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NALOXONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Naloxone is an opioid antagonist that appears to be devoid of agonist actions. It appears to exert its opioid antagonist effects by competing for the same receptor sites.

Specific Substances

    1) 6-allylnoroxymorphone
    2) 17-allyl-6-deoxy-7,8-dihydro-14-hydroxy-6-oxo-
    3) 17-normorphone
    4) Morphinan-6-one, 4,5-alpha-epoxy,3,
    5) 14-dihydroxy-17-(2-propenyl)-
    6) CAS 465-65-6 (hydrochloride salt)
    7) CAS 357-08-4 (anhydrous naloxone)
    8) CAS 51481-60-8 (naloxone dihydrate)
    9) Molecular Formula: C19-H21-N-O4
    1.2.1) MOLECULAR FORMULA
    1) NALOXONE HYDROCHLORIDE: C19H21NO4 HCl

Available Forms Sources

    A) FORMS
    1) Naloxone is available as 0.4 mg/mL and 1 mg/mL solution for injection (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    2) Naloxone Evzio(TM) is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
    3) Narcan(R) nasal spray is available as a carton containing 2 blister packages, each with a single nasal spray (single 4 mg dose of naloxone hydrochloride) (Prod Info NARCAN(R) nasal spray, 2015)
    B) USES
    1) Naloxone is indicated for partial or complete reversal of opioid CNS depression, including respiratory depression, induced by natural or synthetic opioids such as methadone and mixed agonist-antagonist analgesics including nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone injection is also indicated for the diagnosis of known or suspected acute opioid overdose (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    2) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration (Prod Info EVZIO(TM) injection solution, 2014). Narcan(R) nasal spray is indicated in the emergency treatment of patients with known or suspected opioid overdose with respiratory or central nervous system depression (Prod Info NARCAN(R) nasal spray, 2015).
    3) Naloxone hydrochloride may be useful as an adjunct for increasing blood pressure during the management of septic shock (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). However, the benefits of naloxone treatment in septic shock patients have been variable. It may have a temporizing effect through elevation of mean arterial pressure (Howland, 2002).
    4) NEW YORK STATE PASSED LEGISLATION (AUGUST 2005): This legislation allows clinicians to prescribe naloxone explicitly for potential future opiate overdose, including administration by someone else (Strang et al, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Naloxone is used to reverse the effects of opioid medications and is indicated for the reversal of life threatening respiratory depression secondary to opioid overdose. It is also used in combination with other agents as an abuse deterrent.
    B) PHARMACOLOGY: Naloxone is a pure opioid antagonist that competes with and displaces narcotics at opioid receptor sites.
    C) TOXICOLOGY: The antagonistic effects of naloxone at opioid receptors may precipitate acute withdrawal symptoms in opioid dependent patients.
    D) EPIDEMIOLOGY: Overdose of naloxone is rare. It is used commonly in a variety of settings including prehospital care settings, emergency departments, and operating rooms.
    E) WITH THERAPEUTIC USE
    1) The adverse effects of naloxone are related to its antagonistic effects to narcotics and the resulting withdrawal symptoms. Symptoms include pain, hypertension, diaphoresis, piloerection, muscle cramping, diarrhea, nausea, vomiting, and agitation. Pulmonary edema and dysrhythmias, including ventricular fibrillation, have been reported in association with the use of naloxone. There have also been reports of acute lung injury, seizures, dysphagia, urinary urgency, and increases of cortisol and growth hormone. NEONATES: In neonates, withdrawal symptoms also include excessive crying, hyperactive reflexes, and convulsions.
    F) WITH POISONING/EXPOSURE
    1) Naloxone is not a drug of abuse and there is essentially no overdose phenomenon. Increased blood pressure may occur following overdose.
    0.2.20) REPRODUCTIVE
    A) Naloxone hydrochloride and the combination products of naloxone/pentazocine, buprenorphine/naloxone, oxycodone/naloxone are classified as FDA pregnancy category C. Naloxone hydrochloride brand Evzio(TM) is classified as FDA pregnancy category B. When naloxone is administered during pregnancy, there is the possibility for naloxone to precipitate withdrawal symptoms in narcotic-addicted mothers and their infants. Naloxone/pentazocine was shown to increase the incidences of resorptions and extra ribs in rat studies.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

