STADOL NS Bristol-Myers Squibb Butorphanol Tartrate Analgesic
Action and Clinical
Butorphanol acts as an agonist at kappa-opioid receptors and a mixed agonist-antagonist at mu-opioid receptors in the CNS to alter the perception of pain. The drug is believed to act at sites in the periventricular and periaqueductal gray matter, and at sites in the spinal cord.:
In an animal model, the dose of butorphanol 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 analgesic activity of 2 mg of butorphanol administered parenterally is approximately equivalent to 10 mg morphine sulfate, 80 mg meperidine HCl or 40 mg pentazocine. In normal volunteers, the same doses of these drugs produced nearly equivalent respiratory depression. Butorphanol, in contrast to morphine or meperidine, produces respiratory depression in a limited dose range, reaching a plateau at approximately 4 mg. The magnitude of respiratory depression with butorphanol is not appreciably increased at a dose of 4 mg; however, the duration of respiratory depression appears to be dose-related. Respiratory rates were monitored in controlled clinical studies with therapeutic doses of butorphanol and no untoward effects were observed. Respiratory depression noted after administration of butorphanol by any route is reversed by treatment with naloxone, a specific opioid antagonist (see Overdose: Symptoms and Treatment).
Butorphanol has a marked sedative effect that is dose-related and this property should be considered in its clinical application (see Precautions).
The hemodynamic changes after the i.v. administration of butorphanol are similar to those produced by pentazocine. These include increased pulmonary artery pressure, pulmonary wedge pressure, left ventricular end diastolic pressure, systemic arterial pressure and pulmonary vascular resistance. Although smaller than those associated with pentazocine, these changes are nevertheless in a direction that increases the work of the heart, especially in the pulmonary circuit.
Butorphanol, like other mixed agonist-antagonists with a high affinity for the kappa receptor, produced unpleasant psychotomimetic effects in some individuals.
Pharmacokinetics: The pharmacokinetics (including absorption times and peak blood levels) of a nasal spray dose and an i.m. dose of butorphanol are similar. In addition, after an initial absorption phase, the pharmacokinetics of a nasal spray dose are also similar to those of an i.v. dose.
Butorphanol is rapidly absorbed without significant biotransformation following nasal administration. In both young and elderly normal volunteers, peak blood levels occur around one-half hour following nasal administration. Peak plasma concentrations after a 1 mg dose vary from a mean of 0.9 to 1.04 ng/mL. Elderly subjects may have a somewhat decreased ability to eliminate butorphanol, with an apparent elimination half-life of 6.6 hours as opposed to 4.7 hours for younger subjects. The mean absolute bioavailability may be somewhat less for elderly women (48%) than for elderly men or younger subjects (75% and 69% respectively).
The mean plasma half-life of butorphanol is 5.1 hours after a 2 mg intranasal administration.
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%. Butorphanol crosses the blood brain and placental barriers and is found in human milk (see Precautions).
The volumes of distribution of butorphanol varies from 305 to 901 L and total body clearance from 52 to 154 L/h.
Intranasal butorphanol pharmacokinetics studies determined that steady-state plasma levels of butorphanol were dose proportional (in doses up to 4 mg every 6 hours). Steady-state is achieved within 2 days, and plasma concentrations are approximately 1.8 times those following a single dose.
Butorphanol is extensively metabolized in the liver and is eliminated as oxidized and conjugated metabolites. Metabolism is qualitatively and quantitatively similar with nasal, i.v., or i.m. administration. Less than 5% of an i.v. dose is recovered in the urine as unchanged drug. Because of extensive first-pass metabolism, the bioavailability of oral butorphanol is less than 10%.
Hydroxybutorphanol is the main urinary metabolite of butorphanol (49% of dose); small amounts of norbutorphanol (<5%) are also excreted in urine. The analgesic activity of these two metabolites has not been determined in humans.
Patients with Renal Insufficiency: Eighteen female volunteers (age 30 to 65 years) with normal or varying degrees of renal impairment were given single 1 mg intranasal doses of butorphanol. The elimination half-life of butorphanol was prolonged, and the AUC increased, in patients with reduced creatinine clearance (CrCl). No effect, however, was observed on C max or T max.
