Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3138
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Naloxone Hydrochloride (Injection, Solution)
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Naloxone hydrochloride injection 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.<br/>Intravenous Infusion: Naloxone hydrochloride injection may be diluted for
intravenous infusion in 0.9% sodium chloride 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 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.<br/>General: Parenteral drug products
should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
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Naloxone hydrochloride, 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. It is known chemically as 17-allyl-4,5��-epoxy,3-14-dihydroxymorphinan-6-one
hydrochloride. It has a molecular weight of 363.84, and the followingstructural formula: 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 chloroform. Naloxone hydrochloride injection is available as a sterile
solution for intravenous, intramuscular, and subcutaneous administration.
Each mL contains 0.4 mg of naloxone hydrochloride. Each mL contains
8.9 mg of sodium chloride. The pH is adjusted between 3.0 to 6.5 with
hydrochloric acid or sodium hydroxide. The air in the cartridges has
been displaced by nitrogen gas.
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Naloxone prevents or reverses the effects of opioids
including respiratory depression, sedation and hypotension. Also,
it 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 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, withdrawal
symptoms will 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 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
(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 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 dissipate. The requirement for repeat doses of naloxone will also
be dependent upon the amount, type and route of administration of
the opioid being antagonized.<br/>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
any of the other ingredients contained in the formulation.
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Naloxone hydrochloride injection, USP for intravenous,
intramuscular, and subcutaneous administration is available as: 0.4 mg/mL (1 mL fill in 2 mL cartridge) CARPUJECT sterile cartridge unit, with Luer Lock box of 10 (NDC
0409-1782-69). Protect from light. Store at 20 to 25��C (68 to 77��F). [See USP Controlled
Room Temperature.] Revised: January, 2008
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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, PostoperativeOpioid 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 hasnot 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 catacholamine response leading
to a dramatic shift of bloodvolume 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.<br/>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.<br/>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.<br/>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.<br/>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.<br/>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.<br/>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).<br/>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).<br/>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 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, 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 flushes, 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.<br/>Repeat Administration: The patient who has satisfactorily responded to naloxoneshould 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.<br/>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 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).
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Naloxone Hydrochloride
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