    A) No laboratory studies are needed after naloxone use or overdose unless otherwise clinically indicated.
    B) Naloxone concentrations are not widely available or clinically useful.
    C) Monitor respiratory and mental status when naloxone is used to reverse opioid toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Naloxone has a poor bioavailability when given orally, thus systemic adverse effects would be limited and gastrointestinal decontamination is rarely needed.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treatment of mild to moderate withdrawal induced by naloxone includes the use of benzodiazepines for agitation and antiemetics for nausea and vomiting. Because naloxone has a short duration of action compared with most opioids, no further treatment is generally needed. In mild cases, symptoms usually subside within 1 to 2 hours. Clonidine has also been used to treat opioid withdrawal symptoms and dicyclomine has been used to treat diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive and may include benzodiazepines for agitation and antiemetics for nausea and vomiting. Because naloxone has a short duration of action compared with most opioids, no further treatment is generally needed. In mild cases, symptoms usually subside within 1 to 2 hours. Clonidine has also been used to treat opioid withdrawal symptoms and dicyclomine to treat diarrhea. If pulmonary edema develops, oxygen, bilevel positive airway pressure, or endotracheal intubation may be required. Seizures should be treated with standard antiepileptic agents such as benzodiazepines, barbiturates, and propofol.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    2) HOSPITAL: Because naloxone is not active orally, gastrointestinal decontamination is not necessary.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation. Provide bilevel positive airway pressure as required and perform endotracheal intubation early in patients with pulmonary edema or serious toxicity.
    E) ANTIDOTE
    1) None
    F) HYPERTENSIVE EPISODE
    1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.
    G) SEIZURE
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    H) ENHANCED ELIMINATION
    1) LACK OF EFFECT
    a) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the large volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Naloxone exposures in general should be very safe. Asymptomatic patients may remain at home with inadvertent exposures to naloxone alone. However, if naloxone was administered to reverse opioid toxicity, the patient should be brought in to a health care facility for further evaluation.
    2) OBSERVATION CRITERIA: Patients who are symptomatic, those with deliberate overdose, and patients in whom naloxone was used to reverse opioid toxicity should be referred to a health care facility for evaluation and observation.
    3) ADMISSION CRITERIA: Patients with pulmonary edema or those who are persistently symptomatic should be admitted. Admission is almost never necessary.
    4) CONSULT CRITERIA: Consult a toxicologist or a poison center for advice if there are concerns.
    J) PITFALLS
    1) Significant toxicity is not anticipated from naloxone alone. If there are manifestations other than those of opioid withdrawal, the diagnosis should be reconsidered.
    K) PHARMACOKINETICS
    1) Onset of action depends on the mode of delivery. Onset is about 2 minutes after IV administration, 2 to 5 minutes after endotracheal, intramuscular, or subcutaneous administration, and approximately 13 minutes after intranasal administration. After ingestion naloxone is rapidly inactivated. Low protein binding, volume of distribution 200 L. Metabolism is primarily hepatic via glucuronidation and it does cross the placenta. The elimination half-life of naloxone is 30 to 81 minutes in adults and 2.5 to 3.5 hours in neonates. Metabolites of naloxone are excreted in the urine.
    L) PREDISPOSING CONDITIONS
    1) Patients with a history of opioid dependence have a much higher likelihood of experiencing opioid withdrawal symptoms upon receiving naloxone. In heroin-using asthmatic patients, naloxone may lead to worsening asthma symptoms or respiratory failure. Patients with pre-existing cardiac disease or who have received cardiotoxic drugs may be at higher risk of complications such as hypotension, hypertension, dysrhythmias, and pulmonary edema.
    M) DIFFERENTIAL DIAGNOSIS
    1) The use of other opioid antagonists such as naltrexone would look similar to naloxone use.

Range Of Toxicity

    A) TOXICITY: There is no specific known toxic dose with naloxone, though deaths have occurred in varying doses associated with its use. However, these case reports do not provide any direct evidence that the use of naloxone was solely responsible for mortality.
    B) THERAPEUTIC DOSE: ADULT: Standard dosing in adults may range widely, as the drug should be titrated to effect. Initial IV doses usually range from 0.1 to 2 mg, which may be repeated every 2 to 3 minutes. Additional doses may be needed every 20 to 60 minutes. Atypical opioids (eg, fentanyl, propoxyphene) or massive opioid overdoses may require much larger doses to reverse respiratory depression. In addition, to avoid precipitating acute withdrawal lower doses should be titrated incrementally in opioid-dependent patients. Continuous infusion of naloxone has also been used for respiratory depression with one suggestion of using 2/3 of the initial effective naloxone bolus per hour with titrations to effect. INTRANASAL: Intranasal dosing is usually 2 mg (1mg/nostril) with repeat dosing every 5 minutes if respiratory depression continues. PEDIATRIC/PALS GUIDELINES: Pediatric dosing is initially 0.1 mg/kg to a maximum of 2 mg and repeated every 2 to 5 minutes as needed. ALTERNATIVE DOSING: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal.

