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Butorphanol Nasal Spray

Pronunciation

Generic Name: butorphanol tartrate
Dosage Form: nasal spray

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION

Addiction, Abuse, and Misuse
Butorphanol tartrate nasal solution 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 butorphanol tartrate nasal solution, and monitor all patients regularly for the development of these behaviors or conditions [see WARNINGS].

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of butorphanol tartrate nasal solution. Monitor for respiratory depression, especially during initiation of butorphanol tartrate nasal solution or following a dose increase [see WARNINGS].

Accidental Ingestion
Accidental ingestion of even one dose of butorphanol tartrate nasal solution, especially by children, can result in a fatal overdose of butorphanol tartrate nasal solution [see WARNINGS].

Neonatal Opioid Withdrawal Syndrome
Prolonged use of butorphanol tartrate nasal solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS].

Cytochrome P450 3A4 Interaction
The concomitant use of butorphanol tartrate nasal solution with all cytochrome P450 3A4 inhibitors may result in an increase in butorphanol tartrate plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in butorphanol tartrate plasma concentration. Monitor patients receiving butorphanol tartrate nasal solution and any CYP3A4 inhibitor or inducer [see
CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions].

Butorphanol Nasal Spray 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-dihydroxy-butanedioate (1:1) (salt). The molecular formula is C21H29NO2•C4H6O6, 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 Nasal Solution, USP is an aqueous solution of butorphanol tartrate for administration as a metered spray to the nasal mucosa. Each bottle of Butorphanol Tartrate Nasal Solution, 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 4.6 to 5.4. 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 mg of butorphanol tartrate and the 2.5 mL bottle will deliver an average of 14 to 15 doses of Butorphanol Tartrate Nasal Solution, 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 Solution, USP depending on how much repriming is necessary.

  

 

Butorphanol Nasal Spray - Clinical Pharmacology

General Pharmacology and Mechanism of Action

Butorphanol is a mixed agonist-antagonist with low intrinsic activity at receptors of the µ-opioid type (morphine-like).  It is also an agonist at K -opioid receptors.  

Its interactions with these receptors in the central nervous system apparently mediate most of its pharmacologic effects, including analgesia.

In addition to analgesia, CNS effects include depression of spontaneous respiratory activity and cough, stimulation of the emetic center, miosis and sedation.  Effects possibly mediated by non-CNS mechanisms include alteration in cardiovascular resistance and capacitance, bronchomotor tone, gastrointestinal secretory and motor activity and bladder sphincter activity.

In an animal model, the dose of butorphanol tartrate required to antagonize morphine analgesia by 50% was similar to that for nalorphine, less than that for pentazocine and more than that for naloxone.

The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity.

In human studies of butorphanol (see 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, like other mixed agonist-antagonists with a high affinity for the ĸ-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 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: Treatment).

Butorphanol tartrate demonstrates antitussive effects in animals at doses less than those required for analgesia.

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.

Pharmacodynamics

The analgesic effect of butorphanol is influenced by the route of administration.  Onset of analgesia is within a few minutes for intravenous administration, within 15 minutes for intramuscular injection, and within 15 minutes for the nasal solution doses.

Peak analgesic activity occurs within 30 to 60 minutes following intravenous and intramuscular administration and within 1 to 2 hours following the nasal spray administration.

The duration of analgesia varies depending on the pain model as well as the route of administration, but is generally 3 to 4 hours with IM and IV doses as defined by the time 50% of patients required remedication.  In postoperative studies, the duration of analgesia with IV or IM butorphanol was similar to morphine, meperidine, and pentazocine when administered in the same fashion at equipotent doses (see Clinical Trials).  Compared to the injectable form and other drugs in this class, butorphanol tartrate nasal solution has a longer duration of action (4 to 5 hours) (see Clinical Trials).

Pharmacokinetics

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 solution 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 Solution 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/hour (see Table 1).

