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Naloxone

Class: Opiate Antagonists
VA Class: CN102
CAS Number: 357-08-4
Brands: Evzio, Narcan, Suboxone

Medically reviewed by Drugs.com on Mar 29, 2021. Written by ASHP.

Introduction

Essentially a pure opiate antagonist.

Uses for Naloxone

Opiate-induced Depression and Acute Opiate Overdosage

Treatment of opiate-induced depression, including respiratory depression, caused by natural and synthetic opiates such as anileridine, codeine, diphenoxylate, fentanyl, heroin, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, concentrated opium alkaloids hydrochlorides, and propoxyphene.

Useful for the treatment of opiate-induced depression, including respiratory depression, caused by certain opiate partial agonists including butorphanol, nalbuphine, pentazocine, and cyclazocine. However, reversal of respiratory depression resulting from overdosage of opiate partial agonists may be incomplete and require higher or more frequent naloxone doses.

May be used in community (nonmedical) settings for emergency treatment of known or suspected opiate overdosage, as manifested by respiratory and/or CNS depression. Availability as auto-injector and nasal spray facilitates administration by family members or other caregivers; such treatment is not a substitute for emergency medical care.

Routinely discuss the availability of naloxone with all patients receiving new or reauthorized opiate prescriptions for pain management or new or reauthorized prescriptions for medications for treatment of opiate use disorder (OUD).

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose); strongly consider prescribing naloxone for all patients receiving medications for treatment of OUD. Also consider prescribing naloxone when patients receiving opiates for pain management or for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate for pain management or medication for treatment of OUD, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).

Experts also support greater access to naloxone by first responders (e.g., emergency medical service personnel, police officers, fire fighters) and workers in other settings where overdoses may be witnessed (e.g., nursing homes, home visiting nurses, school nurses and college campuses, outreach programs, substance abuse treatment programs, halfway houses, homeless shelters, correctional facilities).

Useful for the treatment of mild or moderate as well as severe opiate-induced respiratory depression.

Administration should be accompanied by other resuscitative measures such as administration of oxygen, mechanical ventilation, or artificial respiration.

Duration of respiratory depression following opiate agonist overdosage may be longer than the duration of naloxone action and other more immediate supportive and symptomatic treatment also should be initiated.

Use in patients physically dependent on opiate agonists may precipitate an acute withdrawal syndrome that cannot be readily suppressed while the action of the antagonist (naloxone) persists.

If opiate abstinence syndrome is precipitated by naloxone, symptoms will be apparent within a few minutes and maximal within 30 minutes after administration; effects usually will be more severe than those following withdrawal of the opiate agonist.

Some value in the management of buprenorphine overdosage but should not be relied on for treatment of respiratory depression. Reversal of agonist effects develops slowly.

Diagnosis of Opiate Overdosage

Aid in the diagnosis of suspected acute opiate overdosage (e.g., in the absence of confirmatory history and/or definitive diagnostic clinical findings).

Diagnosis of Chronic Opiate Abuse (Naloxone Challenge Test)

Has been used as an aid in the diagnosis of chronic opiate abuse, but preferable to use chemical methods to detect the presence of opiates in urine, since naloxone may precipitate severe withdrawal symptoms in patients physically dependent on opiates.

Screening test (the naloxone challenge test) prior to induction of naltrexone therapy for opiate cessation in patients formerly dependent on opiates who have completed detoxification. Such screening can avoid precipitating opiate withdrawal following administration of naltrexone.

Clonidine-induced Coma

Has been used to reverse clonidine-induced coma and respiratory depression.

Detoxification and Maintenance Treatment of Opiate Dependence

A combination of methadone hydrochloride and naloxone hydrochloride in a ratio of 20:1 has been administered orally in the detoxification or maintenance treatment of opiate dependence in conjunction with appropriate social and medical services.

May prevent opiate euphoria and thus decrease the desire for opiates.

Has been used for rapid or ultrarapid detoxification in the management of opiate withdrawal in opiate-dependent individuals, both in inpatient and outpatient settings.

Rapid opiate detoxification involves the administration of opiate antagonists such as naloxone and/or naltrexone to shorten the time period of detoxification.

