Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2309
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Butorphanol Tartrate (Injection, Solution)
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Factors to be considered in determining the
dose are age, body weight, physical status, underlying pathological condition,
use of other drugs, type of anesthesia to be used, and surgical procedure
involved. Use in the elderly, patients with hepatic or renal disease, or in
labor requires extra caution (see PRECAUTIONS section
and CLINICAL PHARMACOLOGY: Individualization of
Dosage section). The following doses are for patients who do not
have impaired hepatic or renal function and who are not on CNS active agents. Use for Pain Intravenous���The usual recommended single dose for IV administration
is 1 mg repeated every three to four hours as necessary. The effective dosage
range, depending on the severity of pain, is 0.5 to 2 mg repeated every three
to four hours. Intramuscular���The usual recommended single dose for IM administration
is 2 mg in patients who will be able to remain recumbent, in the event drowsiness
or dizziness occurs. This may be repeated every three to four hours, as necessary.
The effective dosage range depending on the severity of pain is 1 to 4 mg
repeated every three to four hours. There are insufficient clinical data to
recommend single doses above 4 mg. Use
as Preoperative/Preanesthetic Medication The
preoperative medication dosage of butorphanol tartrate injection should be
individualized (see CLINICAL PHARMACOLOGY: Individualization
of Dosage section). The usual adult dose is 2 mg IM, administered
60 to 90 minutes before surgery. This is approximately equivalent in sedative
effect to 10 mg morphine or80 mg meperidine. Use in Balanced Anesthesia The
usual dose of butorphanol tartrate injection is 2 mg IV shortly before induction
and/or 0.5 to 1 mg IV in increments during anesthesia. The increment
may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous
sedative, analgesic, and hypnotic drugs administered. The total dose of butorphanol
injection will vary; however, patients seldom require less than 4 mg or more
than 12.5 mg (approximately 0.06 to 0.18mg/kg). Labor In patients at full
term in early labor a 1 to 2 mg dose of butorphanol tartrate IV or IM may
be administered and repeated after 4 hours. Alternative analgesia should be
used for pain associated with delivery or if delivery is expected to occur
within 4 hours. If concomitant use of butorphanol with
drugs that may potentiate its effects is deemed necessary (see PRECAUTIONS:
Drug Interactions section) the lowest effective dose should be employed. Safety and Handling Butorphanol
tartrate injection is supplied in sealed delivery systems that have a low
risk of accidental exposure to health care workers. Ordinary care should be
taken to avoid aerosol generation while preparing a syringe for use. Following
skin contact, rinsing with cool water is recommended. The
disposal of Schedule IV controlled substances must be consistent with State
and Federal Regulations. Parenteral drug products should
be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit.
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Butorphanol tartrate is a synthetically derived opioid agonist-antagonist
analgesic of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl)
morphinan-3, 14-diol D-(-)- tartrate (1:1) (salt). The molecular formula is
CHNO���CHO,
which corresponds to a molecular weight of 477.56 and the following structural
formula: Butorphanol tartrate is a white
crystalline substance. The dose is expressed as the tartrate salt. One milligram
of the salt is equivalent to 0.68 mg of the free base. The n-octanol/aqueous
buffer partition coefficient of butorphanol is 180:1 at pH 7.5. Butorphanol
tartrate injection is a sterile, nonpyrogenic parenteral aqueous solution
of butorphanol tartrate for intravenous or intramuscular administration. Each
milliliter (mL) contains butorphanol tartrate 1 or 2 mg; sodium citrate, dihydrate,
6.4 mg; citric acid hydrous 3.3 mg; sodium chloride 6.4 mg. The pH is 4.5
(3.0 to 5.5).
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General Pharmacology and Mechanism
of Action Butorphanol is a mixed agonist-antagonist
with low intrinsic activity at receptors of the��-opioid type (morphine-like). It is also an agonist at k-opioid receptors. Its
interactions with these receptors in the central nervous system apparently
mediate most of its pharmacologic effects, including analgesia. In
addition to analgesia, CNS effects include depression of spontaneous respiratory
activity and cough, stimulation of the emetic center, miosis and sedation.
