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Naloxone

PubChem CID
5284596
Structure
Naloxone_small.png
Naloxone_3D_Structure.png
Molecular Formula
Synonyms
  • naloxone
  • 465-65-6
  • l-Naloxone
  • n-Allylnoroxymorphone
  • (-)-Naloxone
Molecular Weight
327.4 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-11
Description
Naloxone is a synthetic morphinane alkaloid that is morphinone in which the enone double bond has been reduced to a single bond, the hydrogen at position 14 has been replaced by a hydroxy group, and the methyl group attached to the nitrogen has been replaced by an allyl group. A specific opioid antagonist, it is used (commonly as its hydrochloride salt) to reverse the effects of opioids, both following their use of opioids during surgery and in cases of known or suspected opioid overdose. It has a role as a mu-opioid receptor antagonist, a central nervous system depressant and an antidote to opioid poisoning. It is an organic heteropentacyclic compound, a morphinane alkaloid and a tertiary alcohol. It is a conjugate base of a naloxone(1+). It derives from a hydride of a morphinan.
Naloxone is an opioid antagonist medication used to block or reverse the effects of opioid drugs, particularly within the setting of drug overdoses which are rapidly becoming a leading cause of death worldwide. More specifically, naloxone has a high affinity for μ-opioid receptors, where it acts as an inverse agonist, causing the rapid removal of any other drugs bound to these receptors. When taken in large quantities, opioid medications such as [morphine], [hydromorphone], [methadone], [heroin], or [fentanyl] are capable of causing life-threatening symptoms such as respiratory depression, reduced heart rate, slurred speech, drowsiness, and constricted pupils. If untreated, this can progress to vomiting, absent pulse and breathing, loss of consciousness, and even death. Naloxone is indicated for the rapid reversal of these symptoms of central nervous system depression in opioid overdose. It's important to note that naloxone only works on opioid receptors within the body, and is therefore not capable of reversing the effects of non-opioid medications such as stimulants like [methamphetamine] or [cocaine], or benzodiazepines like [lorazepam] or [diazepam]. Also known as the brand name product Narcan, naloxone is currently available by intramuscular (IM) or subcutaneous (SubQ) injection, nasal spray, or intravenous (IV) infusion. Naloxone IM injections are commonly available in the form of "kits", which is ideal for making overdose treatment accessible and readily available for administration by minimally trained individuals within the community. Kits commonly include the supplies necessary to treat an overdose in a non-medical setting such as alcohol swabs, syringes, a rescue breathing mask, and instructions for use. Frequently also carried by medical and emergency personnel and at events known to be associated with heavy drug use like music festivals, naloxone kits are considered a key component of harm reduction strategies. There are over-the-counter nasal sprays available. When injected intramuscularly (IM), naloxone acts within three to five minutes. Administration of naloxone is associated with very few side effects. Notably, if injected into a person not currently using opioid medications, there would be no noticeable effects at all. However, for individuals using opioid medications or experiencing an overdose, IM injection of naloxone rapidly reverses opioid effects and can cause the injected individual to immediately experience withdrawal symptoms. Common symptoms of opioid withdrawal include nausea, vomiting, sweating, runny nose, aches, and diarrhea. Although certainly physically uncomfortable, opioid withdrawal symptoms are not life-threatening; administration of naloxone is, therefore, appropriate for any person appearing to have any symptoms of an opioid overdose. Due to its short duration of action, persons injected with naloxone should be monitored for responsiveness and potentially injected a second time or taken to the hospital. Naloxone is also available within the combination product Suboxone with the opioid medication [buprenorphine]. Suboxone is used for the maintenance treatment of opioid dependence and addiction. When taken orally, naloxone has no pharmacological effect and does not reduce the effectiveness of the opioid effect of buprenorphine. The primary purpose of including naloxone within Suboxone is to act as a deterrent to injection, as injected naloxone would rapidly reverse the effects of buprenorphine. Naloxone was granted FDA approval on 13 April 1971.
Naloxone is an Opioid Antagonist. The mechanism of action of naloxone is as an Opioid Antagonist.
See also: Naloxone Hydrochloride (has salt form); Naloxone hydrochloride dihydrate (is active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Naloxone.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

UZHSEJADLWPNLE-GRGSLBFTSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

C=CCN1CC[C@]23[C@@H]4C(=O)CC[C@]2([C@H]1CC5=C3C(=C(C=C5)O)O4)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C19H21NO4
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

465-65-6

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Abello, Naloxone
  • Curamed, Naloxon
  • Dihydride, Naloxone Hydrochloride
  • Hydrobromide, Naloxone
  • Hydrochloride Dihydride, Naloxone
  • Hydrochloride, Naloxone
  • MRZ 2593
  • MRZ 2593 Br
  • MRZ 2593-Br
  • MRZ 2593Br
  • MRZ-2593
  • MRZ2593
  • Nalone
  • Naloxon Curamed
  • Naloxon ratiopharm
  • Naloxon-ratiopharm
  • Naloxone
  • Naloxone Abello
  • Naloxone Hydrobromide
  • Naloxone Hydrochloride
  • Naloxone Hydrochloride Dihydride
  • Naloxone Hydrochloride, (5 beta,9 alpha,13 alpha,14 alpha)-Isomer
  • Naloxone, (5 beta,9 alpha,13 alpha,14 alpha)-Isomer
  • Narcan
  • Narcanti

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
327.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3
Property Value
2.1
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
327.14705815 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
327.14705815 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
70 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
24
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
594
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
4
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Crystals from ethyl acetate
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 3-402

3.2.3 Melting Point

177 °C
International Pharmacopoeia
178 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 3-402
MP: 184 °C (Lewistein), 177-178 °C (Sankyo Co)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1185
Crystals from ethanol and ether. Soluble in water, dilute acids, stong alkali; slightly soluble in alcohol; practically insoluble in ether, chloroform. MP: 200-205 °C /Naloxone hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1185
200 - 205 °C

3.2.4 Solubility

Soluble
FDA Label
Soluble in chloroform; practically insoluble in petroleum ether
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1185
5.64e+00 g/L

