Last winter, public health and harm reduction groups raised concerns about the skyrocketing price of an off-label version of nasal naloxone. Since then, two on-label formulations have been developed, and one was approved. This follow-up story looks at how the new product will play out in the real world.
First responders and harm reduction groups have long been cobbling together a nasal delivery system for the opioid overdose reversal agent naloxone. They'd pop atomizers atop cartridges that held a higher dose of the drug than the one used for regular injection, to make it easier for emergency teams and bystanders to save someone from an overdose. No need to find a clear injection site, no risk of needle sticks.
The problem: nasal delivery was an off-label use, which meant manufacturing issues and reimbursement challenges when dealing with insurers.
But last month the FDA approved the first on-label nasal-spray naloxone, which will be marketed under the very first brand name for naloxone, Narcan. Drugmaker Adapt Pharma licensed the name from Endo Pharmaceuticals.
The reaction in the public health community was initially positive: "Another option is always welcome," , executive director of Project Lazarus, told ľֱ. "Hopefully this will provide an easier avenue to obtain intranasal naloxone than putting naloxone kits together and adding an off-label nasal atomizer like we have had to do and then provide to pharmacy/patient/person."
But several experts contacted by ľֱ on the day the Adapt product was approved noted that they were eager for real-world results, because only pharmacokinetic and usability data were needed for FDA approval. Adapt didn't have to conduct any field trials.
"Because it was approved with no field testing to get it approved quickly, we don't know how it works in the real world," said , of the University of Washington.
Within a few weeks, researchers started raising questions about the dose of the new nasal formulation: 4 mg. The off-label nasal naloxone was given at a dose of 1 mg, and the injectable at 0.4 mg.
"My concern is that withdrawal symptoms might be much more substantial at this dose than at our traditionally administered dose," , of the San Francisco Department of Public Health, told ľֱ. "It may be more challenging to manage those symptoms in the lay environment."
Experts have also questioned why a competing nasal naloxone product made by Indivior (formerly Reckitt Benckiser Pharmaceuticals), at a dose of 1.8 mg, was denied approval just days after Adapt's product was given the green light. In a press release announcing a complete response letter from the FDA, Indivior said it was denied because "early stage uptake of naloxone nasal spray did not fully meet the FDA's threshold as determined by the reference product," which was the 0.4 mg intramuscular injection dose.
Injectable naloxone came on the market in the 1970s and has been available as an inexpensive generic. But the rising toll of the nation's opioid addiction woes, paired with concerns about bystanders having difficulty with needles, provided an incentive to get companies back into the labs to develop alternate delivery strategies.
The first new naloxone formulation was Evzio, an auto-injector approved in April 2014. But many groups, including first responders and harm reduction community groups, couldn't afford its wholesale $700 price tag, and so they stuck with regular injectables or an off-label nasal formulation.
The nasal formulation, made by Amphastar, was preferred because it was easier to administer. But after Evzio hit the market, its price started to climb as well -- more than doubling from $13 to $30 per dose in fall 2014.
Adapt Pharma was keen to put the price for first responders and community groups right in its press release announcing approval: $37.50 per dose, rivaling the current price for off-label nasal naloxone.
Christy Maginn, a spokesperson for Adapt Pharma, said the 4-mg nasal dose was "selected in collaboration with NIDA, which supported the work, for its balance between an adequate dose for rapid restoration of respiratory function (to potentially avoid death or CNS side effects) and the known potential risk of opioid withdrawal symptoms."
Maginn noted that injectable naloxone "has been available since 1971 and approved at significantly larger doses" up to 10 mg -- although this dose is rarely used in overdose reversal settings.
"We have seen in just the past year how changes in the opioids consumed -- like nonpharmaceutical fentanyl or fentanyl-laced heroin -- can significantly impact opioid overdose death," Maginn said, referencing recent CDC data on rising opioid overdose deaths, many linked to illicit fentanyl. "Indeed, CDC recommended first responders stock extra naloxone as fentanyl is much more potent than heroin."
Indivior's nasal naloxone would be delivered at about half the dose, at 1.8 mg, given as two sprays of 0.9 mg -- one in each nostril.
That drug was originally developed by Daniel Wermeling, a pharmacist at the University of Kentucky, and his company AntiOp, but he sold the drug to Indivior in June 2015. Indivior was granted priority review a month later, but received its in November.
As Reckitt Benckiser, the company had clashed with FDA when it tried to block generic versions of its best-selling addiction therapy drug Suboxone, a combination of buprenorphine and naloxone.
The FDA , saying it acted disingenuously when it decided to stop selling tablets and switch all patients to a sublingual film instead, right around the time its patent was set to expire.
The film was supposed to be less prone to accidental use by children -- but the FDA didn't buy those claims and ended up approving Suboxone generics.
Federal officials raided Reckitt's Virginia headquarters in December 2013. A year later, the company changed the name of its pharmaceuticals business to Indivior.
While Indivior may have lost the race to be first to market with an on-label nasal naloxone -- and it lost access to the brand-name Narcan, too -- questions remain about which product will ultimately be the most widely used for preventing opioid overdose: Will Adapt's drug become the favorite? Will the Indivior product ever be approved? Will Amphastar discontinue its off-label naloxone?
Banta-Green warned it could be hard to measure "if people are reversing overdose, getting extreme behavioral or medical consequences [such as withdrawal] and start to warn others not to use naloxone and those people not distinguishing which product was used. And, ultimately LESS naloxone gets used and fewer overdoses reversed."
While he said he doesn't think that's a likely outcome, it's "important to consider that it is unlikely that this is a one size fits all product."