Ultrarapid detoxification is similar, but involves the administration of opiate antagonists (i.e., naloxone, naltrexone) while the patient is sedated or under general anesthesia.

Risk of adverse respiratory and cardiovascular effects associated with this procedure must be considered as well as the costs of general anesthesia and hospitalization.

Minimization of Pentazocine or Buprenorphine Abuse Potential

Used orally in fixed combination with pentazocine hydrochloride or sublingually or intrabuccally in fixed combination with buprenorphine hydrochloride to minimize abuse potential of pentazocine or buprenorphine; antagonistic effect of naloxone will predominate if the combinations are administered parenterally and/or if usual oral doses are exceeded.

Adjunctive Use in Septic Shock

Has been used as adjunctive therapy in a limited number of patients to increase BP in the management of septic shock. Rise in BP may last up to several hours, but not shown to improve survival. Not included in current Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock.

Naloxone Dosage and Administration

Administration

Administer by IV, sub-Q, or IM injection; by IV infusion; or intranasally.

IV use recommended for emergency situations in medically supervised settings. Because absorption may be erratic or delayed, AAP does not endorse sub-Q or IM injection for emergency medical management of opiate intoxication in children or neonates. When IV access cannot be established in emergency situations, consider intraosseous (IO) injection in pediatric patients or administration via an endotracheal tube in adults and pediatric patients.

IV Infusion

For drug compatibility information, see Compatibility under Stability.

Continuous IV infusions may be most appropriate in patients who require higher doses, continue to experience recurrent respiratory or CNS depression after effective therapy with repeated doses, and/or in whom the effects of long-acting opiates are being antagonized.

Dilution

Continuous IV infusion: Dilute 2 mg of naloxone hydrochloride in 500 mL of 0.9% sodium chloride or 5% dextrose injection to produce a solution containing 0.004 mg/mL (4 mcg/mL).

Rate of Administration

Titrate in accordance with patient’s response.

IM or Sub-Q Injection Using Auto-injector (Evzio)

May be administered by family members or other caregivers prior to emergency medical response to individuals with known or suspected opiate overdosage. Caregivers should seek emergency medical care immediately after administering the initial dose.

Each carton contains 2 auto-injectors and 1 training device.

Depending on thickness of adipose tissue at injection site, injection via auto-injector may be either sub-Q or IM.

Technique for Using Auto-injector

Remove an auto-injector from the outer case, then remove red safety guard and firmly press black base of auto-injector against anterolateral aspect of thigh for 5 seconds until dose is delivered. Administer through clothing if necessary. Do not remove red safety guard until ready to use.

For pediatric patients <1 year of age, pinch thigh prior to administration to provide a thicker injection area (to minimize risk that the needle might strike bone and break); following administration, observe injection site for residual needle fragments and/or signs of infection.

After use, needle will retract into case and auto-injector will indicate that dose was delivered; auto-injectors cannot be reused.

If the electronic voice instruction system of the auto-injector malfunctions, the intended dose will be delivered when the device is activated according to the printed instructions.

Intranasal Administration

May be administered by family members or other caregivers prior to emergency medical response to individuals with known or suspected opiate overdosage. Caregivers should seek emergency medical care immediately after administering the initial dose.

Each carton contains 2 single-use nasal spray units; each unit delivers a 2- or 4-mg dose.

Do not remove nasal spray units from carton until time of administration; do not prime or test units prior to administration.

Intranasal Administration Technique

Place patient in supine position, then remove nasal spray unit from carton and blister package. Hold device with thumb on the bottom of the plunger and first and middle fingers on either side of the nozzle. Tilt patient's head back, with one hand supporting the patient's neck. Gently insert nozzle into one nostril until the fingers on either side of the nozzle are against the patient's nose. Firmly press plunger to administer the dose, then remove nozzle from nostril and place patient in left lateral decubitus position.

If additional doses are required, administer each dose into alternate nostrils using a new nasal spray unit.

Dosage

Available as naloxone hydrochloride; dosage expressed in terms of the salt. However, manufacturers of some preparations (e.g., Bunavail, Suboxone, Zubsolv) calculate potency in terms of the base.

