2 ML butorphanol tartrate 2 MG/ML Injection

INDICATIONS AND USAGE Butorphanol tartrate nasal spray is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use : Because of the risks of addiction, abuse, and misuse, with opioids, which can occur at any dosage or duration [see WARNINGS ] reserve butorphanol tartrate nasal spray for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia Butorphanol tartrate nasal spray should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Butorphanol tartrate nasal spray should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of butorphanol tartrate nasal spray for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with butorphanol tartrate nasal spray. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with butorphanol tartrate nasal spray (see WARNINGS , Life-Threatening Respiratory Depression ; PRECAUTIONS , Information for Patients ). Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient (see WARNINGS , Addiction, Abuse, and Misuse , Life-Threatening Respiratory Depression , Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ). Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. Initial Dosage Use of Butorphanol Tartrate Nasal Spray as the first Opioid Analgesic Factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly and in patients with hepatic or renal disease requires extra caution ( see PRECAUTIONS and CLINICAL PHARMACOLOGY: Individualization of Dosage ). The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents. Use for Pain: Initiate treatment with butorphanol tartrate nasal spray in a dosing range of 1 mg (1 spray in one nostril) to 2 mg (1 spray in each nostril) every 3 to 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of butorphanol tartrate nasal spray. The usual recommended dose for initial nasal administration of butorphanol tartrate nasal spray is 1 mg (1 spray in one nostril). Adherence to this dose reduces the incidence of drowsiness and dizziness. If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given. The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence. Depending on the severity of the pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients single additional 2 mg doses should not be given for 3 to 4 hours. Use in Balanced Anesthesia: The use of butorphanol tartrate nasal spray is not recommended because it has not been studied in induction or maintenance of anesthesia. Labor: The use of butorphanol tartrate nasal spray is not recommended as it has not been studied in labor. Conversion from Other Opioids to Butorphanol Tartrate Nasal Spray There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of butorphanol tartrate nasal spray. It is safer to underestimate a patient’s 24-hour butorphanol tartrate nasal spray dosage than to overestimate the 24-hour butorphanol dosage and manage an adverse reaction due to overdose. Dosage Modifications in Elderly Patients and Patients with Renal or Hepatic Impairment The initial dose sequence in elderly patients and patients with hepatic or renal impairment should be limited to 1 mg followed, if needed, by 1 mg in 90 to 120 minutes. The repeat dose sequence should be determined by the patient’s response rather than at fixed times but will generally be no less than at 6 hours intervals [see CLINICAL PHARMACOLOGY: Individualization of Dosage and PRECAUTIONS ]. Titration and Maintenance of Therapy Individually titrate butorphanol tartrate nasal spray to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving butorphanol tartrate nasal spray to assess the maintenance of pain control and the relative incidence of adverse reaction as well as reassessing for the development of addiction, abuse, or misuse [see WARNINGS ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the butorphanol tartrate nasal spray dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Safe Reduction or Discontinuation of Butorphanol Tartrate Nasal Spray Do not abruptly discontinue butorphanol tartrate nasal spray in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking butorphanol tartrate nasal spray, there are a variety of factors that should be considered, including the dose of butorphanol tartrate nasal spray the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up p

WARNINGS Addiction, Abuse, and Misuse Butorphanol tartrate nasal spray contains butorphanol, a Schedule IV controlled substance. As an opioid, butorphanol tartrate nasal spray exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed butorphanol tartrate nasal spray. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing butorphanol tartrate nasal spray, and reassess all patients receiving butorphanol tartrate nasal spray for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as butorphanol tartrate nasal spray, but use in such patients necessitates intensive counseling about the risks and proper use of butorphanol tartrate nasal spray along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose (see WARNINGS , Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION , Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ). Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing butorphanol tartrate nasal spray. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of butorphanol tartrate nasal spray, the risk is greatest during the initiation of therapy or following a dosage increase of butorphanol. To reduce the risk of respiratory depression, proper dosing and titration of butorphanol tartrate nasal spray are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the butorphanol tartrate nasal spray dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental exposure to even one dose of butorphanol tartrate nasal spray, especially by children, can result in respiratory depression and death due to an overdose of butorphanol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose (see PRECAUTIONS , Information for Patients ). Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with butorphanol tartrate nasal spray. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered (see PRECAUTIONS , Information for Patients ). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone (see WARNINGS , Addiction, Abuse, and Misuse , Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ; PRECAUTIONS , Information for Patients ). Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of butorphanol tartrate nasal spray with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose (see WARNINGS , Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION , Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ). Advise both patients and caregivers about the risks of respiratory depression and sedation when butorphanol tartrate nasal spray is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcoho

CONTRAINDICATIONS Butorphanol Tartrate Nasal Spray is contraindicated in: • Patients with significant respiratory depression [see WARNINGS ] . • Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] . • Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] . • Patients with hypersensitivity to butorphanol tartrate, the preservative benzethonium chloride, or any of the formulation excipients (e.g., anaphylaxis) [see WARNINGS ] .

