Hydrochloride Injection, USP)Opioid
naloxone hydrochloride injection Endo Pharmaceuticals Inc.
Hydrochloride Injection, USP) Opioid
Antagonist Rx only
NARCAN (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 allyl group.
Naloxone hydrochloride 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
NARCAN injection is available as a sterile solution for
intravenous, intramuscular and subcutaneous administration in three
concentrations: 0.02 mg, 0.4 mg and 1 mg of naloxone hydrochloride per
pH is adjusted to 3.5 ± 0.5 with hydrochloric acid.
The 0.02 mg/mL strength is an unpreserved, paraben-free
formulation containing 9 mg/mL sodium chloride.
The 0.4 mg/mL vial contains 8.6 mg/mL of sodium chloride and 2
mg/mL of methylparaben and propylparaben as preservatives in a ratio of
9:1. The 0.4 mg/mL ampul is also available in an unpreserved,
paraben-free formulation containing 9 mg/mL of sodium chloride.
The 1 mg/mL vial contains 8.35 mg/mL of sodium chloride and 2
mg/mL of methylparaben and propylparaben as preservatives in a ratio of
9:1. The 1 mg/mL ampul is also available in an unpreserved, paraben-free
formulation containing 9 mg/mL of sodium chloride.
Complete or Partial Reversal of Opioid Depression
NARCAN prevents or reverses the effects of opioids
including respiratory depression, sedation and hypotension.
Also, NARCAN can reverse the psychotomimetic and dysphoric
effects of agonist-antagonists such as pentazocine.
NARCAN 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.
NARCAN has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of
physical dependence on opioids, NARCAN will produce withdrawal
symptoms. However, in the presence of opioid dependence, opiate
withdrawal symptoms may appear within minutes of NARCAN
administration and subside in about 2 hours. The severity and
duration of the withdrawal syndrome are related to the dose of
NARCAN and to the degree and type of opioid dependence. While the mechanism of action of NARCAN is not fully
understood, in vitro
evidence suggests that NARCAN antagonizes opioid effects by
competing for theμ, κ and σ opiate
receptor sites in the CNS, with the greatest affinity for theμ receptor.
When NARCAN is administered intravenously (I.V.), the
onset of action is generally apparent within two minutes. The
onset of action is slightly less rapid when it is administered
subcutaneously (S.C.) or intramuscularly (I.M.). The duration of
action is dependent upon the dose and route of administration of
NARCAN. Intramuscular administration produces a more prolonged
effect than intravenous administration. Since the duration of
action of NARCAN may be shorter than that of some opiates, the
effects of the opiate may return as the effects of NARCAN
dissipates. The requirement for repeat doses of NARCAN will also
be dependent upon the amount, type and route of administration
of the opioid being antagonized.
Adjunctive Use in Septic Shock
NARCAN 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
NARCAN 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 NARCAN 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
Following parenteral administration, NARCAN 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
Metabolism and Elimination
NARCAN 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
25-40% of the drug is excreted as metabolites in urine
within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.
INDICATIONS AND USAGE
NARCAN 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. NARCAN is also indicated for diagnosis of
suspected or known acute opioid overdosage.
NARCAN is contraindicated in patients known to be hypersensitive
to naloxone hydrochloride or to any of the other ingredients in
NARCAN 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
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
The patient who has satisfactorily responded to NARCAN
should be kept under continued surveillance and repeated doses
of NARCAN should be administered, as necessary, since the
duration of action of some opioids may exceed that of
Respiratory Depression due to Other Drugs
NARCAN 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
In addition to NARCAN, 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 NARCAN 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, NARCAN 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 NARCAN 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
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 NARCAN have not been conducted. NARCAN 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/m2), demonstrated no
embryotoxic or teratogenic effects due to NARCAN.
Use in Pregnancy
Teratogenic Effects: Pregnancy Category C
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/m2), demonstrated no embryotoxic or
teratogenic effects due to NARCAN. There are, however,
no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response, NARCAN should be
used during pregnancy only if clearly
Risk-benefit must be considered before NARCAN 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 NARCAN (naloxone hydrochlorideinjection, USP) affects the duration of labor and/or delivery.
