PRECAUTIONS General Hypotension associated with syncope during the first hour of dosing with Butorphanol Tartrate Injection 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. Risks of Driving and Operating Machinery Butorphanol Tartrate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butorphanol Tartrate Injection and know how they will react to the medication (see PRECAUTIONS; Information for Patients/Caregivers ). 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 Butorphanol Tartrate Injection should generally be half the recommended adult dose (0.5 mg IV and 1 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 (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization of Dosage sections). Information for Patients Addiction, Abuse, and Misuse Inform patients that the use of butorphanol tartrate, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS ]. Instruct patients not to share butorphanol tartrate with others and to take steps to protect butorphanol tartrate from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting butorphanol tartrate or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS ]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if butorphanol tartrate is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see WARNINGS, PRECAUTIONS; Drug Interactions] . Serotonin Syndrome Inform patients that butorphanol tartrate could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see PRECAUTIONS; Drug Interactions ] Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Butorphanol Tartrate Injection. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS, ADVERSE REACTIONS ). Pregnancy Neonatal Opioid Withdrawal Syndrome Inform patients that prolonged use of butorphanol tartrate during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS , PRECAUTIONS; Pregnancy ] Embryo-Fetal Toxicity Inform female patients of reproductive potential that butorphanol tartrate can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy ]. Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers ]. Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS ). Driving or Operating Heavy Machinery Inform patients that Butorphanol Tartrate Injection may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery and to avoid such tasks while taking this product, until they know how they will react to the medication. Drug Interactions Benzodiazepines and Other Central Nervous System (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants such as alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS ]. Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome. [see PRECAUTIONS; INFORMATION FOR PATIENTS ] If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue butorphanol tartrate if serotonin syndrome is suspected. Cytochrome P450 (CYP 450) Interactions It is not known if the effects of Butorphanol Tartrate Injection are altered by concomitant medications that affect hepatic metabolism of drugs (CYP 450 inhibitors or inducers) (e.g., erythromycin, theophylline, etc.), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed. Monoamine Oxidase inhibitors (MAOIs) No information is available about the use of butorphanol concurrently with MAO inhibitors. Advise patient to avoid concomitant use of these drugs. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies were conducted in mice and rats given butorphanol tartrate in the diet up to 60 mg/kg/day (12 and 24 times the human daily dose of 24 mg/day based on a body surface area comparison, respectively). There was no evidence of carcinogenicity in either species in these studies. Mutagenesis Butorphanol was not genotoxic in the in vitro bacterial reverse mutation assay (Ames) or in an in vitro unscheduled DNA synthesis and repair assay conducted in cultured human fibroblast cells. Impairment of Infertility In a study where male rats were treated subcutaneously with 0.5 or 2.5 mg/kg butorphanol for 75 days prior to mating to female rats treated subcutaneously with 0.5 or 2.5 mg/kg butorphanol for 14-days prior to mating and throughout gestation and lactation, no adverse effects on fertility were noted (0.2- and 1-times the human daily dose of 24 mg based on body surface area). In a study where male rats were treated orally with 10, 40, or 160 mg/kg for 63 days prior to mating to female rats treated orally with the same doses of butorphanol for 14 days prior to mating, reduced pregnancy rates were reported in the high dose group (65-times the human daily dose of 24 mg based on body surface area). 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 Butorphanol Tartrate Injection in pregnant women before 37 weeks of gestation. Butorphanol Tartrate Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the infant. Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Butorphanol tartrate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including butorphanol tartrate, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Butorphanol has been detected in milk following administration of Butorphanol Tartrate 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). There have been rare reports of infant respiratory distress/apnea following the administration of Butorphanol Tartrate 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 Butorphanol Tartrate Injection during labor was associated with transient (10–90 minutes) sinusoidal fetal heart rate patterns, but 16 was not associated with adverse neonatal outcomes. In the presence of an abnormal fetal heart rate pattern, Butorphanol Tartrate Injection should be used with caution. Nursing Mothers Butorphanol has been detected in milk following administration of Butorphanol Tartrate 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). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for butorphanol tartrate and any potential adverse effects on the breastfed infant from butorphanol tartrate or from the underlying maternal condition. Infants exposed to butorphanol tartrate through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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 Elderly patients (aged 65 years or older) may have increased sensitivity to butorphanol tartrate. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of butorphanol tartrate slowly in geriatric patients [see WARNINGS ]. This drug is known to be substantially excreted by the kidney, and the risk of adverse 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, and it may be useful to monitor renal function.