Patients with Hepatic Disease: The pharmacokinetics and absolute bioavailability of a 1 mg dose of transnasal butorphanol was studied in 12 (8M, 4F) subjects with hepatic impairment, and 12 normal subjects matched for sex, age and weight. Compared to normal subjects, patients with hepatic impairment had on average a 3-fold increase in t 1/2 and a 2- to 3-fold increase in AUC. Absolute bioavailability was 99% in the subjects with hepatic impairment compared to 73% in controls. C max and T max, however, remained unaltered regardless of the liver conditions.
Pharmacodynamics: Following intranasal administration of butorphanol, onset of analgesia is within 15 to 30 minutes, and peak analgesic activity generally occurs within 1 to 2 hours. The duration of analgesia varies depending on the pain model but is generally 3 to 6 hours with intranasal doses of 1 to 2 mg.
Clinical Studies: Migraine Headache Pain: The analgesic efficacy of two 1 mg doses 1 hour apart of butorphanol in migraine headache pain was compared with a single dose of 10 mg i.m. methadone or placebo (32 patients per treatment group). Significant onset of analgesia occurred within 15 minutes for both butorphanol and i.m. methadone. Peak analgesic effect occurred at 2 hours for butorphanol and 1.5 hours for methadone. The median duration of pain relief was 6 hours with butorphanol and 4 hours with methadone as judged by the time when approximately half of the patients remedicated.
In the two other trials in patients with migraine headache pain, a 2 mg initial dose of butorphanol followed by an additional 1 mg dose 1 hour later (76 patients) was compared with either 75 mg i.m. meperidine (24 patients) or placebo (72 patients). Onset peak activity and duration were similar with both active treatments; however, the incidence of adverse experiences (nausea, vomiting, dizziness) was higher in these two trials with the 2 mg initial dose of butorphanol than in the trial with the 1 mg initial dose.
Postoperative Analgesia: The analgesic efficacy of butorphanol was investigated in placebo-controlled studies in postoperative surgical pain (abdominal, orthopedic, gynecologic) and in postoperative caesarian section pain. Patients had moderate to severe pain at baseline.
In the general surgery study, a single 1 or 2 mg dose of butorphanol (33 to 36 patients per treatment group) was compared to a single dose of 37.5 or 75 mg i.m. meperidine. In this blinded study, the effects of the lower doses of each drug could be distinguished from those of the higher doses. Analgesia provided by the 1 and 2 mg doses of butorphanol was equivalent to that of 37.5 and 75 mg meperidine respectively. The duration of pain relief was 2 to 3 hours with 1 mg butorphanol and 3 to 4 hours with 2 mg butorphanol, as judged by the time when approximately half of the patients required a repeat dose.
In the caesarian section study, a single dose of 2 mg butorphanol nasal spray (37 patients) or two 1 mg doses butorphanol nasal spray given 1 hour apart (35 patients), were compared to a single dose of 2 mg i.v. butorphanol (37 patients) or placebo (37 patients). Significant pain relief began within 5 minutes for i.v. butorphanol, 15 minutes for 2 mg butorphanol nasal spray, and 30 minutes for the two 1 mg doses of butorphanol nasal spray. Peak analgesic effects were similar for the 3 butorphanol treatments. The duration of pain relief, as judged by this time when approximately half of the patients required a repeat dose, was 2 to 3 hours for 2 mg i.v. butorphanol and 4 to 5 hours for 2 mg butorphanol nasal spray administered either as a single dose or two 1 mg doses given 1 hour apart.
Indications And Clinical Uses:
For the relief of moderate to severe acute pain. The efficacy of butorphanol for periods longer than 3 days has not been established.
Contra-Indications:
Patients hypersensitive to butorphanol or to any component of the preparation.