Effects possibly mediated by non-CNS mechanisms include alteration in cardiovascular
resistance and capacitance, bronchomotor tone, gastrointestinal secretory
and motor activity and bladder sphincter activity. In
an animal model, the dose of the butorphanol tartrate required to antagonize
morphine analgesia by 50% was similar to that for nalorphine, less than that
for pentazocine and more than that for naloxone. The
pharmacological activity of butorphanol metabolites has not been studied in
humans; in animal studies, butorphanol metabolites have demonstrated some
analgesic activity. In human studies of butorphanol
(see Clinical Trials), sedation is commonly
noted at doses of 0.5 mg or more. Narcosis is produced by 10 to 12 mg doses
of butorphanol administered over 10 to 15 minutes intravenously. Butorphanol,
like other mixed agonist-antagonists with a high affinity for the kappa receptor,
may produce unpleasant psychotomimetic effects in some individuals. Nausea
and/or vomiting may be produced by doses of 1 mg or more administered by any
route. In human studies involving individuals without
significant respiratory dysfunction, 2 mg of butorphanol IV and 10 mg of morphine
sulfate IV depressed respiration to a comparable degree. At higher doses,
the magnitude of respiratory depression with butorphanol is not appreciably
increased; however, the duration of respiratory depression is longer. Respiratory
depression noted after administration of butorphanol to humans by any route
is reversed by treatment with naloxone, a specific opioid antagonist (see OVERDOSAGE: Treatment section). Butorphanol
tartrate demonstrates antitussive effects in animals at doses less than those
required for analgesia. Hemodynamic changes noted during
cardiac catheterization in patients receiving single 0.025 mg/kg intravenous
doses of butorphanol have included increases in pulmonary artery pressure,
wedge pressure and vascular resistance, increases in left ventricular end
diastolic pressure and in systemic arterial pressure. Pharmacodynamics The analgesic
effect of butorphanol is influenced by the route of administration. Onset
of analgesia is within a few minutes for intravenous administration and within
15 minutes for intramuscular injection. Peak analgesic
activity occurs within 30 to 60 minutes following intravenous and intramuscular
administration. The duration of analgesia varies depending
on the pain model as well as the route of administration, but is generally
3 to 4 hours with IM and IV doses as defined by the time 50% of patients required
remedication. In postoperative studies, the duration of analgesia with IV
or IM butorphanol was similar to morphine, meperidine and pentazocine when
administered in the same fashion at equipotent doses (see Clinical
Trials). Pharmacokinetics Butorphanol tartrate injection is rapidly
absorbed after IM injection and peak plasma levels are reached in 20 to 40
minutes. Following its initial absorption/distribution
phase, the single dose pharmacokinetics of butorphanol by the intravenous
and intramuscular routes of administration are similar (see Figure 1). Serum protein binding is independent of concentration over
the range achieved in clinical practice (up to 7 ng/mL) with a bound fraction
of approximately 80%. The volume of distribution of
butorphanol varies from 305 to 901 liters and total body clearance from 52
to 154 liters/hr (see Table 1). Table
1���Mean Pharmacokinetic Parameters of Intravenous Butorphanol in Young
and Elderly Subjects a) Young subjects (n=24) are from 20 to 40 years old and
elderly (n=24) are greater than 65 years of age. b)
Area under plasma concentration-time curve after a 1 mg dose. c)
Derived from IV data. d) Mean (1S.D.). e)
(range of observed values). The drug is transported
across the blood-brain and placental barriers and into human milk (see PRECAUTIONS: Labor and Delivery and Nursing Mothers sections). Butorphanol
is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively
similar following intravenous or intramuscular administration. Oral bioavailability
is only 5 to 17% because of extensive first pass metabolism of butorphanol. The
major metabolite of butorphanol is hydroxybutorphanol, while norbutorphanol
is produced in small amounts. Both have been detected in plasma following
administration of butorphanol, with norbutorphanol present at trace levels
at most time points. The elimination half-life of hydroxybutorphanol is about
18 hours and, as a consequence, considerable accumulation (~5-fold) occurs
when butorphanol is dosed to steady state. Elimination
occurs by urine and fecal excretion. WhenH labeled butorphanol
is administered to normal subjects, most (70 to 80%) of the dose is recovered
in the urine, while approximately 15% is recovered in the feces. About
5% of the dose is recovered in the urine as butorphanol. Forty-nine percent
is eliminated in the urine as hydroxybutorphanol. Less than 5% is excreted
in the urine as norbutorphanol. Butorphanol pharmacokinetics
in the elderly differ from younger patients (see Table 1). In
renally impaired patients with creatinine clearances<30 mL/min, the elimination
half-life was approximately doubled and the total body clearance was approximately
one half (10.5 hours [clearance 150 L/h] compared to 5.8 hours [clearance
260 L/h] in healthy subjects). No effect on Cor Twas
observed after a single dose. After intravenous administration
to patients with hepatic impairment, the elimination half-life of butorphanol
was approximately tripled and total body clearance was approximately one half
(half-life 16.8 hours, clearance 92 L/h) compared to healthy subjects (half-life
4.8 hours, clearance 175 L/h). The exposure of hepatically impaired patients
to butorphanol was significantly greater (about 2-fold) than that in healthy
subjects. For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, Drug Interactions and Geriatric Use sections
and to the CLINICAL PHARMACOLOGY: Individualization
of Dosage section below.