Clinical Effects

Summary Of Exposure

    A) USES: Naloxone is used to reverse the effects of opioid medications and is indicated for the reversal of life threatening respiratory depression secondary to opioid overdose. It is also used in combination with other agents as an abuse deterrent.
    B) PHARMACOLOGY: Naloxone is a pure opioid antagonist that competes with and displaces narcotics at opioid receptor sites.
    C) TOXICOLOGY: The antagonistic effects of naloxone at opioid receptors may precipitate acute withdrawal symptoms in opioid dependent patients.
    D) EPIDEMIOLOGY: Overdose of naloxone is rare. It is used commonly in a variety of settings including prehospital care settings, emergency departments, and operating rooms.
    E) WITH THERAPEUTIC USE
    1) The adverse effects of naloxone are related to its antagonistic effects to narcotics and the resulting withdrawal symptoms. Symptoms include pain, hypertension, diaphoresis, piloerection, muscle cramping, diarrhea, nausea, vomiting, and agitation. Pulmonary edema and dysrhythmias, including ventricular fibrillation, have been reported in association with the use of naloxone. There have also been reports of acute lung injury, seizures, dysphagia, urinary urgency, and increases of cortisol and growth hormone. NEONATES: In neonates, withdrawal symptoms also include excessive crying, hyperactive reflexes, and convulsions.
    F) WITH POISONING/EXPOSURE
    1) Naloxone is not a drug of abuse and there is essentially no overdose phenomenon. Increased blood pressure may occur following overdose.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Increased blood pressure may occur following overdose (Cohen et al, 1983; Ward & Corall, 1983).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been associated with the use of naloxone hydrochloride injection in postoperative patients, with some cases resulting in encephalopathy, coma, and death. Most patients had preexisting cardiovascular disorders or received other medications which may have contributed to the adverse cardiovascular event. A direct causal relationship to the drug has not been established (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    b) CASE REPORT: Slight increases in blood pressure were seen when volunteers received 0.3 to 4 mg/kg (Cohen et al, 1983).
    c) CASE REPORT: Hypertension following naloxone was reported in a 51-year-old man following coronary artery bypass grafting surgery. The patient received 210 mg of morphine sulfate, which resulted in respiratory insufficiency approximately 6 hours following surgery. At that time, 0.4 mg of naloxone (5 mcg/kg) was given IV resulting in elevation of blood pressure approximately 3 minutes later and resulting in a pressure of 340/150 mmHg over a period of ten minutes. Central venous pressure decreased to zero, and paroxysmal atrial tachycardia developed. The hypertension failed to respond to chlorpromazine; a sodium nitroprusside infusion resulted in normalization of blood pressure. A definite cause-effect relationship is difficult to establish. The postulated mechanism was that naloxone may have triggered catecholamine release resulting in paradoxical hypertension; however, there is no other evidence to support this theory in the literature (Tanaka, 1974)
    d) CASE REPORT: Intravenous doses of naloxone exceeding 3 mcg/kg were associated with hypertensive responses in several patients. The drug was used postoperatively to reverse fentanyl-induced respiratory depression. All patients had cardiovascular disease. Patients most prone to developing hypertension were those with pre-existing hypertension, and especially those on beta-2-agonist therapy, with these patients developing an increase in arterial pressure 25% above baseline.(Ward & Corall, 1983).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been associated with the use of naloxone hydrochloride injection in postoperative patients, with some cases resulting in encephalopathy, coma, and death. Most patients had preexisting cardiovascular disorders or received other medications which may have contributed to the adverse cardiovascular event (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Ventricular fibrillation has been associated with the use of naloxone hydrochloride injection in postoperative patients, with some cases resulting in encephalopathy, coma, and death. Most patients had preexisting cardiovascular disorders or received other medications which may have contributed to the adverse cardiovascular event (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    b) Two cases of ventricular tachycardia and ventricular fibrillation have been reported following injection of naloxone to reverse the effects of morphine following cardiopulmonary bypass procedures. Subsequent studies carried out in dogs given morphine did not support the hypothesis that naloxone increases ventricular irritability (Michaelis, 1974).
    c) CASE REPORT: A patient developed ventricular tachycardia and atrial fibrillation following administration of naloxone to reverse the effects of a suspected cocaine-heroin injection. The patient was already experiencing sinus tachycardia, most likely due to the cocaine, before the administration of naloxone (Merigian, 1993).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Respiratory rate was increased in healthy volunteers given doses of 0.3 to 4 mg/kg of naloxone (Cohen et al, 1983).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema has been associated with the use of naloxone hydrochloride injection in postoperative patients, with some cases resulting in encephalopathy, coma, and death. Most patients had preexisting cardiovascular disorders or received other medications which may have contributed to the adverse cardiovascular event (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    b) Several case reports link acute lung injury (non-cardiogenic pulmonary edema) to naloxone administered post-operatively to reverse narcotic-induced respiratory depression (Flacke et al, 1977; Harrington, 1988; Wride et al, 1989; Olson, 1990; Brimacombe et al, 1991). Some of the reactions occurred almost immediately after administration of the naloxone.
    c) CASE REPORTS
    1) A healthy 28-year-old man operated for laparoscopic donor nephrectomy developed pulmonary edema with hypertension 2 hours following the administration of naloxone 200 mcg IV for poor postoperative recovery due to an overdose effect of fentanyl. The patient was placed on respiratory support and given furosemide 20 mg intravenously and IV aminophylline 0.5 mg/kg/hr. The patient fully recovered and was discharged 3 days later. The overloading of fluids (Ringer's lactate, 2100 mL; 0.9% sodium chloride, 900 mL; 6% Hetastarch, 500 mL) during surgery per transplant protocol may have predisposed this patient to acute pulmonary edema (Nath et al, 2009).
    2) A 59-year-old woman developed laryngospasm and pulmonary edema following naloxone administration, 0.4 mg given over 5 minutes after receiving fentanyl during a laryngoscopic procedure. Laryngospasm occurred immediately following administration and pulmonary edema developed 1 hour later; effects resolved with supportive care. It is believed that the laryngospasm, in part, could be due to laryngeal irritation in combination with stimulation caused by reversing the effects of fentanyl, although naloxone administration may be an additional factor (Olson, 1990).
    3) A 27-year-old man developed pulmonary edema and subsequent cardiac arrest following the administration of IV naloxone. Pulmonary edema occurred 60 seconds after the administration of naloxone, 0.2 mg IV. The patient died after developing profound bradycardia, cyanosis, and an unrecordable blood pressure (Wride et al, 1989).
    4) A 17-year-old adolescent was admitted for surgery of toe lacerations sustained in an accident and underwent an uneventful surgical procedure with general anesthesia (fentanyl infusion) and received 200 mcg of IV naloxone as a reversal agent. Almost immediately the patient's chest became rigid. He could not be ventilated by mask, and pulmonary aspirates showed thin, pink, frothy secretions. The patient was reintubated and taken to the intensive care unit where he recovered (Harrington, 1988).
    5) A 70-year-old man with a 2 month history of precordial pain and congestive heart failure (CHF) was admitted for mitral valve replacement and aorto-coronary bypass grafts. Postoperatively the patient remained unresponsive to stimuli 3 hours after the 4-hour surgery. Naloxone 0.4 mg was administered IV over 1.5 minutes. The patient responded immediately, became agitated, fought the ventilator and tried to sit up. His blood pressure rose to 170/100 mmHg and red-tinged fluid poured from the endotracheal tube (approximately 2 liters total). Over the next 20 minutes, morphine 30 mg IV was needed to quiet the patient and stop the pulmonary edema. The patient recovered and was discharged on the 12th postoperative day (Flacke et al, 1977).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) AMNESIA
    1) WITH THERAPEUTIC USE
