Naloxone
Generic Name: Naloxone hydrochloride
Dosage Form: Injection
Ampul
Fliptop Vial
Opioid
Antagonist
Protect
from light.
Rx
Naloxone Description
Naloxone Hydrochloride Injection, USP is a sterile, nonpyrogenic
solution of Naloxone hydrochloride in water for injection. Each milliliter
(mL) contains 0.4 mg Naloxone hydrochloride and sodium chloride to adjust
tonicity in water for injection. May contain hydrochloric acid for pH adjustment;
pH 4.0 (3.0 to 6.5).
The single-dose solution contains
no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment)
and is intended for use only as a single-dose injection. When smaller doses
are required, the unused portion should be discarded.
The
multiple-dose solution contains, in addition, 1.8 mg/mL methylparaben and
0.2 mg/mL propylparaben added as preservatives.
Naloxone
Hydrochloride Injection, USP may be administered intravenously, intramuscularly,
or subcutaneously.
Naloxone, an opioid antagonist, is
a synthetic congener of oxymorphone. It differs from oxymorphone in that the
methyl group on the nitrogen atom is replaced by an allyl group.
Naloxone
Hydrochloride, USP is chemically designated 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
hydrochloride (C19H21NO4• HCl), a
white to slightly off-white powder soluble in water, in dilute acids, and
in strong alkali; slightly soluble in alcohol; practically insoluble in ether
and chloroform. It has a molecular weight of 363.84. It has the following
structural formula:
Naloxone - Clinical Pharmacology
Complete or Partial Reversal of
Opioid Depression
Naloxone prevents or reverses
the effects of opioids including respiratory depression, sedation and hypotension.
Also, Naloxone can reverse the psychotomimetic and dysphoric effects of agonist-antagonists,
such as pentazocine.
Naloxone is an essentially pure
opioid antagonist, i.e., it does not possess the “agonistic”
or morphine-like properties characteristic of other opioid antagonists. When
administered in usual doses and in the absence of opioids or agonistic effects
of other opioid antagonists, it exhibits essentially no pharmacologic activity.
Naloxone
has not been shown to produce tolerance or cause physical or psychological
dependence. In the presence of physical dependence on opioids, Naloxone will
produce withdrawal symptoms. However, in the presence of opioid dependence,
opiate withdrawal symptoms may appear within minutes of Naloxone administration
and will subside in about 2 hours. The severity and duration of the withdrawal
syndrome are related to the dose of Naloxone and to the degree and type of
opioid dependence.
While the mechanism of action of
Naloxone is not fully understood, in vitro evidence
suggests that Naloxone antagonizes opioid effects by competing for the mu,
kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity
for the mu receptor.
Mechanisms
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 may be shorter than that of some opiates, the
effects of the opiate may return as the effects of Naloxone dissipates. The
requirement for repeat doses of Naloxone, however, will also be dependent
upon the amount, type and route of administration of the opioid being antagonized.
Adjunctive Use in Septic Shock
Naloxone
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 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 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.
PHARMACOKINETICS
Distribution
Following
parenteral administration Naloxone 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
is metabolized in the liver primarily by glucuronide conjugation with Naloxone-3-glucuronide
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 for Naloxone
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 is also indicated for
the diagnosis of suspected or known acute opioid overdosage.
Naloxone
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).
Contraindications
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.
Warnings
Drug Dependence
Naloxone
hydrochloride injection should be administered cautiously to persons, including
newborns of mothers, who are known or suspected to be physically dependent
on opioids. In such cases, an abrupt and complete reversal of opioid effects
may precipitate an acute withdrawal syndrome.
The signs
and symptoms of opioid withdrawal in a patient physically dependent on opioids
may include but are not limited to, the following: body aches, diarrhea, tachycardia,
fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting,
nervousness, restlessness or irritability, shivering or trembling, abdominal
cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal
may also include: convulsions, excessive crying, and hyperactive reflexes.
Repeat Administration
The
patient who has satisfactorily responded to Naloxone should be kept under
continued surveillance and repeated doses of Naloxone should be administered,
as necessary, since the duration of action of some opioids may exceed that
of Naloxone.
