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  • CLASSES

    Drugs Used In Opioid Dependence

    DEA CLASS

    Rx

    DESCRIPTION

    Opioid antagonist; derivative of oxymorphone
    For reversal of clinical effects of opioid analgesics
    Auto-injector and nasal formulations available to treat overdose outside of healthcare setting

    COMMON BRAND NAMES

    EVZIO, Narcan

    HOW SUPPLIED

    EVZIO/Naloxone Hydrochloride/Narcan Intramuscular Inj Sol: 0.4mg, 0.4mL, 1mL, 1mg, 2mg
    EVZIO/Naloxone Hydrochloride/Narcan Subcutaneous Inj Sol: 0.4mg, 0.4mL, 1mL, 1mg, 2mg
    Naloxone Hydrochloride/Narcan Intravenous Inj Sol: 0.4mg, 1mL, 1mg
    Narcan Nasal Spray: 0.1mL, 4mg

    DOSAGE & INDICATIONS

    For the treatment of opiate agonist-induced respiratory depression.
    NOTE: Doses should be individualized. Constant monitoring is necessary to ensure that the respiratory depressant effects of the opiate do not outlast the beneficial effects of naloxone.
    For known or suspected opiate agonist overdose (full reversal).
    Intermittent Intravenous, Intramuscular, Subcutaneous, or Intraosseous† dosage (standard syringe)
    Adults

    0.4 to 2 mg IV, IM, or subcutaneously, up to a total dose of 10 mg; doses may be repeated every 2 to 3 minutes, as needed. In emergency settings, clinical practice guidelines recommend 0.4 to 2 mg IV; alternatively, 0.4 to 0.8 mg may be given by IM or subcutaneous injection if systemic perfusion is adequate. Repeat doses as needed to attain desired response. Some opiate overdoses may require titration to a total naloxone dose of 6 to 10 mg over a short period; for patients with chronic opioid addiction, use smaller doses and titrate slowly to minimize cardiovascular adverse effects and withdrawal symptoms. There is no good evidence to suggest that naloxone improves outcome in patients with opioid-induced cardiac arrest. Thus, once arrest has occurred, airway control is a priority before administration of naloxone. If there is no significant clinical response after administering a total dosage of 10 mg, the diagnosis of narcotic-induced depression should be questioned.

    Children and Adolescents 5 to 17 years or weighing more than 20 kg

    2 mg IV or IO is recommended for total reversal of narcotic effect (PALS recommendation); may require repeated doses to prevent recurrent apnea. The FDA-approved labeling recommends an initial dose of 0.01 mg/kg IV, IM, or subcutaneously; may repeat dose every 2 to 3 minutes until sufficient response. If there is no significant clinical response, a subsequent dose of 0.1 mg/kg IV may be given.

    Infants and Children younger than 5 years or weighing 20 kg or less

    0.1 mg/kg/dose IV or IO is recommended for total reversal of narcotic effect (PALS recommendation); may require repeated doses to prevent recurrent apnea. The FDA-approved labeling recommends an initial dose of 0.01 mg/kg/dose IV, IM, or subcutaneously; may repeat dose every 2 to 3 minutes until sufficient response. If there is no significant clinical response, a subsequent dose of 0.1 mg/kg IV may be given.

    Neonates

    0.1 mg/kg/dose IV is recommended by clinical practice guidelines; may require repeated doses to prevent recurrent apnea. If IV access is not available, IM administration is acceptable. The FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained. Additional doses may be necessary depending on patient response, as well as the dosage and duration of action of the opiate agonist administered.

    Intermittent Intramuscular or Subcutaneous dosage (Evzio auto-injector only)
    Adults, Adolescents, and Children

    0.4 mg or 2 mg IM or subcutaneously into the anterolateral aspect of the thigh. Seek immediate medical attention after administration of the first injection. May repeat dose every 2 to 3 minutes as needed until the desired response is obtained. Each device contains a single dose. Additional doses may be necessary depending on patient response, as well as the dosage and duration of action of the opiate agonist administered. If patient responds, but again experiences respiratory depression before emergency assistance arrives, an additional dose may be administered.

    Neonates and Infants

    0.4 mg or 2 mg IM or subcutaneously into the anterolateral aspect of the thigh; the caregiver should pinch the thigh muscle prior to and during administration. Seek immediate medical attention after administration of the first injection. May repeat dose every 2 to 3 minutes as needed until the desired response is obtained. Each device contains a single dose. Additional doses may be necessary depending on patient response, as well as the dosage and duration of action of the opiate agonist administered. If patient responds, but again experiences respiratory depression before emergency assistance arrives, an additional dose may be administered.

    Intranasal dosage (Narcan nasal spray)
    Adults, Adolescents, Children, Infants, and Neonates

    1 spray, which delivers 2 mg or 4 mg of naloxone, by intranasal administration. Seek immediate medical attention after administration of the first dose. If additional doses are available, may repeat dose in alternate nostrils every 2 to 3 minutes as needed if the desired response is not attained or if the patient relapses into respiratory depression. Each device contains a single dose. Family or caregiver should monitor the patient closely until emergency medical personal arrive. Pediatric patients should continue to be monitored for at least 24 hours after administration.

    Endotracheal† dosage
    Adults

    The optimal endotracheal (ET) dosage has not been determined for naloxone. In emergency settings, clinical practice guidelines recommend 0.4 to 2 mg via the endotracheal tube. Repeat dose as needed to attain desired response. Some opiate overdoses may require titration to a total naloxone dose of 6 to 10 mg over a short period; for patients with chronic opioid addiction, use smaller doses and titrate slowly to minimize cardiovascular adverse effects and withdrawal symptoms. There is no good evidence to suggest that naloxone improves outcome in patients with opioid-induced cardiac arrest. ET administration during emergency settings should only be used if access to IV or IO routes cannot be achieved or access is delayed. ET administration is generally associated with lower systemic drug concentrations compared to IV administration and may be less effective.

