Get your patient on Butorphanol Tartrate - Butorphanol Tartrate spray, Metered (Butorphanol Tartrate)

Butorphanol Tartrate Nasal Spray 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 Nasal Spray 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.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

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 Nasal Spray. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS ] .

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see WARNINGS ; Addiction, Abuse, and Misuse ; Life-Threatening Respiratory Depression ; Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ] .

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Use of Butorphanol Tartrate Nasal Spray as the First Opioid Analgesic

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 and in patients with hepatic or renal disease requires extra caution [see PRECAUTIONS and 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: Initiate treatment with Butorphanol Tartrate Nasal Spray in a dosing range of 1 mg (1 spray in one nostril) to 2 mg (1 spray in each nostril) every 3 to 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Butorphanol Tartrate Nasal Spray. The usual recommended dose for initial nasal administration of Butorphanol Tartrate Nasal Spray is 1 mg (1 spray in one nostril). Adherence to this dose reduces the incidence of drowsiness and dizziness. If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given.

The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence.

Depending on the severity of the pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients single additional 2 mg doses should not be given for 3 to 4 hours.

Use in Balanced Anesthesia: The use of Butorphanol Tartrate Nasal Spray is not recommended because it has not been studied in induction or maintenance of anesthesia.

Labor: The use of Butorphanol Tartrate Nasal Spray is not recommended as it has not been studied in labor.

Conversion from Other Opioids to Butorphanol Tartrate Nasal Spray

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Butorphanol Tartrate Nasal Spray. It is safer to underestimate a patient’s 24-hour Butorphanol Tartrate Nasal Spray dosage than to overestimate the 24-hour butorphanol dosage and manage an adverse reaction due to overdose.

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 hour intervals [see CLINICAL PHARMACOLOGY: Individualization of Dosage and PRECAUTIONS ] .

Individually titrate Butorphanol Tartrate Nasal Spray to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Butorphanol Tartrate Nasal Spray to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess 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 Nasal Spray 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.

Do not rapidly reduce or abruptly discontinue Butorphanol Tartrate Nasal Spray in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Butorphanol Tartrate Nasal Spray, there are a variety of factors that should be considered, including the total daily dose of opioid (including Butorphanol Tartrate Nasal Spray) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Butorphanol Tartrate Nasal Spray who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see WARNINGS: Withdrawal , DRUG ABUSE AND DEPENDENCE ] .

Butorphanol Tartrate Nasal Spray is an open delivery system with increased risk of exposure to health care workers.

In the priming process, a certain amount of butorphanol may be aerosolized; therefore, the pump sprayer should be aimed away from the patient or other people or animals.

The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations. The unit should be disposed of by unscrewing the cap, rinsing the bottle, and placing the parts in a waste container.

A total of 788 patients were studied in premarketing clinical trials of Butorphanol Tartrate Nasal Spray. 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 intranasal butorphanol, except acute studies in normal subjects. There has been no attempt to correct for placebo effect or to subtract the frequencies reported by placebo-treated patients in controlled trials.

The most frequently reported adverse experiences across all clinical trials with Butorphanol Tartrate Nasal Spray were somnolence (49%), dizziness (23%), nausea and/or vomiting (8%). In long-term trials with Butorphanol Tartrate 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, pain

Cardiovascular: Hypertension, hypotension

Digestive: Anorexia, constipation, dry mouth, nausea and/or vomiting, diarrhea

Nervous: Anxiety, confusion, dizziness, euphoria, floating feeling, insomnia, nervousness, paresthesia, somnolence, tremor

Respiratory: Epistaxis, nasal congestion, nasal irritation, rhinitis, sinus congestion, sinusitis, nose pain

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 due to their clinical significance.

Body as a Whole: Edema

Cardiovascular: Chest pain, hypertension, tachycardia

Nervous: Depression

Respiratory: Shallow breathing

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).

The following adverse reactions have been identified during post approval use of Butorphanol Tartrate Nasal Spray. 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 Nasal Spray.
• 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 ] .

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.

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.

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, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).

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 opioid agonists. 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 ] .

After nasal administration, mean peak blood levels of 0.9 to 1.04 ng/mL occur at 30 to 60 minutes after a 1 mg dose (see Table 1 ). The absolute bioavailability of Butorphanol Tartrate Nasal Spray is 60 to 70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. The peak plasma concentrations were approximately half those achieved in the absence of the vasoconstrictor.

Following its initial absorption/distribution phase, the single dose pharmacokinetics of butorphanol by the intravenous, intramuscular, and nasal routes of administration are similar (see Figure 1 ).

