NALOXONE HCL
  • NALOXONE HCL

  • (Generic for EVZIO)
  • QTY 1 • 0.4 MG/ML • VIAL • Near 77381

NALOXONE (nal OX one) is a narcotic blocker. It is used to treat narcotic (opioid) drug overdose. It is used to temporarily reverse the effects of opioid medicines. This medicine has no effect in people who are not taking opioid medicines.

NALOXONE HCL Pediatric Monographs
  • General Administration Information
    For storage information, see the specific product information within the How Supplied section.

    Route-Specific 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; 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 pediatric patients. 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 and adolescents 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 pediatric patients. 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.



    Other Administration Route(s)
    Intranasal Administration
    Preparation of Caregivers and Family
    -Instruct the prescription recipient and/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/or 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 FDA-approved 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.
    -Administer the drug with or diluted in 1 to 5 mL of saline solution and deliver 5 consecutive positive-pressure ventilations.

    Abrupt reversal of opioid depression may result in significant reversal of analgesia. Adverse events such as agitation, nausea, vomiting, hyperhidrosis, tremor, sinus tachycardia, seizures, and circulatory stress may occur as a result of the reversal of opioid analgesia and sedation. During postmarketing use of the naloxone auto-injector, agitation was reported. Several instances of hypotension, hypertension, ventricular tachycardia, ventricular fibrillation, dyspnea, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. Such events have occurred most often in patients with cardiovascular disorders or who have received other drugs with similar adverse cardiovascular effects; use with caution in this population and monitor appropriately. The pathogenesis of pulmonary edema is thought to be similar to neurogenic pulmonary edema (i.e., caused by a centrally-mediated massive catecholamine response causing a dramatic shift in blood volume into the pulmonary vascular bed and increased hydrostatic pressures). For the partial reversal of opioid depression after surgery, smaller doses of naloxone are usually sufficient; the drug should be titrated in small increments to the patient's response.

    Other adverse events associated with the postoperative use of naloxone include non-specific injection site reaction, hot flashes or flushing, paresthesias, hallucinations, and respiratory depression with hypoxia. Specific incidence rates for these events are not available. During postmarketing use of the naloxone auto-injector, disorientation, confusion, and anger were reported. Dizziness and injection site erythema were both reported in more than one subject during naloxone auto-injector pharmacokinetic studies in healthy adults.

    Acute withdrawal symptoms may occur if naloxone is administered to patients who are physically dependent on opioids. Signs and symptoms of opioid withdrawal include body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia. Naloxone administration can induce an acute neonatal abstinence syndrome in newly born babies of mothers who were taking opioids during pregnancy; this is a life-threatening condition if not recognized and properly treated. Symptoms specific to neonatal withdrawal include poor feeding, rapid breathing, excessive or high-pitched crying, hyperactive reflexes, trembling, and seizure.

    Common adverse reactions associated with intranasal naloxone administration include constipation, dental pain, increased blood pressure, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal irritation/inflammation, rhinalgia, and xeroderma.

    The duration of action of most opioids is likely to exceed that of naloxone resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Patients requiring naloxone should be continuously monitored; repeat doses of naloxone or additional supportive and/or resuscitative measures may be required. For patients receiving naloxone outside of a medical setting, it is imperative that immediate emergency medical assistance is sought after delivering the first dose of naloxone.

    Reversal of respiratory depression by partial agonists or mixed agonist/antagonists (e.g., buprenorphine and pentazocine) may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as necessary. Naloxone is not effective against non-opioid medications.

    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.

    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 tachycardia, nausea/vomiting, 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 restricted 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.

    Naloxone is contraindicated in patients with hypersensitivity to naloxone or any of its excipients. 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.

    Because naloxone crosses the placenta, in utero exposure may precipitate opioid withdrawal in the fetus and/or newborn of an opioid-dependent mother. Opioid withdrawal in neonates can be life-threatening if not recognized and treated properly; carefully monitor the fetus and/or newborn for signs of distress after maternal naloxone use.