    Children and Adolescents 5 to 17 years or weighing more than 20 kg

    The optimal endotracheal (ET) dosage has not been determined for naloxone. A dose of 2 to 3 times the IV dose has been recommended (equivalent to 4 to 6 mg/dose ET). ET administration during emergency PALS setting should only be used if access to IV or IO routes cannot be achieved or access is delayed. ET administration is generally associated with lower systemic drug concentrations compared to IV administration and may be less effective.

    Infants and Children younger than 5 years or weighing 20 kg or less

    The optimal endotracheal (ET) dosage has not been determined for naloxone. A dose of 2 to 3 times the IV dose has been recommended (equivalent to 0.2 to 0.3 mg/kg/dose ET). ET administration during emergency PALS setting should only be used if access to IV or IO routes cannot be achieved or access is delayed. ET administration is generally associated with lower systemic drug concentrations compared to IV administration and may be less effective.

    Oral inhalation dosage (nebulized solution)†
    Adults

    2 mg via oral inhalation. May repeat if needed; in an observational study, median time to a second dose (IV/intranasal/nebulized) was 33 minutes (range 15 to 300 minutes). Nebulized naloxone was well-tolerated and resulted in a reduction in the need for supplemental oxygen as well as improving median Glasgow Coma Scale (GCS) and Richmond Agitation Sedation Scale (RASS) scores in patients with known or suspected opioid intoxication.

    Continuous Intravenous or Intraosseous† Infusion dosage
    Adults

    Initially, a loading dose of 0.005 mg/kg IV followed by 0.0025 mg/kg/hour IV.

    Neonates, Infants, Children, and Adolescents

    Limited data available. If repeated intermittent doses are required, it has been suggested to calculate the initial infusion rate based on the effective intermittent dose used; use two-thirds up to the full intermittent dose as the initial hourly infusion rate (i.e., if a 0.02 mg/kg IV dose was effective, initiate the infusion at 13 to 20 mcg/kg/hour [0.013 to 0.02 mg/kg/hour]). Titrate upward if respiratory depression develops. A continuous infusion rate of 2 to 160 mcg/kg/hour IV or IO has been suggested ; however, most reports in neonates, infants, and young children have utilized a rate of 24 to 44 mcg/kg/hour IV. A single case in a 17-year-old adolescent male reports an infusion of 0.8 mg/hour IV; weight was not reported but it appears the infusion rate was based on a 0.4 mg IV dose (adult dose) given every 30 minutes. The decision to wean should take into account the half-life of the ingested substance, the amount ingested, and conditions that may predispose the patient to slow opioid metabolism. When appropriate, wean in 25% increments and carefully monitor the patient for recurrence of opioid-induced respiratory depression.

    For respiratory depression associated with therapeutic opioid use (e.g., postoperative).
    Intermittent Intravenous dosage
    Adults

    0.1 to 0.2 mg IV at 2 to 3 minute intervals until the desired response is obtained. Additional doses may be necessary at 1 to 2 hour intervals depending on patient response, as well as the dosage and duration of action of the opiate agonist.

    Infants, Children, and Adolescents

    1 to 5 mcg/kg/dose IV to reverse respiratory depression due to therapeutic opioid use (PALS recommendation). The FDA-approved labeling recommends an initial dose of 0.005 to 0.01 mg IV at 2 to 3 minute intervals until the desired degree of reversal is obtained. Additional doses may be necessary at 1 to 2 hour intervals depending on patient response, as well as the dosage and duration of action of the opiate agonist.

    Continuous Intravenous Infusion dosage
    Adults

    0.0037 mg/kg/hour continuous IV infusion. If necessary, higher doses may be used.

    For the reversal of opiate agonist-induced respiratory depression during neonatal resuscitation in the delivery room.
    Intravenous, Intramuscular, or Subcutaneous dosage

    NOTE: Naloxone is not recommended as part of the initial resuscitation of neonates with respiratory depression in the delivery room. Do not give naloxone to newborns of mothers suspected of having chronic opiate agonist exposure.

    Neonates

    0.1 mg/kg/dose IV was recommended in previous guidelines; however, the efficacy of this dose has not been established in the neonatal population and naloxone is not recommended for routine use during neonatal resuscitation. Heart rate and oxygenation should be restored by supporting ventilation in the newborn with respiratory depression due to maternal opiate exposure. If IV access is not available, IM administration is acceptable. The FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained. Additional doses may be necessary depending on patient response, as well as the dosage and duration of action of the opiate agonist administered to the mother.

    For the treatment of pruritus† due to specific conditions.
    For the treatment of pruritus associated with cholestasis.
    Intravenous dosage
    Adults

    In a double-blind, placebo-controlled, crossover trial, naloxone significantly decreased pruritus associated with cholestatic liver disease. Pruritus was assessed by patients' perception of pruritus, visual analog scales, and monitoring of scratching activity. In this study, naloxone was administered as an initial IV bolus of 0.4 mg in 1 mL of normal saline followed by a 4 hour IV infusion of 0.2 mcg/kg/minute in dextrose 5%/0.45% NaCl.

    For the treatment of opioid-induced pruritus.
    Intermittent Intravenous dosage
    Adults

    0.2 mg naloxone IV may be helpful during continuous infusion morphine.

    Continuous Intravenous Infusion dosage
    Children and Adolescents

    Limited data available. A dose range of 1 to 3 mcg/kg/hour by continuous IV infusion has been reported during continuous opioid infusions (Max: 5 mcg/kg/hour). Doses of 3 mcg/kg/hour or greater were associated with higher opioid dosage requirements.