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Butorphanol tartrate injection is contraindicated in patients
hypersensitive to butorphanol tartrate.
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Butorphanol Tartrate Injection, USP is supplied as follows: Store at 20 to 25��C (68 to 77��F). [See USP Controlled
Room Temperature.] Protect from light. October, 2004 HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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Head Injury and Increased Intracranial
Pressure As with other opioids, the use of
butorphanol in patients with head injury may be associated with carbon dioxide
retention and secondary elevation of cerebrospinal fluid pressure, drug-induced
miosis, and alterations in mental state that would obscure the interpretation
of the clinical course of patients with head injuries. In such patients, butorphanol
should be used only if the benefits of use outweigh the potential risks. Disorders of Respiratory Function or Control Butorphanol
may produce respiratory depression, especially in patients receiving other
CNS active agents, or patients suffering from CNS diseases or respiratory
impairment. Hepatic and Renal
Disease In patients with hepatic or renal
impairment, the initial dose of butorphanol tartrate injection should generally
be half the recommended adult dose (0.5 mg IV and 1 mg IM). Repeat doses in
these patients should be determined by the patient's response rather
than at fixed intervals but will generally be no less than 6 hours apart (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization
of Dosage sections). Cardiovascular
Effects Because butorphanol may increase the
work of the heart, especially the pulmonary circuit, the use of butorphanol
in patients with acute myocardial infarction, ventricular dysfunction, or
coronary insufficiency should be limited to those situations where the benefits
clearly outweigh the risk (see CLINICAL PHARMACOLOGY). Severe hypertension has been reported
rarely during butorphanol therapy. In such cases, butorphanol should be discontinued
and the hypertension treated with antihypertensive drugs. In patients who
are not opioid dependent, naloxone has also been reported to be effective. Use in Ambulatory Patients<br/>Drug Interactions: Concurrent use of butorphanol with central nervous system
depressants (e.g., alcohol, barbiturates, tranquilizers, and antihistamines)
may result in increased central nervous system depressant effects. When used
concurrently with such drugs, the dose of butorphanol should be the smallest
effective dose and the frequency of dosing reduced as much as possible when
administered concomitantly with drugs that potentiate the action of opioids. It
is not known if the effects of butorphanol are altered by other concomitant
medications that affect hepatic metabolism of drugs (erythromycin, theophylline,
etc.), but physicians should be alert to the possibility that a smaller initial
dose and longer intervals between doses may be needed. No
information is available about the use of butorphanol concurrently with MAO
inhibitors.<br/>Information for Patients: (see PRECAUTIONS: Use in Ambulatory
Patients)<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Two year carcinogenicity studies were conducted in mice and
rats given butorphanol tartrate in the diet up to 60 mg/kg/day (180 mg/mfor
mice and 354 mg/mfor rats). There was no evidence of carcinogenicity
in either species in these studies. Butorphanol was
not genotoxic in S. typhimurium or E. coli assays or in unscheduled DNA synthesis
and repair assays conducted in cultured human fibroblast cells. Rats
treated orally with 160 mg/kg/day (944 mg/m) had a reduced pregnancy
rate. However, a similar effect was not observed with a 2.5 mg/kg/day (14.75
mg/m) subcutaneous dose.<br/>Pregnancy: Pregnancy Category C: Reproduction
studies in mice, rats and rabbits during organogenesis did not reveal any
teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously
with butorphanol at 1 mg/kg (5.9 mg/m) had a higher frequency
of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m)
and 60 mg/kg/oral (720 mg/m) also showed higher incidences of