3.2.5 LogP

2.09
HANSCH,C ET AL. (1995)
log Kow = 2.09
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 162
0.6

3.2.6 Optical Rotation

Specific optical rotation: -194.5 deg at 20 °C/D (c = 0.93 in HCl)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1185

3.2.7 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592

3.2.8 Dissociation Constants

Basic pKa
7.94
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
At 20 °C: pKa1 (for the proton on the nitrogen) = 7.94; pKa2 (for the phenolic hydrogen) = 9.44 /Naloxone hydrochloridel/
Kaufman JJ et al; J Med Chem 18: 647-55 (1976)

3.2.9 Collision Cross Section

171.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

177 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

166.12 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

169.33 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
173 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

3.2.10 Other Experimental Properties

Soluble in water, dilute acids and in strong alkali /Naloxone hydrochloride/
Thomson Health Care Inc.; Physicians' Desk Reference 63 ed., Montvale, NJ 2009, p. 2601
FORM: SLIGHTLY OFF-WHITE /HYDROCHLORIDE/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1043

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Narcotic Antagonists
Human drug -> Prescription; Discontinued
Human drug -> Over-the-counter; Discontinued
Human drugs -> All other therapeutic products -> Human pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664
Antidotes and other substances used in poisonings > Specific

3.3.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
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2 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
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4.2.2 MS-MS

1 of 5
View All
Spectra ID
Instrument Type
LC-ESI-qTof
Ionization Mode
Positive
Top 5 Peaks

171.08107 38336

172.084396 2996

128.06189 1556

228.113098 820

156.057419 816

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Notes
From GNPS Library
2 of 5
View All
Spectra ID
Ionization Mode
positive
Top 5 Peaks

328.156586 100

310.144501 43.25

329.158752 20.11

253.109604 9.93

311.146881 8.12

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Notes
instrument=qTof

4.2.3 LC-MS

1 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
328.1551
Instrument
Agilent 6530 Q-TOF
Instrument Type
LC-ESI-QTOF
Ionization Mode
positive
Collision Energy
10 V
Retention Time
2.2935
Top 5 Peaks

328.1555 100

310.1450 30.13

253.1103 1.01

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2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
328.1551
Instrument
Agilent 6530 Q-TOF
Instrument Type
LC-ESI-QTOF
Ionization Mode
positive
Collision Energy
20 V
Retention Time
2.2935
Top 5 Peaks

310.1434 100

328.1541 34.53

253.1094 11.29

268.1333 7.26

269.1162 4.38

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4.2.4 Other MS

1 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
Other
Precursor Type
[M+Na]+
Top 5 Peaks

91.05385049003485 0.14

77.03663749003485 0.09

115.05244349003485 0.06

65.03781849003484 0.05

308.09160931777086 0.04

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2 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
Other
Precursor Type
[M+H]+
Top 5 Peaks

140.05770428255178 9.82

225.05629886216207 9.72

219.11312316056228 9.62

308.10349638805997 9.52

262.089614834573 9.21

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4.3 Other Spectra

Intense mass spectral peaks: 242 m/z, 286 m/z, 327 m/z
Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 575

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Naloxone nasal sprays are indicated for the reversal of an opioid overdose or suspected opioid overdose: it is intended for immediate administration as emergency therapy in settings where opioids may be present. Intramuscular, intravenous, and subcutaneous injections are indicated for complete or partial reversal of opioid depression, diagnosis of known or suspected opioid overdose, and as an adjunct therapy in the treatment of septic shock. Sublingual tablets and films are formulated with [buprenorphine] for the treatment of opioid dependence. Naloxone is also formulated with [pentazocine] as an oral tablet for severe pain. Intramuscular or subcutaneous naloxone autoinjectors are used for the emergency treatment of people 12 years of age and older where the use of high-potency opioids such as fentanyl analogues as a chemical weapon, is suspected. Naloxone has been used off-label for the treatment of neuraxial opioid-induced pruritus.
Nyxoid is intended for immediate administration as emergency therapy for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression in both non-medical and healthcare settings. Nyxoid is indicated in adults and adolescents aged 14 years and over. Nyxoid is not a substitute for emergency medical care.

7.2 LiverTox Summary

Naloxone is an opiate antagonist which is used intravenously in emergency situations to reverse the respiratory depression caused by overdoses of heroin, morphine or other opioids. Naloxone has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Narcotic Antagonists
Opioid Antagonists

7.4 WHO Essential Medicines

Drug
Drug Classes
Antidotes and other substances used in poisonings > Specific
Formulation
Parenteral - General injections - unspecified: 400 µg per 1 mL in ampoule (naloxone hydrochloride)
Indication
Unintentional exposure to or harmful effects of opioids or related analgesics

7.5 FDA National Drug Code Directory

7.6 Drug Labels

Drug and label
Active ingredient and drug

7.7 Clinical Trials

7.7.1 ClinicalTrials.gov

7.7.2 EU Clinical Trials Register

7.7.3 NIPH Clinical Trials Search of Japan

7.8 EMA Drug Information

Medicine
Category
Human drugs
Therapeutic area
Opioid-Related Disorders
INN/Common name
naloxone
Pharmacotherapeutic Classes
All other therapeutic products
Status
This medicine is authorized for use in the European Union
Company
Mundipharma Corporation (Ireland) Limited
Market Date
2017-11-09

7.9 Therapeutic Uses

Narcotic Antagonists
National Library of Medicine's Medical Subject Headings. Naloxone. Online file (MeSH, 2016). Available from, as of January 20, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Naloxone is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of March 17, 2016: https://clinicaltrials.gov/ct2/results?term=naloxone&Search=Search
Naloxone Hydrochloride Injection, USP 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, USP is also indicated for diagnosis of suspected or known acute opioid overdosage. /Included in US product label/
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae
Naloxone Hydrochloride Injection, USP may be useful as an adjunctive agent to increase blood pressure in the management of septic shock. /Included in US product label/
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae
For more Therapeutic Uses (Complete) data for NALOXONE (14 total), please visit the HSDB record page.

