Eric Edwards, MD, PhD

The tide of deaths due to unintentional prescription opioid toxicity must be stemmed.

There was a time in the United States when going to your medicine cabinet was much safer than taking a trip in your car. However, the most recent data (2011) reveal that deaths related to drug overdoses surpass the number of deaths caused by motor vehicle accidents. The stark reality is the fact that over 75% of those drug overdose deaths involve prescription opioids. At least 83% of the 16,917 opioid-related deaths were accidental,

 which means that 1 person dies every 39 minutes from an unintentional opioid overdose.

Clearly, a public health issue, which some have labeled an epidemic, is occurring in our society. The need to stem the tide of deaths that occur each day from unintentional prescription opioid toxicity is obvious. To date, efforts have been limited to increased education surrounding the risks of opioids, programs to assist in identifying and monitoring for opioid abuse, and a small number of community naloxone distribution programs. On April 3, 2014, the FDA announced its approval of EVZIO (naloxone hydrochloride injection) autoinjector, with a proven route of administration and first-in-class indication for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/ or central nervous system depression. It is intended for immediate administration as emergency therapy in settings where opioids may be present and is not a substitute for emergency medical care.

For the first time, EVZIO makes naloxone available via prescription in a convenient and easy-to-use dosage form for administration by family members and other caregivers in non—health care settings. We recognized the opioid overdose crisis facing America and began development of EVZIO to meet that need. After 5 years of research, and a 15-week priority review process by the FDA, EVZIO was granted approval and is now available in retail pharmacies throughout the United States. You can now place this potentially lifesaving product into the hands of your patients and their caregivers.

EVZIO is consistent with kaléo’s mission, which is to use established drugs, such as naloxone, with the company’s innovative, proprietary technology to deliver products that provide a combination of efficacy, safety, ease of use, and cost-effectiveness. In order to do this, we employ human factors engineering (HFE) to help remove the potential for error during life-threatening situations. In your pharmacy setting, you witness the confusion, and hear the concern in the voices, of patients and family members at the thought of administering a medication incorrectly. Add the stress and anxiety of facing a life-threatening situation during an opioid overdose, and the potential for serious harm is real. HFE takes what we know about our own human limitations and applies it to create a more intuitive, instinctive product.

The use of HFE created a product that uses visual and audio cues to assist in guiding caregivers and family members through the correct administration process. This is because many individuals who may need to respond to an opioid overdose emergency may have never been trained on how to administer naloxone. Approximately the size of a credit card and thickness of a small cell phone, EVZIO can easily slip into a pocket or purse. The auto-injector contains a fully retractable needle system, so the needle is never seen before, during, or after injection; this helps to prevent the potential for infectious disease transmission. The product is designed so that the voice prompts move at the pace of the users, and they do not require the voice instructions to be complete before moving to the next step.

As the pharmacist, it is important for you to know that the trade package comes with 2 prefilled, single-use EVZIO autoinjectors, each with 0.4 mg of naloxone as well as a separate trainer for practice. You can differentiate the trainer from the EVZIO auto-injectors by their labels. The trainer label is black and white, while the EVZIO auto-injector labels are purple and yellow. Trainers have been provided to pharmacists for hands-on education with patients, family members, or other caregivers, and additional trainers are available upon request. Kaléo is proud to be bringing EVZIO to market. We believe that with the assistance of the entire health care professional community, EVZIO will help reduce the number of deaths that occur every year due to unintentional opioid overdose. Be sure to view the important safety information for EVZIO as well as additional educational material by visiting www.evzio.com.

Dr. Eric Edwards is the chief medical officer and vice president of research and development at kaléo. He is the co-inventor of EVZIO. Dr. Edwards received his MD at the School of Medicine and PhD in pharmaceutical science at the School of Medicine at Virginia Commonwealth University. He is an affiliate faculty member at the School of Pharmacy, where he instructs pharmacy students in the use of specialty injectable pharmaceuticals intended for self-administration as well as the regulation of drug/device combination products.

		Vital signs: variation among States in prescribing of opioid pain relievers and benzodiazepines—United States, 2012. Centers for Disease Control and Pre&shy;vention website. www.cdc.gov/mmwr/preview/mmwrhtml/mm6326a2.htm?s_cid=mm6326a2_w. Accessed July 15, 2014.

		EVZIO [prescribing information]. Richmond, VA: kaleo, Inc; 2014.

Articles

Meeting the Need

A new combination drug-device product uses novel technology.

Drug poisoning has now surpassed automobile collisions as the leading cause of accidental death in the United States, and its surge is primarily driven by a rise in prescription opioid deaths. In 2010, the most recent year for which data are available, 16,651 people died from prescription opioid overdose, and at least 82% of those deaths were unintentional.

That means, on average, 1 person dies every 36 minutes. The death rate quadrupled in just 10 years (1999-2010), with the rate increasing faster in women than in men. In 2010, the number of deaths attributed to prescription opioids was more than the combined total for heroin (~3000), cocaine (~4000), and benzodiazepines (~6000). Another sobering statistic is that for each death from opioids there are 10 admissions for abuse, 26 emergency department (ED) visits, 108 persons with abuse/dependence, and 733 nonmedical users. The economic burden has been estimated to be $20.4 billion (2010), with $2.2 billion in direct medical costs.

A closer look at the data on prescription opioid deaths reveals that up to 60% occur in patients without a history of substance abuse who are taking opioids prescribed by 1 practitioner.

 This group, in which the largest amount of opioid overdose harm is occurring, is not likely to be impacted by current harm-reduction strategies such as prescription drug monitoring programs, substance abuse screening tools, or abuse-deterrent formulations. Opioid overdose affects children as well. For example, on average, over 3000 children under the age of 5 years suffer from accidental opioid overdose poisoning each year.