Table 1: Mean Pharmacokinetic Parameters of Butorphanol in Young and Elderly Subjectsa
  Intravenous Nasal
Parameters Young Elderly Young Elderly
Tmaxb (hr)     0.62 (0.32)c
(0.15 to 1.50)d
1.03 (0.74)
(0.25 to 3.00)
Cmaxe (ng/mL) 1.04(0.40)
(0.35 to 1.97)
0.90 (0.57)
(0.10 to 2.68)
AUC (inf)f (hr·ng/mL) 7.24 (1.57)
(4.40 to 9.77)
8.71 (2.02)
(4.76 to 13.03)
4.93 (1.24)
(2.16 to 7.27)
5.24 (2.27)
(0.30 to 10.34)
Half-life (h) 4.56 (1.67)
(2.06 to 8.70)
5.61 (1.36)
(3.25 to 8.79)
4.74 (1.57)
(2.89 to 8.79)
6.56 (1.51)
(3.75 to 9.17)
Absolute Bioavailability (%)     69 (16)
(44 to 113)
61 (25)
(3 to 121)
Volume of Distributiong(L) 487 (155)
(305 to 901)
552 (124)
(305 to 737)
   
Total Body Clearance (L/h) 99 (23)
(70 to 154)
82 (21)
(52 to 143)
   

a Young subjects (n=24) are from 20 to 40 years old and elderly (n=24) are greater than 65 years of age.

b Time to peak plasma concentration.

c Mean (1 S.D.)

d (range of observed values)

e Peak plasma concentration normalized to 1 mg dose.

f Area under the plasma concentration-time curve after a 1 mg dose.

g Derived from IV data

Dose proportionality for butorphanol tartrate nasal solution 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: 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 solution 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] compared to 5.8 hours [clearance 260 L/h] in healthy subjects).  No effect on Cmax or Tmax 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 Cmax or Tmax was observed after a single intranasal dose.

For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, Drug Interactions, and CLINICAL PHARMACOLOGY: Individualization of Dosage.

Clinical Trials

The effectiveness of opioid analgesics varies in different pain syndromes. 

Studies with butorphanol tartrate nasal solution 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 solution was evaluated (approximately 35 patients per treatment group) in a general and orthopedic surgery trial.  Single doses of butorphanol tartrate nasal solution (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 solution 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 solution, 3.5 hours with 2 mg butorphanol tartrate nasal solution and 3.3 hours with either dose of meperidine.

In a postcesarean section trial, butorphanol tartrate nasal solution administered to 35 patients as two 1 mg doses 60 minutes apart was compared with a single 2 mg dose of butorphanol tartrate nasal solution 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 nasal solution were similar in magnitude.  The duration of pain relief provided by both 2 mg butorphanol tartrate nasal solution 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 one hour apart of butorphanol tartrate nasal solution 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 solution and IM methadone.  Peak analgesic effect occurred at 2 hours for butorphanol tartrate nasal solution and 1.5 hours for methadone.  The median duration of pain relief was 6 hours with butorphanol tartrate nasal solution 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 solution 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 solution than in the trial with the 1 mg initial dose.

Individualization of Dosage

Use of butorphanol tartrate nasal solution in geriatric patients, patients with renal impairment, and patients with hepatic impairment requires extra caution (see below and 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).

Indications and Usage for Butorphanol Nasal Spray

Butorphanol tartrate nasal solution is indicated 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 for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]

  • Have not been tolerated, or are not expected to be tolerated,
  • Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Contraindications

Butorphanol tartrate nasal solution is contraindicated in patients with:

  • Significant respiratory depression [see WARNINGS]
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS]
  • Hypersensitivity to butorphanol tartrate or the preservative benzethonium chloride.

