Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/549
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Buprenorphine Hydrochloride (Injection, Solution)
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Adults: The usual dosage
for persons 13 years of age and over is 1 mL buprenorphine hydrochloride injection
(0.3 mg buprenorphine) given by deep intramuscular or slow (over at least
2 minutes) intravenous injection at up to 6-hour intervals, as needed. Repeat
once (up to 0.3 mg) if required, 30 to 60 minutes after initial dosage, giving
consideration to previous dose pharmacokinetics, and thereafter only as needed.
In high-risk patients (e.g., elderly, debilitated, presence of respiratory
disease, etc.) and/or in patients where other CNS depressants are present,
such as in the immediate postoperative period, the dose should be reduced
by approximately one-half. Extra caution should be exercised with the intravenous
route of administration, particularly with the initial dose. Occasionally,
it may be necessary to administer single doses of up to 0.6 mg to adults depending
on the severity of the pain and the response of the patient. This dose should
only be given IM and only to adult patients who are not in a high risk category
(see WARNINGS and PRECAUTIONS). At this time, there are insufficient data
to recommend single doses greater than 0.6 mg for long-term use. Children: Buprenorphine hydrochloride has been
used in children 2 to 12 years of age at doses between 2 to 6 micrograms/kg
of body weight given every 4 to 6 hours. There is insufficient experience
to recommend a dose in infants below the age of two years, single doses greater
than 6 micrograms/kg of body weight, or the use of a repeat or second
dose at 30 to 60 minutes (such as is used in adults). Since there is some
evidence that not all children clear buprenorphine faster than adults, fixed
interval or "round-the-clock" dosing should not be undertaken until the proper
inter-dose interval has been established by clinical observation of the child.
Physicians should recognize that, as with adults, some pediatric patients
may not need to be remedicated for 6 to 8 hours. Safety and Handling: Buprenorphine hydrochloride
injection is supplied in sealed cartridges and poses no known environmental
risk to health care providers. Accidental dermal exposure should be treated
by removal of any contaminated clothing and rinsing the affected area with
water. Buprenorphine is a potent narcotic, and like
all drugs of this class has been associated with abuse and dependence among
health care providers. To control the risk of diversion, it is recommended
that measures appropriate to the health care setting be taken to provide rigid
accounting, control of wastage, and restriction of access. Parenteral
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
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| dailymed-instance:descripti... |
Buprenorphine hydrochloride is a narcotic under the Controlled
Substances Act due to its chemical derivation from thebaine. Chemically, it
is 17-(cyclopropylmethyl)-��-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-��-methyl-6,14-ethenomorphinan-7-methanol,
hydrochloride [5��, 7��(S)]. Buprenorphine hydrochloride is a white
powder, weakly acidic and with limited solubility in water. Buprenorphine
hydrochloride injection is a clear, sterile, injectable agonist-antagonist
analgesic intended for intravenous or intramuscular administration. Each mL
of buprenorphine hydrochloride injection contains 0.324 mg buprenorphine hydrochloride
(equivalent to 0.3 mg buprenorphine), 50 mg anhydrous dextrose, water for
injection, and HCl to adjust pH to 3.5 to 5.5. Buprenorphine hydrochloride
has the molecular formula, CHNO���HCl
and the molecular weight of 504.09. It has the following structural formula:
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Buprenorphine hydrochloride is a parenteral opioid analgesic
with 0.3 mg buprenorphine being approximately equivalent to 10 mg morphine
sulfate in analgesic and respiratory depressant effects in adults. Pharmacological
effects occur as soon as 15 minutes after intramuscular injection and persist
for 6 hours or longer. Peak pharmacologic effects usually are observed at
1 hour. When used intravenously, the times to onset and peak effect are shortened. The
limits of sensitivity of available analytical methodology precluded demonstration
of bioequivalence between intramuscular and intravenous routes of administration.