Respiratory Depression
Due to Other Drugs
Naloxone is not effective
against respiratory depression due to non-opioid drugs and in the management
of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression
by partial agonists or mixed agonist/antagonists, such as buprenorphine and
pentazocine, may be incomplete or require higher doses of Naloxone. If an
incomplete response occurs, respirations should be mechanically assisted as
clinically indicated.
Precautions
General
In addition to Naloxone, other resuscitative measures such
as maintenance of a free airway, artificial ventilation, cardiac massage,
and vasopressor agents should be available and employed when necessary to
counteract acute opioid poisoning.
Abrupt postoperative
reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness,
tachycardia, increased blood pressure, seizures, ventricular tachycardia and
fibrillation, pulmonary edema, and cardiac arrest which may result in death.
Excessive doses of Naloxone in postoperative patients may result in significant
reversal of analgesia and may cause agitation (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 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 is similar to neurogenic pulmonary edema, i.e., a
centrally mediated massive catecholamine response leading to a dramatic shift
of blood volume into the pulmonary vascular bed resulting in increased hydrostatic
pressures.
Drug Interactions
Large doses of Naloxone are required to antagonize buprenorphine
since the latter has a long duration of action due to its slow rate of binding
and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism
is characterized by a gradual onset of the reversal effects and a decreased
duration of action of the normally prolonged respiratory depression. The barbiturate
methohexital appears to block the acute onset of withdrawal symptoms induced
by Naloxone in opiate addicts.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals to assess the carcinogenic potential of
Naloxone have not been conducted. Naloxone was weakly positive in the Ames
mutagenicity and in the 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 Naloxone.
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 Naloxone. There
are, however, no adequate and well controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, Naloxone
hydrochloride should be used during pregnancy only if clearly needed.
Non-teratogenic effects:Risk-benefit must be considered before Naloxone is administered
to a pregnant woman who is known or suspected to be opioid-dependent since
maternal dependence may often be accompanied by fetal dependence. Naloxone
crosses the placenta, and may precipitate withdrawal in the fetus as well
as in the mother. Patients with mild to moderate hypertension who receive
Naloxone during labor should be carefully monitored as severe hypertension
may occur.
Use in Labor and Delivery
It is not known if Naloxone hydrochloride injection affects
the duration of labor and/or delivery. However, published reports indicated
that the administration of Naloxone during labor did not adversely affect
maternal or neonatal status.
Nursing Mothers
It is not known whether Naloxone is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised
when Naloxone hydrochloride is administered to a nursing woman.
Pediatric Use
Naloxone hydrochloride injection may be administered intravenously,
intramuscularly, or subcutaneously in children and neonates to reverse the
effects of opiates. The American Academy of Pediatrics, however, does not
endorse subcutaneous or intramuscular administration in opiate intoxication
since absorption may be erratic or delayed. Although the opiate-intoxicated
child responds dramatically to Naloxone hydrochloride injection, he/she must
be carefully monitored for at least 24 hours as a relapse may occur as Naloxone
is metabolized.
When Naloxone hydrochloride injection
is given to the mother shortly before delivery, the duration of its effects
lasts only for the first two hours of neonatal life. It is preferable to administer
Naloxone hydrochloride injection directly to the neonate if needed after delivery.
Naloxone has no apparent benefit as an additional method of resuscitation
in the newly born infant with intrauterine asphyxia, which is not related
to opioid use.
Usage
in Pediatric Patients and Neonates for Septic Shock:The safety and effectiveness of Naloxone hydrochloride injection
in the treatment of hypotension in pediatric patients and neonates with septic
shock have not been established. One study of two neonates in septic shock
reported a positive pressor response; however, one patient subsequently died
after intractable seizures.
Geriatric Use
Clinical studies of Naloxone hydrochloride injection did
not include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Renal
Insufficiency/Failure
The safety and effectiveness
of Naloxone hydrochloride injection in patients with renal insufficiency/failure
have not been established in well-controlled clinical trials. Caution should
be exercised when Naloxone is administered to this patient population.
