A joint FDA advisory panel was split on whether the injectable 0.4-mg dose of naloxone should remain the current standard by which products containing the opioid overdose reversal drug should be measured -- though they agreed that a lack of data made their decision more challenging.
Slightly more panelists voted to increase the minimum acceptable dose rather than maintain it (15-to-13) during the joint meeting of the Anasthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM).
A vote on whether to have the same minimum dose standard for adults and children was a bit more straightforward, at 21-to-7 in favor of keeping those figures consistent -- but some said that dose should be higher, while others said it was fine as-is.
Panelists who voted to raise the minimum dose largely cited the increasing use of more potent opioids like fentanyl and, more recently, carfentantil, which might require more doses or higher doses of naloxone to revive patients.
Those who voted to maintain the 0.4-mg standard said that dose -- in its intravenous, intramuscular, or subcutaneous forms -- works just fine, and that higher doses could send patients into withdrawal.
Most agreed that there wasn't sufficient evidence to make the decision. Despite several presentations from drug industry stakeholders developing naloxone products -- including Adapt, Amphastar, Kaleo, and Insys -- as well as from the CDC and FDA, there were no hard outcomes as to whether the 0.4-mg dose failed to resuscitate patients more frequently than a higher dose; nor was there evidence that overdoses involving more potent opioids require higher doses of naloxone to resolve.
"I have more questions now than when I got here," said panelist , of Drexel University in Philadelphia, who voted to maintain the current minimum standard. "Since so many questions remain unanswered, I couldn't drift from the current standard."
, of the Moffitt Cancer Center in Tampa, Fla., said there wasn't enough evidence "that the current dose is ineffective, and indeed the majority of the data say it was effective. I would hate to move away from what's most effective."
"We should continue to use [all doses] until we find out more," said , of the University of Florida. "We need better pharmacokinetic and pharmacodynamic studies to get a better idea of what is needed."
, of Columbia, who voted to increase the minimum standard, said it was "remarkable" that some of the available products on the market have labeled on their packaging the possible need for a second dose.
"That sends the message that they're not confident the first dose is going to be adequate," he said. "Three more minutes of continued hypoxia is not innocuous."
, of the University of Colorado, who also voted to raise the dose, said the decision should be more focused on "saving more lives than worrying about withdrawal syndrome."
Injectable naloxone at a dose of 0.4 mg was first approved in 1971 under the brand name Narcan. In the mid-2000s, as the opioid abuse epidemic in the U.S. worsened, companies became more interested in its commercial potential and several new products were created.
The first, approved in April 2014, was the Evzio autoinjector from Kaleo Pharma. Its square cartridge talked bystanders through delivering a 0.4-mg dose of naloxone.
Then Adapt Pharma's branded nasal spray, developed with the help of the National Institute of Drug Abuse, was approved in November 2015 -- at a much higher dose of 4 mg of naloxone per spray. Adapt licensed the brand name Narcan from Endo Pharmaceuticals.
Prior to those approvals, the only option was Amphastar's generic naloxone, packaged either in a 0.4-mg injection, or in a 1-mg formulation that was ideal for home-brewed nasal sprays when adding an atomizer. Although it was off-label, this was the method favored by first responders and community groups: it was cheap, and it was simple for the public to use.
When Adapt's high-dose nasal spray first came on the market, experts told ľֱ they were concerned that it would send patients into withdrawal.
, director of the FDA's anesthesia, analgesia, and addiction products division, acknowledged those complaints during the meeting; but over time, she said, the agency began to hear concerns that lower doses of naloxone wouldn't be sufficient to reverse overdoses involving more potent opioids like fentanyl, which were turning up more frequently.
During the hearing, panelists noted that there were many ways in which naloxone could be dispensed, and that different products work differently in various settings. An overdose patient treated in the emergency department, for example, may do just fine on a single intravenous dose of 0.4 mg naloxone. At the other end of the spectrum, someone who overdoses on a potent opioid out in the community may need a higher dose that can be given easily by a bystander, they said.
Having a wide range of options allows for more flexibility, said panelist , of the University of Florida.
During an hour-long open public hearing, most of the speakers came from the harm reduction community. These groups were concerned that if the minimum standard was changed, they would no longer be able to access less expensive generic naloxone, thus putting their entire programs at risk.
"Community organizations serve many people who are homeless and living in poverty," said , executive director of the Los Angeles Community Health Project. "We are generally poorly funded, and we're extremely price sensitive."
"We're concerned that by putting out guidelines that favor more expensive novel products, it will influence government entities and legislation meant to expand our existing programs," she said. "We can't afford to lose any more lives."
, medical director of Utah Naloxone, said at the current pricing, her organization can give out 3,200 kits with Hospira's 0.4-mg/mL product. If that's off the table, those numbers would drop to 1,200 kits of Adapt's Narcan nasal spray, or just 21 kits with the Evzio autoinjector.
"The dose available influences what happens in these communities," Plumb said. "I hope I have the ability to continue to save lives."
In 2015, the price of the Amphastar off-label nasal formulation jumped from $13 to $30 per dose, and kits typically involve two doses. Adapt said it priced its product to be competitive with that price, at $37.50 per dose or $75 for a typical two-pack. The price of the Evzio device was unclear, but estimates during the meeting ranged from $1,000 to $2,000.
Other new branded naloxone products could be on the horizon. During the meeting, Amphastar said it was developing a higher-dose nasal spray, and Insys Therapeutics -- currently under scrutiny for its role in pushing its fentanyl spray Subsys to non-cancer pain patients -- said it was working on an under-the-tongue naloxone spray.