BUTORPHANOL TARTRATE

Butorphanol tartrate is a synthetically derived opioid agonist-antagonist analgesic of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol D-(-)- tartrate (1:1) (salt). The molecular formula is C 21 H 29 NO 2 ∙ C 4 H 6 O 6 , which corresponds to a molecular weight of 477.56 and the following structural formula: Butorphanol tartrate is a white crystalline substance. The dose is expressed as the tartrate salt. One milligram of the salt is equivalent to 0.68 mg of the free base. The n-octanol/aqueous buffer partition coefficient of butorphanol is 180:1 at pH 7.5. Butorphanol Tartrate Injection is a sterile, nonpyrogenic parenteral aqueous solution of butorphanol tartrate for intravenous or intramuscular administration. Each milliliter (mL) contains butorphanol tartrate 1 or 2 mg; sodium citrate, dihydrate, 6.4 mg; citric acid hydrous 3.3 mg; sodium chloride 6.4 mg. The pH is 4.5 (3.0 to 5.5). Chemical Structure

Butorphanol Tartrate Injection is indicated - as a preoperative or pre-anesthetic medication - as a supplement to balanced anesthesia - for the relief of pain during labor, and - 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, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see WARNINGS ], reserve opioid analgesics, including butorphanol tartrate, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Important Dosage and Administration Instructions Butorphanol Tartrate Injection 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 Injection 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.‎ 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 Injection. Consider this risk when selecting an initial dose and when ‎making dose adjustments [see WARNINGS ]‎. Initial Dosage 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, patients with hepatic or renal disease, or in labor requires extra caution [see PRECAUTIONS ; 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 Intravenous The usual recommended single-dose for IV administration is 1 mg repeated every three to four hours as necessary. The effective dosage range, depending on the severity of pain, is 0.5 to 2 mg repeated every three to four hours. Intramuscular The usual recommended single-dose for IM administration is 2 mg in patients who will be able to remain recumbent, in the event drowsiness or dizziness occurs. This may be repeated every three to four hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4 mg repeated every three to four hours. There are insufficient clinical data to recommend single-doses above 4 mg. Use as Preoperative/Preanesthetic Medication The preoperative medication dosage of Butorphanol Tartrate Injection should be individualized [see CLINICAL PHARMACOLOGY: Individualization of Dosage ]. The usual adult dose is 2 mg IM, administered 60 to 90 minutes before surgery. This is approximately equivalent in sedative effect to 10 mg morphine or 80 mg meperidine. Use in Balanced Anesthesia The usual dose of Butorphanol Tartrate Injection is 2 mg IV shortly before induction and/or 0.5 to 1 mg IV in increments during anesthesia. The increment may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of butorphanol injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 to 0.18 mg/kg). Labor In patients at full term in early labor a 1 to 2 mg dose of butorphanol tartrate IV or IM may be administered and repeated after 4 hours. Alternative analgesia should be used for pain associated with delivery or if delivery is expected to occur within 4 hours. If concomitant use of butorphanol with drugs that may potentiate its effects is deemed necessary [see PRECAUTIONS: Drug Interactions ] the lowest effective dose should be employed. 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 , PRECAUTIONS ]. Titration and Maintenance of Therapy Individually titrate Butorphanol Tartrate Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Butorphanol Tartrate Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions 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 Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage ‎[see WARNINGS ]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Discontinuation of Butorphanol Tartrate Injection When a patient who has been taking Butorphanol Tartrate Injection regularly and may be physically dependent no longer requires therapy with Butorphanol Tartrate Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not rapidly reduce or abruptly discontinue Butorphanol Tartrate Injection in patients who may be physically-dependent on opioids [see WARNINGS , DRUG ABUSE AND DEPENDENCE ]. Safety and Handling Butorphanol Tartrate Injection is supplied in sealed delivery systems that have a low risk of accidental exposure to healthcare workers. Ordinary care should be taken to avoid aerosol generation while preparing a syringe for use. Following skin contact, rinsing with cool water is recommended. The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Butorphanol Tartrate Injection is contraindicated in: • Patients with significant respiratory depression [see WARNINGS ] • Patients with acute of 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 or any of the formulation excipients (e.g., anaphylaxis) [see WARNINGS ]

Clinical Trial Experience A total of 1658 patients were studied in premarketing clinical trials of Butorphanol Tartrate Injection. In nearly all cases the type and incidence of side effects with butorphanol 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 Tartrate Injection. 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%). 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: Cough, Dyspnea Skin and Appendages: Sweating, 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 due to their clinical significance: Body as a Whole: Edema Cardiovascular: Chest Pain, Hypertension, Tachycardia Nervous: Depression Respiratory: Shallow Breathing Postmarketing Experience The following adverse reactions have been identified during post approval use of Butorphanol Tartrate Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. • Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. • Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Butorphanol Tartrate Injection. • Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY ]. • Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of any duration [see WARNINGS ].‎ • Hypoglycemia: Cases of hypoglycemia have been reported in patients ‎taking opioids. Most reports were in patients with at least one ‎predisposing risk factor (e.g., diabetes).‎ • Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see WARNINGS ]. Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in DRUG ABUSE AND DEPENDENCE ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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. Monitor patients closely for signs of respiratory depression and sedation [see WARNINGS ]. If concomitant use is warranted, consider ‎prescribing naloxone for the emergency treatment of opioid overdose. 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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (eg., cyclobenzaprine, metaxalone), 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, regularly monitor the patient, particularly during treatment initiation and dose adjustment. Discontinue Butorphanol Tartrate Injection 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.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from light.