FDA Approves One Intranasal Naloxone Product, Disapproves Another

FDA Approves One Intranasal Naloxone Product, Disapproves Another

The Food and Drug Administration (FDA) has approved Narcan nasal spray, the first FDA-approved intranasal naloxone hydrochloride spray. Naloxone is used to arrest the potentially fatal effects of an opioid overdose, particularly potentially fatal respiratory failure. Adapt Pharma Inc., licensed the popular Narcan brand name from Endo Pharmaceuticals for the nasal spray product. FDA approval was received in mid November. Narcan brand injectable naloxone hydrochloride has been so widely used, for so many years, that "Narcan" has become something of a synonym for naloxone, like calling all tissues "Kleenex." Just a couple of days after the Narcan approval, a competing intranasal naloxone spray was disapproved by the FDA. Indivior, formerly Reckitt Benkiser Pharmaceuticals, submitted its new naloxone nasal spray product for approval in July and received the FDA's negative response in November. Indivior already markets Evzio, a unique, easy-to-use auto-injectable naloxone hydrochloride cartridge that caused quite a stir when it was introduced a couple of years ago. The problem with Indivior's new naloxone nasal spray appears to be some concern about appropriate dosages. Adapt's product delivers a 4 mg dose, while the Indivior product delivers only 1.8 mg of naloxone hydrochloride as two 0.9 mg sprays, one for each nostril. The traditional naloxone hypodermic injectable has been standardized at 0.4 mg since its approval back in the early 1970s. But dosages up to 10 mg are approved, although rarely used. Too much naloxone can initiate uncomfortable withdrawal symptoms. Indivior's Evzio auto-injectable cartridge also delivers 0.4 mg dosages.

Fast track applications lacked some dosage science

With the opioid epidemic of heroin and narcotic painkillers raging across the country and overdose deaths - some 17,000 a year - now exceeding motor vehicle crash deaths, the potential for saving more lives with an incredibly easy-to-use naloxone nasal spray cannot be over-emphasized. This led the FDA to encourage "fast-track" designation and "priority review" submissions for intranasal naloxone devices. The FDA's priority program expedites speedy review and hopefully approvals of drugs that offer "a significant improvement in the safety or effectiveness of the treatment, prevention, or diagnosis of a serious condition." Both Adapt (Narcan) and Indivior submitted fast track applications. Adapt worked with the National Institute on Drug Abuse (NIDA) on working out dosages in clinical trials, and came up with the 4 mg intranasal dose as the closest match to the results of the standard 0.4 mg intramuscular injectable. Adapt didn't have to conduct any field trials - just the clinical trials performed in cooperation with NIDA. Several experts told MedPage Today that they were "eager for real-world results" because only pharmacokinetic and usability data were needed for the fast-track FDA approval. Indivior's dosage raised some questions with the FDA, which decided to disapprove based on the lack of science supporting the 1.8 mg dosage. In a press release announcing the FDA decision, 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" - the standard 0.4 mg intramuscular injection dose.

Dosage questions still remain for intranasal naloxone

EMT personnel have been putting together their own (and unapproved) naloxone nasal-spray gadgets for years. They would marry some injectable naloxone to a simple atomizer, and spray it up an overdose victim's nose. This "off label" use of injectable naloxone wasn't FDA approved, but it was legal and delivered acceptable results in the field. In fact, those home-made nasal naloxone atomizers are what prompted the idea for a commercial naloxone nasal spray. But the standard dosage for the off-label intranasal naloxone in the field has been standardized at 1 mg, not the 4 mg dosage approved for Adapt's Narcan. Researchers with naloxone experience are questioning the 4 mg dose, suggesting that it's too high and could precipitate withdrawal on some patients. "My concern is that withdrawal symptoms might be much more substantial at this dose than at our traditionally administered dose," Phillip Coffin, MD, of the San Francisco Department of Public Health, told MedPage Today. "It may be more challenging to manage those symptoms in the lay environment." And Caleb Banta-Green, PhD, MPH, of the University of Washington, said: "Because it was approved with no field testing to get it approved quickly, we don't know how it works in the real world." Another problem might arise if Indivior's 1.9 mg product eventually receives approval. With the 4 mg Narcan already out there, Banta-Green warned, it could be hard to measure results if people are reversing overdose, and some are getting extreme behavioral or medical consequences such as withdrawal. People might start to warn others not to use naloxone without distinguishing which product was used. Ultimately, he said, less naloxone might get used and fewer overdoses reversed. While he thinks that's an unlikely outcome, it's "important to consider that it is unlikely that this is a one size fits all product."

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