FDA Panel Supports Greater Community Access to Naloxone

Pauline Anderson

October 07, 2016

In light of a growing opioid epidemic that includes a spike in overdose deaths and increasing availability of potent, rapid-onset synthetic products such as fentanyl derivatives, a joint US Food and Drug Administration (FDA) advisory committee has voted to increase the current minimum acceptable exposure to the opioid antagonist naloxone (multiple brands).

Committee members also decided that adults and children should have the same minimum standard when it comes to potentially lifesaving naloxone products.

During a day-long meeting, members of the Anesthetic and the Analgesic Drug Products and Drug Safety and Risk Management Advisory Committees discussed the adequacy of the current pharmaceutical standard, which is based on exposures associated with 0.4 mg of intramuscular (IM) naloxone.

Some believe this standard is too low, as it does not always reverse the effects of the more potent street drugs, but others were against increasing the standard dose, as it appears to work in most cases, and increasing it would raise the risk for opioid withdrawal.

At the end of the day, though, the committee leaned slightly in favor of providing more rescue medicine to save more lives.

"You can resuscitate withdrawal, but you cannot resuscitate death; death is final," said Athena F. Zuppa, MD, associate professor of anesthesiology and critical care and associate professor of pediatrics, University of Pennsylvania School of Medicine, Philadelphia.

Committee members heard about the dramatic rise in opioid overdoses and related deaths. Data from the Centers for Disease Control and Prevention (CDC) indicate that in 2014, drug overdose deaths from prescription opioids and heroin reached almost 29,000, a number that represents 61% of all drug overdose fatalities.

Opioids include illegal drugs such as heroin and illicitly manufactured synthetic products such as fentanyl, as well as prescription opioid medications such as morphine, codeine, methadone, oxycodone, hydrocodone, hydromorphone, fentanyl, and buprenorphine. The CDC data suggest that in 2014, heroin was implicated in about 30% of all fatalities, and prescription opioids were implicated in about 70% of cases.

Overdose Risk Factors

Most of these opioid-related overdose deaths – 76% – occur in the community, the committee heard.

Many factors – some unknown – determine a risk for opioid overdose. These include opioid-related factors, such as the type and strength of opioid consumed and the mode of administration; patient-related factors, such as the presence of respiratory illnesses or other underlying disease; opioid tolerance; genetic make up; and naloxone-related factors, such as dose and formulation.

As a narcotic antagonist, naloxone displaces opiates from receptor sites in the brain and can reverse respiratory depression that is usually the cause of overdose deaths. The committee heard about the safety and efficacy of naloxone and that, although there is a risk for opioid withdrawal in opioid-dependent people, these side effects are rarely life-threatening.

An injectable form of naloxone hydrochloride (HCL) was first approved in 1971 (Narcan) to reverse opioid intoxication or overdose through IM, intravenous (IV), and subcutaneous (SC) routes of delivery. Although injectable Narcan has been discontinued, generic products of injectable naloxone HCL are commercially available in prefilled syringes and vials.

To help combat overdoses outside the hospital setting, treatment with naloxone has expanded into the community, where, in emergency cases, it can be easily and rapidly administered by a caregiver or other witness of an overdose. Such emergency care should be viewed as a bridge to medical attention.

The FDA has approved two formulations of naloxone intended for community use:

  1. Narcan Nasal Spray (4 mg/0.1 mL naloxone HCL nasal spray) (Adapt Pharma), which is a single-dose, needle-free, drug-device combination product.

  2. Evzio (0.4 mg/0.4 mL naloxone HCL) (Kaléo Inc), which is a single-use, fixed-dose autoinjector designed to deliver 0.4 mg of naloxone HCL IM or SC. It comes with audio instructions.

A third product that is used in the community but that is not FDA approved is the improvised nasal naloxone kit. It uses naloxone HCL injection vials in combination with a mucosal atomizer device.

There is some suggestion that alternative routes of administration should be available for out-of-hospital management of opioid overdose. Committee members learned about a product from Insys Therapeutics Inc that can be taken sublingually.

Rural Patients

Steve Sherman, senior vice president of regulatory affairs, Insys, discussed the "unmet needs" of those unable to use naloxone via IV or IM routes. These might include drug users who are HIV or hepatitis C positive (in whom IV routes are problematic) or those with nasal trauma, allergies, colds, or the flu (in whom the intranasal route does not work sufficiently).