Warnings

Addiction, Abuse, and Misuse

Butorphanol tartrate nasal solution is a Schedule IV controlled substance. As an opioid, butorphanol tartrate exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed butorphanol tartrate nasal solution. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing butorphanol tartrate nasal solution, and monitor all patients receiving butorphanol tartrate nasal solution for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as butorphanol tartrate, but use in such patients necessitates intensive counseling about the risks and proper use of butorphanol tartrate along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing butorphanol tartrate nasal solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for Patients]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of butorphanol tartrate nasal solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of butorphanol tartrate nasal solution.

To reduce the risk of respiratory depression, proper dosing and titration of butorphanol tartrate nasal solution is essential [see DOSAGE AND ADMINISTRATION]. Overestimating the butorphanol tartrate nasal solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of butorphanol tartrate nasal solution, especially by children, can result in respiratory depression and death due to an overdose of [active moiety].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of butorphanol tartrate nasal solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of butorphanol tartrate nasal solution with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g.,ritonavir), may increase plasma concentrations of butorphanol tartrate and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS], particularly when an inhibitor is added after a stable dose of butorphanol tartrate nasal solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in butorphanol tartrate-treated patients may increase butorphanol tartrate plasma concentrations and prolong opioid adverse reactions. When using butorphanol tartrate nasal solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in butorphanol tartrate-treated patients,monitor patients closely at frequent intervals and consider dosage reduction of butorphanol tartrate nasal solution until stable drug effects are achieved [see PRECAUTIONS; Drug Interactions, DOSAGE AND ADMINISTRATION].

Concomitant use of butorphanol tartrate nasal solution with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease butorphanol tartrate plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to butorphanol tartrate nasal solution. When using butorphanol tartrate nasal solution with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS; Drug Interactions, DOSAGE AND ADMINISTRATION].

Risks due to Interactions with Central Nervous System Depressants

Hypotension, profound sedation, respiratory depression, coma, and death may result if butorphanol tartrate nasal solution is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., benzodiazepines and other sedatives/hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). When considering the use of butorphanol tartrate nasal solution in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin butorphanol tartrate nasal solution is made, start with a lower dosage of butorphanol tartrate nasal solution, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant [see PRECAUTIONS; Drug Interactions].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of butorphanol tartrate nasal solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease
Butorphanol tartrate nasal solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of butorphanol tartrate nasal solution [see WARNINGS].

Elderly, Cachetic, or Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS].

Monitor such patients closely, particularly when initiating and titrating butorphanol tartrate nasal solution and when butorphanol tartrate nasal solution is given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Patients Dependent on Narcotics

Because of its opioid antagonist properties, butorphanol is not recommended for use in patients dependent on narcotics. Such patients should have an adequate period of withdrawal from opioid drugs prior to beginning butorphanol therapy. In patients taking opioid analgesics chronically, butorphanol has precipitated withdrawal symptoms such as anxiety, agitation, mood changes, hallucinations, dysphoria, weakness and diarrhea.

Because of the difficulty in assessing opioid tolerance in patients who have recently received repeated doses of narcotic analgesic medication, caution should be used in the administration of butorphanol to such patients.

Drug Abuse and Dependence

Drug Abuse
Butorphanol tartrate, by all routes of administration, has been associated with episodes of abuse. Of the cases received, there were more reports of abuse with the nasal solution formulation than with the injectable formulation.

Physical Dependence, Tolerance and Withdrawal
Prolonged, continuous use of butorphanol tartrate may result in physical dependence or tolerance (a decrease in response to a given dose). Abrupt cessation of use by patients with physical dependence may result in symptoms of withdrawal.

Note: Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and physical dependence (see DRUG ABUSE AND DEPENDENCE).

Precautions

General

Hypotension associated with syncope during the first hour of dosing with butorphanol tartrate nasal solution has been reported rarely, particularly in patients with past history of similar reactions to opioid analgesics. Therefore, patients should be advised to avoid activities with potential risks.

Head Injury and Increased Intracranial Pressure

As with other opioids, the use of butorphanol in patients with head injury may be associated with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, drug-induced miosis, and alterations in mental state that would obscure the interpretation of the clinical course of patients with head injuries. In such patients, butorphanol should be used only if the benefits of use outweigh the potential risks.