Pediatric Patients

Postoperative Opiate Depression
IV

Initial dosage: Usually, 0.005–0.01 mg, given at 2- to 3-minute intervals until desired response (i.e., adequate ventilation and alertness without substantial pain or discomfort) is obtained.

Additional doses may be necessary at 1- to 2-hour intervals depending on response and dosage and duration of action of the opiate administered. (See Excessive Dosage in Surgery under Cautions.)

Opiate Overdosage
Diagnosis
IV

Children: Initially, 0.01 mg/kg; if this dose does not produce the expected response, may give a subsequent 0.1-mg/kg dose.

Treatment in Health Care Setting

Duration of opiate action often exceeds that of naloxone; opiate depressant effects may return as the effects of naloxone diminish, and additional naloxone doses (or a continuous IV infusion) may be required.

Manufacturers recommend that pediatric patients be closely observed for a day or longer regardless of degree of apparent improvement.

IV

Children: Initially, 0.01 mg/kg; if this dose does not produce the desired degree of response, may give a subsequent 0.1-mg/kg dose.

Alternatively, children <5 years of age or weight ≤20 kg: 0.1 mg/kg; repeat as necessary.

Alternatively, children ≥5 years of age or weight >20 kg: 2 mg; repeat as necessary.

For reversal of respiratory depression associated with therapeutic opiate use, some experts recommend lower dosages (e.g., 0.001–0.015 mg/kg for reversal of peri-arrest respiratory depression, 0.001–0.005 mg/kg for respiratory depression during procedural sedation to maintain some opiate analgesia).

Continuous IV infusion dosage regimens have not been well established; titrate rate of administration according to the patient’s response.

Experience with continuous IV infusions in children is limited, but children may require higher infusion rates on a mg/kg basis than adults.

Infusion rates in children usually have ranged from 0.024–0.16 mg/kg per hour; alternatively, a pediatric infusion rate of 0.4 mg/hour has been suggested.

IO or Endotracheal

Children <5 years of age or weighing ≤20 kg: Some experts suggest dose of 0.1 mg/kg.

Children ≥5 years of age or weighing >20 kg: Some experts suggest dose of 2 mg.

Optimum dose for administration via an endotracheal tube not established (higher doses as compared with other routes may be necessary).

Community-based Treatment

Duration of opiate action often exceeds that of naloxone; opiate depressant effects may return as the effects of naloxone diminish, and additional naloxone doses may be required.

Caregivers should seek emergency medical care immediately after administering the initial naloxone dose and closely monitor the patient until emergency care arrives.

Optimal dosage for use in community settings not fully established. While large doses may increase risk of acute opiate withdrawal, lower doses may require titration and risk further hypoxic injury to the patient.

Original auto-injector delivered 0.4-mg dose; dose per auto-injector subsequently was increased to 2 mg.

Both 2- and 4-mg nasal spray units are commercially available. Prescribe the 2-mg strength for opiate-dependent patients expected to be at risk for severe opiate withdrawal only when the risk for accidental or intentional opiate exposure by household contacts is low. There are limited data to indicate whether the 2-mg intranasal dose will avoid precipitation of severe opiate withdrawal in opiate-dependent patients; however, the 2-mg dose may not provide adequate and timely reversal of opiate effects in individuals exposed to an overdose involving a potent opiate or very high opiate dose.

IM or Sub-Q

2 mg (contents of one Evzio auto-injector); if patient fails to respond or if patient responds but subsequently relapses into respiratory depression, repeat as necessary (if additional auto-injectors available) at 2- to 3-minute intervals until emergency care arrives.

Intranasal

One spray (2 or 4 mg [contents of one spray unit]); if patient fails to respond or if patient responds but subsequently relapses into respiratory depression, repeat as necessary (if additional spray units available) at 2- to 3-minute intervals until emergency care arrives. Prescribe the 2-mg strength for opiate-dependent patients expected to be at risk for severe opiate withdrawal only when the risk for accidental or intentional opiate exposure by household contacts is low.

Adults

Postoperative Opiate Depression
IV

Initial dosage: Usually, 0.1–0.2 mg, given at 2- to 3-minute intervals until desired response (i.e., adequate ventilation and alertness without substantial pain or discomfort) is obtained; additional doses may be necessary at 1- to 2-hour intervals depending on response and dosage and duration of action of the opiate administered.

