BETHESDA, MD 10 Nov 2016—A panel of advisers recently offered a mixed message to FDA about whether new naloxone products should deliver a greater amount of drug per dose than current formulations.
The nationwide epidemic of opioid overdose deaths formed the backdrop for the October 5 joint meeting of FDA's Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee in Silver Spring, Maryland. The specific focus of the meeting was naloxone products intended for administration by laypersons in community settings who witness an overdose.
"Naloxone saves lives," said FDA Medical Officer Jennifer Nadel.
Currently, two naloxone products—Kaléo Inc.'s Evzio autoinjector and Adapt Pharma's Narcan Nasal Spray—are labeled for emergency use in community settings and come with instructions for administration by laypersons who witness an opioid overdose.
The Evzio formulation that was approved in 2014 delivers a 0.4-mg subcutaneous or intramuscular dose of naloxone, and Narcan Nasal Spray, which was approved last year, delivers a 4-mg intranasal dose of the opioid antagonist.
FDA Approves New Naloxone Strength
FDA on October 19 approved a version of Kaléo Inc.'s Evzio autoinjector that delivers 2 mg of naloxone in a volume of 0.4 mL—or five times the dose delivered by the original autoinjector product.
Mark Herzog, vice president of corporate affairs at Kaléo, said he expects the 2-mg autoinjectors to be available "in the first half of 2017."
The 0.4-mg autoinjectors are sold in packaging with purple and yellow markings. The 2-mg version will have purple and blue markings.
Herzog stated in October that the company has not decided whether to discontinue the original product or market both formulations.
Repeat doses may be administered every two to three minutes, and naloxone products that are labeled for community use come in packages of two to allow for repeat dosing.
"The duration of action of most opioids is longer than the effects of naloxone. The effects of the opioid will return as the naloxone is cleared," Nadel explained.
FDA-approved naloxone products are available in formulations intended for intravenous, intramuscular, subcutaneous, or intranasal administration. Other manufacturers are interested in bringing additional new products—some with new delivery systems—to the market, Nadel said.
She said the agency requires that new naloxone formulations produce, at a minimum, an exposure equivalent to that of a 0.4-mg intramuscular dose of the opioid antagonist.
FDA officials said that after the first community-use naloxone product was approved, stakeholders expressed concerns that the standard minimum dose was too high and could precipitate potentially deadly severe opioid withdrawal syndrome in susceptible people.
"More recently, we became concerned that the dose is too low," Nadel said. "There are reports in the news of heroin being laced with extremely potent opioids, such as 'street fentanyl' or carfentanil."
Patients who overdose on these high-potency synthetic opioids or extended-release opioid products may not respond to standard doses of naloxone, she said.
The Drug Enforcement Administration (DEA) on September 22 issued a warning to police and the public about the emergence of carfentanil, a large-animal sedative, in U.S. communities. DEA described the synthetic opioid as "10,000 times more potent than morphine and 100 times more potent than fentanyl."
Nadel cited media reports of carfentanil overdose outbreaks in Ohio, Indiana, and Florida. The Michigan Department of Health and Human Services on September 19 reported a suspected case of carfentanil overdose and announced that the drug "is now likely circulating in the state."
And that's not all, said meeting Chairman Raeford Brown, professor of anesthesiology and pediatrics at the University of Kentucky College of Medicine in Lexington.
"Carfentanil has moved into Kentucky. And there have been dramatic increases in the number of folks that have been coming into our emergency department for which 0.4 milligrams of naloxone do nothing," Brown said. "So I believe, based on my experience, that an increase in dose would salvage more patients."
Brown's view was shared by a bare majority of the committee members, who voted 15–13 in support of a higher minimum naloxone dose for new products.
Those in favor of increasing the minimum dose were swayed by Centers for Disease Control and Prevention (CDC) data on how often emergency medical service (EMS) responders provide multiple doses of naloxone to overdose victims.
"The national picture is pointing to more and more administrations" of naloxone per overdose, said Mark Faul, a senior health scientist for CDC.
He also said it's clear that the overdose landscape has changed over time, with deaths from heroin and synthetic opioids now exceeding those from prescription opioid abuse.
Faul said a soon-to-be-published study of data from the National EMS Information System indicates that 14.49% of naloxone administrations by EMS personnel in 2012 involved more than one dose of the opioid antagonist. That number rose to 18.24% last year.
During 2015, Faul said, EMS staff reported administering 214,611 doses of naloxone to 173,016 patients. A total of 25,131 patients received two doses of naloxone while being cared for by EMS personnel, 4,018 patients received three doses, 1,590 received four doses, 615 received five doses, and 200 received six or more doses.
Those totals don't include naloxone doses administered after the patients were transported to a hospital.
Faul cautioned that the study doesn't directly link the recent increase in multiple naloxone administrations to an increase in the potency of opioids in patients who overdose. And the database doesn't identify the specific naloxone products used by EMS responders.
Advisers who recommended against raising the minimum dose standard for new naloxone products generally said that the current standard works, despite the need for redosing. And some advisers called for new studies to support the use of higher doses.
"It's a real pharmacokinetic–pharmacodynamic conundrum," acknowledged T. Mark Woods, clinical coordinator for pharmacy at St. Luke's Hospital in Kansas City, Missouri.
Woods, nevertheless, voted in favor of increasing the dosing standard.
"I see too many things telling me that current dosing based on reviving patients in hospital settings really doesn't apply in the community," he said.
The committee members also discussed whether FDA should use different minimum standards for naloxone dosing in children and adults. The group voted 21–7 in support of a single standard, citing confidence in naloxone's safety profile and a desire to avoid the confusion that could be caused by having to choose among multiple dose options at the scene of an overdose.
"I don't think we have enough data to support that the dose would be something different than the minimum standard dosage. . . . And that seems to apply to both populations," said Almut Winterstein, professor of pharmaceutical outcomes and policy at the University of Florida College of Pharmacy in Gainesville.
But Winterstein gave a nod to the concerns raised by those who didn't vote in favor of the single minimum standard.
"We definitely need more research in, specifically, children," she said.