    a) Memory impairment was experienced by volunteers given doses of 0.3 to 4 mg/kg (Cohen et al, 1983).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Convulsions, including grand mal convulsions, have been associated with the use of naloxone hydrochloride injection in postoperative patients (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    b) NEONATES: Neonatal symptoms of opioid withdrawal include hyperactive reflexes, convulsions and excessive crying (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    c) CASE REPORT: Grand mal seizures were observed within 30 seconds of 0.8 mg IV naloxone in a 51-year-old man with a history of non-Hodgkins lymphoma transferred from a nursing home for evaluation of fever, tachypnea, and hypotension. On arrival the patient was obtunded and received naloxone because of previous morphine use for bone pain. The patient responded to 5 mg IV diazepam, but died within 1 week due to Pseudomonas sepsis with negative CSF cultures (Mariani, 1989).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Rapid reversal of narcotic depression may cause nausea and/or vomiting, particularly in postoperative or opioid-dependent patients (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Reversal of narcotic depression may cause diarrhea in opioid-dependent patients (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    C) DYSPHAGIA
    1) WITH THERAPEUTIC USE
    a) Dysphagia was noted in volunteers given doses of 0.3 to 4 mg/kg (Cohen et al, 1983).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URGENT DESIRE TO URINATE
    1) WITH THERAPEUTIC USE
    a) Two patients developed feelings of urinary urgency after being given IV infusions of naloxone (Sandyk & Gillman, 1986).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) WITH THERAPEUTIC USE
    a) Prolongation of the partial thromboplastin time (PTT) was reported in an uncontrolled observation in several patients after receiving 3.2 mg of naloxone for 8 consecutive days. However, other investigators have found no effect of naloxone administration on the thrombin time, partial thromboplastin time, and prothrombin consumption. These findings were supported by performing prothrombin and blood clotting factors (V, VII, X, and VII) following oral naloxone administration of doses ranging from 200 to 3000 mg daily for 7 to 59 days were supported. In all 7 patients studied, there were no abnormalities in these hematological tests. Therefore, at this time there is no conclusive evidence to indicate a causal relationship of naloxone in altering any hematological test, including partial thromboplastin time (Zaks et al, 1971a).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Increased levels of growth hormone were noted in volunteers given 0.3 to 4 mg/kg (Cohen et al, 1983)
    B) INCREASED HORMONAL ACTIVITY
    1) WITH THERAPEUTIC USE
    a) Increases in cortisol levels were noted in volunteers given 0.3 to 4 mg/kg (Cohen et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Naloxone hydrochloride and the combination products of naloxone/pentazocine, buprenorphine/naloxone, oxycodone/naloxone are classified as FDA pregnancy category C. Naloxone hydrochloride brand Evzio(TM) is classified as FDA pregnancy category B. When naloxone is administered during pregnancy, there is the possibility for naloxone to precipitate withdrawal symptoms in narcotic-addicted mothers and their infants. Naloxone/pentazocine was shown to increase the incidences of resorptions and extra ribs in rat studies.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) NALOXONE
    a) At the time of this review, no human data were available to assess the potential teratogenic effects of exposure to naloxone hydrochloride during pregnancy (Prod Info NARCAN(R) nasal spray, 2015; Prod Info EVZIO(TM) injection solution, 2014; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014).
    B) ANIMAL STUDIES
    1) NALOXONE
    a) Animal studies showed no teratogenic or embryotoxic effects in animals given doses up to 12 times the human dose of naloxone (Prod Info NARCAN(R) nasal spray, 2015; Prod Info EVZIO(TM) injection solution, 2014; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014). No adverse affects were reported in offspring of pregnant animals administered subQ naloxone hydrochloride at doses up to 12 times the human dose from gestation day 15 through postnatal day 21 (Prod Info NARCAN(R) nasal spray, 2015).
    2) NALOXONE/PENTAZOCINE
    a) RATS, RABBITS: The incidences of extra ribs increased when rats were given naloxone 0.64 mg/kg/pentazocine 64 mg/kg by oral gavage (0.2 times the maximum daily human dose (MDHD) of pentazocine via 12 tablets based on mg/m(2)). In rabbits, there was no evidence of teratogenicity at the same naloxone/pentazocine dose given by oral gavage (0.3 times the MDHD of pentazocine via 12 tablets based on mg/m(2)) (Prod Info TALWIN(R) Nx oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) NALOXONE
    a) At the time of this review, no data were available to assess the potential effects of exposure to naloxone during pregnancy in humans (Prod Info EVZIO(TM) injection solution, 2014; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014).
    2) NALOXONE/PENTAZOCINE
    a) There are no adequate and well-controlled studies of naloxone/pentazocine use during pregnancy; the effects on the mother or fetus, on the duration of labor or delivery, or on the later growth, development, or functional maturation of the child are not known. The possibility of a forceps delivery or other intervention/resuscitation of the neonate being necessary following the maternal use of the combination is not known (Prod Info TALWIN(R) Nx oral tablets, 2011).
    B) PREGNANCY CATEGORY
    1) NALOXONE HYDROCHLORIDE brand Evzio(TM) is classified as FDA pregnancy category B (Prod Info EVZIO(TM) injection solution, 2014).
    2) NALOXONE HYDROCHLORIDE generic is classified as FDA pregnancy category C (Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014).
    3) BUPRENORPHINE/NALOXONE is classified as FDA pregnancy category C (Prod Info SUBOXONE(R) sublingual tablets, 2011).
    4) NALOXONE/PENTAZOCINE is classified as FDA pregnancy category C (Prod Info TALWIN(R) Nx oral tablets, 2011).
    5) OXYCODONE/NALOXONE is classified as FDA pregnancy category C (Prod Info TARGINIQ(TM) ER oral extended release tablets, 2014)
    C) FETAL ADVERSE EFFECTS
    1) Naloxone hydrochloride crosses the placental barrier and withdrawal may be precipitated in the fetus as well as the opioid-dependent mother (Prod Info NARCAN(R) nasal spray, 2015; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014). Monitor for signs of fetal distress after naloxone hydrochloride use including the nasal spray formulation. Continue monitoring until both mother and fetus are stable (Prod Info NARCAN(R) nasal spray, 2015). Withdrawal in neonates may be life-threatening without treatment (Prod Info EVZIO(TM) injection solution, 2014).
    D) ANIMAL STUDIES
    1) NALOXONE/PENTAZOCINE
    a) RATS: The incidences of resorptions increased when rats were given naloxone 0.64 mg/kg/pentazocine 64 mg/kg by oral gavage (0.2 times the maximum daily human dose (MDHD) of pentazocine via 12 tablets based on mg/m(2)) (Prod Info TALWIN(R) Nx oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to naloxone hydrochloride during lactation in humans (Prod Info NARCAN(R) nasal spray, 2015; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014; Prod Info EVZIO(TM) injection solution, 2014).
    B) BREAST MILK
    1) Use caution when considering the use of naloxone in lactating women (Prod Info NARCAN(R) nasal spray, 2015; Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014; Prod Info EVZIO(TM) injection solution, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Administration of naloxone at doses up to 12 times the recommended human dose in male and female animals had no adverse effects on fertility (Prod Info NARCAN(R) nasal spray, 2015).
    2) Reproduction studies showed no fertility effects in animals who were given both 4 and 8 times the human dose of naloxone hydrochloride (10 mg/day in a person who weighs 50 kg) (Prod Info NALOXONE HCl intravenous, intramuscular, subcutaneous injection, 2014; Prod Info EVZIO(TM) injection solution, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No laboratory studies are needed after naloxone use or overdose unless otherwise clinically indicated.
    B) Naloxone concentrations are not widely available or clinically useful.
    C) Monitor respiratory and mental status when naloxone is used to reverse opioid toxicity.
    4.1.2) SERUM/BLOOD
    A) SUMMARY
    1) No laboratory studies are needed after naloxone use or overdose unless otherwise clinically indicated.
    2) Naloxone concentrations are not widely available or clinically useful.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor respiratory and mental status when naloxone is used to reverse opioid toxicity.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Although naloxone can be analyzed by gas chromatography with FID, there is generally NO clinical utility to obtain these levels (USP, 1980).
    2) Gas-liquid chromatography (Meffin & Smith, 1980), radio-immunoassay (Berkowitz et al, 1975; Hahn et al, 1983), and HPLC methods (Asali, 1983; Terry et al, 1984) have all been used to measure naloxone.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with pulmonary edema or those who are persistently symptomatic should be admitted. Admission is almost never necessary.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Naloxone exposures in general should be very safe. Asymptomatic patients may remain at home with inadvertent exposures to naloxone alone. However, if naloxone was administered to reverse opioid toxicity, the patient should be brought in to a health care facility for further evaluation.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a toxicologist or a poison center for advice if there are concerns.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients who are symptomatic, those with deliberate overdose, and patients in whom naloxone was used to reverse opioid toxicity should be referred to a health care facility for evaluation and observation.