    For the prevention of opioid-induced pruritus.
    Continuous Intravenous Infusion dosage
    Children and Adolescents

    Limited data are available. A dose range of 0.25 to 1 mcg/kg/hour by continuous IV infusion has been used during continuous opioid infusions. In one double-blind, prospective, randomized, placebo-controlled study (n = 46), children and adolescents received 0.25 mcg/kg/hour by continuous IV infusion. Patients who received this dose experienced a decreased incidence and severity of opioid-induced side effects (i.e., pruritus, nausea); pain control was not affected. In another study in sickle cell patients (n = 16), patients receiving 1 mcg/kg/hour experienced less pruritus compared to patients receiving 0.25 mcg/kg/hour; pain control was also not affected.

    For the treatment of unexplained coma† in an unresponsive patient.
    Intravenous, Intramuscular, Subcutaneous, or Endotracheal dosage
    Adults

    Initially, 0.4—0.8 mg IV bolus (may also give 0.8 mg IM, subcutaneously, or via tracheal route). Up to 6—10 mg IV may be required for suspected opiate overdose (especially propoxyphene or China White overdose), if there is no response the diagnosis should be questioned.

    For opiate agonist dependence diagnosis†.
    For the detection of opioid use.
    Intravenous or Intramuscular dosage
    Adults

    Give 0.16 mg IM. If no withdrawal symptoms are noted after 20—30 minutes, give a second dose of 0.24 mg IV. A negative test result is assumed if no withdrawal symptoms were apparent within 30 minutes following the second dose.

    Prior to induction of naltrexone (ReVia) therapy (Narcan Challenge test).
    NOTE: Used for the diagnosis of suspected opioid tolerance or acute opioid overdosage. Do not perform this test in a patient showing clinical signs or symptoms of opioid withdrawal, or in patients whose urine contains opioids.
    Intravenous challenge
    Adults

    Following appropriate screening of the patient, 0.8 mg of naloxone should be drawn into a sterile syringe. Inject 0.2 mg. While the needle is still in the patient's vein, the patient should be observed for 30 seconds for evidence of withdrawal signs or symptoms. If there is no evidence of withdrawal, the remaining 0.6 mg IV should be given and the patient observed for an additional 20 minutes for signs and symptoms of withdrawal.

    Subcutaneous challenge
    Adults

    Following appropriate screening of the patient, inject 0.8 mg subcutaneously and observe the patient for 20 minutes for signs and symptoms of withdrawal.

    For adjunctive therapy of sepsis-induced hypotension† (e.g., to increase blood pressure).
    Intravenous dosage
    Adults

    This use of naloxone is described in the manufacturer's product literature and clinical literature, however, the optimal dosage or duration of therapy has not been established. The literature describes reports of a naloxone pressor effect early in the course of treatment of septic shock with naloxone 0.4 mg IV over 3—5 minutes, repeated for 3—5 doses, depending on the response. Bolus infusions ranging from 0.03—0.2 mg/kg IV over 5 minutes have also been used. If a response was seen, treatment was continued using continuous infusions ranging 0.03—0.3 mg/kg/hour IV for 1—24 hours or more, depending on clinical response.

    For the management of nausea/vomiting† from continuous infusion morphine.
    Intravenous dosage
    Adults

    0.2 mg IV may be helpful.

    For the management of urinary retention† from continuous infusion morphine.
    Intravenous dosage
    Adults

    0.2 mg IV may be helpful.

    For the management of opiate agonist-induced constipation†.
    Oral dosage† (oral dosage is investigational)
    Adults

    Naloxone has been studied in the management of opiate agonist-induced constipation. Doses of 1—12 mg PO 3 times daily have been used. In 1 series of 17 patients, oral naloxone was started at a dose of 3 mg PO 3 times daily and was increased up to 12 mg PO 3 times daily (by increasing dosage in 3-mg increments on consecutive days, if a bowel movement did not occur with the previous dose). Laxative use decreased in 9 patients and stooling increased in 14 patients. Serious withdrawal effects were seen in 4 patients, but resolved quickly; 3 of these patients were continued on reduced dosages of naloxone.

    For the management of constipation-predominant irritable bowel syndrome†.
    Oral dosage† (oral dosage is investigational)
    Adults

    Naloxone has been studied in the management of constipation-predominant IBS, but more data are needed to assess efficacy. In 1 randomized, controlled trial, patients (n = 28) received naloxone 10 mg PO twice daily or placebo for 8 weeks. Six of 14 (42%) patients receiving naloxone reported symptomatic relief (decreased symptoms like bloating, pain, straining) vs. 3 of 11 (27%) patients receiving placebo. The trial lacked sufficient power to achieve statistical significance.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2 mg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal. The FDA reports a maximum recommended therapeutic dosage of 0.1 mg/kg/day but does not specify the route for which their data is reported or the data source; clinical studies have used varying protocols depending on indication for use, patient's underlying dependency status, route and method of administration, and other parameters. No maximum daily dosage information can be definitively assigned at this time. The manufacturer reports that doses of 2 mg/kg (route not specified) in normal subjects have produced adverse symptomatology.

    Geriatric

    2 mg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal. The FDA reports a maximum recommended therapeutic dosage of 0.1 mg/kg/day but does not specify the route for which their data is reported or the data source; clinical studies have used varying protocols depending on indication for use, patient's underlying dependency status, route and method of administration, and other parameters. No maximum daily dosage information can be definitively assigned at this time. The manufacturer reports that doses of 2 mg/kg (route not specified) in normal subjects have produced adverse symptomatology.

    Adolescents

    2 mg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.

    Children

    5 to 12 years and weighing more than 20 kg: 2 mg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.
    1 to 4 years or weighing 20 kg or less: 0.1 mg/kg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.

    Infants

    0.1 mg/kg/dose IV/IO/IM/SC; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.

    Neonates

    0.1 mg/kg/dose IV/IM; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use with caution; naloxone is metabolized by the liver. The safety and efficacy of naloxone in patients with hepatic disease have not been established in well-controlled clinical trials.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    The duration of action of some opioids may exceed that of naloxone. When used as an opioid antagonist, monitor patients carefully and repeat doses as necessary.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The solution should be clear; do not administer if the solution is discolored, cloudy, or contains solid particles.

    Intravenous Administration

    IV Push
    Administer undiluted by IV push; if necessary, may also dilute in Sterile Water for Injection.
    In neonates, may administer via the umbilical vein.
     
    Continuous IV Infusion
    Dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a concentration of 4 to 8 mcg/mL.
    Do not mix naloxone with preparations that contain bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solutions with an alkaline pH. Do not add any drug or chemical agent to naloxone unless the effect of the substance on the chemical and physical stability of the naloxone solution has been established.
    Rate of administration should be titrated to the patient's response.
    Storage: Diluted injection is stable for 24 hours; discard any unused solution.

    Intramuscular Administration

    NOTE: Absorption after intramuscular administration of naloxone may be erratic or delayed. In cases of emergency, intravenous administration is preferred if an intravenous route is immediately available.
     
    Intramuscular Injection with Standard Syringe
    Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children, adolescents, and adults only]). Aspirate prior to injection to avoid injection into a blood vessel.
     
    Intramuscular Injection with Auto-injector (Evzio)
    Preparation of Caregivers and Family
    Because treatment of suspected opioid overdose must be performed by someone other than the patient, caregivers and people in close contact with the recipient should be informed of the presence of Evzio and its instructions for use before the need for the medication arises.
    Caregivers and family members should practice administration technique using the Trainer injector that is supplied with the product before naloxone is needed.
    Evzio must be administered according to the printed instructions on the device label or the electronic voice instructions provided through the speaker on the device. If the voice instruction system does not operate correctly, Evzio will still deliver the intended dose of naloxone when used according to the printed instructions.
    Those who administer Evzio should be aware that the use of naloxone in patients who are opioid dependent may cause an acute abstinence syndrome. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
    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. Higher than usual doses of naloxone may be needed.
    Administration
    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.
    Administer intramuscularly, as quickly as possible, into the anterolateral aspect of the thigh, through clothing if necessary. Press firmly and hold in place for 5 seconds.
    For neonates and infants: The caregiver should pinch the middle of the outer thigh muscle prior to and during drug administration. Carefully observe the administration site for evidence of residual needle parts and/or signs of infection.
    Upon activation, the needle is automatically inserted, delivers the injection, and then retracts fully into its housing.
    After the injection, the black base locks in place, a red indicator appears in the viewing window, and electronic visual and audible instructions signal that the dose has been delivered.
    After the initial injection, seek immediate medical attention. Keep the patient under continued surveillance because the duration of action of most opioids is longer than that of naloxone. Repeat doses every 2 to 3 minutes as needed to achieve desired response until emergency medical assistance arrives.
    Do NOT attempt to reuse Evzio; each device contains a single dose of naloxone. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency assistance.
    Storage: Store in outer case at room temperature. Replace the product before its expiration date.

    Subcutaneous Administration

    NOTE: Subcutaneous administration of naloxone may be erratic or delayed. In cases of emergency, intravenous administration is preferred if an intravenous route is immediately available.
    Subcutaneous Injection with Standard Syringe
    Inject undiluted solution subcutaneously taking care not to inject intradermally.
    Subcutaneous Injection with Auto-Injector (Evzio)
    Preparation of Caregivers and Family
    Because treatment of suspected opioid overdose must be performed by someone other than the patient, caregivers and people in close contact with the recipient should be informed of the presence of Evzio and its instructions for use before the need for the medication arises.
    Caregivers and family members should practice administration technique using the Trainer injector that is supplied with the product before naloxone is needed.
    Evzio must be administered according to the printed instructions on the device label or the electronic voice instructions provided through the speaker on the device. If the voice instruction system does not operate correctly, Evzio will still deliver the intended dose of naloxone when used according to the printed instructions.
    Those who administer Evzio should be aware that the use of naloxone in patients who are opioid dependent may cause an acute abstinence syndrome. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
    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. Higher than usual doses of naloxone may be needed.
    Administration
    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.
    Administer as quickly as possible into the anterolateral aspect of the thigh, through clothing if necessary. Press firmly and hold in place for 5 seconds.
    For neonates and infants: The caregiver should pinch the middle of the outer thigh muscle prior to and during drug administration. Carefully observe the administration site for evidence of residual needle parts and/or signs of infection.
    Upon activation, the needle is automatically inserted, delivers the injection, and then retracts fully into its housing.
    After the injection, the black base locks in place, a red indicator appears in the viewing window, and electronic visual and audible instructions signal that the dose has been delivered.
    After the initial injection, seek immediate medical attention. Keep the patient under continued surveillance because the duration of action of most opioids is longer than that of naloxone. Repeat doses every 2 to 3 minutes as needed to achieve desired response until emergency medical assistance arrives.
    Do NOT attempt to reuse Evzio; each device contains a single dose of naloxone. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency assistance.
    Storage: Store in outer case at room temperature. Replace the product before its expiration date.

    Other Injectable Administration

    Intraosseous Administration
    NOTE: Naloxone is not FDA-approved for intraosseous administration.
    During cardiopulmonary resuscitation, naloxone may be given via the intraosseous route when IV access is not available. Of note, intraosseous lines are not commonly used in neonates because of the availability of the umbilical vein, the fragility of small bones, and the small intraosseous space available.
    After injection, flush with saline to promote medication entry into the central circulation.

    Inhalation Administration
    Oral Inhalation Administration

    NOTE: Naloxone is not FDA-approved for oral inhalation administration.
    Dilute 2 mg in 3 mL of 0.9% Sodium Chloride Injection.
    Administer through a standard face mask.

