Opioid overdose is a leading cause of accidental death in the United States, and the number of drug overdose deaths has been steadily increasing for more than a decade.
 
In response, the FDA in April 2014 approved naloxone auto-injector (Evzio), the first opioid overdose antidote specifically designed to be administered by family members or caregivers. Then, in November 2015, the FDA approved the first naloxone nasal spray (Narcan).
 
This article highlights several key therapeutics areas with Evzio and Narcan that every pharmacist should know.
 
History
Naloxone has been used for more than 40 years to reverse respiratory depression during opioid-related emergencies. Prior to the approval of Evzio and Narcan, the medication had to be administered as an intravenous (IV) injection.
 
This was problematic for several reasons. First, peripheral venous access may be difficult to obtain in IV drug abusers, making the medication difficult to administer. Second, exposure to their blood could mean exposure to a blood-borne disease like hepatitis or HIV.
 
Notably, intranasal naloxone using a mucosal atomizer device has been available off-label for about 15 years.
 
Indications
Evzio and Narcan are opioid antagonists indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory or central nervous system (CNS) depression. Both products are indicated for use in adults or children, but neither product should be used as a substitute for emergency medical care.
 
Mechanism of Action
Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. Naloxone is believed to act as a competitive antagonist at mc, κ, and σ opiate receptors in the CNS, with the highest affinity for the μ receptor.
 
Naloxone reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists like pentazocine.
 
Formulation
Evzio is available as a handheld, single-use auto-injector that is prefilled to quickly deliver a single 0.4-mg dose of naloxone. Each carton of Evzio contains a pair of 0.4-mg auto-injectors and a single needle-free Evzio Trainer to practice using the device. Every device is equipped with visual and voice instructions for guidance to inject the medication.
 
Narcan is available as a needle-free, ready-to-use nasal spray to deliver a single 4-mg dose of naloxone. One carton contains 2 blister packages, each with a single nasal spray that can’t be reused.
Dosing
Evzio is administered via an intramuscular or subcutaneous injection into the anterolateral aspect of the thigh, through clothing if necessary. Additional doses may be administered every 2 to 3 minutes until emergency medical assistance arrives. In children younger than 1 year, the caregiver should pinch the thigh muscle while administering the dose. Although the location of injection should always occur in the middle of the patient's outer thigh, the route of injection is dependent on patient characteristics like body fat percentage.
 
Narcan is administered as a single spray into 1 nostril. Most patients respond in 2 to 3 minutes; however, if the patient doesn’t respond or responds and then relapses into respiratory depression, additional doses can be administered using a new nasal spray with each dose, alternating nostrils. Additional doses are recommended to be given every 2 to 3 minutes until emergency medical assistance arrives.
 
For both products, emergency medical care should be sought immediately after use.
 
Efficacy
Evzio’s efficacy was demonstrated in a pharmacokinetic study of 30 patients. In the study, a single Evzio injection provided equivalent naloxone compared with a single dose of naloxone injection using a standard syringe.
 
Narcan’s efficacy was demonstrated in a pharmacokinetic study in 30 healthy adult subjects. Intranasal administration of either 1 or 2 doses resulted in serum concentrations higher than those achieved with a single dose of the intramuscular formulation. The time to reach peak serum concentrations was similar with intranasal administration and intramuscular injection (20 minutes with 2 doses of the intranasal formulation, 23 minutes with intramuscular administration, and 30 minutes with a single intranasal dose).
 
Safety
The most common adverse reactions of Evzio are based on those seen with naloxone hydrochloride use in the postoperative setting, which include hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest.
 
The most common adverse reactions of Narcan are increased blood pressure, musculoskeletal pain, headache, and nasal symptoms (dryness, edema, congestion, inflammation).
 
The use of either product in opioid-dependent patients may result in severe opioid withdrawal. Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, uncontrollable trembling, seizures, and cardiac arrest.
 
Product Comparison
  Evzio Narcan
Administration Intramuscular/Subcutaneous Injection Intranasal
Uniqueness ·  Audio directions guide caregivers on proper administration
·  Trainer device accompanies each Evzio carton
·  Manufacturer has offered a free carton to all US high schools
·  Ease of administration + low cost
Potential disadvantages ·  Audio directions only available in English
·  High cost
·  Intranasal adverse effects
·  Potential absorption concern in users whose nasal mucosa may be damaged from drug snorting, obstructed by vomit during overdose, or experiencing severe rhinitis
Cost $2250 $75
 Cost based on AWP, per Lexi-Drugs. Cost to the patient will vary based on insurance coverage.
 
Regulatory Action
In February 2016, the Obama Administration proposed $1.1 billion in funding to address the prescription opioid abuse epidemic. The budget included increased funding to expand state-level prescription drug overdose prevention strategies, increase the availability of medication-assisted treatment programs, and improve access to naloxone.
 
Several retail pharmacies have also implemented initiatives to combat drug abuse. In February 2016, Walgreens announced plans to install safe medication disposal kiosks in more than 500 drugstores in 39 states and Washington, DC, as well as make naloxone available without a prescription at its pharmacies in 35 states. Meanwhile, naloxone can be purchased without a prescription at CVS pharmacies in 23 states through physician-approved protocols.
 
Conclusion
Both Evzio and Narcan are more convenient to administer than conventional naloxone and are beneficial for use by health care professionals, first responders, and caregivers.