Liver Disease
The safety
and effectiveness of Naloxone hydrochloride injection in patients with liver
disease have not been established in well-controlled clinical trials. Caution
should be exercised when Naloxone is administered to patients with liver disease.
Adverse Reactions
Postoperative
The
following adverse events have been associated with the use of Naloxone hydrochloride
injection in postoperative patients: hypotension, hypertension, ventricular
tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest.
Death, coma, and encephalopathy have been reported as sequelae of these events.
Excessive doses of Naloxone in postoperative patients may result in significant
reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE
and ADMINISTRATION; Usage in Adults-Postoperative Opioid Depression).
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).
Opioid
Dependence
Abrupt reversal of opioid effects
in persons who are physically dependent on opioids may precipitate an acute
withdrawal syndrome which may include, but not limited to the following signs
and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection,
yawning, weakness, shivering or trembling, nervousness, restlessness or irritability,
diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure,
and tachycardia. In the neonate, opioid withdrawal may also include: convulsions,
excessive crying, and hyperactive reflexes (See WARNINGS).
Adverse
events associated with the postoperative use of Naloxone hydrochloride injection
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
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 injection is an opioid antagonist.
Physical dependence associated with the use of Naloxone hydrochloride injection
has not been reported. Tolerance to the opioid antagonist effect of Naloxone
is not known to occur.
Overdosage
There is limited clinical experience with Naloxone hydrochloride
injection overdosage in humans.
Adult
Patients
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 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).
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.
Pediatric Patients
Up to 11 doses of 0.2 mg 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 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 sequelae.
Patient Management
Patients
who experience a Naloxone 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.
Naloxone Dosage and Administration
Naloxone Hydrochloride Injection, USP may be administered
intravenously, intramuscularly, or subcutaneously. The most rapid onset of
action is achieved by intravenous administration and it is recommended in
emergency situations.
Since the duration of action of
some opioids may exceed that of Naloxone, the patient should be kept under
continued surveillance and repeated doses of Naloxone should be administered,
as necessary.
Intravenous
Infusion: Naloxone Hydrochloride Injection, USP may be diluted for
intravenous infusion in 0.9% sodium chloride injection or 5% dextrose injection.
The addition of 2 mg of Naloxone hydrochloride 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 solution must be discarded. The
rate of administration should be titrated in accordance with the patient’s
response.
Naloxone Hydrochloride Injection, USP 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,
USP 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 may be administered intravenously. If the desired
degree of counteraction and improvement in respiratory functions is not obtained,
it may be repeated at 2 to 3 minute intervals. If no response is observed
after 10 mg of Naloxone hydrochloride 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
are usually sufficient. The dose of Naloxone should be titrated according
to the patient’s response. For the initial reversal of respiratory
depression, Naloxone hydrochloride 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 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 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 opioid. Supplemental intramuscular doses have been
shown to produce a longer lasting effect.
Septic
Shock: The optimal dosage of Naloxone 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 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, Naloxone Hydrochloride may be administered I.M. or S.C. in divided
doses. If necessary, Naloxone Hydrochloride Injection, USP 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 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 reversal.
Usage in Neonates
When using
Naloxone hydrochloride injection in neonates a product containing 0.02 mg/mL
should be used.
Opioid-Induced
Depression: 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 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.
How is Naloxone Supplied
Naloxone Hydrochloride Injection, USP is supplied
in the following:
List |
Container |
Concentration |
1212 |
Single-dose Ampul |
0.4 mg/1 mL (0.4 mg/mL) |
1215 |
Single-dose Fliptop Vial |
0.4 mg/1 mL (0.4 mg/mL) |
1219 |
Multiple-dose Fliptop Vial |
4 mg/10 mL (0.4 mg/mL) |
Store at 20 to 25°C (68 to 77°F). [See USP Controlled
Room Temperature.]
Protect
from light.
Revised: May, 2006
©Hospira
2006 EN-1215 Printed in USA
HOSPIRA,
INC., LAKE FOREST, IL 60045 USA
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Revised: 01/2007
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