In postoperative adults, pharmacokinetic studies have shown elimination half-lives
ranging from 1.2 to 7.2 hours (mean 2.2 hours) after intravenous administration
of 0.3 mg of buprenorphine. A single, ten-patient, pharmacokinetic study of
doses of 3 mcg/kg in children (age 5 to 7 years) showed a high inter-patient
variability, but suggests that the clearance of the drug may be higher in
children than in adults. This is supported by at least one repeat-dose study
in postoperative pain that showed an optimal inter-dose variable of 4 to 5
hours in pediatric patients as opposed to the recommended 6 to 8 hours in
adults. Buprenorphine, in common with morphine and other
phenolic opioid analgesics, is metabolized by the liver and its clearance
is related to hepatic blood flow. Studies in patients anesthetized with 0.5%
halothane have shown that this anesthetic decreases hepatic blood flow by
about 30%. Mechanism of Analgesic
Action: Buprenorphine hydrochloride exerts its analgesic effect
via high affinity binding to��subclass opiate receptors in the central
nervous system. Although buprenorphine may be classified as a partial agonist,
under the conditions of recommended use it behaves very much like classical��agonists such as morphine. One unusual property of buprenorphine observed
in in vitro studies is its very slow
rate of dissociation from its receptor. This could account for its longer
duration of action than morphine, the unpredictability of its reversal by
opioid antagonists, and its low level of manifest physical dependence. Narcotic Antagonist Activity: Buprenorphine demonstrates
narcotic antagonist activity and has been shown to be equipotent with naloxone
as an antagonist of morphine in the mouse tail flick test. Cardiovascular Effects: Buprenorphine may cause
a decrease or, rarely, an increase in pulse rate and blood pressure in some
patients. Effects on Respiration: Under usual conditions of use in adults, both buprenorphine and
morphine show similar dose-related respiratory depressant effects. At adult
therapeutic doses, buprenorphine hydrochloride (0.3 mg buprenorphine) can
decrease respiratory rate in an equivalent manner to an equianalgesic dose
of morphine (10 mg). (See WARNINGS.)
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Store at 20��to 25��C (68��to 77��F)
[see USP Controlled Room Temperature.] Protect from
prolonged exposure to light. Retain in carton until
time of use. Do not freeze. HOSPIRA, INC., LAKE FOREST,
IL 60045, USA
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General:: Buprenorphine hydrochloride should be administered with caution
in the elderly, debilitated patients, in children and those with severe impairment
of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenal
cortical insufficiency (e.g., Addison's disease); CNS depression or
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute
alcoholism; delirium tremens; or kyphoscoliosis. Because
buprenorphine is metabolized by the liver, the activity of buprenorphine may
be increased and/or extended in those individuals with impaired hepatic function
or those receiving other agents known to decrease hepatic clearance. Buprenorphine
has been shown to increase intracholedochal pressure to a similar degree as
other opioid analgesics, and thus should be administered with caution to patients
with dysfunction of the biliary tract.<br/>Information for Patients:: The effects of buprenorphine, particularly drowsiness, may
be potentiated by other centrally acting agents such as alcohol or benzodiazepines.
It is particularly important that in these circumstances patients must not
drive or operate machinery. Buprenorphine has some pharmacologic effects similar
to morphine which in susceptible patients may lead to self-administration
of the drug when pain no longer exists. Patients must not exceed the dosage
of buprenorphine prescribed by their physician. Patients should be urged to
consult theirphysician if other prescription medications are currently being
used or are prescribed for future use.<br/>Drug Interactions:: Drug interactions common to other potent opioid analgesics
also may occur with buprenorphine. Particular care should be taken when buprenorphine
hydrochloride is used in combination with central nervous system depressant
drugs (see WARNINGS). Although specific information is not presently available,
caution should be exercised when buprenorphine hydrochloride is used in combination
with MAO inhibitors. There have been reports of respiratory and cardiovascular
collapse in patients who received therapeutic doses of diazepam and buprenorphine.
