2.1 Important Administration Instructions

EVZIO is for intramuscular and subcutaneous use only.

Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of EVZIO and the Instructions for Use.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for EVZIO. Emphasize the following instructions to the patient or caregiver:

• Seek emergency medical care immediately after use. Since the duration of action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer repeated doses of EVZIO as necessary. Always seek emergency medical assistance in the event of a suspected potentially life-threatening opioid emergency after administration of the first dose of EVZIO.
• Additional doses of EVZIO may be required until emergency medical assistance becomes available.
• Do not attempt to reuse EVZIO. Each EVZIO contains a single dose of naloxone.
• Visually inspect EVZIO through the viewing window for particulate matter and discoloration prior to administration. Do not administer unless the solution is clear and the glass container is undamaged.
• EVZIO must be administered according to the printed instructions on the device label or the electronic voice instructions (EVZIO contains a speaker that provides voice instructions to guide the user through each step of the injection). If the EVZIO electronic voice instruction system does not operate properly, EVZIO will still deliver the intended dose of naloxone hydrochloride when used according to the printed instructions on its label.
• Once the red safety guard is removed, EVZIO must be used immediately or disposed of properly. Do not attempt to replace the red safety guard once it is removed.

Upon actuation, EVZIO automatically inserts the needle intramuscularly or subcutaneously, delivers the naloxone hydrochloride injection, and retracts the needle fully into its housing. Post injection, the black base locks in place, a red indicator appears in the viewing window, and electronic visual and audible instructions signal that EVZIO has delivered the intended dose of naloxone hydrochloride and instructs the user to seek emergency medical attention.

2.2 Dosing Information

Initial Dosing

Administer the initial dose of EVZIO to adult or pediatric patients intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary, and seek emergency medical assistance. Administer EVZIO as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.

Repeat Dosing

The requirement for repeat doses of EVZIO depends upon the amount, type, and route of administration of the opioid being antagonized.

If the desired response is not obtained after 2 or 3 minutes, an additional dose of EVZIO may be administered. If there is still no response and additional doses are available, additional doses of EVZIO may be administered every 2 to 3 minutes until emergency medical assistance arrives. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

If the patient responds to EVZIO and relapses back into respiratory depression before emergency assistance arrives, an additional dose of EVZIO may be administered.

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of EVZIO.

Dosing in Adults and Pediatric Patients over Age One Year

Instruct patients or their caregivers to administer EVZIO according to the Instructions for Use, intramuscularly or subcutaneously.

Dosing in Pediatric Patients under Age One Year

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering EVZIO. Carefully observe the administration site for signs of infection following injection and resolution of the opioid emergency.

There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone product which can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Populations (8.4)].

5.1 Risk of Recurrent Respiratory and Central Nervous System Depression

The duration of action of most opioids may exceed that of EVZIO resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after delivering the first dose of EVZIO. Keep the patient under continued surveillance, and administer additional doses of EVZIO as necessary [see Dosage and Administration (2.2)]. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration (2.3)]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

5.3 Precipitation of Severe Opioid Withdrawal

The use of EVZIO in patients who are opioid dependent may precipitate an acute abstinence syndrome characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying and hyperactive reflexes. Monitor patients for the development of the signs and symptoms of opioid withdrawal.

Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

8.1 Pregnancy

Risk Summary

The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are risks to the fetus of the opioid-dependent mother with use of naloxone [see Clinical Considerations]. In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus as well as in the opioid-dependent mother [see Warnings and Precautions (5.3)]. The fetus should be evaluated for signs of distress after EVZIO is used. Careful monitoring is needed until the fetus and mother are stabilized.

Data

Animal Data

Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 4-times and 8-times, respectively, the dose of 10 mg/day given to a 50 kg human (when based on body surface area or mg/m2). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

8.2 Lactation

Risk Summary

There is no information regarding the presence of naloxone in human milk, or the effects of naloxone on the breastfed infant or on milk production. Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EVZIO and any potential adverse effects on the breastfed infant from EVZIO or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of EVZIO (for intramuscular and subcutaneous use) have been established in pediatric patients of all ages for the emergency treatment of known or suspected opioid overdose. Use of naloxone hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of another naloxone hydrochloride injectable product. No pediatric studies were conducted for EVZIO.

Absorption of naloxone hydrochloride following subcutaneous or intramuscular administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. Unlike acute opioid withdrawal in adults, acute opioid withdrawal in neonates manifesting as seizures may be life-threatening if not recognized and properly treated. Other signs and symptoms in neonates may include excessive crying and hyperactive reflexes. In these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative, naloxone hydrochloride product that can be dosed according to weight and titrated to effect. [see Warnings and Precautions (5.3)].

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering EVZIO. Carefully observe the administration site for evidence of residual needle parts, signs of infection, or both. [see Dosing Information (2.2)].

8.5 Geriatric Use

Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone can be higher in these patients.

Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

12.1 Mechanism of Action

Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.

Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2 Pharmacodynamics

When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration.

The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

12.3 Pharmacokinetics

In a pharmacokinetic study in 30 healthy subjects, a single 0.4 mg subcutaneous or intramuscular naloxone injection administered using EVZIO provides equivalent naloxone AUC and 15% greater naloxone Cmax in comparison to a single 0.4 mg subcutaneous or intramuscular naloxone injection administered using a standard syringe.

Following a single 0.4 mg EVZIO injection, the median Tmax of naloxone was reached at 0.25 hours (range 0.08 to 1.23 hours), with a mean Cmax value of 1.24 (51.4% CV) ng/mL. The mean plasma half-life of naloxone in healthy adults was 1.28 (38.0% CV) hours. In the same study, following administration of a single dose of 0.4 mg naloxone injection using a standard syringe, the median Tmax was 0.33 hours (range 0.08 to 2.03 hours) and the mean Cmax value was 1.07 (45.1% CV) ng/mL. The mean plasma half-life was 1.36 (23.5% CV) hours.

A second pharmacokinetic study in 24 healthy subjects using a crossover design, evaluated a single 0.4 mg EVZIO injection, a single 2 mg EVZIO injection, and two 0.4 mg EVZIO injections administered two minutes apart (0.8 mg naloxone hydrochloride total). The pharmacokinetic parameters obtained in this study are shown in Table 1 and the plasma concentration time profiles of naloxone are in Figure 1.

Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intramuscular/Subcutaneous Administration using EVZIO

Distribution
Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

Elimination
Following a single 0.4 mg EVZIO injection, the mean plasma half-life of naloxone in healthy adults was 1.58 (28.9% CV) hours and 1.53 (25% CV) hours following a single 2 mg EVZIO injection. In a neonatal study of naloxone injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.

Metabolism
Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major metabolite.

Excretion
After an oral or intravenous dose, about 25-40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.

Mutagenesis

Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.

Impairment of Fertility

Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m2), demonstrated no adverse effect of naloxone hydrochloride on fertility.

16.1 How Supplied

Carton containing two EVZIO (naloxone hydrochloride injection, USP) 2 mg auto-injectors and a single Trainer for EVZIO - NDC 60842-051-01

16.2 Storage and Handling

Store EVZIO in the outer case provided.

Store at controlled room temperature 15°C to 25°C (59°F to 77°F) excursions permitted between 4°C and 40°C (between 39°F and 104°F).

Before using, check to make sure the solution in the auto-injector is not discolored. Replace EVZIO if the solution is discolored or contains a precipitate.