post-implantation loss in rabbits. There are no adequate
and well-controlled studies of butorphanol in pregnant women before 37 weeks
of gestation. Butorphanol tartrate injection should be used during pregnancy
only if the potential benefit justifies the potential risk to the infant.<br/>Labor and Delivery: There have been rare reports of infant respiratory distress/apnea
following the administration of butorphanol tartrate during labor. The reports
of respiratory distress/apnea have been associated with administration of
a dose within two hours of delivery, use of multiple doses, use with additional
analgesic or sedative drugs, or use in preterm pregnancies (see OVERDOSAGE:
Treatment). In a study of 119 patients, the
intravenous administration of 1 mg butorphanol tartrate during labor was associated
with transient (10 to 90 minutes) sinusoidal fetal heart rate patterns, but
was not associated with adverse neonatal outcomes. In the presence of an abnormal
fetal heart rate pattern, butorphanol injection should be used with caution.<br/>Nursing Mothers: Butorphanol has been detected in milk following administration
of butorphanol tartrate injection to nursing mothers. The amount an infant
would receive is probably clinically insignificant (estimated 4 mcg/liter
of milk in a mother receiving 2 mg IM four times a day).<br/>Pediatric Use: Butorphanol is not recommended for use in patients below
18 years of age because safety and efficacy have not been established in this
population.<br/>Geriatric Use: Of the approximately 1500 patients treated with butorphanol
tartrate injection in clinical studies, 15% were 61 years of age or older
and 1% were 76 years or older. Due to changes in clearance, the mean half-life
of butorphanol is increased by 25% in patients over the age of 65 years (see CLINICAL PHARMACOLOGY: Pharmacokinetics section).
Elderly patients may be more sensitive to the side effects of butorphanol.
There are insufficient efficacy data for patients���65 years to determine
whether they respond differently from younger patients. The
initial dose of butorphanol tartrate injection recommended for elderly patients
should generally be half the recommended adult dose (0.5 mg IV and 1 mg IM).
Repeat dose should be determined by the patient's response rather than
at fixed intervals, but will generally be no less than 6 hours apart (see CLINICAL PHARMACOLOGY: Individualization of Dosage section. Butorphanol
and its metabolites are known to be substantially excreted by the kidney,
and the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection.
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Clinical Manifestations The
clinical manifestations of butorphanol overdose are those of opioid drugs
in general. Consequences of overdose vary with the amount of butorphanol ingested
and of individual response to the effects of opiates. The most serious symptoms
are hypoventilation, cardiovascular insufficiency, coma and death. Butorphanol
overdose may be associated with ingestion of multiple drugs (see ADVERSE REACTIONS: Postmarketing Experience section). Overdose
can occur due to accidental or intentional misuse of butorphanol, especially
in young children who may gain access to the drug in the home. Treatment The management
of suspected butorphanol overdosage includes maintenance of adequate ventilation,
peripheral perfusion, normal body temperature, and protection of the airway.
Patients should be under continuous observation with adequate serial measures
of mental state, responsiveness and vital signs. Oxygen and ventilatory assistance
should be available with continual monitoring by pulse oximetry if indicated.
In the presence of coma, placement of an artificial airway may be required.
An adequate intravenous portal should be maintained to facilitate treatment
of hypotension associated with vasodilation. The use
of a specific opioid antagonist such as naloxone should be considered. As
the duration of butorphanol action usually exceeds the duration of action
of naloxone, repeated dosing with naloxone may be required. In
managing cases of suspected butorphanol overdosage, the possibility of multiple
drug ingestion should always be considered.
