"The US Food and Drug Administration (FDA) is investigating the "rare but serious" risk for slowed or difficult breathing in children 17 and younger treated with the opioid analgesic tramadol.
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Duration Of Effect
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. Therefore, it is necessary to seek immediate emergency medical assistance after delivering the first dose of EVZIO, keep the patient under continued surveillance, and repeat doses of EVZIO as necessary. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.
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. Large doses of naloxone hydrochloride are 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. 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.
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 occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects should be monitored 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 (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
- Practice using the Trainer before EVZIO is needed.
- Each EVZIO (which is purple and yellow) can only be used one time; however, the Trainer (which is black and white) can be re-used for training purposes and its red safety guard can be removed and replaced.
- Both EVZIO and the Trainer for EVZIO incorporate the electronic voice instruction system.
- 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).
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.
Instruct them that when in doubt, if a patient is unresponsive, and an opioid overdose is suspected, administer EVZIO as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Instruct them to seek emergency medical assistance after administering the first dose of EVZIO.
Duration of Effect
Instruct patients and their family members or caregivers that since the duration of action of most opioids may exceed that of naloxone, seek immediate emergency medical assistance, keep the patient under continued surveillance, and administer repeated doses of EVZIO as necessary.
Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists
Instruct patients and their family members or caregivers that the reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete.
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.
Instruct patients and their family members or caregivers about the following important information:
- 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 are not required 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.
- It is recommended that patients and caregivers become familiar with the training device 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.
- 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.
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 Category B
There are no adequate and well-controlled studies with EVZIO in pregnant women. Animal studies were conducted with naloxone hydrochloride given during organogenesis in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day. These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Because animal reproduction studies are not always predictive of human response, EVZIO should be used during pregnancy only if clearly needed.
Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus as well as in the opioid-dependent mother. The fetus should be evaluated for signs of distress after EVZIO is used. Careful monitoring is needed until the fetus and mother are stabilized.
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.
It is not known whether naloxone hydrochloride is present in human milk. Because many drugs are present in human milk, exercise caution when EVZIO is administered to a nursing woman.
The safety and effectiveness of EVZIO (for intramuscular and subcutaneous use) have been established in pediatric patients for known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in pediatric patients is supported by evidence from adequate and well-controlled studies of naloxone hydrochloride in adults with additional data from 15 clinical studies (controlled and uncontrolled) in which neonates and pediatric patients received parenteral naloxone in doses ranging from 0.005 mg/kg to 0.01 mg/kg. Safety and effectiveness are also supported by use of other naloxone hydrochloride products in the post-marketing setting as well as data available in the medical literature and clinical practice guidelines.
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 dramatically 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 may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. 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 [see WARNINGS AND PRECAUTIONS].
In neonates and pediatric patients less than 1 year of age, careful observation of the administration site for evidence of residual needle parts and/or signs of infection is warranted [see DOSAGE AND ADMINISTRATION].
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: 4/14/2014
Additional Evzio Information
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