Warnings in Clinical States:
Patients Dependent on Narcotics: Because of the opioid antagonist properties of butorphanol, patients who are physically dependent on narcotics should not be given butorphanol as they may experience withdrawal symptoms. Such patients should have an adequate period of withdrawal from opioid drugs prior to beginning butorphanol therapy.
Butorphanol has precipitated opioid withdrawal symptoms in patients taking opioid analgesics chronically. Adverse experiences include those of the CNS (anxiety, agitation, mood changes, hallucinations, and dysphoria) more frequently than typical somatic opioid withdrawal symptoms. 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.
Precautions:
General: Hypotension associated with syncope during the first hour of dosing with butorphanol has been reported rarely, particularly in patients with past history of similar reactions to opioid analgesics. Therefore, patients should be advised to avoid activities with potential risks.
The sedative property should be considered in the clinical use of butorphanol. In addition, patients receiving recommended therapeutic doses may experience severe dizziness, nausea and vomiting and confusion. Infrequently, hallucinations have also occurred at 2 mg. The patient should be advised accordingly (see Adverse Effects).
Limited clinical experience appears to suggest that patients with migraine headache may be more susceptible to certain adverse reactions associated with butorphanol (see Adverse Effects).
Head Injury and Increased Intracranial Pressure: As with other opioids, butorphanol used in patients with head injury may be associated with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, miosis, and alterations in mental state that would obscure the interpretation of the clinical course of head injuries. In such patients, butorphanol should be used only if the benefits of use outweigh the risks.
Respiratory Depression: As a class, the mixed agonist-antagonist opioid drugs are less likely than morphine to produce significant respiratory depression. Nevertheless, drugs of this class may produce respiratory depression in susceptible individuals, especially patients receiving other CNS-active agents or suffering from CNS diseases or respiratory impairment.
Hepatic Disease: Butorphanol should be administered with caution to patients with liver disease (see , Pharmacokinetics, and Dosage, Dosage Adjustments).
Renal Disease: Impaired renal function necessitates alterations in dosing schedule (see , Pharmacokinetics and Dosage, Dosage Adjustments).
Cardiovascular Effects: Because butorphanol increases the work of the heart, especially the pulmonary circuit, the use of this drug in acute myocardial infarction or in cardiac patients with ventricular dysfunction or coronary insufficiency should be limited to those patients for whom the benefits clearly outweigh the risk.
Severe hypertension has been reported rarely during parenteral administration of butorphanol. Because of the similarity in pharmacokinetics, this adverse event could potentially occur during use of butorphanol nasal spray. 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.
Anesthesia: Butorphanol has not been evaluated for use in anesthesia.
Occupational Hazards: Ambulatory Patients: Drowsiness and dizziness related to the use of butorphanol may impair mental and/or physical abilities required for the performance of potentially hazardous tasks (e.g., driving, operating machinery, etc.). Patients should be told to use caution in such activities until their individual response to butorphanol has been well characterized.
Pregnancy: There are no adequate and well-controlled studies of butorphanol in pregnant women before 37 weeks of gestation. The use of butorphanol in women of childbearing potential requires that the expected benefit of the drug be weighed against the potential risk to the mother and fetus.
Reproduction studies in mice, rats and rabbits during organogenesis did not reveal any teratogenic potential of butorphanol. Pregnant rats treated s.c. with butorphanol at 1 mg/kg (5.9 mg/m).
Labor and Delivery: Butorphanol is not recommended during labor or delivery because there is no clinical experience with its use in this setting. Butorphanol injection has been used during labor, and there have been rare reports of neonatal respiratory depression of the newborn occurring after delivery.
Lactation: There is no clinical experience with the use of butorphanol in nursing mothers. If butorphanol is administered to a nursing mother, consideration should be given to the possibility that pharmacologically active drug could be available to a nursing infant. Butorphanol administered i.v. or i.m. is secreted in low concentrations in human milk; however, the clinical significance of this finding has not been systematically evaluated.
Children: Safety and efficacy in patients under 18 years of age have not been established.
Geriatrics: The mean half-life of butorphanol is increased to 6 hours in patients over the age of 65 (see ). In addition to having a somewhat reduced ability to eliminate butorphanol, elderly patients may be more sensitive to its side effects, particularly dizziness (see Dosage).
Dependence Liability: Although, as a class, the mixed agonist-antagonist opioid analgesics have a much lower abuse potential than morphine, all such drugs have been reported to be abused.
Among 161 patients who used butorphanol for 2 months or longer, during a controlled clinical trial, there were 5 reports suggestive of possible abuse, including 3 reports of clinically significant overuse. Post-treatment symptoms such as anxiety, agitation and diarrhea were observed in 6 patients. Symptoms suggestive of opioid withdrawal occurred in 2 patients who stopped the drug abruptly after using 16 mg a day or more for longer than 3 months. Neither withdrawal nor symptoms suggestive of withdrawal occurred when the drug was used for less than a week or when the dose was tapered if use exceeded 1 to 2 weeks. Special care should be exercised in administering butorphanol to emotionally unstable patients and to those with a history of drug abuse.
Drug Interactions:
Concurrent use of butorphanol with CNS depressants (e.g., alcohol, barbiturates, tranquilizers and antihistamines) may result in additive CNS depressant effects. The dose of butorphanol should be minimized and the frequency of dosing reduced when it is administered concomitantly with drugs that potentiate the action of opioids.
It is not known if the effects of butorphanol are altered by concomitant medications that affect hepatic metabolism of drugs (erythromycin, theophylline, etc.), but physicians should be alert to the possibility that longer intervals between doses may be needed.
Caution should be exercised in using butorphanol concomitantly with MAO inhibitors, as the latter have been associated with severe and sometimes fatal adverse reactions in certain susceptible individuals when used with meperidine and other narcotic analgesics.
Administration of a single 2 mg dose of butorphanol to 18 subjects with allergic rhinitis resulted in a higher C max and shorter T max compared to healthy subjects, although bioavailabilities were similar. When these 18 subjects were pretreated with the nasal vasoconstrictor, oxymetazoline, bioavailability of butorphanol was not affected, however, C max was reduced and T max was increased to values similar to those observed in healthy subjects.
No significant pharmacokinetic interactions between butorphanol (1 mg) and sumatriptan (6 mg s.c.) were observed in a single dose clinical trial involving 24 healthy volunteers. However, the safety and efficacy of butorphanol in the treatment of migraine headache pain refractory to sumatriptan has not been established.
In another study among 16 healthy male volunteers, the plasma concentrations of a 1 mg dose of butorphanol nasal spray (q.i.d. for 4 days) were not affected when cimetidine was coadministered (300 mg q.i.d. for 4 days). Conversely, the pharmacokinetics of cimetidine (300 mg q.i.d. for 4 days) were not altered when butorphanol nasal spray (1 mg q.i.d.) was coadministered for 4 days.
Adverse Reactions:
Commonly Observed: Across all controlled and uncontrolled acute treatment clinical trials (799 patients exposed to butorphanol) the most commonly observed adverse experiences (with incidence of at least 10%) regardless of relationship to butorphanol were: drowsiness (35%), somnolence (17%), dizziness (25%) and nausea and vomiting (11%). These adverse events appeared dose-related. They also occurred more frequently in patients given butorphanol for migraine. In nearly all cases, the type and incidence of side effects were those expected of a potent opioid analgesic, and no unforseen or unusual toxicity was reported.
Severe Adverse Reactions: During controlled and uncontrolled acute clinical trials involving 799 patients exposed to butorphanol, the following adverse events regardless of relationship (incidence in parentheses) were rated as severe in greater than 1% of patients: drowsiness and somnolence (7.7%), dizziness (4.4%), nausea and vomiting (3.4%) and confusion (1%).
Controlled Clinical Studies: The incidences of adverse reactions (>3%) to butorphanol are derived from placebo-controlled trials (N=662) in a variety of postoperative pain models at doses of 1 or 2 mg, and from two placebo-controlled trials involving the treatment of migraine pain at doses of 2 to 3 mg.
Summary of Adverse Events in Patients Receiving Stadol NS or Placebo in Postoperative Pain and Migraine Trials (only adverse events reported by >3% of patients treated with Stadol NS at the specified dose are included)
Migraine Pain Trials Postoperative Pain
Stadol NS (% of Patients) Placebo (% of Patients) Stadol NS (% of Patients) Placebo (% of Patients)
1+1 mg N=32 2 mg N=33 2+1 mg N=16 N=78 1 mg N=128 1+1 mg N=70 2 mg N=149 N=156
Body as a Whole
Asthenia 9 18 6 3
Chills – 6 – 3
Headache 4 4 – 3
Pain – 6 – 1
Sensation of Heat 6 12 6 3 – – 5 1
Cardiovascular
Chest Pain – 6 –
Palpitation 6
Syncope – 9
Vasodilation 6 – 6 1
Digestive
Dry Mouth 6 21 12
Increased Appetite – 6 –
Nausea/ Vomiting 22 61 37 4 – – 8 1
Thirst – – 6
Nervous System
Abnormal Feelings 6 12 6
Abnormal Thinking – 6
Anxiety – 6
Confusion 9 24 6 – – 6
Dizziness 50 85 75 10 23 6 25 1
Drowsiness 41 51 50 5 26 33 40 16
Euphoria – 3 6
Incoordination – 6
Nervousness 16 9 6
Paresis – 15 6
Paresthesia 6 21
Somnolence 23 36 39 12
Vertigo 9 6 – 1
Respiratory
Epistaxis – – 6
Nasal Irritation – 6 6 1
Dermatological
Pruritus 6 12 6
Sweating 6 30 19 – – 4 – 1
Special Senses
Blurred Vision 12 9 12 1
Diplopia 6
Ear Disorder – 6
Hearing Loss – – 6
Unpleasant Taste 12 9 6
Other adverse reactions (£ 3%) that were reported with butorphanol in all acute (controlled and non-controlled) clinical trials (N=799) are listed below.
These adverse events, regardless of relationship to butorphanol, are listed in order of decreasing frequency according to the following definitions: Frequent events were reported on one or more occasions by at least 1/100 individuals; Infrequent events by 1/100 to 1/1 000 individuals.
Body as a Whole: Infrequent: sensation of cold, fever, edema, accidental injury, back pain.
Gastrointestinal: Infrequent: pharyngitis, stomach pain, abdominal pain, dysphagia, flatulence.
Cardiovascular: Frequent: hypotension. Infrequent: blood pressure elevated, hypertension, tachycardia, pallor, arrhythmia.
Musculoskeletal: Infrequent: muscle relaxation, leg pain.
Nervous System: Infrequent: hallucinations, feel calm, insomnia, abnormal dreams, agitation, abnormal gait, dysarthria, ataxia, tremor, derealization, intoxication, spasms, stupor, hyperesthesia, motor retardation, vivid imagination, abnormal involuntary movement, slowed movement.
Respiratory: Infrequent: dyspnea, cough, hypoventilation, respiratory disorder, sinus congestion, nasal congestion.
Dermatological: Infrequent: rash, erythema.
Genitourinary: Infrequent: impaired urination, libido increased.
Nasal Experiences: Infrequent: nasal symptoms, nose pain.
Special Senses: Infrequent: visual disturbance, photophobia, hyperacusia, eye pain, ear pain, tinnitus, eye disorder, taste loss.
Hemic and Lymphatic: Infrequent: petechiae.
Postmarketing Experience: The following adverse events also have occurred in less than 1% of patients in short-term butorphanol trials and postmarketing experience.
Body as a Whole: excessive drug effect associated with transient difficulty speaking and/or executing purposeful movements.
Cardiovascular: chest pain, hypertension, tachycardia.
Nervous System: convulsions, drug dependence
Symptoms and Treatment of Overdose:
Symptoms: Based on its pharmacology, butorphanol overdosage could produce signs of respiratory depression, cardiovascular failure (especially in predisposed patients), or CNS depression. There have been no clinical reports of fatal overdosage of butorphanol as a single drug in healthy individuals, but the injectable product has been reported in a fatal overdose in combination with other drugs or alcohol.
Treatment: The specific treatment of suspected butorphanol overdosage is immediate establishment of adequate airway and ventilation, followed (if necessary) by an opioid antagonist such as i.v. naloxone. Physicians are reminded that the duration of butorphanol action exceeds the duration of action of naloxone, and repeated dosing of naloxone may be required. The patient should be carefully monitored, especially the respiratory and cardiac status, and appropriate supportive measures, such as oxygen, i.v. fluids and/or vasopressors, should be instituted if necessary.
Dosage And Administration:
Butorphanol has an onset of effect within 15 to 30 minutes and requires individualization of dosage based on clinical response.
Adults: The usual recommended dose for initial nasal administration is 1 spray in one nostril (1 mg). Adherence to this dose may reduce the likelihood of drowsiness, dizziness, and nausea and vomiting. If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given.
The initial dose sequence may be repeated in 3 to 4 hours as needed. Due to limited clinical experience with higher doses, total daily doses of more than 16 mg are not recommended.
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 occur. In such patients, additional doses should not be given for 3 to 4 hours.
Dosage Adjustments: Patients with Hepatic Impairment: The elimination half-life of butorphanol is prolonged in patients with impaired hepatic function. Butorphanol should thus be used with caution in this population. The initial dosage interval should be increased to 6 to 12 hours until the response is well characterized. Subsequent dosings should be determined by patient response rather than being scheduled at fixed intervals.
Patients with Renal Impairment: The elimination half-life of butorphanol is prolonged in patients with impaired renal function. Dosage adjustments may thus be necessary. In patients with severe renal disease (i.e., creatinine clearance <30 mL/min), the initial dosage interval should be increased to 6 to 8 hours until the response has been well characterized. Subsequent dosings of butorphanol should be determined by patient response rather than being scheduled at fixed intervals.
Geriatrics: Because elderly patients may have a somewhat decreased ability to eliminate butorphanol and may be more sensitive to butorphanol’s side effects, the effects of the initial dose should be carefully assessed, and it may be appropriate to modify the frequency of subsequent dosing.
Initially a 1 mg dose of butorphanol should generally be used in elderly patients, and 90 to 120 minutes should elapse before deciding whether a second 1 mg dose is needed. The repeat dose sequence should be determined by the patient’s response rather than at fixed times, but will generally be no less than at 6-hour intervals (see Precautions).
Special Instructions: Stadol NS is an open delivery system that has a risk of accidental 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 animals.
Significant absorption from accidental dermal exposure is unlikely, and the contents of a spilled system should be washed from the skin by rinsing with cool water.
The best way to dispose of the unit safely is to unscrew the cap, rinse the bottle and spray assembly under the water faucet, then dispose of the parts in a waste can where children cannot get to them easily.
Information for the Pharmacist: Instructions for Assembly of Nasal Spray Unit: Assemble Stadol NS prior to dispensing to the patient, according to the following instructions.
1. Open the container and remove the spray pump and solution bottle.
2. Assemble by first unscrewing the white cap from the solution bottle and screwing the pump unit tightly onto the bottle. Make sure the clear cover is on the pump unit.
3. Return bottle to the container for dispensing to the patient.
Patients should be instructed in the proper use of Stadol NS.
Availability And Storage:
Each mL of aqueous solution contains: butorphanol tartrate 10 mg. Nonmedicinal ingredients: benzethonium chloride as a preservative, citric acid, sodium chloride, in purified water with sodium hydroxide and/or hydrochloric acid added to adjust the pH to 5.0. Bottles of 2.5 mL with a metered-dose spray pump with protective clip and dust cover and a patient instruction leaflet. After priming, each metered spray delivers 1.0 mg of butorphanol tartrate. The 2.5 mL bottle will deliver on average 14 to 15 metered doses, if no repriming is necessary. Store at room temperature (15 to 30°C).
STADOL NS Bristol-Myers Squibb Butorphanol Tartrate Analgesic
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