Figure 1: Butorphanol Plasma Levels after IV, IM and Nasal Spray Administration of 2 mg Dose

Serum protein binding is independent of concentration over the range achieved in clinical practice (up to 7 ng/mL) with a bound fraction of approximately 80%.

The volume of distribution of butorphanol varies from 305 to 901 liters and total body clearance from 52 to 154 liters/hr (see Table 1 ).

Dose proportionality for Butorphanol Tartrate Nasal Spray has been determined at steady state in doses up to 4 mg at 6 hour intervals. Steady state is achieved within 2 days. The mean peak plasma concentration at steady state was 1.8-fold (maximal 3-fold) following a single dose.

The drug is transported across the blood brain and placental barriers and into human milk [see PRECAUTIONS : Labor and Delivery and Nursing Mothers ] .

Butorphanol is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively similar following intravenous, intramuscular, or nasal administration. Oral bioavailability is only 5% to 17% because of extensive first pass metabolism of butorphanol.

The major metabolite of butorphanol is hydroxybutorphanol, while norbutorphanol is produced in small amounts. Both have been detected in plasma following administration of butorphanol, with norbutorphanol present at trace levels at most time points. The elimination half-life of hydroxybutorphanol is about 18 hours and, as a consequence, considerable accumulation (~5-fold) occurs when butorphanol is dosed to steady state (1 mg transnasally q6h for 5 days).

Elimination occurs by urine and fecal excretion. When 3H labelled butorphanol is administered to normal subjects, most (70% to 80%) of the dose is recovered in the urine, while approximately 15% is recovered in the feces.

About 5% of the dose is recovered in the urine as butorphanol. Forty-nine percent is eliminated in the urine as hydroxybutorphanol. Less than 5% is excreted in the urine as norbutorphanol.

Butorphanol pharmacokinetics in the elderly differ from younger patients (see Table 1 ). The mean absolute bioavailability of Butorphanol Tartrate Nasal Spray in elderly women (48%) was less than that in elderly men (75%), young men (68%), or young women (70%). Elimination half-life is increased in the elderly (6.6 hours as opposed to 4.7 hours in younger subjects).

In renally impaired patients with creatinine clearances <30 mL/min, the elimination half-life was approximately doubled and the total body clearance was approximately one half (10.5 hours [clearance 150 L/h] as compared to 5.8 hours [clearance 260 L/h] in healthy subjects). No effect on C _max or T _max was observed after a single dose.

After intravenous administration to patients with hepatic impairment, the elimination half-life of butorphanol was approximately tripled and total body clearance was approximately one half (half-life 16.8 hours, clearance 92 L/h) compared to healthy subjects (half-life 4.8 hours, clearance 175 L/h). The exposure of hepatically impaired patients to butorphanol was significantly greater (about 2-fold) than that in healthy subjects. Similar results were seen after nasal administration. No effect on C _max or T _max was observed after a single intranasal dose.

For further recommendations refer to PRECAUTIONS : Hepatic and Renal Disease , Drug Interactions , and Geriatric Use sections and to the DOSAGE AND ADMINISTRATION section below.

Sumatriptan

In healthy volunteers, the pharmacokinetics of a 1 mg dose of butorphanol administered as Butorphanol Tartrate Nasal Spray were not affected by the coadministration of a single 6 mg subcutaneous dose of sumatriptan. However, in another study in healthy volunteers, the pharmacokinetics of butorphanol were significantly altered (29% decrease in AUC and 38% decreases in C _max ) when a 1 mg dose of Butorphanol Tartrate Nasal Spray was administered 1 minute after a 20 mg dose of sumatriptan nasal spray. (The two drugs were administered in opposite nostrils.) When the Butorphanol Tartrate Nasal Spray was administered 30 minutes after the sumatriptan nasal spray, the AUC of butorphanol increased 11% and C _max decreased 18%.

In neither case were the pharmacokinetics of sumatriptan affected by coadministration with Butorphanol Tartrate Nasal Spray. These results suggest that the analgesic effect of Butorphanol Tartrate Nasal Spray may be diminished when it is administered shortly after sumatriptan nasal spray, but by 30 minutes any such reduction in effect should be minimal.

The safety of using Butorphanol Tartrate Nasal Spray and IMITREX ^®1 (sumatriptan) Nasal Spray during the same episode of migraine has not been established. However, it should be noted that both products are capable of producing transient increases in blood pressure.

Cimetidine

The pharmacokinetics of a 1 mg dose of butorphanol administered as Butorphanol Tartrate Nasal Spray were not affected by the coadministration of cimetidine (300 mg QID). Conversely, the administration of Butorphanol Tartrate Nasal Spray (1 mg butorphanol QID) did not alter the pharmacokinetics of a 300 mg dose of cimetidine.

Oxymetazoline

The fraction of Butorphanol Tartrate Nasal Spray absorbed is unaffected by the concomitant administration of a nasal vasoconstrictor (oxymetazoline), but the rate of absorption is decreased. Therefore, a slower onset can be anticipated if Butorphanol Tartrate Nasal Spray is administered concomitantly with, or immediately following, a nasal vasoconstrictor.

The effectiveness of opioid analgesics varies in different pain syndromes.

Studies with Butorphanol Tartrate Nasal Spray have been performed in postoperative (general, orthopedic, oral, cesarean section) pain, in postepisiotomy pain, in pain of musculoskeletal origin, and in migraine headache pain (see below).

Use in the Management of Pain

Postoperative Pain: The analgesic efficacy of Butorphanol Tartrate Nasal Spray was evaluated (approximately 35 patients per treatment group) in a general and orthopedic surgery trial. Single doses of Butorphanol Tartrate Nasal Spray (1 or 2 mg) and IM meperidine (37.5 or 75 mg) were compared. Analgesia provided by 1 and 2 mg doses of Butorphanol Tartrate Nasal Spray was similar to 37.5 and 75 mg meperidine, respectively, with onset of analgesia within 15 minutes and peak analgesic effect within 1 hour. The median duration of pain relief was 2.5 hours with 1 mg Butorphanol Tartrate Nasal Spray, 3.5 hours with 2 mg Butorphanol Tartrate Nasal Spray and 3.3 hours with either dose of meperidine.

In a postcesarean section trial, Butorphanol Tartrate Nasal Spray administered to 35 patients as two 1 mg doses 60 minutes apart was compared with a single 2 mg dose of Butorphanol Tartrate Nasal Spray or a single 2 mg IV dose of butorphanol tartrate injection (37 patients each). Onset of analgesia was within 15 minutes for all butorphanol tartrate regimens. Peak analgesic effects of 2 mg intravenous butorphanol tartrate injection and Butorphanol Tartrate Nasal Spray were similar in magnitude. The duration of pain relief provided by both 2 mg Butorphanol Tartrate Nasal Spray regimens was approximately 4.5 hours and was greater than intravenous butorphanol tartrate injection (2.6 hours).

Migraine Headache Pain: The analgesic efficacy of two 1 mg doses 1 hour apart of Butorphanol Tartrate Nasal Spray in migraine headache pain was compared with a single dose of 10 mg IM methadone (31 and 32 patients, respectively). Significant onset of analgesia occurred within 15 minutes for both Butorphanol Tartrate Nasal Spray and IM methadone. Peak analgesic effect occurred at 2 hours for Butorphanol Tartrate Nasal Spray and 1.5 hours for methadone. The median duration of pain relief was 6 hours with Butorphanol Tartrate Nasal Spray and 4 hours with methadone as judged by the time when approximately half of the patients remedicated.

In two other trials in patients with migraine headache pain, a 2 mg initial dose of Butorphanol Tartrate Nasal Spray followed by an additional 1 mg dose 1 hour later (76 patients) was compared with either 75 mg IM meperidine (24 patients) or placebo (72 patients). Onset, peak activity and duration were similar with both active treatments; however, the incidence of adverse experiences (nausea, vomiting, dizziness) was higher in these two trials with the 2 mg initial dose of butorphanol tartrate nasal spray than in the trial with the 1 mg initial dose.

Use of butorphanol in geriatric patients, patients with renal impairment, patients with hepatic impairment, and during labor requires extra caution (see below and the appropriate sections in PRECAUTIONS ).

The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given.

The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence.

For the management of severe pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients additional doses should not be given for 3 to 4 hours. The incidence of adverse events is higher with an initial 2 mg dose [see Clinical Trials ] .

The initial dose sequence in elderly patients and patients with renal or hepatic impairment should be limited to 1 mg followed, if needed, by 1 mg in 90 to 120 minutes. The repeat dose sequence in these patients should be determined by the patient’s response rather than at fixed times but will generally be no less than at 6 hour intervals [see PRECAUTIONS ] .

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

¹ IMITREX ^® is a registered trademark of Glaxo-Wellcome, Inc.

Store Butorphanol Tartrate Nasal Spray securely and dispose of properly [see PRECAUTIONS: Information for Patients ] .