7.10 Drug Warnings

Nausea and vomiting have been reported rarely in postoperative patients who were receiving a parenteral dose of naloxone hydrochloride greater than that usually recommended; however, a causal relationship has not been established. Tremor and hyperventilation associated with an abrupt return to consciousness has occurred in some patients receiving naloxone for opiate overdosage.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2183
Although a causal relationship to the drug has not been established, severe cardiopulmonary effects (eg, hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have been reported in patients following postoperative administration of naloxone hydrochloride. Adverse cardiopulmonary effects have occurred most frequently in postoperative patients with preexisting cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2183
Seizures have occurred rarely following administration of naloxone hydrochloride; however, a causal relationship to the drug has not been established.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2183
When high oral doses of naloxone have been used in the treatment of opiate addiction, some patients have experienced mental depression, apathy, inability to concentrate, sleepiness, irritability, anorexia, nausea, and vomiting. These adverse effects usually occurred in the first few days of treatment and abated rapidly with continued therapy or dosage reduction. One case of erythema multiforme cleared promptly after naloxone was discontinued.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2183
For more Drug Warnings (Complete) data for NALOXONE (23 total), please visit the HSDB record page.

7.11 Drug Tolerance

Tolerance to the opioid antagonist effect of naloxone is not known to occur.
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Naloxone is an opioid receptor antagonist indicated in the reversal of opioid overdoses. Naloxone has a shorter duration of action than opioids and multiple doses may be required. The therapeutic window of naloxone is wide, as it has no effect if a patient has not taken opioids. Patients treated with naloxone may experience opioid withdrawal and a person administering naloxone should be aware that reversal of opioid overdoses may not resolve all the symptoms a patient is experiencing if other drugs are involved.

8.2 MeSH Pharmacological Classification

Narcotic Antagonists
Agents inhibiting the effect of narcotics on the central nervous system. (See all compounds classified as Narcotic Antagonists.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
36B82AMQ7N
Active Moiety
NALOXONE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Opioid Antagonist
Pharmacological Classes
Mechanisms of Action [MoA] - Opioid Antagonists
FDA Pharmacology Summary
Naloxone is an Opioid Antagonist. The mechanism of action of naloxone is as an Opioid Antagonist.
2 of 2
Non-Proprietary Name
NALOXONE
Pharmacological Classes
Opioid Antagonists [MoA]; Opioid Antagonist [EPC]

8.4 ATC Code

V03AB15
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

A - Alimentary tract and metabolism

A06 - Drugs for constipation

A06A - Drugs for constipation

A06AH - Peripheral opioid receptor antagonists

A06AH04 - Naloxone

V - Various

V03 - All other therapeutic products

V03A - All other therapeutic products

V03AB - Antidotes

V03AB15 - Naloxone

8.5 Absorption, Distribution and Excretion

Absorption
An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a Cmax of 12.3-12.8 ng/mL, with a Tmax of 0.25 hours, and an AUC of 16.7-19.0 h\*ng/mL. A 0.4 mg intramuscular dose reaches a Cmax of 0.876-0.910 ng/mL, with a Tmax of 0.25 hours, and an AUC of 1.94-1.95 h\*ng/mL. A 2 mg intravenous dose reaches a Cmax of 26.2 ng/mL with an AUC of 12.8 h\*ng/mL.
Route of Elimination
After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours. The metabolites naloxone-3-glucuronide, noroxymorphone, and naloxol are all detected in the urine.
Volume of Distribution
The volume of distribution of naloxone is 200 L. Naloxone distributes into tissues rapidly. It can also cross the placenta and blood-brain barrier.
Clearance
The clearance of naloxone is 2500 L/day.
Naloxone is distributed rapidly throughout the body with high levels found in the brain, kidneys, spleen, skeletal muscle, lung, and heart. The drug also readily crosses the placenta.
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 1031
Naloxone is only minimally absorbed when given orally as it is rapidly destroyed in the GI tract. Much higher doses are required if using this route of administration for any pharmacologic effect. When given IV, naloxone has a very rapid onset of action (usually 1-2 minutes). If given IM, the drug generally has an onset of action with 5 minutes of administration. The duration of action usually persists from 45-90 minutes, but may act for up to 3 hours.
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 1031
Naloxone is rapidly inactivated following oral administration. Although the drug is effective orally, doses much larger than those required for parenteral administration are required for complete antagonism. In one study, a single 3-g oral dose of naloxone hydrochloride was required to effectively antagonize the effects of 50 mg of heroin for 24 hours. Naloxone has an onset of action within 1-2 minutes following iv administration and within 2-5 minutes following subcutaneous or im administration. The duration of action depends on the dose and route of administration and is more prolonged following im administration than after iv administration.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
Following administration of 35 or 70 ug of naloxone hydrochloride into the umbilical vein in neonates in one study, peak plasma naloxone concentrations occurred within 40 minutes and were 4-5.4 ng/mL and 9.2-20.2 ng/mL, respectively. After im administration of 0.2 mg to neonates in the same study, peak plasma naloxone concentrations of 11.3-34.7 ng/mL occurred within 0.5-2 hours.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
For more Absorption, Distribution and Excretion (Complete) data for NALOXONE (14 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Naloxone primarily undergoes glucuronidation to form naloxone-3-glucuronide. Naloxone is also N-dealkylated to noroxymorphone or undergoes 6-keto reduction to naloxol.
Naloxone is rapidly metabolized in the liver, principally by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2185
Yields N-allyl-7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphinone in man; Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M, J Pharm Sci, 60, 1567 (1971). Yields naloxone-3-beta-d-glucuronide in man; Fujimoto, JM, J Pharmac Exp Ther, 168, 180(1969). /From table/
Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. N-1
... Oxidative N-deallylation, redn of 6-keto-group, and glucuronidation occur in man.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 189
... Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. ...
Misra AL et al; J Pharmacol Exp Ther 196 (2): 257-68 (1976)

8.7 Biological Half-Life

The mean half life of naloxone hydrochloride is 1.8-2.7 hours intranasally, 1.4 hours intramuscularly, and 1.2 hours intravenously. In neonates, the mean half life is 3.1 ± 0.5 hours.
The mean plasma half-life of naloxone was 1.28 hours following IM or subcutaneous injection of naloxone hydrochloride using an auto-injector, compared with 1.36 hours following IM or subcutaneous injection using a standard syringe.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
The half-life of naloxone has been reported to be 30-81 minutes in adults and about 3 hours in neonates.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
Plasma naloxone levels were determined by RIA over a period of 6--36 hr in three groups of neonates, (1) those given 35 microgram iv (n = 6), (2) those given 70 microgram iv (n = 6) and (3) those given 200 microgram im (n = 17) naloxone HCl within 1 min of birth. After intravenous administration of 35 and 70 microgram of naloxone peak levels of 4--15 ng/mL and 9--20 ng/mL respectively were reached in 5--40 min and the mean plasma half-life after both doses was 3.1 +/- 0.5 hr.
Moreland TA et al; Br J Clin Pharmacol 9 (6): 609-12 (1980).