According to the FDA, an initial dose of 0.4 mg to 2 mg of naloxone HCL may be administered intravenously. If the desired degree of improvement in respiratory function is not obtained, this may be repeated at 2- to 3-minute intervals.

Increasingly, patients who experience overdoses in the community need more than one dose of naloxone. Mark Faul, PhD, senior health scientist, National Center for Injury Prevention and Control, CDC, told the committee that the percentage of patients who require multiple naloxone administrations in an emergency medical service setting rose from 14.49% in 2012 to 18.24% in 2015.

When the vote was taken, the results were close: 15 members wanted to increase the minimum acceptable naloxone exposure, and 13 voted to continue the current standard.

Some members were moved by the plight of rural patients. It takes much longer for emergency medical services to arrive on scene in rural communities than in more urban areas.

"There has been a dramatic increase in the number of folks coming into our emergency department," said committee chair Raeford E. Brown Jr, professor of anesthesiology and pediatrics, University of Kentucky College of Medicine, Lexington. "When we get patients from the Appalachian region who have traveled a long way, 0.4 mg of naloxone is not going to take care of them."

Because the opioid epidemic coincides with another epidemic, obesity, Dr Zuppa said that a "one-size-fits-all” approach might be appropriate, in that a higher dose would be appropriate for the obese patient as well as the person of normal body weight.

Many committee members, including Ruth Parker, MD, professor of medicine, pediatrics, and public health, Emory University School of Medicine, Atlanta, Georgia, were swayed by the increasing need for a second naloxone dose. Dr Parker said she is concerned about the increasing number of overdoses, as well as the recent increase in multiple naloxone administrations.

No Downside of Higher Doses

The interval between administration of current doses was a concern to some. "Three minutes or more of additional hypoxia is not an innocuous consideration," said Charles W. Emala Sr, MD, professor and vice-chair for research, Department of Anesthesiology, Columbia University College of Physicians and Surgeons, New York City.

"We have not heard any data today that higher doses have a significant downside other than withdrawal," said Jeffrey Brent, MD, PhD, Distinguished Clinical Professor of Medicine, University of Colorado School of Medicine, Aurora.

However, withdrawal was a concern for some members, including Louis S. Nelson, MD, professor and chair, Department of Emergency Medicine, New Jersey Poison Information and Education System, Rutgers New Jersey Medical School, Newark, who said, "I don't think withdrawal is as benign as we consider it to be sometimes."

According to some some emergency department personnel, addicts who are administered naloxone are sometimes belligerent and violent when brought to the hospital.

Other committee members felt there was not good evidence to suggest that the 0.4-mg dose fails more frequently than the higher dose.

"Keeping it at the 0.4 gives us more flexibility of products and allows us to basically let the research set the recommendations for lower or higher dosing, depending on the circumstances identified in the field," said Mark Hudak, MD, professor and chairman of pediatrics, University of Florida College of Medicine, Gainesville.

Committee members also discussed the use of naloxone in children. Currently, the usual dose in the pediatric population is 0.01 mg/kg IV. A subsequent dose of 0.1 mg/kg may be administered if needed.

What About Children?

Committee members agreed that in most pediatric cases that do not involve neonates, children who overdose on opioids in the home are not dependent, and so withdrawal is not a problem, and that having different standards might be confusing.

"Based on the epidemiology of poisoning in children, it's unlikely that most children would be harmed by even the highest dose of naloxone," said Dr Brown.

"It's much simpler if there's a single drug in the house for emergency use," said Muriel Ellen McCann, MD, associate professor of anesthesia, Harvard Medical School, Boston, Massachusetts.

But some members thought pediatric cases should be viewed separately.

"Children are different than adults, and even though the dosing may be similar, I think they should be examined as different populations," said Jonathan Davis, MD, chief of newborn medicine, Floating Hospital for Children, Tufts Medial Center, and professor of pediatrics, Tufts University School of Medicine, Boston, Massachusetts.

For Anita Gupta, DO, PharmD, vice chair and associate professor, Division of Pain Medicine and Regional Anesthesiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, the information presented on pediatric cases was insufficient for her to draw conclusions. "I understand the need for one single dose – absolutely – but I could not draw a clear conclusion on whether or not 0.4 was adequate."

Like many of her colleagues, Dr Gupta called for more research to better understand "how naloxone works in neonates and children."

Source: Background information and webcast of joint FDA Advisory Committee meeting, October 5, 2016.


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