Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2046
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Naloxone Hydrochloride (Injection, Solution)
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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. 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.
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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-4,5��-epoxy-3,14-dihydroxymorphinan-6-one
hydrochloride (CHNO���HCl), a white to slightly off-white powder soluble in water, in dilute
acids, and in strong alkali; slightly soluble in alcohol; practically
insoluble in ether and chloroform. It has a molecular weight of 363.84.
It has the following structural formula:
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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 withdrawalsyndrome 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. 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.
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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.
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Naloxone Hydrochloride Injection, USP is supplied
in the following: Store at 20 to 25��C (68 to 77��F). [See
USP Controlled Room Temperature.] Protect from light. Revised: January, 2007
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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 pathogenesisof 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.<br/>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.<br/>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/m), demonstrated no
embryotoxic or teratogenic effects due to naloxone.<br/>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/m), demonstrated no embryotoxic or teratogenic effects
due to naloxone. There are, however, no adequate and well controlled
studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, naloxone hydrochloride should
be used during pregnancy only if clearly needed. 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.<br/>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.<br/>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.<br/>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.<br/>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.
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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/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). 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.
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Naloxone Hydrochloride
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Naloxone Hydrochloride (Injection, Solution)
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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
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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.
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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).
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Naloxone Hydrochloride
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