8.8 Mechanism of Action

Naloxone is a competitive inhibitor of the µ-opioid receptor. Naloxone antagonizes the action of opioids, reversing their effects. If a patient has not taken opioids, naloxone does not have a significant effect on patients.
Naloxone hydrochloride is essentially a pure opiate antagonist. The precise mechanism of action of the opiate antagonist effects of naloxone is not fully understood. Naloxone is thought to act as a competitive antagonist at mu, kappa, and sigma opiate receptors in the CNS; it is thought that the drug has the highest affinity for the mu receptor. In contrast to levallorphan or nalorphine, naloxone has little or no agonistic activity. When administered in usual doses to patients who have not recently received opiates, naloxone exerts little or no pharmacologic effect. Even extremely high doses of the drug (10 times the usual therapeutic dose) produce insignificant analgesia, only slight drowsiness, and no respiratory depression, psychotomimetic effects, circulatory changes, or miosis.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
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. There is an increase in respiratory rate and minute volume, arterial PCO2 decreases toward normal, and blood pressure returns to normal if depressed. Unlike nalorphine or levallorphan, naloxone antagonizes mild respiratory depression caused by small doses of opiates. 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. Naloxone antagonizes opiate-induced sedation or sleep. Reports are conflicting on whether or not the drug modifies opiate-induced excitement or seizures.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
Heat shock protein (HSP)60 is primarily a mitochondrial protein. Previous experiments have found that changes in the location of intracellular HSP60 have been associated with apoptosis. Extracellular HSP60 mediates apoptosis via its ligand, Toll-like receptor (TLR)-4. TLR-4 is an important factor expressed on microglia, with a central role in generating neuroimmune responses in the pathogenesis of neurodegenerative disorders. Naloxone is a highly effective nonselective opioid receptor antagonist, and has been reported to be pharmacologically beneficial for the treatment of brain diseases through inhibiting microglia activation. However, the mechanisms underlying these beneficial effects of naloxone remain poorly understood. The present study aimed to investigate the role of HSP60 in the neuroprotective effects of naloxone on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells and the possible signaling pathways involved. The results demonstrated that naloxone significantly inhibited the expression and release of HSP60 in BV2 cells. The expression levels of heat shock factor (HSF)-1 were upregulated in LPS-activated BV2 cells, which indicated that the increased expression of HSP60 was driven by HSF-1 activation. However, increased HSF-1 levels may be downregulated by naloxone. The levels of TLR-4 were elevated in activated BV2 cells, and then inhibited by naloxone. Activation of TLR-4 is characterized by activation of nuclear factor-kB (NF-kB) followed by the production of various proinflammatory and neurotoxic factors. Data from the present study demonstrated that naloxone reduced the expression levels of NF-kB and its upstream protein caspase-3, and reduced the LPS-induced production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor a, interleukin-1beta and interleukin-6 in BV2 microglia. In light of this data, it was concluded that naloxone may exert its neuroprotective and anti-inflammatory effects by inhibiting microglia activation through a HSP60-TLR-4-NF-kB signaling pathway.
Cheng W et al; Mol Med Rep 10 (4): 2172-6 (2014)
Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110delta and p110gamma isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kdelta and PI3Kgamma in mediating the anti-inflammation effects of naloxone. MATERIALS AND METHODS: Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kdelta inhibitor IC87114, the PI3Kgamma inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-kB (NF-kB) activation and Akt activation (indicator of PI3K activity) among these groups were compared. The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-alpha, interleukin-1beta, andd cyclooxygenase-2/prostaglandin E2) and the levels of NF-kB activation (p-NF-kB p65 and p-inhibitor-kB concentrations and NF-kB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kdelta and PI3Kgamma, as the concentrations of inflammatory molecules and the levels of NF-?B activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). PI3Kdelta and PI3Kgamma play crucial roles in mediating the anti-inflammation effects of naloxone.
Wang TY et al; J Surg Res 192 (2): 599-606 (2014)
For more Mechanism of Action (Complete) data for NALOXONE (7 total), please visit the HSDB record page.

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Cytoplasm
  • Membrane

8.9.2 Metabolite Pathways

9 Use and Manufacturing

9.1 Uses

MEDICATION
MEDICATION (VET)
Narcotic Antagonists
National Library of Medicine's Medical Subject Headings. Naloxone. Online file (MeSH, 2016). Available from, as of January 20, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html

Use (kg; approx.) in Germany (2009): >2500

Consumption (g per capita; approx.) in Germany (2009): 0.0305

Excretion rate: 0.5

Calculated removal (%): 2.3

9.1.1 Use Classification

Human drugs -> All other therapeutic products -> Human pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Friderichs E et al; Analgesics, Centrally Acting. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2016). NY, NY: John Wiley & Sons. Online Posting Date: October 15, 2011
Oxymorphone is demethylated and resulting 4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one is n-allylated by reaction in ethanol with allyl bromide in presence of NaHCO3. Resulting naloxone is reacted with ethanolic hydrochloride. US Patent 3,254,088. /Naloxone hydrochloride/
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1529

9.3 Impurities

3-O-allylnaloxone
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5064 (2006)
10alpha-hydroxynaloxone
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5064 (2006)
10beta-hydroxynaloxone
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5064 (2006)
2,2'-binaloxone
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5064 (2006)
For more Impurities (Complete) data for NALOXONE (7 total), please visit the HSDB record page.

9.4 Formulations / Preparations

Oral: Tablets: Pentazocine hydrochloride 50 mg (of pentazocine) and Naloxone hydrochloride 0.5 mg (of naloxone); Pentazocine and Naloxone Hydrochloride Tablets, C-IV (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2185
Table: Naloxone Hydrochloride Preparations
Route of Administration
Parenteral
Dosage Form
Injection
Strength
0.4 mg/mL
Brand or Generic Form (Manufacturer)
Naloxone Hydrochloride Injection (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Parenteral
Dosage Form
Injection
Strength
1 mg/mL
Brand or Generic Form (Manufacturer)
Enzio, available as kit with 2 prefilled, single-use 0.4 mL auto-injectors and 1 drug-free, needleless, reusable training device (Keleo)
Route of Administration
Parenteral
Dosage Form
Injection
Strength
1 mg/mL
Brand or Generic Form (Manufacturer)
Naloxone Hydrochloride Injection (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2185
Table: Naloxone Hydrochloride DihydrateCombinations Preparations
Route of Administration
Sublingual
Dosage Form
Strips, sublingually dissolving
Strength
0.5 mg (of naloxone) with Buprenorphine Hydrochloride 2 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Suboxone, C-III (Reckitt Benckiser)
Route of Administration
Sublingual
Dosage Form
Strips, sublingually dissolving
Strength
1 mg (of naloxone) with Buprenorphine Hydrochloride 4 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Suboxone, C-III (Reckitt Benckiser)
Route of Administration
Sublingual
Dosage Form
Strips, sublingually dissolving
Strength
2 mg (of naloxone) with Buprenorphine Hydrochloride 8 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Suboxone, C-III (Reckitt Benckiser)
Route of Administration
Sublingual
Dosage Form
Strips, sublingually dissolving
Strength
3 mg (of naloxone) with Buprenorphine Hydrochloride 12 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Suboxone, C-III (Reckitt Benckiser)
Route of Administration
Sublingual
Dosage Form
Tablets
Strength
0.5 mg (of naloxone) with Buprenorphine Hydrochloride 2 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets, C-III (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Sublingual
Dosage Form
Tablets
Strength
2 mg (of naloxone) with Buprenorphine Hydrochloride 8 mg (of buprenorphine)
Brand or Generic Form (Manufacturer)
Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets, C-III (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2185
Naloxone is available in injectable vials with preservatives in 0.4 or 1 mg/mL, without preservatives in 0.02 mg (20 ug) 0.4 mg or 1 mg per mL, as Trexonil in 50 mg/mL.
Papich, M.G. Saunders Handbook of Veterinary Drugs Small and Large Animal. 3rd ed. St. Louis, MO: Elsevier Saunders, 2011, p. 533

9.5 General Manufacturing Information

Incompatibilities - physical: long-chain or high-mol wt anions (forms relatively insol salts) and with alkaline soln (base PPT if concn is high enough); however, injection is compatible with bulk in soln that are slightly alkaline. Chemical: oxygen, oxidizing agents, bisulfites, and metabisulfites. /Naloxone hydrochloride/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1043
Naloxone is an antagonist at the mu-opioid receptor
Thomson Health Care Inc.; Physicians' Desk Reference 63 ed., Montvale, NJ 2009, p. 2601

10 Identification

10.1 Analytic Laboratory Methods

Analyte: naloxone hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Naloxone hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2752 (2008)
Analyte: naloxone hydrochloride; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with ultraviolet detection at 229 nm and comparison to standards (chemical purity) /Naloxone hydrochloride/
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5063 (2006)
Analyte: naloxone hydrochloride dihydrate; matrix: chemical identification; procedure: thin-layer chromatography with comparison to standards /Naloxone hydrochloride dihydrate/
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5063 (2006)
Analyte: naloxone hydrochloride dihydrate; matrix: chemical purity; procedure: dissolution in ethanol; addition of hydrochloric acid; potentiometric titration with ethanolic sodium hydroxide /Naloxone hydrochloride dihydrate/
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5064 (2006)

10.2 Clinical Laboratory Methods

Analyte: naloxone hydrochloride; matrix: pharmaceutical preparation (injection solution); procedure: retention time of the major peak of the liquid chromatogram with comparison to standards (chemical identification) /Naloxone hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2753 (2008)
Analyte: naloxone hydrochloride; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with ultraviolet detection at 229 nm and comparison to standards (chemical purity) /Naloxone hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2753 (2008)
Analyte: naloxone; matrix: blood (whole); procedure: high-performance liquid chromatography with ultraviolet detection at 230 nm; limit of detection: 0.30 ppm
Bernal JL et al; Chromatographia 38: 617-23 (1994). As cited in Lunn G; HPLC and CE methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: naloxone; matrix: blood (plasma); procedure: high-performance liquid chromatography with electrochemical detection; limit of detection: 1 ng/mL
Reid RW et al; J Chromatogr 614: 117-22 (1993). As cited in Lunn G; HPLC and CE methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: naloxone; matrix: blood (plasma); procedure: high-performance liquid chromatography with mass spectrometry detection
Selenka JM; Talaat RE; Pharm Res 13: S60 (1996). As cited in Lunn G; HPLC and CE methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (89.1%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (87%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (87%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 46 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (100%)

Skin Irrit. 2 (89.1%)

Eye Irrit. 2 (87%)

STOT SE 3 (87%)

11.2 Accidental Release Measures

11.2.1 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

11.3 Handling and Storage

11.3.1 Storage Conditions

Store at 20 deg to 25 °C (68 deg to 77 °F). Protect from light. Store in carton until contents have been used.
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae

11.4 Regulatory Information

REACH Registered Substance

11.4.1 FDA Requirements

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Naloxone hydrochloride is included on this list. /Naloxone hydrochloride/
US FDA/Center for Veterinary Medicine; The Green Book - On Line, Active Ingredients. Naloxone Hydrochloride (357-08-4). Available from, as of March 23, 2016: https://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/default.htm
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naloxone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naloxone hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 23, 2016: https://www.fda.gov/cder/ob/

11.5 Other Safety Information

Chemical Assessment

IMAP assessments - Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-,(5.alpha.)-: Environment tier I assessment

IMAP assessments - Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-,(5.alpha.)-: Human health tier I assessment

