BUTORPHANOL TARTRATE

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

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, and misuse, with opioids, even at recommended doses [see WARNINGS ], reserve Butorphanol Tartrate Injection 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

Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Butorphanol Tartrate Injection and adjust the dosage accordingly [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 section and CLINICAL PHARMACOLOGY: Individualization of Dosage section ). 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 3 to 4 hours as necessary. The effective dosage range, depending on the severity of pain, is 0.5 to 2 mg repeated every 3 to 4 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 3 to 4 hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4 mg repeated every 3 to 4 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 section). 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 mg to 1 mg IV in increments during anesthesia. The increment may be higher, up to 0.06 mg/kg (4mg/70kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of Butorphanol Tartrate Injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 mg/kg to 0.18 mg/kg). Labor In patients at full term in early labor a 1 to 2 mg dose of Butorphanol Tartrate Injection 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 Tartrate Injection 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 [see CLINICAL PHARMACOLOGY : Individualization of Dosage and 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 and the relative incidence of adverse reactions, as well as monitoring 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 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. 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 abruptly discontinue Butorphanol Tartrate Injection in a physically-dependent patient (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 health care 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 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 )

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-term 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%). In long-term trials with the nasal spray 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: 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 Spray trials or trials of Butorphanol Tartrate Injection and under circumstances where the association between these events and butorphanol administration is unknown. They are being listed as alerting information for the physician 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 chronic use of opioids (see CLINICAL PHARMACOLOGY ). To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .