Naloxone Hydrochloride

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Overview

What is Naloxone Hydrochloride?

Naloxone, an opioid antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group.

Naloxone hydrochloride, USP is chemically designated 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (CHNO • HCl), a white to slightly off-white powder soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and chloroform. It has a molecular weight of 363.84. It has the following structural formula:

Naloxone hydrochloride injection is a sterile, nonpyrogenic solution of naloxone hydrochloride in water for injection. Each milliliter (mL) contains 0.4 mg naloxone hydrochloride and sodium chloride to adjust tonicity in water for injection. May contain hydrochloric acid for pH adjustment; pH 4 (3 to 6.5).

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously.

The multiple-dose solution contains, in addition, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives.

What does Naloxone Hydrochloride look like?

What are the available doses of Naloxone Hydrochloride?

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What should I talk to my health care provider before I take Naloxone Hydrochloride?

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How should I use Naloxone Hydrochloride?

Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids including propoxyphene, methadone, and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol and cyclazocine. Naloxone hydrochloride injection is also indicated for diagnosis of suspected or known acute opioid overdosage.

Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see ).

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is recommended in emergency situations.

Since the duration of action of some opioids may exceed that of naloxone, the patient should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary.

What interacts with Naloxone Hydrochloride?

Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the formulation.

What are the warnings of Naloxone Hydrochloride?

Drug Dependence

Naloxone hydrochloride injection should be administered cautiously to persons, including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes.

Repeat Administration

The patient who has satisfactorily responded to naloxone should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone.

Respiratory Depression Due to Other Drugs

Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.

What are the precautions of Naloxone Hydrochloride?

General

In addition to naloxone, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning.

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (seeand ).

Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

Drug Interactions

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to assess the carcinogenic potential of naloxone have not been conducted. Naloxone was weakly positive in the Ames mutagenicity and in the human lymphocyte chromosome aberration test but was negative in the Chinese hamster V79 cell HGPRT mutagenicity assay and in the rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4 times and 8 times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m), demonstrated no embryotoxic or teratogenic effects due to naloxone.

Use in Pregnancy

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Teratology studies conducted in mice and rats at doses 4 times and 8 times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m), demonstrated no embryotoxic or teratogenic effects due to naloxone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed.

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Risk-benefit must be considered before naloxone is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur.

Use in Labor and Delivery

It is not known if naloxone hydrochloride injection affects the duration of labor and/or delivery. However, published reports indicated that the administration of naloxone during labor did not adversely affect maternal or neonatal status.

Nursing Mothers

It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a nursing woman.

Pediatric Use

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

When naloxone hydrochloride injection is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride injection directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use.

The safety and effectiveness of naloxone hydrochloride injection in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use

Clinical studies of naloxone hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Insufficiency/Failure

The safety and effectiveness of naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to this patient population.

Liver Disease

The safety and effectiveness of naloxone hydrochloride injection in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to patients with liver disease.

What are the side effects of Naloxone Hydrochloride?

Postoperative

The following adverse events have been associated with the use of naloxone hydrochloride injection in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see and ).

Opioid Depression

Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see ).

Opioid Dependence

Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but not limited to, the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes (see ).

Adverse events associated with the postoperative use of naloxone hydrochloride injection are listed by organ system and in decreasing order of frequency as follows:

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See also and .

What should I look out for while using Naloxone Hydrochloride?

Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the formulation.

What might happen if I take too much Naloxone Hydrochloride?

There is limited clinical experience with naloxone hydrochloride injection overdosage in humans.

How should I store and handle Naloxone Hydrochloride?

Store at 20˚ to 25˚C (68˚ to 77˚F)Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2Naloxone Hydrochloride Injection, USP is supplied in the following:NDC 67457-299-10carton containing ten multiple-dose vials, 4 mg/10 mL (0.4 mg/mL)Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Store in carton until contents have been used.Manufactured for: Rockford, IL 61103 U.S.A.Manufactured by: Galway, Ireland1017L100Revised: 1/2018MI:NALOIJM:R2

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, naloxone can reverse the psychotomimetic and dysphoric effects of agonist-antagonists, such as pentazocine.

Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the “agonistic” or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.

Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of opioid dependence.

While the mechanism of action of naloxone is not fully understood, evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.

Non-Clinical Toxicology

Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the formulation.

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

In addition to naloxone, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning.

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (seeand ).

Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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