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Naloxone is composed of crystals. Naloxone hydrochloride is used for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids (both human and veterinary cases). It may also be useful as an adjunctive agent to increase blood pressure in the management of septic shock. A formulation for wildlife use (Trexonil) is more concentrated and used to reverse tranquilization in wild animals. HUMAN EXPOSURE AND SYMPTOMS: Adverse effects associated with naloxone use have included seizures, severe hypertension, and hypotension and/or bradycardia. A total of 1.2 mg administered intravenously as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 minutes respectively to nonaddicts caused miosis, decreased core temperature, and systolic blood pressure. Naloxone-induced acute pulmonary edema is an extremely rare but lethal complication. Endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists such as naloxone must be administered with caution to these individuals. Moderate increases in respiratory rate, heart rate, and blood pressure occur after naloxone administration to children, but development of more serious complications is rare. Naloxone was weakly positive in the in vitro human lymphocyte chromosome aberration test. Naloxone may affect some functions of the immune system in humans, but its action is transient. ANIMAL STUDIES: The injection of naloxone into the medial septal nucleus of rats produced a marked increase in hippocampal ACh release in a dose-dependent manner. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection. Administration of naloxone to rats from day 17 of pregnancy significantly increased neonatal death. Body weight increase was slightly retarded by administration of naloxone. Naloxone was weakly positive in the Ames mutagenicity test and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and the in vivo rat bone marrow chromosome aberration study.

12.1.2 Hepatotoxicity

Therapy with naloxone has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with naloxone does not appear to exacerbate those conditions. Naloxone is extensively metabolized in the liver, but largely by conjugation with glucuronide followed by its urinary excretion.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Drug Class: Opioid Antagonists; see also Substance Abuse Treatment Agents

Other Drugs in the Class: Nalmefene; Naloxegol, Naltrexone

12.1.3 Drug Induced Liver Injury

Compound
naloxone
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Naloxone is excreted into milk in very small amounts and is not detectable in the plasma of breastfed infants because of its very poor oral bioavailability. Routine use of naloxone in combination products is of no concern during breastfeeding. However, if naloxone is required by the mother for an opioid overdose, she should withhold nursing until the opioid is out of her system.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

In contrast to its effect in some animal species, naloxone does not affect suckling-induced secretion of oxytocin or prolactin in postpartum women.

◈ What is naloxone?

Naloxone is a medication used to block the effects of opioids. Examples of some opioids are heroin, morphine, codeine, oxycodone, and hydrocodone. Naloxone has also been used to stop someone from dying from an opioid overdose. Brand names for naloxone are Narcan® (nasal spray) and Evzio® (auto-injector).Naloxone combined with buprenorphine (https://mothertobaby.org/fact-sheets/buprenorphine/) is a medication whose brand name is Suboxone®. This combination drug is used to treat opioid use disorder (“OUD”). Much of the information on naloxone in pregnancy involves studies where this combination of medication (naloxone and buprenorphine) was used rather than the study of naloxone used on its own.Naloxone is added to the opioid pain medication pentazocine (Talwin NX®) to prevent pentazocine abuse.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I take naloxone. Can it make it harder for me to get pregnant?

Studies have not been done to see if taking naloxone can make it harder for to get pregnant.

◈ Does taking naloxone increase the chance for miscarriage?

Miscarriage can occur in any pregnancy. There is limited information on naloxone and pregnancy loss. One study found that there was not a greater chance for a stillbirth in pregnancies in which naloxone was used. Overdosing with an opioid might increase the chances for pregnancy loss.

◈ Does taking naloxone increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Very little naloxone from buprenorphine/naloxone gets into the blood when it is taken by mouth. This suggests that only very small amounts of naloxone would be likely to reach the developing baby. There are limited studies on the use of buprenorphine/naloxone combination during their first trimester; these studies did not find an increased chance of birth defects above the background risk in their babies.No studies have been done to see if treatment with naloxone for an opioid overdose in the first trimester can increase the chance for birth defects.

◈ Does taking naloxone in pregnancy increase the chance of other pregnancy related problems?

Studies on the combination buprenorphine/naloxone did not find an increased chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).

◈ Could being treated with naloxone for an overdose cause other pregnancy complications?

Studies have not been done to see if naloxone causes pregnancy complications when it is used to treat an overdose. However, people who misuse opioids could have a greater chance for pregnancy complications. During an opioid overdose a person’s breathing slows down. If a person who is pregnant is not breathing well, the developing baby might not get enough oxygen during that time. Low oxygen might have a harmful effect on the baby’s development. Naloxone helps return breathing to normal. Naloxone can also cause symptoms of withdrawal from the opiod that was being misued. The effects of opioid withdrawal while pregnant are not well understood. After treatment with naloxone for opioid overdose, let your healthcare providers know about it as soon as possible.

◈ Does taking naloxone in pregnancy affect future behavior or learning for the child?

Studies have not been done to see if naloxone can cause behavior or learning issues for the child.

◈ Breastfeeding while taking naloxone:

It is not known if naloxone gets into breastmilk in significant amounts. But if naloxone does get into breastmilk, it is thought that a nursing baby would not be able to absorb it into their body very well from their stomach.If naloxone is used to treat opioid overdose, it may be suggested to stop breastfeeding until the opiate is out of the body of the person who is breastfeeding. If any opioids have been used while breastfeeding, it has been recommended to closely monitor the breastfeeding infant for side effects. If there is an opioid in breastmilk the baby might be sleepy, could have problems with feeding, and might have problems breathing. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

◈ If a male takes naloxone, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?

