WARNINGS
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.
Drug Abuse and Dependence
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.
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.)
PRECAUTIONS
General
Hypotension associated with syncope during the first hour of dosing with STADOL NS 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.
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 STADOL Injection should generally be half the recommended adult dose (0.5 mg IV and 1.0 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. The initial dose sequence of STADOL NS should be limited to 1 mg followed, if needed, by 1 mg in 90–120 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 at intervals of no less than 6 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization of Dosage).
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
- Opioid analgesics, including butorphanol, impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Effects such as drowsiness or dizziness can appear, usually within the first hour after dosing. These effects may persist for varying periods of time after dosing. Patients who have taken butorphanol should not drive or operate dangerous machinery for at least 1 hour and until the effects of the drug are no longer present.
- Alcohol should not be consumed while using butorphanol. Concurrent use of butorphanol with drugs that affect the central nervous system (eg, alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects such as drowsiness, dizziness, and impaired mental function.
- Butorphanol is one of a class of drugs known to be abused and thus should be handled accordingly (see DRUG ABUSE AND DEPENDENCE).
- Patients should be instructed on the proper use of STADOL NS (see PATIENT INSTRUCTIONS).
Drug Interactions
Concurrent use of butorphanol with central nervous system depressants (eg, 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.
In healthy volunteers, the pharmacokinetics of a 1-mg dose of butorphanol administered as STADOL NS were not affected by the coadministration of a single 6-mg subcutaneous dose of sumatriptan. However, in another study in healthy volunteers, the pharmacokinetics of butorphanol were significantly altered (29% decrease in AUC and 38% decrease in Cmax) when a 1-mg dose of STADOL NS was administered 1 minute after a 20-mg dose of sumatriptan nasal spray. (The two drugs were administered in opposite nostrils.) When the STADOL NS was administered 30 minutes after the sumatriptan nasal spray, the AUC of butorphanol increased 11% and Cmax decreased 18%. In neither case were the pharmacokinetics of sumatriptan affected by coadministration with STADOL NS. These results suggest that the analgesic effect of STADOL NS may be diminished when it is administered shortly after sumatriptan nasal spray, but by 30 minutes any such reduction in effect should be minimal.
The safety of using STADOL NS and IMITREX® (sumatriptan) Nasal Spray during the same episode of migraine has not been established. However, it should be noted that both products are capable of producing transient increases in blood pressure.
The pharmacokinetics of a 1-mg dose of butorphanol administered as STADOL NS were not affected by the coadministration of cimetidine (300 mg QID). Conversely, the administration of STADOL NS (1 mg butorphanol QID) did not alter the pharmacokinetics of a 300-mg dose of cimetidine.
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.
The fraction of STADOL NS absorbed is unaffected by the concomitant administration of a nasal vasoconstrictor (oxymetazoline), but the rate of absorption is decreased. Therefore, a slower onset can be anticipated if STADOL NS is administered concomitantly with, or immediately following, a nasal vasoconstrictor.
No information is available about the use of butorphanol concurrently with MAO inhibitors.
Information for Patients
(see PRECAUTIONS: Use in Ambulatory Patients)
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/m2 for mice and 354 mg/m2 for 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/m2) had a reduced pregnancy rate. However, a similar effect was not observed with a 2.5 mg/kg/day (14.75 mg/m2) subcutaneous dose.
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/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m2) and 60 mg/kg/oral (720 mg/m2) also showed higher incidences of post-implantation loss in rabbits.
There are no adequate and well-controlled studies of STADOL in pregnant women before 37 weeks of gestation. STADOL should be used during pregnancy only if the potential benefit justifies the potential risk to the infant.
Labor and Delivery
There have been rare reports of infant respiratory distress/apnea following the administration of STADOL Injection during labor. The reports of respiratory distress/apnea have been associated with administration of a dose within 2 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 administration of 1 mg of IV STADOL Injection during labor was associated with transient (10–90 minutes) sinusoidal fetal heart rate patterns, but was not associated with adverse neonatal outcomes. In the presence of an abnormal fetal heart rate pattern, STADOL Injection should be used with caution.
STADOL NS is not recommended during labor or delivery because there is no clinical experience with its use in this setting.
Nursing Mothers
Butorphanol has been detected in milk following administration of STADOL Injection to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4 µg/L of milk in a mother receiving 2 mg IM four times a day).
Although there is no clinical experience with the use of STADOL NS in nursing mothers, it should be assumed that butorphanol will appear in the milk in similar amounts following the nasal route of administration.
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.
Geriatric Use
Of the approximately 1500 patients treated with STADOL Injection in clinical studies, 15% were 61 years of age or older and 1% were 76 years or older. Of the approximately 1700 patients treated with STADOL NS in clinical studies, 8% were 65 years of age or older and 2% were 75 years or older.
Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6 hours) in patients over the age of 65 years (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Elderly patients may be more sensitive to the side effects of butorphanol. In clinical studies of STADOL NS, elderly patients had an increased frequency of headache, dizziness, drowsiness, vertigo, constipation, nausea and/or vomiting, and nasal congestion compared with younger patients. There are insufficient efficacy data for patients ≥65 years to determine whether they respond differently from younger patients.
The initial dose of STADOL Injection recommended for elderly patients should generally be half the recommended adult dose (0.5 mg IV and 1.0 mg IM). Repeat doses 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).
Initially a 1-mg dose of STADOL NS should generally be used in geriatric patients and 90–120 minutes should elapse before administering a second 1-mg dose, if needed (see CLINICAL PHARMACOLOGY: Individualization of Dosage).
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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