Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1460
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Nalbuphine Hydrochloride (Injection, Solution)
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The usual recommended adult dose is 10 mg for a 70
kg individual administered subcutaneously, intramuscularly, or intravenously;
this dose may be repeated every 3 to 6 hours as necessary. Dosage
should be adjusted according to the severity of the pain, physical
status of the patient, and other medications which the patient may
be receiving (see Interaction With Other
Central Nervous System Depressants under WARNINGS). In nontolerant individuals,
the recommended single maximum dose is 20 mg with a maximum total
daily dose of 160 mg. The use of nalbuphine
hydrochloride injection as a supplement to balanced anesthesia requires
larger doses than those recommended for analgesia. Induction doses
of nalbuphine hydrochloride range from 0.3 mg/kg to 3 mg/kg intravenously
to be administered over a 10 to 15 minute period with maintenance
doses of 0.25 to 0.5 mg/kg in single intravenous administrations as
required. The use of nalbuphine hydrochloride injection may be followed
by respiratory depression which can be reversed with the opioid antagonist
naloxone hydrochloride. Patients Dependent on Opioids: Patients who have been taking
opioids chronically may experience withdrawal symptoms upon the administration
of nalbuphine hydrochloride injection. If unduly troublesome, opioid
withdrawal symptoms can be controlled by the slow intravenous administration
of small increments of morphine, until relief occurs. If the previous
analgesic was morphine, meperidine, codeine, or other opioid with
similar duration of activity, one-fourth of the anticipated dose of
nalbuphine hydrochloride can be administered initially and the patient
observed for signs of withdrawal, i.e., abdominal cramps, nausea and
vomiting, lacrimation, rhinorrhea, anxiety, restlessness, elevation
of temperature or piloerection. If untoward symptoms do not occur,
progressively larger doses may be tried at appropriate intervals until
the desired level of analgesia is obtained with nalbuphine hydrochloride. Parenteral drug products should be inspected visually
for particulate matter and discoloration prior to administration whenever
solution and container permit.
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Nalbuphine hydrochloride is a synthetic opioid agonist-antagonist
analgesic of the phenanthrene series. It is chemically related to
both the widely used opioid antagonist, naloxone, and the potent opioid
analgesic, oxymorphone. Chemically nalbuphine hydrochloride is 17-(cyclobutylmethyl)-4,5��-epoxymorphinan-3,6��,14-triol
hydrochloride. Nalbuphine hydrochloride molecular weight is 393.91
and is soluble in HO (35.5 mg/mL at 25��C) and ethanol
(0.8%); insoluble in CHCland ether. Nalbuphine hydrochloride
has pKa values of 8.71 and 9.96. The molecular formula is CHNO���HCl. The structural formula
is: Nalbuphine Hydrochloride Injection is a sterile,
nonpyrogenic solution of nalbuphine hydrochloride in water for injection.
This product may be administered by subcutaneous, intramuscular or
intravenous injection. Each milliliter (mL)
contains nalbuphine hydrochloride 10 mg or 20 mg; sodium citrate,
dihydrate 0.47 mg and citric acid, anhydrous 0.63 mg added as buffers
and may contain sodium hydroxide and/or hydrochloric acid for pH adjustment;
pH 3.7 (3.0 to 4.5). Contains sodium chloride for tonicity adjustment. Multiple-dose vials contain 1.8 mg/mL methylparaben and
0.2 mg/mL propylparaben added as preservatives. Single-dose products
contain no bacteriostat or antimicrobial agent and unused portions
must be discarded.
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Nalbuphine hydrochloride is a potent analgesic. Its
analgesic potency is essentially equivalent to that of morphine on
a milligram basis. Receptor studies show that nalbuphine hydrochloride
binds to mu, kappa, and delta receptors, but not to sigma receptors.
