ADVERSE REACTIONS 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- 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 butorphanol tartrate injection and nasal spray were somnolence (43%), dizziness (19%). nausea and/or vomiting (13%). In long-term trials with nasal butorphanol 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 sprays 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 Whol e : Edema Cardiovascular: Chest Pain, Hypertension, Tachycardia Nervous: Depression Respiratory: Shallow Breathing Postmarketing Experience Postmarketing experience with butorphanol tartrate 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 butorphanol tartrate 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. serotonin syndrome adrenal insufficiency Androgen deficiency Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms of hypogonadism, such as impotence, erectile dysfunction, or amenorrhea. The causal role of opioids in the syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled tor in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. DRUG ABUSE AND DEPENDENCE Butorphanol tartrate injection is a Schedule IV Controlled Substance. Abuse Butorphanol tartrate is a substance with a high potential for abuse similar to other opioids including. Butorphanol tartrate injection can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS] . All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, tor its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Butorphanol tartrate, like other opioids, can be diverted tor non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia lin the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates tor different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmetene). mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Butorphanol tartrate should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If butorphanol tartrate is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS ; Pregnancy].