Disorders of Respiratory Function or Control

Butorphanol may produce respiratory depression, especially in patients receiving other CNS active agents, or patients suffering from CNS diseases or respiratory impairment.

Hepatic and Renal Disease

In patients with hepatic or renal impairment, the initial dose sequence of butorphanol tartrate nasal solution 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 at intervals of no less than 6 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization of Dosage).

Cardiovascular Effects

Because butorphanol may increase the work of the heart, especially the pulmonary circuit, the use of butorphanol in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency should be limited to those situations where the benefits clearly outweigh the risk (see CLINICAL PHARMACOLOGY).

Severe hypertension has been reported rarely during butorphanol therapy. In such cases, butorphanol should be discontinued and the hypertension treated with antihypertensive drugs. In patients who are not opioid dependent, naloxone has also been reported to be effective.

Use in Ambulatory Patients

1) Opioid analgesics, including butorphanol, impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Effects such as drowsiness or dizziness can appear, usually within the first hour after dosing. These effects may persist for varying periods of time after dosing. Patients who have taken butorphanol should not drive or operate dangerous machinery for at least 1 hour and until the effects of the drug are no longer present.

2) Alcohol should not be consumed while using butorphanol. Concurrent use of butorphanol with drugs that affect the central nervous system (e.g., alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects such as drowsiness, dizziness, and impaired mental function.

3) Butorphanol is one of a class of drugs known to be abused and thus should be handled accordingly (see DRUG ABUSE AND DEPENDENCE).

4) Patients should be instructed on the proper use of butorphanol tartrate nasal solution (see PATIENT INSTRUCTIONS and MEDICATION GUIDE FOR PATIENTS).

Drug Interactions

Concurrent use of butorphanol with central nervous system depressants (e.g., alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects. When used concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids.

In healthy volunteers, the pharmacokinetics of a 1 mg dose of butorphanol administered as butorphanol tartrate nasal solution were not affected by the co-administration 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% decrease in Cmax) when a 1 mg dose of butorphanol tartrate nasal solution was administered 1 minute after a 20 mg dose of sumatriptan nasal solution. (The two drugs were administered in opposite nostrils.) When butorphanol tartrate nasal solution was administered 30 minutes after the sumatriptan nasal solution, the AUC of butorphanol increased 11% and Cmax decreased 18%. In neither case were the pharmacokinetics of sumatriptan affected by co-administration with butorphanol tartrate nasal solution. These results suggest that the analgesic effect of butorphanol tartrate nasal solution may be diminished when it is administered shortly after sumatriptan nasal solution, but by 30 minutes any such reduction in effect should be minimal.

The safety of using butorphanol tartrate nasal solution and IMITREX® (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.

The pharmacokinetics of a 1 mg dose of butorphanol administered as butorphanol tartrate nasal solution were not affected by the co-administration of cimetidine (300 mg QID). Conversely, the administration of butorphanol tartrate nasal solution (1 mg butorphanol QID) did not alter the pharmacokinetics of a 300 mg dose of cimetidine.

It is not known if the effects of butorphanol are altered by other concomitant medications that affect hepatic metabolism of drugs (erythromycin, theophylline, etc.), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

The fraction of butorphanol tartrate nasal solution 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 solution is administered concomitantly with, or immediately following, a nasal vasoconstrictor.

No information is available about the use of butorphanol concurrently with MAO inhibitors.

Information for Patients

(see PRECAUTIONS: Use in Ambulatory Patients and PATIENT INSTRUCTIONS and MEDICATION GUIDE FOR PATIENTS)

Addiction, Abuse, and Misuse
Inform patients that the use of butorphanol tartrate nasal solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share butorphanol tartrate nasal solution with others and to take steps to protect butorphanol tartrate nasal solution from theft or misuse.