    Other Administration Route(s)

    Intranasal Administration
    Preparation of Caregivers and Family
    Instruct the prescription recipient or caregiver to inform those around them about the presence of naloxone nasal spray, as administration must be performed by someone other than the patient. Family members, caregivers, or other people who may have to use naloxone in an opioid emergency should know the signs and symptoms of opioid overdose, where the nasal spray is stored, and how to administer the drug before an opioid emergency occurs.
    Those who administer naloxone should be aware that its use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
    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. Higher than usual doses of naloxone may be needed.
    Administration
    Administer naloxone nasal spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt. Prolonged respiratory depression may result in central nervous system damage or death.
    Hold the device with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.
    Place the patient in the supine position. Assure that the device nozzle is inserted into one of the patient's nostrils and provide support to the back of the neck to allow the head to tilt back. Both of your fingers on either side of the nozzle should be against the bottom of the patient's nose. Do NOT prime or test the device prior to administration.
    Press firmly on the device plunger to administer the dose.
    Remove the device nozzle from the nostril.
    Turn the patient on their side (recovery position) and seek immediate medical assistance after the first dose of naloxone has been administered. Additional supportive and resuscitative measures may be helpful while awaiting emergency medical assistance. Keep the patient under continued surveillance until emergency personnel arrive and administer repeated naloxone doses as necessary.
    Do NOT attempt to reuse the naloxone nasal spray device; each device contains a single dose.
    Using a new nasal spray device, re-administer naloxone every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression. The requirement for repeat doses depends on the amount, type, and route of administration of the opioid being antagonized.
    Administer the nasal spray in alternate nostrils with each dose.
    After use, put the device back into its box and dispose of properly.
    Replace the product before its expiration date.
     
    Endotracheal Administration
    NOTE: Naloxone is not approved by the FDA for endotracheal (ET) administration.
    ET administration should only be used if access to intravenous (IV) or intraosseous (IO) routes cannot be achieved or access via these routes is delayed. ET drug administration is associated with lower systemic drug concentrations compared to IV administration and may be less effective.
    ET administration is not recommended for neonates.
    If CPR is in progress, stop chest compressions briefly to administer the medication. Administer the medication directly into the tube, being careful not to deposit it in along the walls of the tube or in the ET tube connector. Some prefer to use a catheter to give the drug deeply into the tube, however this has not shown to be more effective.
    Adults: Administered the drug diluted in 5 to 10 mL of 0.9% Sodium Chloride Injection or Sterile Water for Injection.
    Infants and Children: Administer the drug with or diluted in 1 to 5 mL of saline solution and deliver 5 consecutive positive-pressure ventilations.

    STORAGE

    EVZIO:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not refrigerate
    - Store at controlled room temperature (59 to 77 degrees F); excursions permitted between 39 to 104 degrees F
    - Store in original package until time of use
    Narcan:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The duration of action of most opioids is likely to exceed that of naloxone, resulting in a return of respiratory or central nervous system depression after an initial improvement in symptoms. Therefore, emergency medical assistance must be sought immediately after delivering the first dose from a naloxone auto-injector or nasal spray. In addition, the patients must remain under continued surveillance, and repeat doses of naloxone from a new auto-injector or nasal spray should be administered as necessary. Additional supportive and resuscitative measures may be helpful while awaiting emergency medical assistance.

    Cardiac disease

    Naloxone should be used with caution in patients with cardiac disease or in patients receiving cardioactive drugs that may cause potential adverse cardiovascular effects such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. Serious adverse cardiovascular effects can occur, especially in postoperative patients.

    Pregnancy

    The limited available data on naloxone use in human pregnancy is insufficient to inform a drug-associated risk. Animal studies have revealed no evidence of teratogenicity. However, there are risks to the fetus of an opioid-dependent mother with use of naloxone. In one study evaluating the effects of naloxone on fetal behavior, 54 pregnant women near term received either 0.4 mg of naloxone or placebo. Significant increases were observed in the number, duration, and amplitude of fetal heart rate accelerations, number of fetal body movements, and percentage of time spent breathing in the naloxone group. Significantly more fetuses in the naloxone-treated group were actively awake than those who were not exposed. During a study in which 40 women in labor received 1 mg of morphine, one group subsequently received a 0.4 mg IV bolus of naloxone after 1 hour plus a 0.4 to 0.6 mg/hour infusion for 23 hours and the second group received an identical placebo regimen. Despite placental transfer of naloxone, neonatal outcomes were not adversely affected. In one newborn, administration of naloxone to treat a flat fetal heart rate was a possible cause of fetal asphyxia leading to fatal respiratory failure. Since naloxone crosses the placenta, evaluate the fetus for signs of withdrawal and distress after naloxone is used. Careful monitoring is needed until the fetus and mother are stabilized.

    Breast-feeding

    There is no information regarding the presence of naloxone in human milk or the effects of naloxone on the breast-fed infant or milk production. Studies in breast-feeding mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. Although the effect of naloxone exposure in the nursing infant has not been evaluated, naloxone has been administered to newborns following in utero exposure to narcotics, and no adverse effects have been reported. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for naloxone and any potential adverse effects on the breast-fed infant from naloxone or the underlying maternal condition.

    Acute opioid withdrawal, infants, neonates, substance abuse

    The use of naloxone in opioid-dependent patients may precipitate acute opioid withdrawal. Patients known to have substance abuse issues and neonates of mothers who are known or suspected to be physically dependent on opioids should receive naloxone cautiously. In overdose situations where neonates or infants are involved, it may be preferable to administer naloxone-containing products that can be dosed according to weight and titrated to effect to avoid abrupt precipitation of withdrawal symptoms. Sudden reversal of opioid dependency can induce a variety of symptoms including aggressive behavior or irritability, restlessness, nervousness, hypertension, tachycardia, abdominal cramps, diarrhea, nausea, vomiting, weakness, trembling or shivering, fever, and sweating. In neonates, opioid withdrawal can be life-threatening if not recognized and properly treated. Signs and symptoms specific to neonatal withdrawal include poor feeding, rapid breathing, excessive or high-pitched crying, hyperactive reflexes, trembling, and convulsions. Data are limited regarding the potential of the 2 mg naloxone nasal spray dose to precipitate opioid withdrawal in the setting of opioid dependence. Similarly, the 2 mg dose may fail to provide adequate and timely reversal in persons exposed to potent or very high opioid doses. Therefore, prescriptions for the 2 mg naloxone nasal spray must be restrict to opioid-dependent patients expected to be at risk for severe opioid withdrawal in situations where there is low risk for accidental or intentional opioid exposure by household contacts.

