Butorphanol

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 subcutaneously with butorphanol at 1 mg/kg (5.9 mg/m²) had a higher frequency of stillbirths than controls. Butorphanol administered orally at 30 mg/kg (5.1 mg/m²) and 60 mg/kg (10.2 mg/m²) also showed higher incidences of post-implantation loss in rabbits.

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 intravenously or intramuscularly is secreted in low concentrations in human milk; however, the clinical significance of this finding has not been systematically evaluated.

Reproduction studies

The results of the fertility and general reproductive performance studies revealed that the subcutaneous administration of butorphanol tartrate at 2.5 or 0.5 mg/kg/day (in terms of butorphanol base) to male rats for 75 days prior to mating and to female rats from Day 14 prior to mating to Day 21 post partum produced no adverse response to spermatogenesis or oogenesis, estrous cycle, mating behaviour, conception rate, gestation, parturition, and viability of the newborns. The survival rate of the newborns between days 4 and 21 post partum, however, was found to be significantly lower in both treated groups (99%), apparently due to drug-induced species-specific (as compared to other species used for toxicologic studies) nervousness exhibited by the dams resulting in decreased care for the newborns.

Parenteral administration of the compound to pregnant female mice and rats subcutaneously at 1.0, 0.5 or 0.1 mg/kg/day (in terms of butorphanol base) and to pregnant female rabbits by the intramuscular route at 1.0 or 0.1 mg/kg/day (in terms of butorphanol base) during organogenesis in the teratology studies did not produce any evidence of teratogenic effects in the offspring of these species.

The subcutaneous treatment of female rats with butorphanol during the last third of pregnancy and for 21 days post partum at 1.0 or 0.1 mg/kg/day (in terms of butorphanol base) in the Periand Postnatal Study had no discernible effect of duration of pregnancy, late fetal development, labour and delivery, lactation, nursing instinct, neonatal viability, and growth of the newborns.

Tumorigenity in rats

Rats were administered butorphanol tartrate in the diet at levels of approximately 1.0 and 2.0 mg/kg/ day for 78 weeks and observed without drug treatment for an additional 26 weeks. Two control groups were included, one which received no drug and one which received pentazocine (40 mg/kg/day). Although no drug-related increase in tumour incidence was reported, a firm conclusion regarding the carcinogenicity of butorphanol in this species is not possible, since the study did not meet full requirements for a bioassay.

Drowsiness and dizziness related to the use of butorphanol nasal spray 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.

Commonly observed

Across all controlled and uncontrolled acute treatment clinical trials (799 patients exposed to butorphanol tartrate nasal spray) the most commonly observed adverse experiences (with incidence of least 10%) regardless of relationship to butorphanol tartrate nasal spray 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 tartrate nasal spray for migraine. In nearly all cases, the type and incidence of side effects were those expected of a potent opioid analgesic, and no unforeseen or unusual toxicity was reported.

Severe adverse reactions

During controlled and uncontrolled acute clinical trials involving 799 patients exposed to butorphanol tartrate nasal spray, 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 tartrate nasal spray in the following table are derived from placebo-controlled trials (N=662) in a variety of post-operative pain models at doses of 1 or 2 mg, and from two placebo-controlled trials involving the treatment of migraine pain at doses of 2-3 mg.

Summary of Adverse Events in Patients Receiving Butorphanol Tartrate Nasal Spray or Placebo in Post Operative Pain and Migraine Trials — *Only adverse events reported by >3% of patients treated with butorphanol tartrate nasal spray at the specified dose are included:

Other adverse reactions (≤3%) that were reported with butorphanol tartrate nasal spray in all acute (controlled and non-controlled) clinical trials (N=799) are listed below.

These adverse events, regardless of relationship to butorphanol tartrate nasal spray, 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 1/1000 individuals. (All events except those already listed in the previous table are included).

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, arrythmia.

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 exprerience

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.