February 21, 2017
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Evzio

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Evzio

Warnings
Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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]. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

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]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

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 preexisting 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.

Patient Counseling Information

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instruct patients and their family members or caregivers to:

  • Become familiar with the following information contained in the carton as soon as they receive EVZIO:
    • EVZIO Instructions for Use
    • Trainer for EVZIO Instructions for Use
    • Trainer for EVZIO
  • Become familiar with the device labeling color scheme of EVZIO and the Trainer for EVZIO
    • The 2 mg dosage form of EVZIO is blue and purple.
    • The Trainer for EVZIO is black and white.
  • Practice using the Trainer before EVZIO is needed.
    • Each EVZIO can only be used one time; however, Trainer for EVZIO can be re-used for training purposes and its red safety guard can be removed and replaced.
    • Both EVZIO and Trainer for EVZIO incorporate the electronic voice instruction system.
  • It is recommended that patients and caregivers become familiar with the Trainer for EVZIO provided and read the Instructions for Use; however, untrained caregivers or family members should still attempt to use EVZIO during a suspected opioid overdose while awaiting definitive emergency medical care.
Recognition Of Opioid Overdose

Instruct the patients and their family members or caregivers how to recognize the signs and symptoms of an opioid overdose requiring the use of EVZIO such as the following:

  • Extreme sleepiness -inability to awaken a patient verbally or upon a firm sternal rub.
  • Breathing problems -this can range from slow or shallow breathing to no breathing in a patient who cannot be awakened.
  • Other signs and symptoms that may accompany sleepiness and breathing problems include the following:
    • Extremely small pupils (the black circle in the center of the colored part of the eye) sometimes called “pinpoint pupils.”
    • Slow heartbeat and/or low blood pressure.
Risk Of Recurrent Respiratory And Central Nervous System Depression

Instruct patients and their family members or caregivers that since the duration of action of most opioids may exceed that of EVZIO, they must seek immediate emergency medical assistance after the first dose of EVZIO and keep the patient under continued surveillance [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Limited Efficacy For/With Partial Agonists Or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused 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 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Precipitation Of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that 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 [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Administration Instructions

Instruct patients and their family members or caregivers about the following important information:

  • Make sure EVZIO is present whenever persons may be intentionally or accidentally exposed to an opioid to treat serious opioid overdose (i.e., opioid emergencies).
  • Administer EVZIO as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. EVZIO is not a substitute for emergency medical care [see DOSAGE AND ADMINISTRATION].
  • EVZIO is user actuated and may be administered through clothing [e.g., pants, jeans, etc.] if necessary.
  • Inject EVZIO while pressing into the anterolateral aspect of the thigh. In pediatric patients less than 1 year of age, pinch the thigh muscle while administering EVZIO.
  • Upon actuation, EVZIO automatically inserts the needle intramuscularly or subcutaneously, delivers the naloxone, and retracts the needle fully into its housing. The needle is not visible before, during, or after injection.
  • Each EVZIO can only be used one time.
  • If the electronic voice instruction system on EVZIO does not work properly, EVZIO will still deliver the intended dose of naloxone hydrochloride when used according to the printed instructions on its label.
  • The electronic voice instructions are independent of activating EVZIO and it is not necessary to wait for the voice instructions to be completed prior to moving to the next step in the injection process.
  • 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.
  • EVZIO’s red safety guard should not be replaced under any circumstances. However, the Trainer is designed for re-use and its red safety guard can be removed and replaced.
  • Periodically visually inspect the naloxone solution through the viewing window. If the solution is discolored, cloudy, or contains solid particles, replace it with a new EVZIO.
  • Replace EVZIO before its expiration date.

Nonclinical Toxicology

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.

Use In Specific Populations

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]. 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 8times, 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.

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.

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 dosed according to weight and titrated to effect. [see WARNINGS AND PRECAUTIONS].

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].

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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/31/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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