    Paraben hypersensitivity

    Naloxone is contraindicated in patients with hypersensitivity to naloxone or to any components of the commercially available product. The multiple-dose solution contains 1.8 mg/mL of methylparaben and 0.2 mg/mL of propylparaben and may be inappropriate for patients with paraben hypersensitivity. Also, naloxone should be used with caution in patients with a known hypersensitivity to nalmefene or naltrexone because these three drugs are all structurally similar; it is not known if cross-sensitivity occurs.

    ADVERSE REACTIONS

    Severe

    ventricular fibrillation / Early / Incidence not known
    seizures / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    dyspnea / Early / Incidence not known
    confusion / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    hot flashes / Early / Incidence not known
    hypoxia / Early / Incidence not known
    hallucinations / Early / Incidence not known
    withdrawal / Early / Incidence not known
    constipation / Delayed / Incidence not known

    Mild

    tremor / Early / Incidence not known
    vomiting / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    nausea / Early / Incidence not known
    agitation / Early / Incidence not known
    dizziness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    nasal dryness / Early / Incidence not known
    dental pain / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    nasal irritation / Early / Incidence not known
    rhinalgia / Early / Incidence not known
    headache / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Naloxone can antagonize the therapeutic efficacy of dihydrocodeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including dihydrocodeine.
    Acetaminophen; Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Acetaminophen; Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: (Major) Naloxone can antagonize the therapeutic efficacy of oxycodone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including oxycodone.
    Acetaminophen; Pentazocine: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Acetaminophen; Propoxyphene: (Major) Propoxyphene is a centrally acting narcotic analgesic agent. Naloxone is a pharmacologic opposite of propoxyphene. Naloxone can block the actions of propoxyphene. Tolerance and physical dependence can occur in patients who take excessive propoxyphene doses over time and thus, acute withdrawal and/or pain recurrence may occur if naloxone is administered.
    Acetaminophen; Tramadol: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Alfentanil: (Major) Naloxone is the pharmacologic opposite of alfentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of alfentanil. During surgery naloxone should be carefully titrated to reverse undesired effects without affecting postoperative pain management. Naloxone also reverses the skeletal muscle rigidity induced by alfentanil. If naloxone is used to reverse respiratory depression caused by alfentanil, additional naloxone doses may be required. The duration of respiratory depression may last longer than the effect of naloxone. Administration of an opiate antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, or implementation of assisted or controlled ventilation for hypoventilation or apnea.
    Alvimopan: (Major) Alvimopan is an opiate antagonist. In general, coadministration with another opiate antagonist should be avoided due to the potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Naloxone can antagonize the therapeutic efficacy of dihydrocodeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Aspirin, ASA; Oxycodone: (Major) Naloxone can antagonize the therapeutic efficacy of oxycodone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including oxycodone.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Atropine; Difenoxin: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate.
    Atropine; Diphenoxylate: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate.
    Belladonna; Opium: (Major) Naloxone can antagonize the therapeutic efficacy of opium in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including opium.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Buprenorphine: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Buprenorphine; Naloxone: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Butorphanol: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Chlorpheniramine; Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Naloxone can antagonize the therapeutic efficacy of dihydrocodeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Naloxone can antagonize the therapeutic efficacy of dihydrocodeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Codeine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Codeine; Guaifenesin: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Codeine; Phenylephrine; Promethazine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Codeine; Promethazine: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Naloxone can antagonize the therapeutic efficacy of dihydrocodeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Fentanyl: (Major) Naloxone is the pharmacologic opposite of fentanyl. Naloxone can block the actions of fentanyl and, if administered to patients who are dependent on fentanyl, can produce acute withdrawal and/or allow pain to recur.
    Guaifenesin; Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Homatropine; Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone; Phenylephrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydrocodone; Pseudoephedrine: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Hydromorphone: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone.
    Ibuprofen; Oxycodone: (Major) Naloxone can antagonize the therapeutic efficacy of oxycodone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including oxycodone.
    Levomethadyl: (Major) Naloxone reverses the analgesic and adverse effects of levomethadyl and will produce withdrawal if given to patients receiving levomethadyl maintenance. If therapy with an opiate antagonist is indicated (e.g., severe respiratory depression), repeat doses may be needed due to levomethadyl's prolonged duration of action.
    Levorphanol: (Major) Naloxone can antagonize the therapeutic efficacy of levorphanol in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including levorphanol.
    Meperidine: (Major) Naloxone can antagonize the therapeutic efficacy of meperidine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including meperidine. Naloxone can block the actions of meperidine and should not be used in the absence of clinically significant respiratory or cardiovascular depression. If naloxone administration is necessary for a physically dependent patient, administer the naloxone with extreme care and use one-fifth to one-tenth the usual dose. Naloxone will not reverse normeperidine-induced seizures and may precipitate seizures in patients taking meperidine by decreasing the seizure threshold. If a patient experiences anxiety, tremors, myoclonus, or generalized seizures that may be associated with meperidine use, the use of naloxone is not recommended.
    Meperidine; Promethazine: (Major) Naloxone can antagonize the therapeutic efficacy of meperidine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including meperidine. Naloxone can block the actions of meperidine and should not be used in the absence of clinically significant respiratory or cardiovascular depression. If naloxone administration is necessary for a physically dependent patient, administer the naloxone with extreme care and use one-fifth to one-tenth the usual dose. Naloxone will not reverse normeperidine-induced seizures and may precipitate seizures in patients taking meperidine by decreasing the seizure threshold. If a patient experiences anxiety, tremors, myoclonus, or generalized seizures that may be associated with meperidine use, the use of naloxone is not recommended.
    Methadone: (Major) Naloxone can antagonize the therapeutic efficacy of methadone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including methadone. Naloxone should only be administered when clinically significant respiratory or cardiovascular depression are present. If therapy with an naloxone is indicated, repeat doses may be needed due to methadone's prolonged duration of action.
    Methylnaltrexone: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Morphine: (Major) Naloxone can antagonize the therapeutic efficacy of morphine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including morphine. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.
    Morphine; Naltrexone: (Major) Naloxone can antagonize the therapeutic efficacy of morphine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including morphine. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.
    Nalbuphine: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Naldemedine: (Major) Avoid coadministration with other opiate antagonists, like naldemedine. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Naloxegol: (Major) Avoid coadministration of naloxegol and other opiate antagonists. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Opiate Agonists-Antagonists: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Oxycodone: (Major) Naloxone can antagonize the therapeutic efficacy of oxycodone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including oxycodone.
    Oxymorphone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of oxymorphone. These drugs can block the actions of oxymorphone and if administered to patients who are have received chronic oxymorphone therapy, can produce acute withdrawal and/or allow pain to recur. An opiate antagonist should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxymorphone overdose.
    Pentazocine: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Pentazocine; Naloxone: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Propoxyphene: (Major) Propoxyphene is a centrally acting narcotic analgesic agent. Naloxone is a pharmacologic opposite of propoxyphene. Naloxone can block the actions of propoxyphene. Tolerance and physical dependence can occur in patients who take excessive propoxyphene doses over time and thus, acute withdrawal and/or pain recurrence may occur if naloxone is administered.
    Remifentanil: (Major) Naloxone is the pharmacologic opposite of remifentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of remifentanil. Naloxone also reverses the skeletal muscle rigidity induced by remifentanil. Naloxone should be carefully used to reverse undesired effects without affecting with pain management. Administration of an naloxone can also lead to sympathetic hyperactivity. Respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose.
    Sufentanil: (Major) Naloxone is the pharmacologic opposite of sufentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of sufentanil. During surgery naloxone should be carefully titrated to reverse undesired effects without affecting postoperative pain management. Naloxone also reverses the skeletal muscle rigidity induced by sufentanil. Respiratory depression produced by sufentanil may last longer than the duration of the opiate antagonist action; closely monitor patients. Respiratory depression may persist or recur during the postoperative period.
    Tapentadol: (Major) Naloxone opposes the mu-opioid agonist effect of tapentadol. Naloxone can block the actions of tapentadol and if administered to patients who have received chronic opioid therapy, can produce acute withdrawal and/or allow pain to recur.
    Tramadol: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.