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Butorphanol Tartrate
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Butorphanol Tartrate (Injection, Solution)
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Clinical Trial Experience: A total of 2446 patients were studied in premarketing clinical
trials of butorphanol. Approximately half received butorphanol tartrate injection
with the remainder receiving butorphanol tartrate nasal spray. In nearly all
cases the type and incidence of side effects with butorphanol by any route
were those commonly observed with opioid analgesics. The
adverse experiences described below are based on data from short- and long-term
clinical trials in patients receiving butorphanol by any route. There has
been no attempt to correct for placebo effect or to subtract the frequencies
reported by placebo treated patients in controlled trials. The
most frequently reported adverse experiences across all clinical trials with
butorphanol tartrate injection and nasal spray were somnolence (43%), dizziness
(19%), nausea and/or vomiting (13%). In long-term trials with nasal butorphanol
only, nasal congestion (13%) and insomnia (11%) were frequently reported. The
following adverse experiences were reported at a frequency of 1% or greater
in clinical trials and were considered to be probably related to the use of
butorphanol: Body as a Whole: Asthenia/Lethargy, Headache, Sensation of Heat Cardiovascular: Vasodilation, Palpitations Digestive: Anorexia, Constipation, Dry Mouth, Nausea
and/or Vomiting, Stomach Pain Nervous: Anxiety, Confusion, Dizziness, Euphoria, Floating Feeling, Insomnia,
Nervousness, Paresthesia, Somnolence, Tremor Respiratory: Bronchitis, Cough, Dyspnea, Epistaxis,
Nasal Congestion, Nasal Irritation, Pharyngitis, Rhinitis, Sinus Congestion,
Sinusitis, Upper Respiratory Infection Skin
and Appendages: Sweating/Clammy, Pruritus Special Senses: Blurred Vision, Ear Pain, Tinnitus,
Unpleasant Taste The following adverse experiences were
reported with a frequency of less than 1% in clinical trials and were considered
to be probably related to the use of butorphanol: Cardiovascular: Hypotension, Syncope Nervous: Abnormal Dreams, Agitation, Dysphoria,
Hallucinations, Hostility, Withdrawal Symptoms Skin and Appendages: Rash/Hives Urogenital: Impaired Urination The
following infrequent additional adverse experiences were reported in a frequency
of less than 1% of the patients studied in short-term butorphanol tartrate
nasal sprays trials and under circumstances where the association between
these events and butorphanol administration is unknown. They are being listed
as alerting information for the physician: Body as a Whole: Edema Cardiovascular: Chest Pain, Hypertension, Tachycardia Nervous: Depression Respiratory: Shallow Breathing Postmarketing Experience Postmarketing
experience with butorphanol tartrate injection has shown an adverse event
profile similar to that seen during the premarketing evaluation of butorphanol
by all routes of administration. Adverse experiences that were associated
with the use of butorphanol tartrate injection and that are not listed above
have been chosen for inclusion below because of their seriousness, frequency
of reporting, or probable relationship to butorphanol. Because they are reported
voluntarily from a population of unknown size, estimates of frequency cannot
be made. These adverse experiences include apnea, convulsion, delusion, drug
dependence, excessive drug effect associated with transient difficulty speaking
and/or executing purposeful movements, overdose and vertigo. Reports of butorphanol
overdose with a fatal outcome have usually but not always been associated
with ingestion of multiple drugs.
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Patients Dependent on Narcotics Because of its opioid antagonist properties,
butorphanol is not recommended for use in patients dependent on narcotics.
Such patients should have an adequate period of withdrawal from opioid drugs
prior to beginning butorphanol therapy. In patients taking opioid analgesics
chronically, butorphanol has precipitated withdrawal symptoms such as anxiety,
agitation, mood changes, hallucinations, dysphoria, weakness and diarrhea. Because
of the difficulty in assessing opioid tolerance in patients who have recently
received repeated doses of narcotic analgesic medication, caution should be
used in the administration of butorphanol to such patients.<br/>Drug Abuse and Dependence:<br/>Drug Abuse: Butorphanol tartrate, by all routes of administration, has
been associated with episodes of abuse. Of the cases received, there were
more reports of abuse with the nasal spray formulation than with the injectable
formulation.<br/>Physical Dependence, Tolerance and Withdrawal: Prolonged continuous use of butorphanol tartrate may result
in physical dependence or tolerance (a decrease in response to a given dose).
Abrupt cessation of use by patients with physical dependence may result in
symptoms of withdrawal. Note���Proper
patient selection, dose and prescribing limitations, appropriate directions
for use, and frequent monitoring are important to minimize the risk of abuse
and physical dependence. (See DRUG ABUSE AND DEPENDENCE section below.)
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Butorphanol tartrate injection is indicated for the management
of pain when the use of an opioid analgesic is appropriate. Butorphanol
tartrate injection is also indicated as a preoperative or preanesthetic medication,
as a supplement to balanced anesthesia, and for the relief of pain during
labor.
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Butorphanol Tartrate
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