CLINICAL PHARMACOLOGY Mechanism of Action Butorphanol is a partial opioid agonist at the mu opioid receptor and a full agonist at the kappa opioid receptor. The principal therapeutic action of butorphanol is analgesia. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. Pharmacodynamics The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is within 15 minutes for the nasal administration doses. Peak analgesic activity occurs within 1 to 2 hours following nasal spray administration. The duration of analgesia varies depending on the pain model as well as the route of administration. Compared to the injectable form and other drugs in this class, butorphanol tartrate nasal spray has a longer duration of action (4 to 5 hours) [see CLINICAL PHARMACOLOGY; Clinical Trials ). Effects on the Central Nervous System Butorphanol produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. In human studies involving individuals without significant respiratory dysfunction, 2 mg of butorphanol IV and 10 mg of morphine sulfate IV depressed respiration to a comparable degree. At higher doses, the magnitude of respiratory depression with butorphanol is not appreciably increased; however, the duration of respiratory depression is longer. Respiratory depression noted after administration of butorphanol to humans by any route is reversed by treatment with naloxone, a specific opioid antagonist [see OVERDOSAGE ]. Butorphanol, like other mixed agonist-antagonists with a high affinity for the κ-receptor, may produce unpleasant psychotomimetic effects in some individuals. Nausea and/or vomiting may be produced by doses of 1 mg or more administered by any route. In human studies of butorphanol [see CLINICAL PHARMACOLOGY; Clinical Trials ), sedation is commonly noted at doses of 0.5 mg or more. Narcosis is produced by 10 to 12 mg doses of butorphanol administered over 10 to 15 minutes intravenously. Butorphanol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Butorphanol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Hemodynamic changes noted during cardiac catheterization in patients receiving single 0.025 mg/kg intravenous doses of butorphanol have included increases in pulmonary artery pressure, wedge pressure and vascular resistance, increases in left ventricular end diastolic pressure, and in systemic arterial pressure. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical 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 for in studies conducted to date [see ADVERSE REACTIONS ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. The minimum effective analgesic concentration of butorphanol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION ]. Concentration–Adverse Reaction Relationships There is a relationship between increasing butorphanol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION ]. Pharmacokinetics After nasal administration, mean peak blood levels of 0.9 to 1.04 ng/mL occur at 30 to 60 minutes after a 1 mg dose (see Table 1 ). The absolute bioavailability of butorphanol tartrate nasal spray is 60 to 70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. The peak plasma concentrations were approximately half those achieved in the absence of the vasoconstrictor. Following its initial absorption/distribution phase, the single dose pharmacokinetics of butorphanol by the intravenous, intramuscular, and nasal routes of administration are similar (see Figure 1 ). Figure 1: Butorphanol Plasma Levels After IV, IM and Nasal Spray Administration of 2 mg Dose Serum protein binding is independent of concentration over the range achieved in clinical practice (up to 7 ng/mL) with a bound fraction of approximately 80%. The volume of distribution of butorphanol varies from 305 to 901 liters and total body clearance from 52 to 154 liters/hr (see Table 1 ). Table 1: Mean Pharmacokinetic Parameters of Butorphanol in Young and Elderly Subjects 1 Intravenous Nasal Parameters Young Elderly Young Elderly Tmax 2 (hr) 0.62 (0.32) 3 (0.15 to 1.50) 4 1.03 (0.74) (0.25 to 3.00) Cmax 5 (ng/mL) 1.04 (0.40) (0.35 to 1.97) 0.90 (0.57) (0.10 to 2.68) AUC (inf) 6 (hr·ng/mL) 7.24 (1.57) (4.40 to 9.77) 8.71 (2.02) (4.76 to 13.03) 4.93 (1.24) (2.16 to 7.27) 5.24 (2.27) (0.30 to 10.34) Half-life (hr) 4.56 (1.67) (2.06 to 8.70) 5.61 (1.36) (3.25 to 8.79) 4.74 (1.57) (2.89 to 8.79) 6.56 (1.51) (3.75 to 9.17) Absolute Bioavailability (%) 69 (16) (44 to 113) 61 (25) (3 to 121) Volume of Distribution 7 (L) 487 (155) (305 to 901) 552 (124) (305 to 737) Total Body Clearance (L/hr) 99 (23) (70 to 154) 82 (21) (52 to 143) 1. Young subjects (n=24) are from 20 to 40 years old and elderly (n=24) are greater than 65 years of age. 2. Time to peak plasma concentration. 3. Mean (1 S.D.) 4. (range of observed values) 5. Peak plasma concentration normalized to 1 mg dose. 6. Area under the plasma concentration-time curve after a 1 mg dose. 7. Derived from IV data. Dose proportionality for butorphanol tartrate nasal spray has been determined at