In addition, recent studies have shown that the daily morphine-equivalent (MEQ) dose that places a patient at significantly higher risk for overdose is lower (≥20 MEQ) than the previously reported amount of ≥100 MEQ.

 Furthermore, many patients with chronic, noncancer pain have numerous comorbidities (ie, chronic obstructive pulmonary disease, sleep apnea, cardiac/renal/liver disease) that increase their risk for opioid-related adverse events, including overdose. Co-prescription of pharmaceuticals that affect opioid metabolism (CYP 450, eg, CYP3A4 inducers or inhibitors) and those that cause central nervous system depression (benzodiazepines, muscle relaxants, antihistamines, certain antidepressants, etc) can result in opioid toxicity without any change in how a given patient is taking their prescription opioid analgesic. Lastly, certain opioid preparations are known to be associated with an increased risk of opioid overdose. This is why methadone and all extended release/long-acting opioids contain black box warnings relating to their potential for life-threatening or fatal respiratory depression.

This underscores the fact that opioid overdose can occur at any time, at any dose, at any place, and in any person who consumes opioids. No matter what the category of increased risk—social factors, comorbidities, concomitant medication use, opioid dose, opioid rotation, or certain opioid preparations in general&mdash;the appearance of a new tool that may prevent morbidity or mortality associated with prolonged respiratory depression that can result from opioids is potentially life-saving for patients requiring opioid therapy.

That new tool is Evzio (naloxone hydrochloride injection; kaléo), which was approved on April 3, 2014, by the FDA for use by family members and caregivers to treat persons known or suspected to have experienced a life-threatening opioid overdose. Naloxone rapidly reverses the effects of opioid overdose, for which it is the standard treatment. However, existing FDA-approved naloxone formulations require administration via syringe and needle (intramuscular/subcutaneous) and are most commonly used by trained pre-hospital medical personnel (eg, emergency medical technicians) or in EDs.

Evzio, a novel handheld auto-injector, is the length and width of a credit card and the thickness of a small cell phone. Utilizing kaléo’s proprietary technology, the “Intelliject Prompt System,” Evzio provides audible instructions and visual cues (flashing red and green LED lights) to direct a caregiver, family member, or first responder through the injection process.

Although considered extremely safe and in use for over 40 years, naloxone has never before been available and approved for use by all patients outside of a health care setting. The FDA reviewed Evzio under the agency’s priority review program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists, or that offer significant improvement compared with marketed products.

As part of the product’s clinical trials, it was compared with a 0.4-mg injection of naloxone using a standard syringe. The findings revealed that Evzio provides equivalent naloxone exposure (as measured by area under the curve), a 15% higher peak plasma concentration (Cmax) with a median Tmax time of 15 minutes, as compared with the standard injection with a median Tmax time of 20 minutes. Bob Rappaport, MD, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research, said in a news release, “Overdose and death resulting from misuse and abuse of both prescription and illicit opioids has become a major public health concern in the United States. Evzio is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting. Making this product available could save lives by facilitating earlier use of the drug in emergency situations.”

What does this mean for those health care providers who come in contact with caregivers, family members, and opioid patients on a daily basis? Instead of only being warned against the dangers associated with prescribing and dispensing of opioid products, they now have an antidote in a user-friendly platform that can be recommended to any patient who may be at risk for opioid harm. The fact of the matter is that many patients may not even realize they are at risk, especially patients on opioids for chronic pain, and the prescribing practitioner may also not be aware. Keeping patients safe from opioid overdose is no longer limited to current harm reduction strategies or the screening of patients who have a history of substance abuse.

As with all new drugs, the pharmacist will play a critical role when Evzio hits the shelves this summer. Patients frequently have a variety of practitioners involved in their care—primary care, emergency medicine, pain management, urgent care, and even dental practitioners&mdash;but the pharmacist often has a more comprehensive view of a patient’s medical and prescription history than the prescriber. The pharmacist can understand a patient’s current medication regimen and may be able to provide useful information regarding possible risk factors present when a patient is prescribed an opioid. Therefore, pharmacists will play a substantial role in ensuring patient education and the proper use of this new, potentially life-saving product for unintentional opioid overdose.

Dr. Eric Edwards is the chief medical officer and vice president of research and development at kaléo. He is the co-inventor of Evzio. Dr. Edwards received his MD at the School of Medicine and PhD in pharmaceutical science at the School of Medicine at Virginia Commonwealth University. He is an adjunct faculty member at the School of Pharmacy, where he instructs pharmacy students in the use of specialty injectable pharmaceuticals intended for self-administration as well as the regulation of drug/device combination products.

Dr. Edward Read received his MD from Jefferson Medical College. He is an assistant professor of emergency medicine at Virginia Commonwealth University and a fellow of the American College of Emergency Physicians. Dr. Read has an interest in pre-hospital pharmaceutical interventions and he is a research consultant for kaléo.

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. February 19, 2013. www.jsonline.com/news/health/opioid-overdose-deaths-topped-16000-in-2010-hl8qh1o-191883611.html#axzz31o8rppSk. Accessed May 15, 2014.

		Inocencio TJ, Carroll NV, Read EJ, Holdford DA. The economic burden of opioid-related poisoning in the United States. 

		Manchikanti L, Helm S II, Fellows B, et al. Opioid epidemic in the United States. 

		Burghardt LC, Ayers JW, Brownstein JS, et al. Adult prescription drug use and pediatric medication exposures and poisonings. 

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		Introduction for the FDA blueprint for prescriber education for extended-release and long-acting opioid analgesics. FDA website; April 2013. www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM277916.pdf. Accessed May 15, 2014.

A new combination drug-device product uses novel technology.