Studies have not been done to see if naloxone could affect male fertility or increase the chance of birth defects.In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

12.1.5 Acute Effects

12.1.6 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.
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 21, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae
The combined admin of flunitrazepam and naloxone to volunteers incr resp frequency and resp min vol but did not alter endexpired pCO2 pressure, resp inhalation vol, or alveolar ventilation when compared with naloxone treatment alone.
Schmitz et al; Anesthesiol Intensiv Med (Berlin) 130(25) 66 (1980)

12.1.7 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1

12.1.8 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ ... Clinical administration of the opiate receptor antagonist naloxone hydrochloride has had little or inconsistent behavioral effects in normals. This may be attributable to the use of doses insufficient to yield a complete endogenous opioid system (EOS) blockade. To assess this explanation, normals were administered increasing doses of naloxone hydrochloride (0.3 to 4 mg/kg) in a single-blind design. Significant dose-dependent behavioral, hormonal, and physiological effects were found. With increasing doses of naloxone, volunteers demonstrated increasingly dysphoric affects, a deterioration of performance on memory testing, increasing systolic BP and respiratory rate, and increasing plasma cortisol and growth hormone levels. These results are consistent with the expected effects of increasing EOS blockade, and thus suggest that lower doses of naloxone used in previous clinical studies may not have been sufficient to produce a complete EOS blockade. ...
Cohen MR et al; Arch Gen Psychiatry 40 (6): 613-9 (1983)
/HUMAN EXPOSURE STUDIES/ 1.2 mg administered iv as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 min respectively to nonaddict caused miosis, decr core temp, and systolic blood pressure. Hand tremor, resp, and heart rates unaffected. May possess slight opiate agonist properties. Interaction with endogenous opiate is possibility
Zilm DH; Neuropharmacology 19(7) 591 (1980)
/SIGNS AND SYMPTOMS/ In /a/ study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/sq m/min) of naloxone hydrochloride injection followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).
NIH; DailyMed. Current Medication Information for Naloxone Hydrochloride Injection (Updated: April 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-baec-49f35a887fae
/SIGNS AND SYMPTOMS/ Although a causal relationship to the drug has not been established, severe cardiopulmonary effects (eg, hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have been reported in patients following postoperative administration of naloxone hydrochloride. Adverse cardiopulmonary effects have occurred most frequently in postoperative patients with preexisting cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2183
For more Human Toxicity Excerpts (Complete) data for NALOXONE (24 total), please visit the HSDB record page.

12.1.9 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ The effects of injections of naloxone, a universal opioid receptor antagonist, into the medial septal nucleus on hippocampal acetylcholine (ACh) release and behavior were investigated in freely moving rats by means of the microdialysis method. The injection of naloxone (2, 10 and 20 micrograms) produced a marked increase in hippocampal ACh release in a dose-dependent manner. These effects of naloxone were reversed by the post-injection of [D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin (DAGO; 10 micrograms), an opioid mu receptor agonist. Furthermore, basal release of hippocampal ACh was significantly reduced by the injection of DAGO alone. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. ...
Mizuno T, Kimura F; Brain Res 713 (1-2): 1-7 (1996)
/LABORATORY ANIMALS: Acute Exposure/ Naloxone is an opioid receptor antagonist. Even when used in modest doses, it has been associated with serious cardiopulmonary side-effects. In this experimental porcine study, we examined the cardiac effects of naloxone during an opioid overdose. Cardiac parameters, changes in the left ventricular compliance and the magnitude of catecholamine release were evaluated in eight spontaneously breathing piglets under propofol sedation. Cardiac parameters were recorded every 30 s and transthoracic echocardiography was used for the continuous assessment of cardiac performance. Respiratory arrest was induced by morphine (8 mg/kg). Ten minutes after morphine administration, naloxone (80 ug/kg) was injected intravenously. Every 5 min, arterial blood gases were measured and, every 10 min, a sample for the analysis of plasma catecholamines was drawn. There were no statistically significant changes in left ventricular ejection fraction and no signs of pulmonary hypertension. There was a statistically significant increase in the mean arterial pressure immediately after naloxone administration and in norepinephrine concentration before naloxone administration. After naloxone administration, the plasma catecholamine levels decreased in all but one animal. Two animals developed cardiac arrest (pulseless electrical activity and ventricular fibrillation) shortly after receiving naloxone. Although they were both administered naloxone prematurely due to hypoxic bradycardia, naloxone could have contributed to the development of ventricular fibrillation. Naloxone did not cause changes in ejection fraction or mean pulmonary artery pressure in hypoxic and hypercarbic conditions. After naloxone administration, the plasma catecholamine levels returned to baseline in all but one animal, and two animals developed cardiac arrest.
Boyd JJ et al; Acta Anaesthesiol Scand 50 (10): 1271-6 (2006)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection: no toxic effects were seen at 10 mg/kg/day for 3 weeks.
US Natl Inst Health; DailyMed. Current Medication Information for Naloxone hydrochloride (naloxone hydrochloride) injection (April 2006). Available from, as of October 15, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=614
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... The goal of this work in the rat is to determine whether treatment with naloxone during the suckling period would influence the propagation of cortical spreading depression (CSD), both in weaned young and adult animals. From the 7th to the 28th postnatal day, male rat pups were treated daily with a single subcutaneous injection of either 10mg/kg/d naloxone (n=21 rats) or equivalent volume (10 mL/kg) of saline (n=16). In both treatment conditions, when the pups were 30-40 days- (young groups; 9 Naloxone- and 10 saline-treated rats), or 90-120-days old (adult groups; 12 Naloxone- and 6 saline-treated rats), a 4hr CSD recording session was performed with electrodes at two points at a fixed distance apart on the parietal cortical surface. CSD propagation velocity was calculated based on the time spent for a CSD-wave to pass between the electrodes. In both young- and adult groups, naloxone-treated animals displayed lower CSD velocities (P<0.05) than the corresponding saline injected animals. ...
Rocha-de-Melo AP et al; Neurosci Lett 441 (3): 315-8 (2008)
For more Non-Human Toxicity Excerpts (Complete) data for NALOXONE (8 total), please visit the HSDB record page.