Nalbuphine hydrochloride is primarily a kappa agonist/partial mu antagonist
analgesic. The onset of action of nalbuphine
hydrochloride occurs within 2 to 3 minutes after intravenous administration,
and in less than 15 minutes following subcutaneous or intramuscular
injection. The plasma half-life of nalbuphine is 5 hours, and in clinical
studies, the duration of analgesic activity has been reported to range
from 3 to 6 hours. The opioid antagonist
activity of nalbuphine is one-fourth as potent as nalorphine and 10 times
that of pentazocine. Nalbuphine hydrochloride
may produce the same degree of respiratory depression as equianalgesic
doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling
effect such that increases in dose greater than 30 mg do not produce
further respiratory depression in the absence of other CNS active
medications affecting respiration. Nalbuphine
hydrochloride by itself has potent opioid antagonist activity at doses
equal to or lower than its analgesic dose. When administered following
or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone,
fentanyl), nalbuphine hydrochloride may partially reverse or block
opioid-induced respiratory depression from the mu agonist analgesic.
Nalbuphine hydrochloride may precipitate withdrawal in patients dependent
on opioid drugs. Nalbuphine hydrochloride should be used with caution
in patients who have been receiving mu opioid analgesics on a regular
basis.
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Nalbuphine hydrochloride injection should not be
administered to patients who are hypersensitive to nalbuphine hydrochloride,
or to any of the other ingredients in nalbuphine hydrochloride injection.
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Nalbuphine Hydrochloride Injection is supplied as
follows: 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. Revised: August, 2007 Revised: August, 2007
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General: Impaired Respiration: At the usual adult dose of 10 mg/70 kg, nalbuphine hydrochloride
causes some respiratory depression approximately equal to that produced
by equal doses of morphine. However, in contrast to morphine, respiratory
depression is not appreciably increased with higher doses of nalbuphine.
Respiratory depression induced by nalbuphine can be reversed by naloxone
hydrochloride when indicated. Nalbuphine hydrochloride injection should
be administered with caution at low doses to patients with impaired
respiration (e.g., from other medication, uremia, bronchial asthma,
severe infection, cyanosis or respiratory obstructions). Impaired Renal or Hepatic Function: Because nalbuphine is metabolized in the liver and excreted by the
kidneys, nalbuphine hydrochloride should be used with caution in patients
with renal or liver dysfunction and administered in reduced amounts. Myocardial Infarction: As with all potent analgesics, nalbuphine hydrochloride should be
used with caution in patients with myocardial infarction who have
nausea or vomiting. Biliary Tract Surgery: As with all opioid analgesics, nalbuphine
hydrochloride should be used with caution in patients about to undergo
surgery of the biliary tract since it may cause spasm of the sphincter
of Oddi. Cardiovascular
System: During evaluation of nalbuphine hydrochloride injection,
in anesthesia, a higher incidence of bradycardia has been reported
in patients who did not receive atropine pre-operatively.<br/>Information for Patients: Patients should be advised of the following information:<br/>Laboratory Tests: Nalbuphine hydrochloride may interfere with enzymatic
methods for the detection of opioids depending on the specificity/sensitivity
of the test. Consult the test manufacturer for specific details.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Long term carcinogenicity studies were performed in rats (24 months)
and mice (19 months) by oral administration at doses up to 200 mg/kg
(1180 mg/m) and 200 mg/kg (600 mg/m) per day,
respectively. There was no evidence of an increase in tumors in either
species related to nalbuphine hydrochloride administration. The maximum
recommend human dose (MRHD) in a day is 160 mg subcutaneously, intramuscularly
or intravenously, or approximately 100 mg/m/day for a
60 kg subject. Mutagenesis: Nalbuphine hydrochloride did not have mutagenic activity in the AMES
test with four bacterial strains, in the Chinese Hamster Ovary HGPRT
assays or in the Sister Chromatids Exchange Assay. However, nalbuphine
hydrochloride induced an increased frequency of mutation in the mouse
lymphoma assay. Clastogenic activity was not observed in the mouse
micronucleus test of the cytogenicity bone marrow assay in rats. Impairment of Fertility: A reproduction study was performed in male and female rats at subcutaneous
doses up to 56 mg/kg/day or 330 mg/m/day. Nalbuphine hydrochloride
did not affect either male or female fertility rats.<br/>Usage in Pregnancy:<br/>Teratogenic Effects:: Pregnancy Category B: Reproduction studies have been performed in rats by subcutaneous
administration of nalbuphine up to 100 mg/kg/day, or 590 mg/m/day which is approximately 6 times the MRHD, and in rabbits
by intravenous administration of nalbuphine up to 32 mg/kg/day, or
378 mg/m/day which is approximately 4 times the MRHD.
