Butorphanol Tartrate

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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 impairmen …

CONTRAINDICATIONS Butorphanol Tartrate Injection 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 in the multiple dose vial, or any of the formulation excipients (e.g., anaphylaxis) (see WARNINGS )

ADVERSE REACTIONS 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 on …

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, 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.

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.

DESCRIPTION Butorphanol tartrate is an opioid agonist-antagonist of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl) morphinan-3,14-diol [S-(R*,R*)]-2,3-dihydroxybutanedioate(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 477.55 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, USP is a sterile, nonpyrogenic, parenteral, aqueous solution of butorphanol tartrate for intravenous or intramuscular administration. Each milliliter (mL) of solution contains, butorphanol tartrate 1 or 2 mg, 3.3 mg of citric acid, 6.4 mg sodium citrate, and 6.4 mg sodium chloride, and 0.1 mg benzethonium chloride (in multiple dose vial only) as a preservative. Structural Formula

OVERDOSAGE Clinical Presentation Acute overdose with butorphanol tartrate can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY ]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to butorphanol tartrate overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. As butorphanol is a mixed opioid agonist/antagonist, larger doses of naloxone or nalmefene may be needed to reverse the effects of an overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to butorphanol tartrate overdose. Because the duration of opioid reversal is expected to be less than the duration of action of butorphanol in Butorphanol Tartrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically-dependent patient, administration of the reversal agent should be begun with care and by titration with smaller than usual doses of the reversal agent.

HOW SUPPLIED Butorphanol Tartrate Injection is supplied as follows: 1 mg/mL, 1 mL vial, 10 vials per carton (NDC 0143-9864-10) 2 mg/mL, 1 mL vial, 10 vials per carton (NDC 0143-9867-10) 4 mg/2 mL, 2 mL vial, 10 vials per carton (NDC 0143-9863-10) 20 mg/10 mL, 10 mL vial, 10 vials per carton (NDC 0143-9866-10) Storage Conditions: Store at 20o-25°C (68o-77°F) [See USP Controlled Room Temperature]. Protect from light. Discard unused portion. Retain in carton until time of use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A. Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL Distributed by: WEST-WARD A HIKMA COMPANY Eatontown, NJ 07724 Revised: July 2020 PIN199-WES/7