Butorphanol Tartrate

BUTORPHANOL TARTRATE- butorphanol tartrate spray
Bryant Ranch Prepack

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WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTORPHANOL TARTRATE NASAL SPRAY

Addiction, Abuse, and Misuse Because the use of butorphanol tartrate nasal spray exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see WARNINGS ].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of butorphanol tartrate nasal spray, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of butorphanol tartrate nasal spray are essential [see WARNINGS ].

Accidental Exposure

Accidental exposure of even one dose of butorphanol tartrate nasal spray, especially in children, can result in a fatal overdose of butorphanol tartrate[see WARNINGS].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of butorphanol tartrate nasal spray and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see WARNINGS, PRECAUTIONS; Drug Interactions].

Neonatal Opioid Withdrawal Syndrome

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see WARNINGS].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see WARNINGS].

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[S-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (salt). The molecular formula is C21 H29 NO2 •C4 H6 O6 , which corresponds to a molecular weight of 477.55 g/mol and the following structural formula:

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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 nasal spray, USP is an aqueous solution of butorphanol tartrate for administration as a metered spray to the nasal mucosa. Each bottle of butorphanol tartrate nasal spray, USP contains 2.5 mL of a 10 mg/mL solution of butorphanol tartrate with sodium chloride, citric acid, and benzethonium chloride in purified water with sodium hydroxide and/or hydrochloric acid added to adjust the pH to 5.0. The pump reservoir must be fully primed [see PATIENT INSTRUCTIONS] prior to initial use. After initial priming each metered spray delivers an average of 1.0 mg of butorphanol tartrate and the 2.5 mL bottle will deliver an average of 14 to 15 doses of butorphanol tartrate nasal spray, USP. If not used for 48 hours or longer, the unit must be reprimed [see PATIENT INSTRUCTIONS]. With intermittent use requiring repriming before each dose, the 2.5 mL bottle will deliver an average of 8 to 10 doses of butorphanol tartrate nasal spray, USP depending on how much repriming is necessary.

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].

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