Alternatively, 0.005 mg/kg, repeated after 15 minutes if necessary.

Continuous IV infusion: 0.0037 mg/kg per hour.

Opiate Overdosage
Diagnosis
IV

Initial dosage: Usually, 0.4–2 mg IV, administered at 2- to 3-minute intervals if necessary; if no response is observed after a total of 10 mg of the drug has been administered, the depressive condition may be caused by a drug or disease process not responsive to naloxone.

Treatment in Health Care Setting

Duration of opiate action often exceeds that of naloxone; opiate depressant effects may return as the effects of naloxone diminish, and additional naloxone doses (or a continuous IV infusion) may be required.

Carefully monitor patient for recurrence of opiate depressant effects.

IV

Initial dosage: Usually, 0.4–2 mg IV, administered at 2- to 3-minute intervals if necessary; if no response is observed after a total of 10 mg of the drug has been administered, the depressive condition may be caused by a drug or disease process not responsive to naloxone.

Higher doses may be required following massive opiate overdosage or overdosage of certain opiates (e.g., propoxyphene [no longer commercially available in US]).

Opiate-dependent individuals: Use initial dose of 0.04–0.4 mg to minimize adverse cardiovascular effects and withdrawal symptoms; if initial response is inadequate, repeat dose or titrate up to 2 mg.

Continuous IV infusion dosage regimens of naloxone have not been well established; titrate rate of administration according to the patient’s response.

IV infusion: IV loading dose of 0.4 mg, followed by a continuous IV infusion at an initial rate of 0.4 mg/hour; alternatively, other clinicians have recommended an IV loading dose of 0.005 mg/kg, followed by continuous infusion of 0.0025 mg/kg per hour.

IV infusion: Alternatively, IV loading dose of 0.005 mg/kg, followed by continuous IV infusion of 0.0025 mg/kg per hour.

Community-based Treatment

Duration of opiate action often exceeds that of naloxone; opiate depressant effects may return as the effects of naloxone diminish, and additional naloxone doses may be required.

Caregivers should seek emergency medical care immediately after administering the initial naloxone dose and closely monitor the patient until emergency care arrives.

Optimal dosage for use in community settings not fully established. While large doses may increase risk of acute opiate withdrawal, lower doses may require titration and risk further hypoxic injury to the patient.

Original auto-injector delivered 0.4-mg dose; dose per auto-injector subsequently was increased to 2 mg.

Both 2- and 4-mg nasal spray units are commercially available. Prescribe the 2-mg strength for opiate-dependent patients expected to be at risk for severe opiate withdrawal only when the risk for accidental or intentional opiate exposure by household contacts is low. There are limited data to indicate whether the 2-mg intranasal dose will avoid precipitation of severe opiate withdrawal in opiate-dependent patients; however, the 2-mg dose may not provide adequate and timely reversal of opiate effects in individuals exposed to an overdose involving a potent opiate or very high opiate dose.

IM or Sub-Q

2 mg (contents of one Evzio auto-injector); if patient fails to respond or if patient responds but subsequently relapses into respiratory depression, repeat as necessary (if additional auto-injectors available) at 2- to 3-minute intervals until emergency care arrives.

Intranasal

One spray (2 or 4 mg [contents of one spray unit]); if patient fails to respond or if patient responds but subsequently relapses into respiratory depression, repeat as necessary (if additional spray units available) at 2- to 3-minute intervals until emergency care arrives. Prescribe the 2-mg strength for opiate-dependent patients expected to be at risk for severe opiate withdrawal only when the risk for accidental or intentional opiate exposure by household contacts is low.

Diagnosis of Chronic Opiate Abuse (Naloxone Challenge Test)

Performed prior to induction of naltrexone therapy in patients formerly physically dependent on opiates who have completed detoxification and in those suspected of having been dependent on opiates.

Do not perform the naloxone challenge test in patients who are exhibiting manifestations of opiate withdrawal, those whose urine shows evidence of opiates, or those in whom there is a high degree of suspicion that opiates are still being used, since naloxone may precipitate potentially severe opiate withdrawal.