    PREGNANCY AND LACTATION

    Pregnancy

    The limited available data on naloxone use in human pregnancy is insufficient to inform a drug-associated risk. Animal studies have revealed no evidence of teratogenicity. However, there are risks to the fetus of an opioid-dependent mother with use of naloxone. In one study evaluating the effects of naloxone on fetal behavior, 54 pregnant women near term received either 0.4 mg of naloxone or placebo. Significant increases were observed in the number, duration, and amplitude of fetal heart rate accelerations, number of fetal body movements, and percentage of time spent breathing in the naloxone group. Significantly more fetuses in the naloxone-treated group were actively awake than those who were not exposed. During a study in which 40 women in labor received 1 mg of morphine, one group subsequently received a 0.4 mg IV bolus of naloxone after 1 hour plus a 0.4 to 0.6 mg/hour infusion for 23 hours and the second group received an identical placebo regimen. Despite placental transfer of naloxone, neonatal outcomes were not adversely affected. In one newborn, administration of naloxone to treat a flat fetal heart rate was a possible cause of fetal asphyxia leading to fatal respiratory failure. Since naloxone crosses the placenta, evaluate the fetus for signs of withdrawal and distress after naloxone is used. Careful monitoring is needed until the fetus and mother are stabilized.

    There is no information regarding the presence of naloxone in human milk or the effects of naloxone on the breast-fed infant or milk production. Studies in breast-feeding mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. Although the effect of naloxone exposure in the nursing infant has not been evaluated, naloxone has been administered to newborns following in utero exposure to narcotics, and no adverse effects have been reported. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for naloxone and any potential adverse effects on the breast-fed infant from naloxone or the underlying maternal condition.

    MECHANISM OF ACTION

    Unlike the older narcotic antagonists levallorphan and nalorphine, which were subsequently removed from the market, naloxone is essentially a pure antagonist, with little or no agonistic activity. In patients who have not recently received opioid drugs, naloxone shows little or no pharmacological effects, even at high doses. Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Mu-receptors are responsible for analgesia, euphoria, respiratory depression, and miosis. Kappa-receptors are responsible for analgesia, dysphoria, some psychomimetic effects (e.g., disorientation and/or depersonalization), and sedation. Delta-receptors mediate analgesia, sedation, and possibly hormonal and neurotransmitter release. Naloxone is thought to antagonize mu- (highest affinity), kappa-, and delta-receptors, thus inhibiting both the toxic and clinical effects of opiates. This antagonism is competitive and short-lived, possibly necessitating repeat doses when long-acting opiates are involved. Naloxone itself produces no physical or psychological dependence and will not worsen respiratory depression if administered for non-opiate overdose.
     
    Naloxone antagonizes both the toxic and clinical effects of opiates. Thus, not only are respiratory depression, hypotension, and sedation reversed, but analgesia as well. Clinicians should use discretion when considering administering naloxone to patients who are sedated from opiates but do not exhibit respiratory depression. Reversal of analgesia is undesirable in patients known to be in severe pain. Naloxone should not be used for drowsiness unless opiate-induced respiratory depression coexists.
     
    Finally, because endorphins and enkephalins (endogenous substances with opiate-like activity) are known to exist in higher concentrations in certain disease states, naloxone has been considered a therapeutic agent for conditions other than opiate overdose. Various respiratory diseases have been associated with elevated circulating concentrations of endorphins, and naloxone has been studied in patients with COPD, obesity-hypoventilation syndrome, and high-altitude pulmonary edema.

