Butorphanol Tartrate

Description

DESCRIPTION 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

What Is Butorphanol Tartrate Used For?

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

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...

Side Effects (Adverse Reactions)

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.

Drug Interactions

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.

Contraindications

CONTRAINDICATIONS Butorphanol Tartrate Injection is contraindicated in:

Pregnancy and Breastfeeding

Pregnancy 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/m 2 ) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m 2 ) and 60 mg/kg/oral (720 mg/m 2 ) 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 Use of opioid analgesics for an extended period of time 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 ].

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.

Overdosage

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...

How Supplied

HOW SUPPLIED Butorphanol Tartrate Injection, USP is supplied as single-dose glass fliptop vials, and available as follows: Unit of Sale Concentration (Total Butorphanol Concentration Per Container) NDC 0409-1623-01 Carton of 10 – 1 mL Single-Dose Glass Fliptop Vials 1 mg/mL NDC 0409-1626-01 Carton of 10 – 1 mL Single-Dose Glass Fliptop Vials 2 mg/mL NDC 0409-1626-02 Carton of 10 – 2 mL Single-Dose Glass Fliptop Vials 4 mg/2 mL (2 mg/mL) Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from light.