If manifestations of opiate withdrawal are evident following naloxone challenge test, naltrexone therapy should not be attempted.

During the appropriate period in the naloxone challenge test, the patient should be closely monitored for the appearance of manifestations of opiate withdrawal and vital signs should be monitored.

If manifestations of opiate withdrawal are evident following the naloxone challenge test, do not initiate naltrexone therapy due to potential risk of precipitating more severe and prolonged withdrawal with naltrexone; naloxone challenge test may be repeated in 24 hours in these patients.

If evidence of withdrawal is absent, naltrexone therapy may be initiated.

Some clinicians caution that even minor and/or transient GI symptoms following naloxone challenge be considered evidence of withdrawal since patients with such symptoms will often develop severe and disturbing GI symptoms if naltrexone therapy is then initiated.

IV

Use a sterile syringe containing 0.8 mg of naloxone hydrochloride.

Initially, a 0.2-mg IV dose and, while the needle remains in the vein, observe the patient for 30 seconds for evidence of opiate withdrawal.

Alternatively, an initial 0.2-mg IV dose, then observe patient for 15 minutes for evidence of withdrawal.

Manifestations of withdrawal include, but are not limited to, nasal stuffiness, rhinorrhea, lacrimation, yawning, sweating, tremor, abdominal cramps, vomiting, piloerection, myalgia, and skin crawling.

If no evidence of withdrawal, inject the remaining 0.6-mg IV dose and observe the patient for an additional 20 minutes for evidence of withdrawal.

Some clinicians recommend that a total IV dose of 2 mg be used in the test since withdrawal has been precipitated by the first oral dose of naltrexone despite a negative naloxone challenge test using lower doses and a false-negative test rarely occurs with the 2-mg naloxone hydrochloride dose.

Sub-Q

Inject the entire 0.8-mg dose and observe the patient for 20 minutes for evidence of opiate withdrawal.

If evidence of opiate withdrawal is present, naltrexone therapy should be delayed and the naloxone challenge test repeated in 24 hours with the 0.8-mg dose and every 24 hours until results are negative.

If it is uncertain whether the patient is opiate free or is undergoing opiate withdrawal following an initial test, the naloxone challenge test should be repeated at that time with a 1.6-mg dose.

To repeat the naloxone challenge test in these patients, a 1.6-mg dose of naloxone hydrochloride should be injected IV and the patient observed for evidence of opiate withdrawal; if evidence of opiate withdrawal is absent, naltrexone therapy may be initiated.

Diagnosis of Opiate Dependence
IM, then IV

Initial single dose of 0.16 mg IM; if no withdrawal manifestations are evident after 20–30 minutes, a second dose of 0.24 mg is given IV.

Negative test results assumed if no withdrawal manifestations are apparent within 30 minutes after the second dose.

Withdrawal manifestations induced by naloxone begin to diminish 20–40 minutes after injection and are essentially gone within 1.5 hours.

Prescribing Limits

Adults

Known or Suspected Opiate Overdosage
IV, IM, or Sub-Q

If no response is observed after a total of 10 mg is been administered, the depressive condition may be caused by a drug or disease process not responsive to naloxone.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations; in general, dose selection should be cautious, usually initiating at the lower end of the normal range.

Cautions for Naloxone

Contraindications

  • Known hypersensitivity to naloxone or any ingredient in the formulation.

Warnings/Precautions

Warnings

Additional Resuscitative Measures

When used in the management of acute opiate overdosage, other resuscitative measures (e.g., maintenance of an adequate airway, artificial respiration, cardiac massage, vasopressor agents) should be readily available and used when necessary.

Excessive Dosage in Surgery

Avoid excessive dosage following the use of opiates during surgery because naloxone may result in excitement, agitation, an increase in BP, and clinically important reversal of analgesia; a reversal of opiate effects achieved too rapidly may induce nausea, vomiting, sweating, tremor, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest, which may result in death.

Physical Opiate Dependence

Caution in patients known or suspected to be physically dependent on opiates (including neonates born to women who are opiate dependent) because severe withdrawal manifestations may be precipitated.