Monitoring

    A) No laboratory studies are needed after naloxone use or overdose unless otherwise clinically indicated.
    B) Naloxone concentrations are not widely available or clinically useful.
    C) Monitor respiratory and mental status when naloxone is used to reverse opioid toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: There is no specific known toxic dose with naloxone, though deaths have occurred in varying doses associated with its use. However, these case reports do not provide any direct evidence that the use of naloxone was solely responsible for mortality.
    B) THERAPEUTIC DOSE: ADULT: Standard dosing in adults may range widely, as the drug should be titrated to effect. Initial IV doses usually range from 0.1 to 2 mg, which may be repeated every 2 to 3 minutes. Additional doses may be needed every 20 to 60 minutes. Atypical opioids (eg, fentanyl, propoxyphene) or massive opioid overdoses may require much larger doses to reverse respiratory depression. In addition, to avoid precipitating acute withdrawal lower doses should be titrated incrementally in opioid-dependent patients. Continuous infusion of naloxone has also been used for respiratory depression with one suggestion of using 2/3 of the initial effective naloxone bolus per hour with titrations to effect. INTRANASAL: Intranasal dosing is usually 2 mg (1mg/nostril) with repeat dosing every 5 minutes if respiratory depression continues. PEDIATRIC/PALS GUIDELINES: Pediatric dosing is initially 0.1 mg/kg to a maximum of 2 mg and repeated every 2 to 5 minutes as needed. ALTERNATIVE DOSING: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal.