    Description: Naloxone is a semisynthetic opioid-receptor antagonist. It is the n-allyl derivative of oxymorphone. Classically, it is used for complete or partial reversal of opioid-induced respiratory and/or central nervous system depression. Naloxone has also been used to prevent and treat opioid-induced pruritus and nausea in children. In emergent situations, naloxone should be administered as an adjunct to supportive or resuscitative measures. The auto-injector and nasal spray formulations are specific for use in overdose outside of a medical setting; however, it is not a substitute for emergency medical care. Both of these formulations are fixed-dose products; 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. Neonatal resuscitation guidelines do not recommend routine use of naloxone in the initial resuscitation of neonates with respiratory depression in the delivery room; positive pressure ventilation should be the first therapy for a newly born baby who is not breathing. Naloxone is FDA-approved for use in pediatric patients as young as neonates.

    For the treatment of opiate agonist-induced respiratory depression:
    -for known or suspected opioid overdose (full reversal):
    Intermittent Intravenous, Intramuscular, Subcutaneous, or Intraosseous* dosage (standard syringe):
    Neonates: 0.1 mg/kg/dose IV or IM; may require repeated doses to prevent recurrent apnea. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.
    Infants and Children younger than 5 years or weighing 20 kg or less: 0.1 mg/kg/dose IV or IO for full reversal; may require repeated doses to prevent recurrent apnea. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.
    Children and Adolescents 5 to 17 years or weighing more than 20 kg: 2 mg IV or IO for full reversal; may require repeated doses to prevent recurrent apnea. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.
    Intermittent Intramuscular or Subcutaneous dosage (Evzio auto-injector only):
    Neonates: 0.4 mg or 2 mg IM or subcutaneously. May repeat dose every 2 to 3 minutes if needed; each device contains a single dose. Seek immediate medical attention after administration of the first dose.
    Infants, Children, and Adolescents: 0.4 mg or 2 mg IM or subcutaneously. May repeat dose every 2 to 3 minutes if needed; each device contains a single dose. Seek immediate medical attention after administration of the first dose.
    Intranasal dosage (Narcan nasal spray):
    Neonates: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat every 2 to 3 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical attention after administration of the first dose. Monitor the patient closely until emergency medical personal arrive and for at least 24 hours after administration.
    Infants, Children, and Adolescents: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat every 2 to 3 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical attention after administration of the first dose. Monitor the patient closely until emergency medical personal arrive and for at least 24 hours after administration.
    Endotracheal* dosage:
    Infants and Children younger than 5 years or weighing 20 kg or less: Optimal endotracheal (ET) dosage has not been determined. A dose of 2 to 3 times the IV dose has been recommended (equivalent to 0.2 to 0.3 mg/kg/dose ET). Use ET administration only in an emergency setting when IV or IO access is delayed or cannot be achieved.
    Children and Adolescents 5 to 17 years or weighing more than 20 kg: Optimal endotracheal (ET) dosage has not been determined. A dose of 2 to 3 times the IV dose has been recommended (equivalent to 4 to 6 mg/dose ET). Use ET administration only in an emergency setting when IV or IO access is delayed or cannot be achieved.
    Continuous Intravenous or Intraosseous* dosage:
    Neonates: 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 0.013 to 0.02 mg/kg/hour). Titrate upward if respiratory depression develops. A continuous infusion rate of 0.002 to 0.16 mg/kg/hour IV or IO has been suggested; however, most reports in neonates have utilized a rate of 0.024 to 0.044 mg/kg/hour IV. 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.
    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 0.013 to 0.02 mg/kg/hour). Titrate upward if respiratory depression develops. A continuous infusion rate of 0.002 to 0.16 mg/kg/hour IV or IO has been suggested; however, most reports in neonates, infants, and young children have utilized a rate of 0.024 to 0.044 mg/kg/hour IV. A single case in a 17-year-old 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):
    Intravenous dosage:
    Infants, Children, and Adolescents: 0.001 to 0.005 mg/kg/dose IV. 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.
    -for the reversal of opioid 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.
    Neonates: 0.1 mg/kg/dose IV or IM 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. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.