A suspected interaction between buprenorphine hydrochloride and phenprocoumon
resulting in purpura has been reported. CYP3A4
Inhibitors: Since the metabolism of buprenorphine is mediated by
the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity
may cause decreased clearance of buprenorphine. Thus patients coadministered
with inhibitors of CYP3A4 such as macrolide antibiotics (e.g., erythromycin),
azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g.,
ritanovir) while receiving buprenorphine should be carefully monitored and
dosage adjustment made if warranted. CYP3A4
Inducers: Cytochrome P450 inducers, such as rifampin, carbamazepine,
and phenytoin, induce metabolism and as such may cause increased clearance
of buprenorphine. Caution is advised when administering buprenorphine to patients
receiving these medications and if necessary dose adjustments should be considered.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility:: Carcinogenesis: Carcinogenicity
studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine
was administered in the diet at doses of 0.6, 5.5 and 56 mg/kg/day for 27
months in rats. These doses were approximately equivalent to 5.7, 52 and 534
times the recommended human dose (1.2 mg) on a mg/mbody surface
area basis. Statistically significant dose-related increases in testicular
interstitial (Leydig's) cell tumors occurred, according to the trend
test adjusted for survival. Pairwise comparison of the high dose against control
failed to show statistical significance. In the mouse study, buprenorphine
was administered inthe diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks. The
high dose was approximately equivalent to 477 times the recommended human
dose (1.2 mg) on a mg/mbasis. Buprenorphine was not carcinogenic
in mice. Mutagenesis: Buprenorphine
was studied in a series of tests. Results were negative in Chinese hamster
bone marrow and spermatogonia cells, and negative in mouse lymphoma L5178Y
assay. Results were equivocal in the Ames test: negative in studies in two
laboratories, but positive in frame shift mutation at high dose (5 mg/plate)
in a third study. Impairment
of Fertility: Reproduction studies of buprenorphine in rats demonstrated
no evidence of impaired fertility at daily oral doses up to 80 mg/kg (approximately
763 times the recommended human daily dose of 1.2 mg on a mg/mbasis)
or up to 5 mg/kg I.M. or S.C. (approximately 48 times the recommended
human daily dose of 1.2 mg on a mg/mbasis).<br/>Pregnancy: Pregnancy Category C.: Teratogenic effects: Buprenorphine
was not teratogenic in rats or rabbits after I.M. or S.C. doses up to 5 mg/kg/day
(approximately 48 and 95 times the recommended human daily dose of 1.2 mg
on a mg/mbasis), I.V. doses up to 0.8 mg/kg/day (approximately
8 times and 15 times the recommended human daily dose of 1.2 mg on a mg/mbasis),
or oral doses up to 160 mg/kg/day in rats (approximately 1525 times the recommended
human daily dose of 1.2 mg on a mg/mbasis) and 25 mg/kg/day in
rabbits (approximately 475 times the recommended human daily dose of 1.2 mg
on a mg/mbasis). Significant increases in skeletal abnormalities
(e.g. extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after
S.C. administration of 1 mg/kg/day and up (approximately 9.5 times the recommended
human daily dose of 1.2 mg on a mg/mbasis) and in rabbits after
I.M. administration of 5 mg/kg/day (approximately 95 times the recommended
human daily dose of 1.2 mg on a mg/mbasis), but these increases
were not statistically significant. Increases in skeletal abnormalities after
oral administration were not observed in rats, and increases in rabbits (1-25
mg/kg/day) were not statistically significant. There
are no adequate and well-controlled studies in pregnant women. Buprenorphine
hydrochloride should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.<br/>Labor and Delivery:: The safety of buprenorphine given during labor and delivery
has not been established.<br/>Nursing Mothers:: An apparent lack of milk production during general reproduction
studies with buprenorphine in rats caused decreased viability and lactation
indices. Use of high doses of sublingual buprenorphine in pregnant women showed
that buprenorphine passes into the mother's milk. Breast-feeding is
therefore not advised in nursing mothers treated with buprenorphine.<br/>Pediatric Use:: The safety and effectiveness of buprenorphine have been established
for children between 2 and 12 years of age. Use of buprenorphine in children
is supported by evidence from adequate and well controlled trials of buprenorphine
in adults, with additional data from studies of 960 children ranging in age
from 9 months to 18 years of age. Data is available from a pharmaco-kinetic
study, several controlled clinical trials, and several large post-marketing
studies and case series. The available information provides reasonable evidence
that buprenorphine may be used safely in children ranging from 2 to 12 yearsof age, and that it is of similar effectiveness in children as in adults.
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Manifestations: Clinical
experience with buprenorphine overdosage has been insufficient to define the
signs of this condition at this time. Although the antagonist activity of
buprenorphine may become manifest at doses somewhat above the recommended
therapeutic range, doses in the recommended therapeutic range may produce
clinically significant respiratory depression in certain circumstances. (See
WARNINGS.) Treatment: The
respiratory and cardiac status of the patients should be monitored carefully.