Therapeutic Dose

    7.2.1) ADULT
    A) NALOXONE
    1) NARCOTIC OVERDOSE
    a) ROUTE: Naloxone may be administered IV, IM or subQ (Prod Info EVZIO(TM) injection solution, 2014; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    b) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with repeat dosing as needed or dose escalation to 2 mg as necessary (Vanden Hoek,TL,et al).
    1) If the desired degree of reversal and improvement in respiratory function is not obtained, the dose may be repeated at 2 to 3 minute intervals (Prod Info EVZIO(TM) injection solution, 2014; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    a) If no response is observed after 8 to 10 mg has been administered, the diagnosis of opioid toxicity should be reevaluated (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    c) LARGE DOSES:
    1) It is not unusual to use up to 8 mg of naloxone in cases of overdose where patients remain unresponsive (Longnecker, 1973).
    2) Doubling the IV dose may not prolong duration, although using a combination of IV and supplemental IM dosing may produce a more lasting effect (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Longnecker, 1973).
    2) POSTOPERATIVE NARCOTIC DEPRESSION
    a) For the partial reversal of narcotic depression following surgery, smaller doses of naloxone are usually sufficient (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    1) INITIAL DOSE: 0.1 to 0.2 mg IV should be repeated at 2 to 3 minute intervals until the desired degree of reversal is achieved, specifically until there is adequate ventilation and alertness without significant pain or discomfort (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    a) Larger doses than necessary of naloxone may result in reversal of analgesia and an increase in blood pressure. Too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses may be required within 1 to 2 hour intervals (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    3) MISCELLANEOUS USES
    a) SEPTIC SHOCK: The optimal dose of naloxone for the treatment of hypotension related to septic shock has not been established (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). However, the benefits of naloxone treatment in septic shock patients have been variable. It may have a temporizing effect through elevation of mean arterial pressure (Howland, 2002).
    b) In a small controlled study of healthy volunteers, naloxone was given to evaluate whether it would augment tolerance to a hypotensive hypovolemic state (lower body negative pressure was the stimulus used in this study). The results indicated that naloxone decreased tolerance to a hypotensive stress. The authors suggested that due to the attenuation of tolerance to a hypovolemic stressor following the administration of naloxone, it may not be safe to administer during hemorrhagic shock (Lightfoot et al, 2000).
    c) OPIOID INDUCED CONSTIPATION: Naloxone was effective in relieving constipation in patients receiving chronic opioid therapy for pain at a mean oral dose of 17.5 mg/day. Side effects included yawning, sweating, shivering and abdominal cramps (Meissner et al, 2000).
    4) ROUTE OF ADMINISTRATION
    a) INTRAMUSCULAR
    1) Give 0.4 mg/0.4 mL of naloxone in a prefilled autoinjector and observe. If desired response is not achieved, repeat every 2 to 3 minutes (Evzio(TM) (Prod Info EVZIO(TM) injection solution, 2014).
    b) INTRAVENOUS INFUSION
    1) Naloxone can be given by continuous IV infusion to avoid repeated doses due to the prolonged effects of narcotic analgesics (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    a) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis. For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
    b) Naloxone requirements may vary during the infusion period necessitating close monitoring of vital signs including respiratory rate, and increasing or decreasing the in rate as needed to achieve the desired antagonist effect without inducing withdrawal.
    c) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).
    c) SUBCUTANEOUS
    1) Give 0.4 mg/0.4 mL of naloxone in a prefilled autoinjector and observe. If desired response is not achieved, repeat every 2 to 3 minutes (Evzio(TM)) (Prod Info EVZIO(TM) injection solution, 2014).
    2) Give 0.8 mg of naloxone and observe for 20 minutes for evidence of withdrawal. If a patient is opioid dependent, lower doses of naloxone may be required (0.1 mg IV has been effective in some cases) (Narcan(R)) (Prod Info Narcan(R), naloxone hydrochloride injection, 1998).
    d) ORAL
    1) Single daily oral doses of 2.4 to 3 g have been given for treatment of opiate dependence. In limited studies, these doses were tolerated without any major subjective or physiological side effects (Kurland, 1976).
    e) INTRANASAL
    1) INITIAL DOSE: 1 spray (4 mg) intranasally into 1 nostril (Prod Info NARCAN(R) nasal spray, 2015).
    2) SUBSEQUENT DOSES: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes for a patient who does not respond or who responds and relapses. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized (Prod Info NARCAN(R) nasal spray, 2015).
    3) Intranasal naloxone has been described for emergency use in the prehospital setting and emergency departments for suspected opiate overdoses (with respiratory depression) in adults. Naloxone can be applied to the nasal mucosa by an atomizer device, spray, or drops. A typical dose is 2 mg intranasally (1 mg per nostril) via a mucosal atomizer device (Robertson et al, 2009). Doses have ranged from 0.4 to 2 mg (Robertson et al, 2009; Ashton & Hassan, 2006; Kelly & Koutsogiannis, 2002).
    4) Based on limited data, this route produces a similar clinical response as compared to the IV route. It also has the advantage of avoiding a needle injury to healthcare personnel (Robertson et al, 2009; Ashton & Hassan, 2006; Kelly & Koutsogiannis, 2002).
    f) NEBULIZED
    1) PREHOSPITAL SETTING: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations. In a pilot study (n=105) of patients with suspected opioid overdose or undifferentiated depressed respirations treated by first-responders, 23 (22%) patients had a complete response, 62 (59%) had a partial response and 20 (19%) had no response to the nebulized naloxone therapy. Eleven (10%) required IV naloxone. No adverse events were reported with nebulized naloxone administration, nor was intubation or bag-valve-mask assisted ventilation needed in any case (Weber et al, 2012).