The results did not reveal evidence of developmental toxicity, including
teratogenicity, or harm to the fetus. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should
be used during pregnancy only if clearly needed.<br/>Non-teratogenic Effects:: Neonatal body weight and survival rates were reduced
at birth and during lactation when nalbuphine was subcutaneously administered
to female and male rats prior to mating and throughout gestation and
lactation or to pregnant rats during the last third of gestation and
throughout lactation at doses approximately 4 times the maximum recommended
human dose.<br/>Use During Labor and Delivery: See WARNINGS.<br/>Nursing Mothers: Limited data suggest that nalbuphine hydrochloride
is excreted in maternal milk but only in a small amount (less than
1% of the administered dose) and with a clinically insignificant effect.
Caution should be exercised when nalbuphine hydrochloride is administered
to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below
the age of 18 years have not been established.
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The immediate intravenous administration of an opiate
antagonist such as naloxone or nalmefene is a specific antidote. Oxygen,
intravenous fluids, vasopressors and other supportive measures should
be used as indicated. The administration of
single doses of 72 mg of nalbuphine hydrochloride subcutaneously to
eight normal subjects has been reported to have resulted primarily
in symptoms of sleepiness and mild dysphoria.
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Nalbuphine Hydrochloride
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Nalbuphine Hydrochloride (Injection, Solution)
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The most frequent adverse reaction in 1066 patients
treated with nalbuphine hydrochloride injection was sedation 381 (36%).
Less frequent reactions were: sweaty/clammy 99 (9%), nausea/vomiting
68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache
27 (3%). Other adverse reactions which occurred
(reported incidence of 1% or less) were: CNS Effects: Nervousness, depression, restlessness,
crying, euphoria, floating, hostility, unusual dreams, confusion,
faintness, hallucinations, dysphoria, feeling of heaviness, numbness,
tingling, unreality. The incidence of psychotomimetic effects, such
as unreality, depersonalization, delusions, dysphoria and hallucinations
has been shown to be less than that which occurs with pentazocine. Cardiovascular: Hypertension,
hypotension, bradycardia, tachycardia. Gastrointestinal: Cramps, dyspepsia, bitter
taste. Respiratory: Depression, dyspnea, asthma. Dermatologic: Itching, burning, urticaria. Miscellaneous: Speech
difficulty, urinary urgency, blurred vision, flushing and warmth. Allergic Reactions: Anaphylactic/anaphylactoid and other serious hypersensitivity reactions
have been reported following the use of nalbuphine and may require
immediate, supportive medical treatment. These reactions may include
shock, respiratory distress, respiratory arrest, bradycardia, cardiac
arrest, hypotension, or laryngeal edema. Some of these allergic reactions
may be life-threatening. Other allergic-type reactions reported include
stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting,
diaphoresis, weakness, and shakiness. Events Observed during Post-marketing Surveillance
of Nalbuphine Hydrochloride Injection Due to the nature and limitations of spontaneous reporting, causality
has not been established for the following adverse events received
for nalbuphine hydrochloride injection: abdominal pain, pyrexia, depressed
level or loss of consciousness, somnolence, tremor, anxiety, pulmonary
edema, agitation, seizures, and injection site reactions such as pain,
swelling, redness, burning, and hot sensations. Death has been reported
from severe allergic reactions to nalbuphine hydrochloride treatment.