Primary attention should be given to the re-establishment of adequate respiratory
exchange through provision of a patent airway and institution of assisted
or controlled ventilation. Oxygen, intravenous fluids, vasopressors, and other
supportive measures should be employed as indicated. Doxapram, a respiratory
stimulant, may be used. NALOXONE MAY NOT BE EFFECTIVE
IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE. THEREFORE,
AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE
THE RE-ESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF
RESPIRATION, IF REQUIRED.
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Buprenorphine Hydrochloride
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Buprenorphine Hydrochloride (Injection, Solution)
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The most frequent side effect in clinical studies involving
1,133 patients was sedation which occurred in approximately two-thirds of
the patients. Although sedated, these patients could easily be aroused to
an alert state. Other less
frequent adverse reactions occurring in 5 to 10% of the patients were: Occurring in 1 to 5% of the patients: The following adverse reactions
were reported to have occurred in less than 1% of the patients: CNS Effect: confusion, blurred vision, euphoria,
weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia. Cardiovascular: hypertension, tachycardia, bradycardia. Gastrointestinal: constipation. Respiratory: dyspnea, cyanosis. Dermatological: pruritus. Ophthalmological: diplopia, visual abnormalities. Miscellaneous: Injection site reaction, urinary
retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis,
Wenckebach block, and psychosis. Other effects observed
infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia,
flatulence, apnea, rash, amblyopia, tremor, and pallor. The
following reactions have been reported to occur rarely: loss of appetite,
dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle coordination. Allergic Reactions: Cases of acute and chronic
hypersensitivity to buprenorphine have been reported both in clinical trials
and in the postmarketing experience of buprenorphine and other buprenorphine-containing
products. The most common signs and symptoms include rashes, hives, and pruritus.
Cases of bronchospasm, angioneurotic edema,and anaphylactic shock have been
reported. A history of hypersensitivity to buprenorphine is a contraindication
to buprenorphine. In the United Kingdom, buprenorphine
hydrochloride was made available under monitored release regulation during
the first year of sale, and yielded data from 1,736 physicians on 9,123 patients
(17,120 administrations). Data on 240 children under the age of 18 years were
included in this monitored release program. No important new adverse effects
attributable to buprenorphine hydrochloride were observed.
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Impaired Respiration: As
with other potent opioids, clinically significant respiratory depression may
occur within the recommended dose range in patients receiving therapeutic
doses of buprenorphine. Buprenorphine hydrochloride should be used with caution
in patients with compromised respiratory function (e.g., chronic obstructive
pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia,
hypercapnia, or preexisting respiratory depression). Particular caution is
advised if buprenorphine is administered to patients taking or recently receiving
drugs with CNS/respiratory depressant effects. In patients with the physical
and/or pharmacological risk factors above, the dose should be reduced by approximately
one-half. NALOXONE MAY NOT
BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE.
THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE
SHOULD BE THE RE-ESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE
OF RESPIRATION, IF REQUIRED. Interaction
with Other Central Nervous System Depressants: Patients receiving
buprenorphine hydrochloride in the presence of other narcotic analgesics,
general anesthetics, antihistamines, benzodiazepines, phenothiazines, other
tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol)
may exhibit increased CNS depression. When such combined therapy is contemplated,
it is particularly important that the dose of one or both agents be reduced. Head Injury and Increased Intracranial Pressure: Buprenorphine
hydrochloride, like other potent analgesics, may itself elevate cerebrospinal
fluid pressure and should be used with caution in head injury, intracranial
lesions and other circumstances where cerebrospinal pressure may be increased.
Buprenorphine can produce miosis and changes in the level of consciousness
which may interfere with patient evaluation. Use In Ambulatory Patients: Buprenorphine may impair
the mental or physical abilities required for the performance of potentially
dangerous tasks such as driving a car or operating machinery. Therefore, buprenorphine
hydrochloride should be administered with caution to ambulatory patients who
should be warned to avoid such hazards. Use
in Narcotic-Dependent Patients: Because of the narcotic antagonist
activity of buprenorphine, use in the physically dependent individual may
result in withdrawal effects.
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Buprenorphine hydrochloride injection is indicated for the
relief of moderate to severe pain.
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Buprenorphine Hydrochloride
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