12.1.10 Non-Human Toxicity Values

LD50 Mouse iv 90 mg/kg /Naloxone hydrochloride/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592
LD50 Rat iv 107 mg/kg /Naloxone hydrochloride/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592
LD50 Rat ip 239 mg/kg /Naloxone hydrochloride/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592
LD50 Rat sc 500 mg/kg /Naloxone hydrochloride/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592
LD50 Mouse sc 286 mg/kg /Naloxone hydrochloride/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2592

12.1.11 Ongoing Test Status

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 17, 2015: http://actor.epa.gov/dashboard/]

12.1.12 Populations at Special Risk

The half-life of naloxone has been reported to be 30-81 minutes in adults and about 3 hours in neonates.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
Naloxone should be used with caution in patients with preexisting cardiovascular disease or in those receiving potentially cardiotoxic drugs, since serious adverse cardiopulmonary effects (eg, ventricular tachycardia and fibrillation, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have occurred in postoperative patients following administration of naloxone ...
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184
Naloxone should be used with caution in patients with preexisting cardiovascular disease or in those receiving potentially cardiotoxic drugs, since serious adverse cardiopulmonary effects (eg, ventricular tachycardia and fibrillation, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have occurred in postoperative patients following administration of naloxone ... .
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2184

12.1.13 Protein Binding

Naloxone is approximately 45% bound to albumin, but there is significant binding to other proteins.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Naloxone's production and administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.3X10-11 mm Hg at 25 °C indicates naloxone will exist solely in the particulate phase in the atmosphere. Particulate-phase naloxone will be removed from the atmosphere by wet and dry deposition. Naloxone contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, naloxone is expected to have low mobility based upon an estimated Koc of 560. The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively, indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Naloxone is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, naloxone is expected to adsorb to suspended solids and sediment based upon the estimated Koc. The estimated pKa values indicate naloxone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 11 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to naloxone may occur through inhalation and dermal contact with this compound at workplaces where naloxone is produced or used. Use data indicate that the general population may be exposed to naloxone via administration under medical supervision after surgery or by emergency or medical personnel in cases of opiate overdose. (SRC)

12.2.2 Artificial Pollution Sources

Naloxone's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1185 (2013)

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 560(SRC), determined from a structure estimation method(2), indicates that naloxone is expected to have low mobility in soil(SRC). The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Naloxone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of feb 10, 2016: https://www2.epa.gov/tsca-screening-tools
(3) ChemSpider; Naloxone. (465-65-6). London, UK: Royal Chemical Society. Available from, as of Feb 10, 2016: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 560(SRC), determined from a structure estimation method(2), indicates that naloxone is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that naloxone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 11(SRC), from its log Kow of 2.09(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 10, 2016: https://www2.epa.gov/tsca-screening-tools
(3) ChemSpider; Naloxone. (465-65-6). London, UK: Royal Chemical Society. Available from, as of Feb 10, 2016: https://www.chemspider.com/Search.aspx
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 162 (1995)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), naloxone, which has an estimated vapor pressure of 4.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase naloxone may be removed from the air by wet and dry deposition(SRC). Naloxone contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 10, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.4 Environmental Abiotic Degradation

Naloxone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Naloxone contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.5 Environmental Bioconcentration

An estimated BCF of 11 was calculated in fish for naloxone(SRC), using a log Kow of 2.09(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 162 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 10, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.6 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of naloxone can be estimated to be 560(SRC). According to a classification scheme(2), this estimated Koc value suggests that naloxone is expected to have low mobility in soil. The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 10, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) ChemSpider; Naloxone. (465-65-6). London, UK: Royal Chemical Society. Available from, as of Feb 10, 2016: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

12.2.7 Volatilization from Water / Soil

The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(1), indicating that naloxone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. Naloxone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.3X10-11 mm Hg(SRC), determined from a fragment constant method(2).
(1) ChemSpider; Naloxone. (465-65-6). London, UK: Royal Chemical Society. Available from, as of Feb 10, 2016: https://www.chemspider.com/Search.aspx
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 10, 2106: https://www2.epa.gov/tsca-screening-tools

12.2.8 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 306 workers (121 of these are female) were potentially exposed to naloxone in the US(1). Occupational exposure to naloxone may occur through inhalation and dermal contact with this compound at workplaces where naloxone is produced or used. Use data indicate that the general population may be exposed to naloxone via administration under medical supervision after surgery or by emergency or medical personnel in cases of opiate overdose(2).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Feb 11, 2016: https://www.cdc.gov/noes/noes1/agtindex.html
(2) MedlinePlus; Naloxone Injection. Available from, as of Feb 10, 2016: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a612022.html

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

Take separate from meals. When formulated as a buccal film or sublingual form, avoid eating or drinking until the film has completely dissolved.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 KEGG: ATC

19.5 KEGG: Target-based Classification of Drugs

19.6 KEGG: Drug Groups

19.7 WHO ATC Classification System

19.8 FDA Pharm Classes

19.9 ChemIDplus

19.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.11 ChEMBL Target Tree

19.12 UN GHS Classification

19.13 NORMAN Suspect List Exchange Classification

19.14 CCSBase Classification

19.15 EPA DSSTox Classification

19.16 LOTUS Tree

19.17 EPA Substance Registry Services Tree

19.18 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-,(5.alpha.)-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
    LICENSE
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  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
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    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  7. European Chemicals Agency (ECHA)
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  8. FDA Global Substance Registration System (GSRS)
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  9. Hazardous Substances Data Bank (HSDB)
  10. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  11. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  12. ChEBI
  13. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  14. LiverTox
  15. LOTUS - the natural products occurrence database
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    https://lotus.nprod.net/
  16. NCI Thesaurus (NCIt)
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  20. Comparative Toxicogenomics Database (CTD)
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  21. IUPHAR/BPS Guide to PHARMACOLOGY
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    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  22. Therapeutic Target Database (TTD)
  23. DailyMed
  24. Drug Induced Liver Injury Rank (DILIrank) Dataset
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  26. Drugs and Lactation Database (LactMed)
  27. Mother To Baby Fact Sheets
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    https://www.ncbi.nlm.nih.gov/books/about/copyright/
  28. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. NORMAN Suspect List Exchange
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    NALOXONE
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  30. WHO Model Lists of Essential Medicines
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  31. EU Clinical Trials Register
  32. WHO Anatomical Therapeutic Chemical (ATC) Classification
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  33. National Drug Code (NDC) Directory
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  34. Japan Chemical Substance Dictionary (Nikkaji)
  35. KEGG
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  36. Natural Product Activity and Species Source (NPASS)
  37. MassBank of North America (MoNA)
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  38. Metabolomics Workbench
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  40. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  41. PharmGKB
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  42. Pharos
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  43. RCSB Protein Data Bank (RCSB PDB)
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  44. SpectraBase
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  46. Thieme Chemistry
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  50. PubChem
  51. GHS Classification (UNECE)
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  53. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  54. PATENTSCOPE (WIPO)
  55. NCBI
CONTENTS