Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2374
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Butorphanol Tartrate (Spray)
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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 and in patients with hepatic or renal disease requires extra caution . The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents.<br/>Use for Pain: The usual recommended dose for initial nasal administration of butorphanol tartrate nasal spray is 1 mg (1 spray in one nostril). Adherence to this dose reduces the incidence of drowsiness and dizziness. If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given. The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence. Depending on the severity of the pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients single additional 2 mg doses should not be given for 3 to 4 hours.<br/>Use in Balanced Anesthesia: The use of butorphanol tartrate nasal spray is not recommended because it has not been studied in induction or maintenance of anesthesia.<br/>Labor: The use of butorphanol tartrate nasal spray is not recommended as it has not been studied in labor.<br/>Safety and Handling: Butorphanol tartrate nasal spray is an open delivery system with increased risk of exposure to health care workers. In the priming process, a certain amount of butorphanol may be aerosolized; therefore, the pump sprayer should be aimed away from the patient or other people or animals. The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations. The unit should be disposed of by unscrewing the cap, rinsing the bottle, and placing the parts in a waste container.
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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 [S-(R*,R*)]���2,3���dihydroxybutanedioate (1:1) (salt). The molecular formula is CHNO���CHO, which corresponds to a molecular weight of 477.55 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. Then-octanol/aqueous buffer partition coefficient of butorphanol is 180:1 at pH 7.5. Butorphanol Tartrate Nasal Spray is an aqueous solution of butorphanol tartrate for administration as a metered spray to the nasal mucosa. Each mL contains 10 mg of butorphanol tartrate, 6.5 mg sodium chloride, 1 mg citric acid, 1.2 mg sodium hydroxide, 0.2 mg benzethonium chloride in purified water; pH adjusted to 5.0 with sodium hydroxide and/or hydrochloric acid, if necessary. The pump reservoir must be fully primed prior to initial use. After initial priming each metered spray delivers an average of 1 mg of butorphanol tartrate and the 2.5 mL bottle will deliver an average of 14 to 15 doses of Butorphanol Tartrate Nasal Spray. If not used for 48 hours or longer, the unit must be reprimed . With intermittent use requiring repriming before each dose, the 2.5 mL bottle will deliver an average of 8 to 10 doses of Butorphanol Tartrate Nasal Spray depending on how much repriming is necessary.
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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��-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 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��-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 . 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.<br/>Pharmacodynamics: The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is within a few minutes for intravenous administration, within 15 minutes for intramuscular injection, and within 15 minutes for the nasal spray doses. Peak analgesic activity occurs within 30 to 60 minutes following intravenous and intramuscular administration and within 1 to 2 hours following the nasal spray 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). Compared to the injectable form and other drugs in this class, butorphanol tartrate nasal spray has a longer duration of action (4 to 5 hours)(see Clinical Trials).<br/>Pharmacokinetics: After nasal administration, mean peak blood levels of 0.9 to 1.04 ng/mL occur at 30 to 60 minutes after a 1 mg dose (see Table 1). The absolute bioavailability of butorphanol tartrate nasal spray is 60% to 70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. The peak plasma concentrations were approximately half those achieved in the absence of the vasoconstrictor. Following its initial absorption/distribution phase, the single dose pharmacokinetics of butorphanol by the intravenous, intramuscular, and nasal routes of administration are similar (see Figure 1). Figure 1 Butorphanol Plasma Levels After IV, IM, and Nasal Spray Administration of 2 mg Dose 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/hour (see Table 1). Dose proportionality for butorphanol tartrate nasal spray has been determined at steady state in doses up to 4 mg at 6 hour intervals. Steady state is achieved within 2 days. The mean peak plasma concentration at steady state was 1.8-fold (maximal 3-fold) following a single dose. The drug is transported across the blood brain and placental barriers and into human milk . Butorphanol is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively similar following intravenous, intramuscular, or nasal 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 (1 mg transnasally q6h for 5 days). Elimination occurs by urine and fecal excretion. When 3H-labelled 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). The mean absolute bioavailability of butorphanol tartrate nasal spray in elderly women (48%) was less than that in elderly men (75%), young men (68%), or young women (70%). Elimination half-life is increased in the elderly (6.6 hours as opposed to 4.7 hours in younger subjects). 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. Similar results were seen after nasal administration. No effect on Cor Twas observed after a single intranasal dose. For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, Drug Interactions, and CLINICAL PHARMACOLOGY: Individualization of Dosage.<br/>Clinical Trials: The effectiveness of opioid analgesics varies in different pain syndromes. Studies with butorphanol tartrate nasal spray have been performed in postoperative (general, orthopedic, oral, cesarean section) pain, in postepisiotomy pain, in pain of musculoskeletal origin, and in migraine headache pain (see below).<br/>Use in the Management of Pain:<br/>Individualization of Dosage: Use of butorphanol tartrate nasal spray in geriatric patients, patients with renal impairment, and patients with hepatic impairment requires extra caution . The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given. The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence. For the management of severe pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients additional doses should not be given for 3 to 4 hours. The incidence of adverse events is higher with an initial 2 mg dose (see Clinical Trials). The initial dose sequence in elderly patients and patients with renal or hepatic impairment should be limited to 1 mg followed, if needed, by 1 mg in 90 to 120 minutes. The repeat dose sequence in these patients should be determined by the patient's response rather than at fixed times but will generally be no less than at 6 hour intervals .
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Butorphanol tartrate nasal spray is contraindicated in patients hypersensitive to butorphanol tartrate or the preservative benzethonium chloride.
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Butorphanol Tartrate Nasal Spray is supplied in a child-resistant vial containing a 2.5 mL bottle of nasal spray solution (10 mg/mL) and a metered-dose spray pump with protective clip and dust cover (NDC 0378-9639-43; individual unit). A patient instructions leaflet and medication guide for patients are enclosed. On average, one bottle will deliver 14 to 15 doses if no repriming is necessary. STORE AT CONTROLLED ROOM TEMPERATURE 15��TO 30��C (59��TO 86��F) [See USP]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
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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 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 . 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.<br/>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 (Spray)
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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-term 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 were somnolence (43%), dizziness (19%), nausea and/or vomiting (13%). In long-term trials with butorphanol tartrate nasal spray 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 spray 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.<br/>Postmarketing Experience: Postmarketing experience with butorphanol tartrate nasal spray 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 nasal spray 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.
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Butorphanol tartrate nasal spray is indicated for the management of pain when the use of an opioid analgesic is appropriate.
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Butorphanol Tartrate
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