    PHARMACOKINETICS

    Naloxone is administered intravenously, intramuscularly, intraosseously, subcutaneously, or intranasally; absorption may be erratic or delayed with subcutaneous, intramuscular, or intranasal routes compared to after intravenous administration. In emergency situations, naloxone has also been administered via endotracheal tube; however, data are limited. Naloxone is rapidly distributed with weak protein binding. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs with other plasma constituents. Naloxone achieves a brain-to-serum ratio 12 to 15 times greater than morphine. Metabolism takes place rapidly in the liver, mainly by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Excretion of the metabolites in the urine indicates that approximately 50% of an intravenous dose is excreted within 24 hours, and 60 to 70% is excreted within 72 hours. The plasma half-life ranges from 0.5 to 2 hours in most populations. In neonates, an elimination half-life of approximately 3 hours has been observed with naloxone injection.
     
    Affected cytochrome P450 isoenzymes: none

    Intravenous Route

    Onset of action occurs within 2 to 3 minutes after IV administration. Duration of action is estimated to be 45 to 90 minutes, but may be dependent on the dose of naloxone given and the duration of action of the opioid being reversed.

    Intramuscular Route

    Onset of action occurs within 15 minutes after IM administration; however, absorption may be erratic or delayed with this route, particularly in pediatric patients. Duration of action is more prolonged with IM administration compared with IV administration. In a pharmacokinetic study comparing naloxone administered via auto-injector or standard syringe in healthy adults, a single 0.4 mg IM or subcutaneous dose administered from the auto-injector provided an equivalent AUC and 15% greater Cmax in comparison to the same dose administered via standard syringe. For the auto-injector, a mean Cmax of 1.24 (+/- 0.64) ng/mL was obtained in a median Tmax of 15 minutes (range: 5 to 72 minutes); corresponding values for the standard syringe were 1.07 (+/- 0.48) ng/mL and 20 minutes (range: 5 to 122 minutes), respectively. The mean half-lives in both groups were similar, 1.28 (+/- 0.48) and 1.36 (+/- 0.32) hours for the auto-injector and standard syringe, respectively. In a second study, a mean Cmax of 1.33 ng/mL (62.9% CV) was obtained in a median Tmax of 0.25 hours (range: 0.09 to 0.84 hours) for the 0.4 mg dose; corresponding values for the 2 mg dose were 7.91 ng/mL (45.8% CV) and 0.25 hours (range: 0.13 to 0.67 hours), respectively. The mean half-lives in both groups were similar, 1.58 hours (28.9% CV) and 1.53 hours (25% CV) for the 0.4 mg and 2 mg auto-injector doses, respectively.

    Subcutaneous Route

    Onset of action occurs within 15 minutes after subcutaneous administration; however, absorption may be erratic or delayed with this route, particularly in pediatric patients. In a pharmacokinetic study comparing naloxone administered via auto-injector or standard syringe in healthy adults, a single 0.4 mg IM or subcutaneous dose administered from the auto-injector provided an equivalent AUC and 15% greater Cmax in comparison to the same dose administered via standard syringe. For the auto-injector, a mean Cmax of 1.24 (+/- 0.64) ng/mL was obtained in a median Tmax of 15 minutes (range: 5 to 72 minutes); corresponding values for the standard syringe were 1.07 (+/- 0.48) ng/mL and 20 minutes (range: 5 to 122 minutes), respectively. The mean half-lives in both groups were similar, 1.28 (+/- 0.48) and 1.36 (+/- 0.32) hours for the auto-injector and standard syringe, respectively. In a second study, a mean Cmax of 1.33 ng/mL (62.9% CV) was obtained in a median Tmax of 0.25 hours (range: 0.09 to 0.84 hours) for the 0.4 mg dose; corresponding values for the 2 mg dose were 7.91 ng/mL (45.8% CV) and 0.25 hours (range: 0.13 to 0.67 hours), respectively. The mean half-lives in both groups were similar, 1.58 hours (28.9% CV) and 1.53 hours (25% CV) for the 0.4 mg and 2 mg auto-injector doses, respectively.

    Other Route(s)

    Intranasal Route
    The pharmacokinetics of intranasal naloxone were assessed in 30 healthy adult subjects, all of whom received 1 nasal spray in 1 nostril (2 mg and 4 mg total doses), 2 nasal sprays in alternate nostrils (4 mg and 8 mg total doses), and 0.4 mg naloxone as an intramuscular (IM) injection. For intranasal administration, participants were instructed not to breathe through nose during nasal spray administration and remain fully supine for at least 1 hour post-dose. IM injections were administered in the gluteus maximus. The dose-normalized relative bioavailability of 1 dose (2 mg and 4 mg total doses) or 2 doses (4 and 8 mg total doses) of intranasal naloxone, compared to the 0.4 mg IM dose, was approximately 52%, 44%, 54% and 43%, respectively. Median Tmax after intranasal administration was 20 minutes after the single and double 2 mg doses, 30 minutes after a single 4 mg dose, and 20 minutes after double 4 mg doses; these values were not significantly different compared to the Tmax after IM administration (23 minutes). The Cmax and AUC were as follows: for a single 2 mg intranasal dose, Cmax was 2.91 ng/mL and AUC was 4.6 ng/mL x hour; for the single 4 mg intranasal dose, Cmax was 4.83 ng/mL and AUC 7.87 ng/mL x hour; for double 2 mg dose, Cmax was 6.3 ng/mL and AUC was 9.64 ng/mL x hour; for double 4 mg doses, Cmax was 9.7 ng/mL and AUC was 15.3 ng/mL x hour. Comparatively, the Cmax and AUC after IM administration was 0.88 ng/mL and 1.7 ng/mL x hour, respectively. Half-life of intranasal naloxone was approximately 2 hours.