General Precautions

Cardiovascular Disease

Caution and monitoring for adverse cardiopulmonary effects advised in patients with preexisting cardiovascular disease and in those receiving potentially cardiotoxic drugs; serious adverse cardiopulmonary effects (e.g., ventricular tachycardia and fibrillation, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have occurred in postoperative patients following administration of naloxone. (See Common Adverse Effects under Cautions.)

Repeat Administration

Carefully monitor patients who have responded to naloxone since the duration of action of most opiates may exceed that of naloxone. Give repeated doses of naloxone to these patients when necessary.

Some experts state that while a brief observation period may be adequate following overdosage of certain opiates with a shorter duration of action (morphine, heroin), patients with life-threatening overdosage of a long-acting or extended-release opiate may require longer periods of observation. The manufacturers recommend that pediatric patients be carefully monitored for ≥24 hours.

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Limited data on use in pregnant women. Use only when clearly needed.

No embryotoxic or teratogenic effects observed in animal studies.

Consider risk-benefit ratio before administering naloxone to a pregnant woman with known or suspected opiate dependence. Naloxone crosses the placenta; risk of opiate withdrawal in both the pregnant woman and fetus. Monitor for fetal distress.

Lactation

Not known whether naloxone is distributed into milk or affects milk production or the breast-fed infant. Does not affect prolactin or oxytocin concentrations in nursing women. Has minimal oral bioavailability. Caution advised if used in nursing women.

Pediatric Use

Naloxone may be used to reverse effects of opiates in infants and children. Safety and efficacy of naloxone administered via auto-injector or nasal spray established in pediatric patients of all ages for emergency treatment of known or suspected opiate overdosage manifested by respiratory and/or CNS depression. Use of naloxone for reversal of opiate effects in pediatric patients is supported by well-controlled studies in adults, additional data from controlled and uncontrolled studies in which neonates and children received parenteral naloxone hydrochloride (0.005–0.01 mg/kg), bioequivalence studies in adults, other published data, and postmarketing experience with the drug.

May precipitate opiate withdrawal in patients who are physically dependent on opiates. Opiate withdrawal in neonates may be life-threatening; treat according to protocols developed by neonatology experts.

To avoid abrupt precipitation of neonatal opiate withdrawal, consider using a naloxone preparation that can be dosed based on weight and titrated to effect rather than a fixed-dose preparation (e.g., auto-injector, nasal spray) in neonates with known or suspected exposure to maternally administered opiates (e.g., illicit use, opiate therapy for chronic pain management, opiate maintenance treatment) who require naloxone for reversal of respiratory depression.

In infants at risk for opiate overdosage (e.g., those receiving a tapering opiate dosage following hospital discharge), consider using a naloxone formulation other than the nasal spray (e.g., naloxone auto-injector); there is some concern that intranasal instrumentation could induce respiratory distress in young infants.

Absorption following intranasal administration or IM or sub-Q injection in pediatric patients may be erratic or delayed. (See Administration under Dosage and Administration.)

Monitor for ≥24 hours after reversal of opiate intoxication; relapse may occur as naloxone is metabolized.

Safety and efficacy in management of hypotension associated with septic shock not established in pediatric patients. In a study of 2 neonates with septic shock, treatment with naloxone produced positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Safety and efficacy not established; use with caution.

Renal Impairment

Safety and efficacy not established; use with caution.

Common Adverse Effects

Nausea and vomiting rarely postoperatively with parenteral dose exceeding that usually recommended; causal relationship not established.

Analgesia reversal, excitement, agitation, and increased BP may occur with excessive postoperative doses.

Postoperative use: Hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest reported; sequelae include death, coma, and encephalopathy. Cardiovascular effects most common in patients with preexisting cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects. (See Cardiovascular Disease under Cautions.)

Opiate overdosage: Tremor and hyperventilation associated with an abrupt return to consciousness.

Opiate dependence: Abrupt reversal of opiate effects may precipitate acute withdrawal and aggressive behavior.

Intranasal administration (in pharmacokinetic study): Hypertension, musculoskeletal pain, headache, local effects (nasal dryness, edema, congestion, and inflammation ).

Auto-injector (in pharmacokinetic studies): Dizziness, erythema at injection site.

