United States - English - NLM (National Library of Medicine)
NALOXONE HYDROCHLORIDE- naloxone hydrochloride injection, solution
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Naloxone Hydrochloride Injection, USP
Naloxone hydrochloride injection USP, 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
Naloxone hydrochloride, USP occurs as a white to slightly off-white powder, and is soluble in water,
in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in
Naloxone hydrochloride injection, USP is available as a sterile, clear colorless solution for
intravenous, intramuscular or subcutaneous administration in the concentration 0.4 mg of naloxone
hydrochloride per mL.
pH is adjusted to 3.0 to 6.5 with hydrochloric acid.
The 0.4 mg/mL vial is available in an unpreserved, paraben-free formulation containing 9 mg/mL of
Complete or Partial Reversal of Opioid Depression
Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression,
sedation and hypotension. Also, naloxone hydrochloride can reverse the psychotomimetic and
dysphoric effects of agonist-antagonists such as pentazocine.
Naloxone hydrochloride 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 hydrochloride has not been shown to produce tolerance or cause physical or psychological
dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce
withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms
may appear within minutes of naloxone hydrochloride administration and will subside in about 2 hours.
The severity and duration of the withdrawal syndrome are related to the dose of naloxone
hydrochloride and to the degree and type of opioid dependence. While the mechanism of action of
naloxone hydrochloride is not fully understood, in vitro evidence suggests that naloxone hydrochloride
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.
Mechanism of Action
When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent
within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously or
intramuscularly. The duration of action is dependent upon the dose and route of administration of
naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than
intravenous administration. Since the duration of action of naloxone hydrochloride may be shorter than
that of some opiates, the effects of the opiate may return as the effects of naloxone hydrochloride
dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon
the amount, type and route of administration of the opioid being antagonized.
Adjunctive Use in Septic Shock
Naloxone hydrochloride has been shown in some cases of septic shock to produce a rise in blood
pressure that may last up to several hours; however, this pressor response has not been demonstrated to
improve patient survival. In some studies, treatment with naloxone hydrochloride in the setting of septic
shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary
edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone hydrochloride in
septic shock should be exercised with caution, particularly in patients who may have underlying pain or
have previously received opioid therapy and may have developed opioid tolerance.
Because of the limited number of patients who have been treated, optimal dosage and treatment regimens
have not been established.
Following parenteral administration, naloxone hydrochloride is rapidly distributed in the body and
readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the
major binding constituent but significant binding of naloxone also occurs to plasma constituents other
than albumin. It is not known whether naloxone is excreted into human milk.
Metabolism and Elimination
Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with
naloxone-3-glucoronide as the major metabolite. In one study the serum half-life in adults ranged from
30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to
be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as
metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.
INDICATIONS AND USAGE
Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid
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 CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock).
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.
Naloxone hydrochloride 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.
The patient who has satisfactorily responded to naloxone hydrochloride should be kept under continued
surveillance and repeated doses of naloxone hydrochloride should be administered, as necessary, since
the duration of action of some opioids may exceed that of naloxone hydrochloride.
Respiratory Depression due to Other Drugs
Naloxone hydrochloride 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.
In addition to naloxone hydrochloride, 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
hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause
agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults-
Postoperative Opioid Depression).
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 pre-
existing 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 hydrochloride should be used with caution in patients with pre-existing 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 hydrochloride 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
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 hydrochloride have not been
conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the in vitro
human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell
HGPRT mutagenicity assay and in the in vivo 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 hydrochloride.
Use in Pregnancy
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 hydrochloride. 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.
Risk-benefit must be considered before naloxone hydrochloride 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 administration of naloxone during labor did not adversely
affect maternal or neonatal status.
It is not known whether naloxone hydrochloride is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a
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, he/she must be carefully monitored for at least 24 hours as a
relapse may occur as naloxone is metabolized.
When naloxone hydrochloride 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
directly to the neonate if needed after delivery. Naloxone hydrochloride 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.
Usage in Pediatric Patients and Neonates for Septic Shock:
The safety and effectiveness of naloxone hydrochloride 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
Clinical studies of naloxone hydrochloride 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.
The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have
not been established in well-controlled clinical trials. Caution should be exercised when naloxone
hydrochloride is administered to this patient population.
The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been
established in well-controlled clinical trials. Caution should be exercised when naloxone
hydrochloride is administered to patients with liver disease.
The following adverse events have been associated with the use of naloxone hydrochloride 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 hydrochloride in postoperative patients may result in
significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION; Usage in Adults-Postoperative 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 PRECAUTIONS).
Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate
an acute withdrawal syndrome which may include, but is 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 WARNINGS).
Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ
system and in decreasing order of frequency as follows:
Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and
ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these
Gastrointestinal Disorders: vomiting, nausea
Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion
Psychiatric Disorders: agitation, hallucination, tremulousness
Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia
Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating
Vascular Disorders: hypertension, hypotension, hot flashes, or flushing.
See also PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults;
Postoperative Opioid Depression.
DRUG ABUSE AND DEPENDENCE
Naloxone hydrochloride is an opioid antagonist. Physical dependence associated with the use of
naloxone hydrochloride has not been reported. Tolerance to the opioid antagonist effect of naloxone
hydrochloride is not known to occur.
There is limited clinical experience with naloxone hydrochloride overdosage in humans.
In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study,
36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m
/min) of naloxone
hydrochloride 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).
At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including
irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have
been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and
stomachaches were also reported. Although complete information is not available, behavioral symptoms
were reported to often persist for 2 to 3 days.
Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose
of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2½ year-old child
who inadvertently received a dose of 20 mg of naloxone for treatment of respiratory depression
following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well
and recovered without adverse sequelae. There is also a report of a 4½ year-old child who received 11
doses during a 12-hour period, with no adverse sequelae.
Patients who experience a naloxone hydrochloride overdose should be treated symptomatically in a
closely supervised environment. Physicians should contact a poison control center for the most up-to-
date patient management information.
DOSAGE AND ADMINISTRATION
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 hydrochloride injection, the
patient should be kept under continued surveillance. Repeated doses of naloxone hydrochloride
injection should be administered, as necessary.
Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5%
dextrose solutions. The addition of 2 mg of naloxone hydrochloride injection in 500 mL of either
solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24
hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in
accordance with the patient’s response.
Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite,
metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No
drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the
chemical and physical stability of the solution has first been established.
Usage in Adults
Opioid Overdose–Known or Suspected:
An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride injection may be administered
intravenously. If the desired degree of counteraction and improvement in respiratory functions are not
obtained, it may be repeated at two- to three-minute intervals. If no response is observed after 10 mg of
naloxone hydrochloride injection have been administered, the diagnosis of opioid-induced or partial
opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be
necessary if the intravenous route is not available.
Postoperative Opioid Depression:
For the partial reversal of opioid depression following the use of opioids during surgery, smaller
doses of naloxone hydrochloride injection are usually sufficient. The dose of naloxone hydrochloride
injection should be titrated according to the patient’s response. For the initial reversal of respiratory
depression, naloxone hydrochloride injection should be injected in increments of 0.1 to 0.2 mg
intravenously at two- to three-minute intervals to the desired degree of reversal, i.e., adequate
ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of
naloxone hydrochloride injection may result in significant reversal of analgesia and increase in blood
pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress.
Repeat doses of naloxone hydrochloride injection may be required within one- to two-hour intervals
depending upon the amount, type (i.e., short or long acting) and time interval since last administration of
an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect.
The optimal dosage of naloxone hydrochloride injection or duration of therapy for the treatment of
hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY).
Usage in Pediatric Population
Opioid Overdose–Known or Suspected:
The usual initial dose in pediatric patients is 0.01 mg/kg body weight given intravenously. If this dose
does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body
weight may be administered. If an intravenous route of administration is not available, naloxone
hydrochloride injection may be administered intramuscularly or subcutaneously in divided doses. If
necessary, naloxone hydrochloride injection can be diluted with sterile water for injection.
Postoperative Opioid Depression:
Follow the recommendations and cautions under Adult Postoperative Depression. For the initial
reversal of respiratory depression, naloxone hydrochloride injection should be injected in increments
of 0.005 mg to 0.01 mg intravenously at two- to three-minute intervals to the desired degree of
Usage in Neonates
The usual initial dose is 0.01 mg/kg body weight administered intravenously, intramuscularly or
subcutaneously. This dose may be repeated in accordance with adult administration guidelines for
postoperative opioid depression.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Naloxone hydrochloride injection, USP is a sterile, clear colorless solution for intravenous,
intramuscular, or subcutaneous administration and is available as:
0.4 mg per mL
1 mL Single-Dose Vials
in a Carton of 10 NDC 55150-327-10
1 mL Single-Dose Vials
in a Carton of 25 NDC 55150-327-25
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.
The vial stopper is not made with natural rubber latex.
AuroMedics Pharma LLC
279 Princeton-Hightstown Rd.
E. Windsor, NJ 08520
Aurobindo Pharma Limited
Hyderabad - 500038
Revised: July 2019
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL- VIAL LABEL
0.4 mg per mL
1 mL Single-Dose Vial
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL- OUTER PACKAGE
1 x 1 mL Single-Dose Vial
0.4 mg per mL
For Intravenous, Intramuscular or Subcutaneous Use.
Protect from light.