    g) ENDOTRACHEAL
    1) One study evaluated the use of naloxone given endotracheally (a dose of 1.6 mg naloxone after several unsuccessful attempts to secure IV access) in a 24-year-old heroin overdose patient. Serial serum naloxone levels over the ensuing 3 hours showed pharmacokinetics which were similar to those reported after IV naloxone. The patient clinically improved with a return of spontaneous breathing and reversal of coma (Tandberg & Ambercrombie, 1982).
    B) BUPRENORPHINE/NALOXONE
    1) BUCCAL FILM
    a) The initial dose is based on final induction dose of buprenorphine/naloxone sublingual tablets. For buprenorphine 8 mg/naloxone 2 mg SL tablets, use buprenorphine 4.2 mg/naloxone 0.7 mg buccal film. Apply to buccal mucosa once daily (Prod Info BUNAVAIL(TM) buccal film, 2014).
    b) For maintenance, the target dose is buprenorphine 8.4 mg/naloxone 1.4 mg applied to buccal mucosa once daily; adjust dose in increments or decrements of buprenorphine 2.1 mg/naloxone 0.3 mg based on patient response. The usual dose range is buprenorphine 2.1 mg/naloxone 0.3 mg to buprenorphine 12.6 mg/naloxone 2.1 mg per day (MAX dose) (Prod Info BUNAVAIL(TM) buccal film, 2014).
    2) SUBLINGUAL FILM
    a) INDUCTION THERAPY: INITIAL DOSE: Buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg. Titrate in increments of 2 mg or 4 mg of buprenorphine at 2-hour intervals, under supervision. MAX dose: buprenorphine 8 mg/naloxone 2 mg (Prod Info SUBOXONE(R) sublingual film, 2014).
    b) TREATMENT DAY 2: A single daily dose of up to buprenorphine 16 mg/naloxone 4 mg sublingual (Prod Info SUBOXONE(R) sublingual film, 2014).
    c) MAINTENANCE THERAPY FROM DAY 3 ONWARD: Generally, adjust dose progressively in increments/decrements of 2 mg/0.5 or 4 mg/1 mg buprenorphine/naloxone to avoid opioid withdrawal symptoms. The typical range: 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on patient response. Recommended target dose: 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Higher dosages (ie, 24 mg/6 mg daily) have not shown any clinical advantage. MAX dose: buprenorphine 24 mg/naloxone 6 mg daily (Prod Info SUBOXONE(R) sublingual film, 2014).
    d) Do NOT cut, chew, or swallow the sublingual film. Place the sublingual film under the tongue, until it is completely dissolved (Prod Info SUBOXONE(R) sublingual film, 2014).
    3) SUBLINGUAL TABLETS
    a) SUBOXONE(R)
    1) The recommended target dose is buprenorphine 16 mg/naloxone 4 mg sublingually once daily; adjust dose in 2 mg/0.5 mg or 4 mg/1 mg increments or decrements to optimal clinical effects; typical dose ranges from buprenorphine 4 mg/naloxone 1 mg to buprenorphine 24 mg/naloxone 6 mg daily (Prod Info SUBOXONE(R) sublingual tablets, 2011).
    b) ZUBSOLV(R)
    1) INDUCTION: The recommended initial dose is buprenorphine 1.4 mg/naloxone 0.36 mg sublingually. For the remainder of Day 1, dose up to buprenorphine 4.2 mg/naloxone 1.08 mg in divided doses of 1 to 2 tablets at 1.5 to 2 hour intervals. On Day 2, a single daily dose of up to buprenorphine 11.4 mg/naloxone 2.9 mg is recommended (Prod Info ZUBSOLV(R) sublingual tablets, 2015).
    2) MAINTENANCE: The recommended target dosage is buprenorphine 11.4 mg/naloxone 2.9 mg in a single daily dose. Adjust in increments/decrements of buprenorphine 1.4 mg/naloxone 0.36 mg or buprenorphine 2.9 mg/naloxone 0.71 mg (Prod Info ZUBSOLV(R) sublingual tablets, 2015).
    C) OXYCODONE/NALOXONE COMBINATION
    1) Initiate dosing at 10 mg/5 mg ORALLY every 12 hours in patients who are opioid-naive or opioid non-tolerant. The dose may be increased by 10 mg/5 mg every 1 to 2 days as needed. MAX dose: 80 mg/40 mg/day (Prod Info TARGINIQ(TM) ER oral extended release tablets, 2014).
    7.2.2) PEDIATRIC
    A) NALOXONE
    1) NEONATES
    a) OPIATE REVERSAL/GUIDELINES: The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kg body weight. The dose may be repeated as needed to maintain opiate reversal (AAP, 1989; None Listed, 1989; Kleinman et al, 2010).
    b) OPIOID-INDUCED DEPRESSION: INITIAL DOSE: 0.01 mg/kg/body weight administered IV, IM, or subQ. The dose may be repeated at 2 to 3 minute intervals until the desired degree of reversal is achieved, specifically until there is adequate ventilation and alertness without significant pain or discomfort (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). IM administration may delay the effects of naloxone (Kleinman et al, 2010).
    2) CHILDREN
    a) OPIOID OVERDOSE/PALS GUIDELINES
    1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/endotracheal, maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006).
    2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg via the IV, intraosseous, or endotracheal tube route may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010).
    b) OPIOID OVERDOSE KNOWN OR SUSPECTED
    1) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). IM administration may delay the effects of naloxone (Kleinman et al, 2010).
    c) OPIOID DEPRESSION
    1) REVERSAL OF RESPIRATORY DEPRESSION ASSOCIATED WITH THERAPEUTIC OPIOID USE: Lower doses of naloxone are recommended to reverse respiratory depression associated with therapeutic opioid use (Kleinman et al, 2010). DOSE: 0.001 mg to 0.01 mg IV push at intervals of 2 to 3 minutes until desired reversal achieved (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Hasan et al, 2003).
    2) POSTOPERATIVE OPIOID DEPRESSION: Initial dose to reverse respiratory depression: Administer 0.005 mg to 0.01 mg IV at 2 to 3 minute intervals to the desired effect (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    d) OPIOID INDUCED PRURITUS AND NAUSEA
    1) PROPHYLAXIS: 6 YEARS OF AGE AND OLDER: A continuous IV infusion of 0.25 mcg/kg/hour has been used in patients receiving morphine PCA postoperatively (n=46) and was associated with decreased incidence and severity of pruritus and nausea when compared with placebo (Maxwell et al, 2005). In a pilot study of sickle cell patients (n=16 evaluable) receiving continuous infusion morphine, a dose of 1 mcg/kg/hour of naloxone was associated with less pruritus compared with patients receiving a lower dose (0.25 mcg/kg/hour); pain control was not compromised (Koch et al, 2008).