Fetal death has been reported where mothers received nalbuphine hydrochloride
during labor and delivery.
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Nalbuphine hydrochloride
injection should be administered as a supplement to general anesthesia
only by persons specifically trained in the use of intravenous anesthetics
and management of respiratory effects of potent opioids. Naloxone hydrochloride
injection, resuscitative and intubation equipment and oxygen should
be readily available.<br/>Drug Abuse: Caution should be observed in prescribing nalbuphine
for emotionally unstable patients, or for individuals with a history
of opioid abuse. Such patients should be closely supervised when long
term therapy is contemplated (See DRUG ABUSE
AND DEPENDENCE). Use in Ambulatory Patients Nalbuphine may impair the mental or physical abilities
required for the performance of potentially dangerous tasks such as
driving a car or operating machinery. Therefore, nalbuphine hydrochloride
injection should be administered with caution to ambulatory patients
who should be warned to avoid such hazards. Use in Emergency
Procedures Maintain patient
under observation until recovered from nalbuphine effects that would
affect driving or other potentially dangerous tasks.<br/>Use in Pregnancy (Other Than
Labor): Severe fetal bradycardia has been reported when nalbuphine
is administered during labor. Naloxone may reverse these effects.
Although there are no reports of fetal bradycardia earlier in pregnancy,
it is possible that this may occur. This drug should be used in pregnancy
only if clearly needed, if the potential benefit outweighs the risk
to the fetus, and if appropriate measures such as fetal monitoring
are taken to detect and manage any potential adverse effect on the
fetus.<br/>Use During Labor and Delivery: The placental transfer of nalbuphine is high, rapid,
and variable with a maternal to fetal ratio ranging from 1:0.37 to
1:6. Fetal and neonatal adverse effects that have been reported following
the administration of nalbuphine to the mother during labor include
fetal bradycardia, respiratory depression at birth, apnea, cyanosis,
and hypotonia. Some of these events have been life-threatening. Maternal
administration of naloxone during labor has normalized these effects
in some cases. Severe and prolonged fetal bradycardia has been reported.
Permanent neurological damage attributed to fetal bradycardia has
occurred. A sinusoidal fetal heart rate pattern associated with the
use of nalbuphine has also been reported. Nalbuphine should be used
during labor and delivery only if clearly indicated and only if the
potential benefit outweighs the risk to the infant. Newborns should
be monitored for respiratory depression, apnea, bradycardia and arrhythmias
if nalbuphine has been used. Head Injury and Increased Intracranial Pressure The possible respiratory depressant effects
and the potential of potent analgesics to elevate cerebrospinal fluid
pressure (resulting from vasodilation following COretention)
may be markedly exaggerated in the presence of head injury, intracranial
lesions or a pre-existing increase in intracranial pressure. Furthermore,
potent analgesics can produce effects which may obscure the clinical
course of patients with head injuries. Therefore, nalbuphine hydrochloride
injection should be used in these circumstances only when essential,
and then should be administered with extreme caution.<br/>Interaction With Other Central
Nervous System Depressants: Although nalbuphine possesses opioid antagonist activity,
there is evidence that in nondependent patients it will not antagonize
an opioid analgesic administered just before, concurrently, or just
after an injection of nalbuphine hydrochloride. Therefore, patients
receiving an opioid analgesic, general anesthetics, phenothiazines,
or other tranquilizers, sedatives, hypnotics, or other CNS depressants
(including alcohol) concomitantly with nalbuphine mayexhibit an additive
effect. When such combined therapy is contemplated, the dose of one
or both agents should be reduced.
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Nalbuphine hydrochloride is indicated for the relief
of moderate to severe pain. Nalbuphine hydrochloride can also be used
as a supplement to balanced anesthesia, for preoperative and postoperative
analgesia, and for obstetrical analgesia during labor and delivery.
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Nalbuphine Hydrochloride
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