Interactions for Naloxone

Specific Drugs

Drug

Interaction

Comments

Cardiotoxic drugs

Serious adverse cardiovascular effects (e.g., ventricular tachycardia and fibrillation, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy reported in postoperative patients

Use concomitantly with caution; monitor for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema

Methohexital

Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts

Naloxone Pharmacokinetics

Absorption

Bioavailability

Rapidly inactivated following oral administration.

Although effective orally, doses much larger than those required for parenteral administration are required for complete antagonism.

Evzio auto-injector: Bioequivalent to naloxone hydrochloride administered by sub-Q or IM injection using a standard syringe.

Narcan nasal spray: Time to peak plasma concentration similar to that observed following IM injection. Dose-normalized bioavailability approximately 43–54% that of IM dose. Peak plasma concentrations and AUC substantially higher following intranasal administration of a 2-mg dose as a single spray in one nostril (approximately 3.3- and 2.6-fold higher, respectively), a 4-mg dose as a single spray in one nostril (approximately 5.5- and 4.4-fold higher, respectively), a 4-mg dose as one 2-mg spray in each nostril (approximately 7.2- and 5.4-fold higher, respectively), or an 8-mg dose as one 4-mg spray in each nostril (approximately 11- and 8.7-fold higher, respectively) compared with a 0.4-mg IM dose.

Onset

IV: Within 1–2 minutes.

Sub-Q or IM: Within 2–5 minutes.

Duration

Depends on the dose and route of administration and is more prolonged following IM than IV administration.

Distribution

Extent

Parenteral: Rapidly distributed into body tissues and fluids.

Readily (within 2 minutes) crosses the placenta.

Unknown whether distributed into milk.

Plasma Protein Binding

Weakly bound to plasma proteins (mainly albumin).

Elimination

Metabolism

Rapidly metabolized in the liver, principally by conjugation with glucuronic acid.

Major metabolite is naloxone-3-glucuronide.

Also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation.

Elimination Route

Oral or IV dose: 25–40% excreted as metabolites in urine in 6 hours, about 50% in 24 hours, and 60–70% in 72 hours.

Half-life

Adults: 30–81 minutes.

Neonates: About 3 hours.

Evzio auto-injector: 1.28–1.5 hours.

Narcan nasal spray: 1.9–2.1 hours.

Stability

Storage

Parenteral

Injection

Vials and ampuls: 20–25°C; protect from light.

Auto-injector: Store in outer case at 15–25°C (may be exposed to 4–40°C).

Nasal spray: Store in carton at 15–20°C; may be exposed to temperatures up to 40°C. Do not freeze. Protect from light.

Stable at pH 2.5–5.

Use diluted solutions (e.g., 4 mcg/mL in 5% dextrose or 0.9% sodium chloride injection) within 24 hours; discard unused portions after 24 hours.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not mix with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH.

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Verapamil HCl

Y-Site CompatibilityHID

Compatible

Fenoldopam mesylate

Linezolid

Propofol

Incompatible

Amphotericin B cholesteryl sulfate complex

Actions

  • Essentially a pure opiate antagonist.

  • In usual doses in patients who have not recently received opiates, naloxone exerts little or no pharmacologic effect.

  • In patients who have received large doses of morphine or other analgesic drugs with morphine-like effects, naloxone antagonizes most of the effects of the opiate.

  • Increase in respiratory rate and minute volume, decrease toward normal in arterial PCO2, and return to normal in blood pressure if depressed.

  • Because the duration of action of naloxone is generally shorter than that of the opiate, the effects of the opiate may return as the effects of naloxone dissipate.

  • Antagonizes opiate-induced sedation or sleep.

  • Does not produce tolerance or physical or psychological dependence.

  • It is thought to act as a competitive antagonist at µ, κ, and σ opiate receptors in the CNS; it is thought that the drug has the highest affinity for the μ receptor.

Advice to Patients

  • Advise patients receiving naloxone to store the drug in a location that will be accessible during an emergency (e.g., not in a locked container with the opiate) and to inform caregivers, household members, and other close contacts of the location. Advise patients who will be taking doses of opiate analgesics when away from home to carry naloxone with them and to advise individuals who are with them of the availability of the drug and its proper use.