    2) TREATMENT: 6 YEARS OF AGE AND OLDER: Continuous IV infusions of 1 to 3 mcg/kg/hour have been used (up to a MAXIMUM of 5 mcg/kg/hour) (Koch et al, 2008; Maxwell et al, 2005; Vrchoticky, 2000). Doses of 3 mcg/kg/hour or greater were associated with an increased opioid dosage requirement (Vrchoticky, 2000).
    e) INTRANASAL
    1) INITIAL DOSE: 1 spray (4 mg) intranasally into 1 nostril (Prod Info NARCAN(R) nasal spray, 2015).
    2) SUBSEQUENT DOSES: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes for a patient who does not respond or who responds and relapses. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized (Prod Info NARCAN(R) nasal spray, 2015).
    3) Intranasal naloxone has been described for emergency use in pediatric patients. For patients less than 10 kg and less than 1 year old, give 0.1 mg/kg intranasally. If no response, IV or IM naloxone may be considered (Robertson et al, 2009).
    B) BUPRENORPHINE/NALOXONE
    1) BUCCAL FILM
    a) The safety and effectiveness of buccal film have not been established in pediatric patients (Prod Info BUNAVAIL(TM) buccal film, 2014).
    2) SUBLINGUAL TABLETS AND FILM
    a) The safety and effectiveness of buprenorphine/naloxone sublingual tablets and sublingual film have not been established for pediatric use (Prod Info ZUBSOLV(R) sublingual tablets, 2015; Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info SUBOXONE(R) sublingual tablets, 2011).
    C) OXYCODONE/NALOXONE COMBINATION
    1) Safety and effectiveness have not been established in pediatric patients less than 18 years of age (Prod Info TARGINIQ(TM) ER oral extended release tablets, 2014).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) LACK OF EFFECT
    a) Although doses of 0.3 to 4 mg/kg (acutely) have been shown to produce some CNS effects (Cohen et al, 1983), doses of 2.5 mg/kg (total, not acutely) have been used therapeutically to reverse opioid intoxication (Hatano et al, 1975).
    b) Naloxone can be given in large doses without significant toxicity. Doses of 24 mg/70 kg of body weight were used in volunteers and morphine-dependent subjects without evidence of toxicity (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Jasinski et al, 1967).
    c) Doses of 2.4 mg (6 ampules) were administered IV to reverse propoxyphene-induced respiratory depression, with several additional doses of naloxone administered following the appearance of spontaneous respirations (Vlasses & Fraker, 1974).
    2) ADVERSE EFFECTS
    a) Memory impairment has been reported at doses of 2 mg/kg in healthy subjects (Prod Info Narcan(R), naloxone hydrochloride injection, 1998).
    b) In a study of 36 patients with acute stroke, a loading dose of 4 mg/kg (10 mg/m(2)/min) of naloxone immediately followed by 2 mg/kg/hr for 24 hours resulted in several cases of serious adverse effects including seizures (2 patients), severe hypotension (1), and hypotension and/or bradycardia (3) (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008).
    3) PEDIATRIC
    a) Doses of up to 20 mg in a child did not produce adverse effects (Handal et al, 1983).
    b) Up to 11 doses of 0.2 mg naloxone (2.2 mg) have been administered to children following Lomotil(R) overdose (Rumack & Temple, 1974). These studies suggest that naloxone is relatively safe when given in large doses or successive doses over a prolonged period of time.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (SUBCUTANEOUS)MOUSE:
    a) 260 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Naloxone is essentially a pure opioid antagonist. Naloxone is a synthetic N-allyl derivative of oxymorphone and like other opioid antagonists (nalorphine and levallorphan) naloxone also antagonizes the analgesic, psychotogenic, dysphoric, miotic, and other pharmacologic effects of opioid analgesics, and is useful in the diagnosis of opioid dependence and has been used in treatment of opioid addiction. Unlike nalorphine, which is a competitive antagonist at the mu receptor site, naloxone is a competitive antagonist at all receptor sites (mu, kappa, sigma). The most important difference between naloxone and other opioid antagonists is that naloxone is almost completely devoid of agonistic effects and has no opioid effects in the absence of opioid agents (respiratory depression, sedation, analgesia, miosis). Thus, naloxone is of extreme importance in the differential diagnosis of mixed drug overdose, and in patients who have not received opioids (Jasinski et al, 1967).
    B) IMMUNOMODULATING EFFECT
    1) The effect of naloxone on immune parameters was evaluated when given at a dose of 0.03 mg/kg IV to 12 men (9 with duodenal ulcer; 3 controls). After a single dose, a transitory (150 minute) decrease in T-lymphocyte counts and lymphocyte proliferation were observed. Spontaneous interleukin-2 receptor expression was not affected. Natural killer cells and interleukin-2 generation increased slightly following naloxone injection. Most of these parameters returned to baseline within 150 minutes (Malec et al, 1989).

Physicochemical

Physical Characteristics

    A) NALOXONE: An 8.07% aqueous solution is isotonic with serum (Hassan et al, 1985).
    B) NALOXONE HYDROCHLORIDE is a white to slightly off-white powder that is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; and practically insoluble in ether and in chloroform (Prod Info NARCAN(R) nasal spray, 2015; Prod Info EVZIO(TM) injection solution, 2014).

Ph

    A) NALOXONE: 3 to 4.5 (aqueous solution) (Hassan et al, 1985).
    B) NALOXONE HYDROCHLORIDE: 3.5 to 5.5 (intranasal) (Prod Info NARCAN(R) nasal spray, 2015); 3 to 6.5 (generic injection) (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008); 3 to 4.5 (Evzio(TM)) (Prod Info EVZIO(TM) injection solution, 2014).

Molecular Weight

    A) NALOXONE: 327.41 (RTECS , 2001).
    B) NALOXONE HYDROCHLORIDE: 363.84 (Prod Info NARCAN(R) nasal spray, 2015; Prod Info EVZIO(TM) injection solution, 2014).

References

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