    For the management of opioid-induced pruritus*:
    -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 opioid-induced pruritus*:
    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 used during continuous opioid infusions (up to a maximum of 5 mcg/kg/hour). Doses of 3 mcg/kg/hour or greater were associated with higher opioid dosage requirements.

    Maximum Dosage Limits:
    -Neonates
    0.1 mg/kg/dose IV/IM; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.
    -Infants
    0.1 mg/kg/dose IV/IO/IM/subcutaneous; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.
    -Children
    1 to 4 years or weighing 20 kg or less: 0.1 mg/kg/dose IV/IO/IM/subcutaneous; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.
    5 to 12 years or weighing more than 20 kg: 2 mg/dose IV/IO/IM/subcutaneous; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.
    -Adolescents
    2 mg/dose IV/IO/IM/subcutaneous; 1 spray (4 mg)/dose intranasally; doses may be repeated to maintain opiate reversal.

    Patients with Hepatic Impairment Dosing
    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; use with caution.

    Patients with Renal Impairment Dosing
    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    *non-FDA-approved indication

    Monograph content under development

    Mechanism of Action: Naloxone is essentially a pure opioid 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. Opioid 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 (i.e., disorientation and/or depersonalization), and sedation; and delta-receptors mediate analgesia, sedation, and possibly hormonal and neurotransmitter release. Naloxone is thought to antagonize mu- (highest affinity), kappa-, and delta-receptors and thus antagonizes both the toxic and clinical effects of opiates. This antagonism is competitive and short-lived. Thus, repeat doses of naloxone may be required when long-acting opiates are involved. Naloxone itself produces no physical or psychological dependence and will not worsen respiratory depression if administered for non-opioid overdose.

    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


    -Route-Specific Pharmacokinetics
    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
    Absorption of intranasal naloxone may be erratic or delayed in pediatric patients. The pharmacokinetics of intranasal naloxone were assessed in 30 healthy adult subjects, all of whom received 1 nasal spray in 1 nostril (2 mg or 4 mg total dose), 2 nasal sprays in alternate nostrils (4 mg or 8 mg total dose), 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 (2 mg or 4 mg) or 2 doses (4 mg or 8 mg) 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 to 30 minutes, which was not significantly different compared to the Tmax after IM administration (23 minutes). For patients receiving a single intranasal dose (2 mg or 4 mg total dose), Cmax was 2.9 and 4.8 ng/mL, respectively; AUC was 4.6 and 7.9 ng/mL x hour, respectively. After 2 intranasal doses (4 mg or 8 mg total dose), Cmax was 6.3 ng/mL and 9.7 ng/mL, respectively; AUC was 9.6 and 15.3 ng/mL x hour, respectively. Comparatively, the Cmax and AUC after IM administration was 0.9 ng/mL and 1.8 ng/mL x hour, respectively. Half-life of intranasal naloxone was approximately 2 hours, which was longer than that observed after IM administration (1.2 hours).


    -Special Populations
    Pediatrics
    Neonates
    The plasma half-life of naloxone is prolonged in neonates (3.1 +/- 0.5 hours) compared to adults (0.5 to 1.7 hours).

    Hepatic Impairment
    Naloxone is metabolized by the liver; pharmacokinetic data in patients with hepatic impairment are not available.

    Renal Impairment
    Naloxone and its metabolites are excreted in urine; pharmacokinetic data in patients with renal impairment are not available.

DISCLAIMER: This drug information content is provided for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always consult their physician with any questions regarding a medical condition and to obtain medical advice and treatment. Drug information is sourced from GSDD (Gold Standard Drug Database ) provided by Elsevier.

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