some cases, the injectable form is adapted so it can be administered through the nose, but there is currently no intranasal form of naloxone approved by FDA.

FDA has now approved  the first naloxone product that is given using an auto-injector, without having to use a separate needle and syringe.  Available via prescription, the product enables anyone – even the general public – to inject naloxone from a pre-filled, single-use device into a person who is overdosing. This is similar to devices used by laypeople to administer epinephrine in cases of severe allergy. In addition, the auto-injector gives recorded instructions to the user describing how to deliver the medication. The instructions also reinforce the need to seek emergency medical attention immediately because while naloxone works rapidly, it only temporarily reverses the effects of opioid overdose. The patient still needs immediate medical care.

The product’s brand name is Evzio, and information on its safe use is available by clicking this hyperlink.

This approval is the culmination of concerted efforts at FDA and throughout the Department of Health and Human Services (HHS) to spur research into alternative forms of naloxone and to expand its availability. On April 12, 2012, FDA co-sponsored a meeting that highlighted the impact of community-based naloxone distribution programs and explained to sponsors the path to FDA approval.

FDA Working on Other Fronts to Combat Opioid Misuse and Abuse

FDA has a responsibility to demand the best science and data to uphold its high standards to ensure a proper benefit/risk profile for drugs that treat pain. We also foster discussion and research that leads to a better understanding of pain and pain drugs. Because we are concerned about the public health issue, the agency has taken a number of actions to help reduce the devastating consequences of opioid misuse, abuse, and fatal overdoses. We are targeting key drivers of the problem with efforts that include:

  • Changing the labeling of certain opioids to help improve their safe use.
  • Requiring that manufacturers conduct studies of the safety of long-term use of certain prescription opioids.
  • Requiring that manufacturers  of certain opioids make training available to practitioners (physicians, dentists and others authorized to prescribe opioids) on responsible prescribing practices and assessing and addressing signs of abuse and/or dependence.
  • Strengthening our surveillance efforts to actively monitor the changing nature of prescription opioid abuse and identify emerging issues.
  • Working with the Drug Enforcement Administration on opioid controls.
  • Encouraging the development of new forms of opioids that are resistant to abuse.
  • Supporting the development of new pain treatments, especially non-addictive treatments.

While FDA plays an important role in mitigating the risks of addiction, abuse and misuse of prescription opioids, we cannot fix the problem alone. A comprehensive approach must be taken by federal and state governments, public health officials, opioid prescribers, addiction experts, researchers, industry, patient organizations, and others. That is why FDA is working closely with our HHS counterparts, including CDC, NIDA, SAMHSA, and throughout the US government.

There’s much work to be done, but today’s approval of the opioid auto-injector could save thousands of lives. FDA will continue to work to prevent the consequences of misuse and abuse of opioids, including preventing fatal overdoses.

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

Crafting better drug labeling to ensure safer use of opioids

By: Margaret A. Hamburg, M.D.

One of the FDA’s primary public health missions is ensuring that healthcare providers and their patients have all the information they need to help decide whether a medication is safe and appropriate to use.

Margaret Hamburg, M.D.Communicating the full risks and benefits of a drug becomes all the more important for those medications that are potentially deadly if used incorrectly. Extended-release long-acting(ER/LA) opioids fall into that category, and can sometimes cause serious harm, like addiction, even when used properly.

These medications, which include drugs such as morphine, oxycodone, and fentanyl, can improve the quality of life for many people who must live every day with pain. But ER/LA opioids often also contain a large amount of the active ingredient, sometimes in sufficient quantity to be lethal, and they are a prime target of drug abusers.

As part of FDA’s efforts to address the serious risks of ER/LA opioids, we looked more closely at the product labeling, known by many as the package insert, to determine whether this essential tool for conveying information about a drug should be revised to encourage safer use.

We closely reviewed medical literature and evaluated public input. We then came to the conclusion that if we improved what the labeling says about proper patient selection and the risks from these drugs, we might be able to reduce the frequency of bad outcomes.

And so today I’m pleased to announce new, proposed labeling changes for ER/LA opioid pain relievers, as well as new postmarket requirements that will include additional studies and clinical trials to better assess certain significant questions about the risks and safety practices of these drugs. The goal is to achieve safer and more appropriate use of these potent pain relievers.

These labeling changes better describe the risks associated with the ER/LA opioid medications and clarify the population for whom the benefits of these products outweigh their risks.

Rather than stating that these medications are indicated “for the relief of moderate to severe pain in patients requiring continuous, around-the clock opioid treatment for an extended period of time,” once final, the updated label will clarify that these products are indicated for “management of pain severe enough to require daily, around the clock, long-term opioid treatment and for which alternative treatment options are inadequate.”

And in the section of the label regarding limitations of use, we have added language plainly stating just how risky these drugs are — even at recommended doses.

In addition, we are requiring changes to the boxed warning for these products to give greater emphasis and prominence to the risk of Neonatal Opioid Withdrawal Syndrome that may occur in newborns due to prolonged opioid exposure during gestation.

We know that the way a patient characterizes pain is always going to be subjective: “moderate” pain for one patient may be “severe” pain to another. And we recognize that there are some women who have an appropriate need for opioids during their pregnancy.

The goal of all of these labeling changes is to help physicians work with their patients to determine whether these potent pain relievers are the most appropriate treatment for their specific situation and if so, to help them in managing their use.

While our intent is to encourage safer and more appropriate use of these products, simply changing the labeling won’t make an impact if these changes are not understood and integrated into practice by healthcare providers. So I am urging prescribers to spend some time going over this new labeling, when final, reflecting on what the language means to their practice, and communicating what they’ve learned to their patients.

The fact is, improving the safe and appropriate use of ER/LA opioids takes the help and commitment of all of us, including our partners in the healthcare community. We are committed to working together to help ensure that healthcare providers can prescribe ER/LA opioids properly and better monitor and educate their patients.

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration