Clinical Trial Experience

A total of 2446 patients were studied in premarketing clinical trials of butorphanol. Approximately half received STADOL Injection with the remainder receiving STADOL NS. 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 with STADOL Injection and STADOL NS were somnolence (43%), dizziness (19%), nausea and/or vomiting (13%). In long-term trials with STADOL NS 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 STADOL NS 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 STADOL NS and STADOL 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 STADOL NS or STADOL 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.

Drug Abuse And Dependence

STADOL (butorphanol tartrate) Injection and STADOL NS (butorphanol tartrate) Nasal Spray are listed in Schedule IV of the Controlled Substances Act (CSA).

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 with butorphanol tartrate. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a continuous basis for an extended period.

Clinical Trial Experience

In all clinical trials, less than 1% of patients using STADOL NS had experiences that suggested the development of physical dependence or tolerance. Much of this information is based on experience with patients who did not have prolonged continuous exposure to STADOL NS. However, in one controlled clinical trial where patients with chronic pain from nonmalignant disease were treated with STADOL NS (n=303) or placebo (n=99) for up to 6 months, overuse (which may suggest the development of tolerance) was reported in nine (2.9%) patients receiving STADOL NS and no patients receiving placebo. Probable withdrawal symptoms were reported in eight (2.6%) patients using STADOL NS and no patients receiving placebo in the chronic nonmalignant pain study. Most of these patients abruptly discontinued STADOL NS after extended use or high doses. Symptoms suggestive of withdrawal included anxiety, agitation, tremulousness, diarrhea, chills, sweats, insomnia, confusion, incoordination, and hallucinations.

Postmarketing Experience

Butorphanol tartrate has been associated with episodes of abuse and dependence. Of the cases received, there were more reports of abuse with the nasal spray formulation than with the injectable formulation.

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.

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