  • Instruct patients receiving naloxone auto-injector or nasal spray and their family members or caregivers about clinical manifestations requiring naloxone administration and proper administration techniques.

  • Encourage familiarity with the auto-injector training device provided in each carton; however, advise that untrained individuals should still attempt to use the auto-injector in case of suspected opiate overdosage.

  • Repeated doses may be required; importance of using a new auto-injector or nasal spray unit for each dose.

  • Seek immediate medical attention after administering naloxone in an out-of-hospital setting. Monitor patient closely until emergency care arrives.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

To facilitate timely naloxone administration following opiate overdosages occurring in community (nonmedical) settings, many states have taken steps to make naloxone available to first responders, community-based organizations, and laypersons (e.g., through legislation permitting prescribing to third parties, prescribing by standing order, or pharmacist prescribing or dispensing in accordance with protocols or standing orders) and to limit adverse legal consequences to prescribers and to laypersons who administer the drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naloxone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Intranasal

Solution

2 mg/0.1 mL

Narcan

Adapt

4 mg/0.1 mL

Narcan

Adapt

Parenteral

Injection

0.4 mg/mL*

Naloxone Hydrochloride Injection

1 mg/mL*

Naloxone Hydrochloride Injection

5 mg/mL (2 mg)

Evzio (available as kit with 2 prefilled, single-use 0.4-mL auto-injectors and 1 drug-free, needleless, reusable training device)

Kaleo

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Pentazocine and Naloxone Hydrochlorides

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

Pentazocine Hydrochloride 50 mg (of pentazocine) and Naloxone Hydrochloride 0.5 mg (of naloxone)*

Pentazocine and Naloxone Hydrochlorides Tablets ( C-IV)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naloxone Hydrochloride Dihydrate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Buccal (Transmucosal)

Strips, intrabuccally dissolving

0.3 mg (of naloxone) with Buprenorphine Hydrochloride 2.1 mg (of buprenorphine)

Bunavail ( C-III)

BioDelivery Sciences

0.7 mg (of naloxone) with Buprenorphine Hydrochloride 4.2 mg (of buprenorphine)

Bunavail ( C-III)

BioDelivery Sciences

1 mg (of naloxone) with Buprenorphine Hydrochloride 6.3 mg (of buprenorphine)

Bunavail ( C-III)

BioDelivery Sciences

Sublingual

Strips, sublingually dissolving

0.5 mg (of naloxone) with Buprenorphine Hydrochloride 2 mg (of buprenorphine)

Suboxone ( C-III)

Indivior

1 mg (of naloxone) with Buprenorphine Hydrochloride 4 mg (of buprenorphine)

Suboxone ( C-III)

Indivior

2 mg (of naloxone) with Buprenorphine Hydrochloride 8 mg (of buprenorphine)

Suboxone ( C-III)

Indivior

3 mg (of naloxone) with Buprenorphine Hydrochloride 12 mg (of buprenorphine)

Suboxone ( C-III)

Indivior

Tablets

0.36 mg (of naloxone) with Buprenorphine Hydrochloride 1.4 mg (of buprenorphine)

Zubsolv ( C-III)

Orexo

0.5 mg (of naloxone) with Buprenorphine Hydrochloride 2 mg (of buprenorphine)*

Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets ( C-III)

0.71 mg (of naloxone) with Buprenorphine Hydrochloride 2.9 mg (of buprenorphine)

Zubsolv ( C-III)

Orexo

1.4 mg (of naloxone) with Buprenorphine Hydrochloride 5.7 mg (of buprenorphine)

Zubsolv ( C-III)

Orexo

2 mg (of naloxone) with Buprenorphine Hydrochloride 8 mg (of buprenorphine)*

Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets ( C-III)

2.1 mg (of naloxone) with Buprenorphine Hydrochloride 8.6 mg (of buprenorphine)

Zubsolv ( C-III)

Orexo

2.9 mg (of naloxone) with Buprenorphine Hydrochloride 11.4 mg (of buprenorphine)

Zubsolv ( C-III)

Orexo

AHFS DI Essentials™. © Copyright 2022, Selected Revisions March 29, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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