Naloxone Nasal Spray: FDA Approves Higher Dose for Opioid Overdose

with Timothy J Atkinson, PharmD, BCPS, CPE

FDA has approved a higher dose naloxone hydrochloride nasal spray as part of increased efforts to stunt surges in opioid-related deaths.¹ Despite a roughly 43% reduction in opioid prescriptions since the peak in 2004, opioid use disorder (OUD) remains one of the United States’ greatest health crises.² A flooded black market – mixed with the pandemic’s isolation, job loss, and barriers to substance use treatment – has resulted in a deadly and inequitable environment, with socioeconomic status weighing heavily.³

Along with recently relaxed guidelines on prescribing buprenorphine, a commonly used agent in medication-assisted treatment (MAT), this newly approved higher dose of naloxone spotlights a movement toward harm reduction in the treatment of substance use disorders overall.

Narcan Nasal Spray 4mg and Kloxxado Nasal Spray 8mg: Comparing Naloxone Hydrochlorides

FDA approved Hikma Pharmaceuticals’ naloxone hydrochloride nasal spray 8 mg (Kloxxado) for emergency or suspected opioid overdose on April 30, 2021, based in part on the safety and effectiveness of the already available NARCAN nasal spray 4mg.

Like NARCAN, Kloxxado is a single use intranasal spray. There was an autoinjector version of naloxone hydrochloride 2mg (Evzio) delivered via intramuscular administration but this product was discontinued in October 2020. In studies comparing equal doses of naloxone administered via the intranasal route to the intramuscular route, the intranasal route has repeatedly shown to be less effective,4 with the largest difference being onset of effect. By increasing the nasal spray dose to 8mg, this newest product may address this gap.

“Based on the information submitted to the FDA, within 10 minutes this new formulation will be at a higher concentration than you can get with intravenous administration,” the latter of which is used by emergency responders, explained Timothy J Atkinson, PharmD, BCPS, CPE, a clinical pharmacy specialist in pain management at the VA Tennessee Valley Healthcare System. Although onset with nasal spray is still slightly slower than IV administration, during a 4-hour trial, 8mg of naloxone hydrochloride sustained higher levels in the blood when compared to 0.4 mg of intramuscular naloxone and 2 mg of intravenous naloxone.⁵

Naloxone’s Effect on Fentanyl, Synthetic Drugs and Polysubstance Use

The FDA has reported the safety of naloxone ­– even in patients who are not experiencing an opioid overdose. While Dr. Atkinson says that a higher dose of naloxone hydrochloride may come with a greater precipitated withdrawal, it may also prevent an overdose that a lower dose would not. “This approval could indicate (in my opinion) that the FDA is recognizing that with all the synthetic opioids that are out there – they are much more difficult to reverse than a standard opioid and a higher dose is more likely to be successful.”

Higher doses of naloxone are indeed recommended for overdoses that are more difficult to reverse, specifically from polydrug reactions, synthetic opioids (fentanyl), and when partial opioid agonists are involved, such as buprenorphine.⁵

Along with the increasing use of methamphetamine in conjunction with opioids, illicit fentanyl is thought to be a core reason for increased rates of overdose, despite reductions in opioid prescriptions.⁶

One study examined random samples (150,000 total) of urine drug monitoring tests ordered by health professionals nationwide 4 months before (November 14, 2019, to March 12, 2020) and after (March 13, 2020, to July 10, 2020) the opioid public health emergency declaration.⁷ The results showed an increase in fentanyl from 3.80 % to 7.32 % and an increase in methamphetamine from 5.89 % to 8.16 %. FDA approval of this higher dose naloxone seems to indicate a necessary augmentation in treatment.

“The ability of Kloxxado to deliver a higher dose of naloxone is much more likely to be effective against illicit fentanyl and partial opioid agonists,” said Dr. Atkinson.

Administering Naloxone: Harm Reduction & Accesss

It’s important to recognize that naloxone as an overdose treatment is likely to be administered by an untrained individual. “We know now, from using naloxone throughout the opioid crisis, the likelihood is that it’s going to be family, friends, or caregivers that are going to administer this,” said Dr. Atkinson. The increased risk of error, means there is a decreased likelihood of delivering the full dose.

“If you look at this from a harm reduction standpoint, even a 10% fail rate is unacceptable because that means patients could not be getting the intended medicine,” he explains. The higher dose may decrease this risk.

Despite being available without a prescription, access to naloxone differs across zipcodes. Whereas certain states such as New York rely on the Good Samaritan Law to make naloxone available in a variety of stores, other states such as Georgia have a limited variety and supply of naloxone products in many pharmacies.⁸˒⁹

Payer coverage of naloxone products is another consideration. Dr. Atkinson points out that we do not yet have studies proving this new higher dose form of naloxone will be more effective than the previously approved versions. “Right now, the advantages are theoretical. Until data is shown to support the need for a higher dose, it is unlikely that payers will justify the cost. I think these are studies that need to be done and I suspect they will be.”

He additionally points out that cost is already an issue for patients whose clinicians recommend naloxone and emphasizes the need to expand access to this life-saving medication.

Kloxxado and Narcan Contraindications

It is recommended that patients over the age of 65 years use a lower dose of naloxone (4mg) if experiencing a known or suspected opioid overdose, and be given a second dose if needed. It is also noted that an alternative form of naloxone hydrochloride may be considered for infants and that absorption of Kloxxado in pediatric patients may be erratic or delayed. Kloxxado is not recommended for people who have a hypersensitivity to naloxone or hydrochloride.⁵