EVZIO (naloxone hydrochloride)-an opioid antagonist-is manufactured as an autoinjector for intramuscular or subcutaneous use as emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. Although not a substitute for emergency medical care, it is intended for immediate administration as emergency therapy in settings where opioids may be present (Market Watch, 2014).
There are at least 21,000 opioid overdose fatalities in the United States each year (CDC, 2012). This formulation of naloxone is the first product to be specifically user tested and labeled for lay administration. Prescribers are encouraged to prescribe EVZIO to family members, friends, caregivers, or other likely bystanders for use on individuals at possible risk of overdose (Kuehn, 2014). The Federal Drug Administration has indicated that this drug can be prescribed to third parties; however, the Federal Drug Administration does not supersede state law and local regulatory provisions governing third-party prescribing. Nor do they automatically extinguish prescribers' concerns about the possible risk of malpractice liability. That being said, there are already state statutes in about one third of the states shielding prescribers when prescribing to third parties as in this case (Beletsky & Rich, 2012). Prescribers should first determine whether such statutes are in place within the state where they practice.
PRODUCT DESCRIPTION
EVZIO (naloxone hydrochloride injection, USP) is a prefilled, single-use autoinjector. It combines the technology of the automated external defibrillator and the Epipen. The device holding the medication contains a speaker that provides voice instructions to guide the user through each step of the injection. Upon actuation, EVZIO automatically inserts the needle intramuscularly or subcutaneously, delivers 0.4-mg naloxone hydrochloride injection, and retracts the needle fully into its housing. After injection, the base locks in place, a red indicator appears in the viewing window, and electronic visual and audible instructions signal that the intended dose has been delivered and then instructs the user to seek emergency medical attention. EVZIO can be administered to adult or pediatric patients intramuscularly or subcutaneously into the anterolateral aspect of the thigh. It can be administered through clothing if necessary (Kaleo, Inc., 2014).
User education should be provided before prescribing EVZIO. Users should be told to administer EVZIO as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. The requirement for repeat doses depends on the amount, type, and route of administration of the opioid being antagonized. The duration of action of most opioids is likely to exceed that of EVZIO resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Users should also be told that, if the desired response is not obtained after 2 or 3 minutes, another dose should be administered. Additional supportive and/or resuscitative measures should be instituted if necessary while awaiting emergency medical assistance. If the patient has been using buprenorphine, reversal of respiratory depression may be incomplete and may require higher doses of naloxone (Kaleo, Inc., 2014).
After administration to the patient who is opioid dependent, an acute abstinence syndrome may occur (precipitated withdrawal). The following signs and symptoms may be seen: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering abdominal cramps, weakness, and increased blood pressure. Treatment of the withdrawal syndrome should be symptomatic.
Third-party insurances may not approve dispensing this product, nor will self-payers readily purchase it because the suggested retail price is between $450 and $600 for a two-unit pack. (Generic naloxone retails for less than $7 per dose in the United States and as little as $1 in Europe.) In addition, community or local government distribution programs may also be reluctant to provide this product because of its cost.
PHARMACOLOGY
EVZIO is a competitive opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. By blocking the opioid drug from stimulating the mu-opiate receptor, there is reversal of the effects of opioids, including respiratory depression, sedation, and hypotension. When administered intravenously, the onset of action is within 2 minutes. The time of onset of action is longer when administered subcutaneously or intramuscularly. The duration of action is dependent on the dose and route of administration of the naloxone. After parenteral administration, naloxone is distributed throughout the body and readily crosses the placenta and blood-brain barrier. Plasma protein binding is relatively weak. The drug is metabolized in the liver, primarily by glucuronidation, and is excreted in the urine within 72 hours. After a single EVZIO injection, the half-life in healthy adults is 1-2 hours. In a neonatal study, the mean half-life was observed to be 2.5-3.5 hours.
USE IN SPECIFIC POPULATIONS
Pregnancy
EVZIO is classified as a Category B drug because there are no adequate and well-controlled studies in pregnant women. In animal studies conducted with naloxone hydrochloride, there were no embryotoxic or teratogenic effects. However, animal reproduction studies are not always predictive of human response, and EVZIO should be used during pregnancy only if clearly needed. In addition, because naloxone crosses the placenta, it may precipitate withdrawal in the fetus as well as in the opioid-dependent mother. If EVZIO is used, the fetus should be evaluated for signs of distress, and careful monitoring is needed until the fetus and mother are stabilized.
Nursing Mothers
It is not known whether naloxone is present in human milk. Caution should be exercised when administering EVZIO to nursing mothers.
Pediatric Use
In pediatric patients manifesting respiratory and/or central nervous system depression and suspected of an opioid overdose situation, the safety and effectiveness of EVZIO for intramuscular and subcutaneous use have been established and supported by evidence from adequate and well-controlled studies in which neonates and pediatric patients received parenteral naloxone. In addition, in the postmarketing setting, data are available supporting the safety and effectiveness of this medication.
Because absorption of naloxone after subcutaneous or intramuscular administration in pediatric patients may be erratic or delayed, the patient must be carefully monitored for at least 24 hours because an overdose situation may occur as naloxone is metabolized. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening and should be treated according to protocols developed by neonatology experts.
Geriatric Use
Because geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and other comorbid disease states, along with the presence of polypharmacy, these patients should be carefully observed. Clinical studies of naloxone in the geriatric population (aged 65 years and over) did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Anecdotal reports have not identified differences in responses between the older adults and younger patients (Kaleo, Inc., 2014).
PATIENT AND FAMILY EDUCATION
Discussing the risk of opioid overdose is most important whether the patient is using prescribed, nonprescribed, licit, or illicit opioids. Some patients may think they are only at increased risk for an overdose if they are misusing the opioid. Patients should be advised that, even when properly prescribed and used, certain medical conditions (e.g., chronic obstructive pulmonary disease) or concomitant medications (e.g., benzodiazepines) may increase the risk of overdose. An "Opioid Overdose Risk Assessment Checklist" is available to help identify patients who may be at increased risk and can be downloaded at EVZIO.com/resources.
Encourage patients to identify a family member, friend, or other caregiver who can administer EVZIO for them, if needed, because a person who is having an opioid overdose is likely to be unconscious and unable to use EVZIO on their own. Thus, patients along with concerned significant others should be advised of the signs and symptoms of opioid overdose.
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