However, published reports indicated that administration of
naloxone during labor did not adversely affect maternal or
It is not known whether NARCAN is excreted in human milk.
Because many drugs are excreted in human milk, caution should be
exercised when NARCAN is administered to a nursing
NARCAN (naloxone hydrochloride injection, USP) 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
NARCAN, he/she must be carefully monitored for at least 24 hours
as a relapse may occur as naloxone is metabolized.
When NARCAN 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
NARCAN directly to the neonate if needed after delivery. NARCAN
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
The safety and effectiveness of NARCAN 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 NARCAN 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
The safety and effectiveness of NARCAN in patients with
renal insufficiency/failure have not been established in
well-controlled clinical trials. Caution should be exercised
when NARCAN is administered to this patient
The safety and effectiveness of NARCAN in patients with liver disease have not been established in well-controlled
clinical trials. Caution should be exercised when NARCAN is
administered to patients with liver disease.
The following adverse events have been associated with
the use of NARCAN 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 NARCAN 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
NARCAN 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 events.
Gastrointestinal Disorders vomiting, nausea
Nervous System Disorders convulsions, paraesthesia,
grand mal convulsion
NARCAN is an opioid antagonist. Physical dependence associated
with the use of NARCAN has not been reported. Tolerance to the opioid antagonist effect of NARCAN is not known to occur.
There is limited clinical experience with NARCAN overdosage in
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/m2/min) of NARCAN
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 2-3 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 2-1/2 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 4-1/2 year-old child who received 11
doses during a 12-hour period, with no adverse
Patients who experience a NARCAN 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
NARCAN may be administered intravenously, intramuscularly, or
subcutaneously. The most rapid onset of action is achieved by
intravenous administration, which is recommended in emergency
Since the duration of action of some opioids may exceed that of
NARCAN, the patient should be kept under continued surveillance.
Repeated doses of NARCAN should be administered, as
NARCAN may be diluted for intravenous infusion in normal
saline or 5% dextrose solutions. The addition of 2 mg of
NARCAN 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
NARCAN 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 NARCAN unless its effect on
the chemical and physical stability of the solution has first
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration
whenever solution and container permit.
Usage in Adults
Opioid Overdose–Known or Suspected
An initial dose of 0.4 mg to 2 mg of NARCAN 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 NARCAN 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 NARCAN are usually sufficient. The dose of
NARCAN should be titrated according to the
patient’s response. For the initial reversal
of respiratory depression, NARCAN 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 NARCAN 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 NARCAN 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
The optimal dosage of NARCAN or duration of
therapy for the treatment of hypotension in septic shock
patients has not been established (see CLINICALPHARMACOLOGY).
Usage in Children
Opioid Overdose–Known or Suspected
The usual initial dose in children is 0.01 mg/kg
body weight given I.V. 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
I.V. route of administration is not available, NARCAN
may be administered I.M. or S.C. in divided doses. If
necessary, NARCAN can be diluted with sterile water for
Postoperative Opioid Depression
Follow the recommendations and cautions underAdult Postoperative Depression. For the initial reversal of respiratory
depression, NARCAN 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 I.V., I.M. or S.C. This dose may be
repeated in accordance with adult administration
guidelines for postoperative opioid
NARCAN (naloxone hydrochloride injection, USP) for intravenous,
intramuscular, and subcutaneous administration is available as:
Multiple Dose Vials 0.4 mg/mL 10
mL multiple dose vial-box of 1, NDC 63481-365-05 1 mg/mL 10
mL multiple dose vial-box of 1, NDC 63481-368-05
Preservative-Free Ampules 0.02 mg/mL 2 mL unit dose ampule-box of 10, NDC 63481-359-10 0.4 mg/mL 1
mL unit dose ampule-box of 10, NDC 63481-358-10 1 mg/mL 2
mL unit dose ampule-box of 10, NDC 63481-377-10
Store at 25ºC (77ºF); excursions permitted to
15º-30ºC (59º-86ºF). [See USP
Controlled Room Temperature]. Protect from light.
Store in carton until contents have been used.
Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317
NARCAN is a Registered Trademark of Endo Pharmaceuticals Inc.