Life-Threatening Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting butorphanol tartrate nasal solution or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store butorphanol tartrate nasal solution securely and to dispose of unused butorphanol tartrate nasal solution.

Interactions with Alcohol and Other CNS Depressants
Inform patients that potentially serious additive effects may occur if butorphanol tartrate nasal solution is used with alcohol or other CNS depressants and not to use such drugs unless supervised by a health care provider [see WARNINGS, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome
Inform patients that butorphanol tartrate nasal solution could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].

Adrenal Insufficiency
Inform patients that butorphanol tartrate nasal solution could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS].

Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of butorphanol tartrate nasal solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy]

Embryo-Fetal Toxicity
Inform female patients of reproductive potential that butorphanol tartrate nasal solution can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].

Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers].

Disposal of Unused Butorphanol Tartrate Nasal Solution
Advise patients to dispose of any remaining drug product as soon as it is no longer needed.

Drug Interactions

CYP3A4
Inhibitor
The concomitant use of butorphanol tartrate nasal solution and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of butorphanol tartrate, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of butorphanol tartrate nasal solution and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of butorphanol tartrate nasal solution is achieved [see WARNINGS].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the butorphanol tartrate plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to butorphanol tartrate nasal solution.

If concomitant use is necessary, consider dosage reduction of butorphanol tartrate nasal solution until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the butorphanol tartrate nasal solution dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION]. Monitor for signs of opioid withdrawal.

Inducer
The concomitant use of butorphanol tartrate nasal solution and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of butorphanol tartrate nasal solution [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to butorphanol tartrate nasal solution [see WARNINGS].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the butorphanol tartrate plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider increasing the butorphanol tartrate nasal solution dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider butorphanol tartrate nasal solution dosage reduction and monitor for signs of respiratory depression.

Central Nervous System Depressants
Due to additive pharmacologic effect, the concomitant use of CNS depressants such as alcohol, benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Consider dose reduction of one or both drugs. Monitor patients for signs of respiratory depression, sedation, and hypotension [see WARNINGS].

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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), 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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue butorphanol tartrate nasal solution if serotonin syndrome is suspected.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies were conducted in mice and rats given butorphanol tartrate in the diet up to 60 mg/kg/day (180 mg/m2 for mice and 354 mg/m2 for rats). There was no evidence of carcinogenicity in either species in these studies.

Butorphanol was not genotoxic in S. typhimurium or E. coli assays or in unscheduled DNA synthesis and repair assays conducted in cultured human fibroblast cells.

Rats treated orally with 160 mg/kg/day (944 mg/m2) had a reduced pregnancy rate. However, a similar effect was not observed with a 2.5 mg/kg/day (14.75 mg/m2) subcutaneous dose.

Infertility
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Pregnancy

Teratogenic Effects
Pregnancy Category C: 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/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m2) and 60 mg/kg/oral (720 mg/m2) also showed higher incidences of post-implantation loss in rabbits.

There are no adequate and well-controlled studies of butorphanol tartrate in pregnant women before 37 weeks of gestation. Butorphanol tartrate should be used during pregnancy only if the potential benefit justifies the potential risk to the infant.

Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics 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].

Labor or Delivery

Butorphanol tartrate nasal solution is not recommended during labor or delivery because there is no clinical experience with its use in this setting.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Butorphanol tartrate nasal solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including butorphanol tartrate nasal solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Nursing Mothers

Although there is no clinical experience with the use of butorphanol tartrate nasal solution in nursing mothers, it should be assumed that butorphanol will appear in the milk in similar amounts following the nasal route of administration

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for butorphanol tartrate nasal solution and any potential adverse effects on the breastfed infant from butorphanol tartrate nasal solution 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.

Pediatric Use

Butorphanol is not recommended for use in patients below 18 years of age because safety and efficacy have not been established in this population.

Geriatric Use

Of the approximately 1700 patients treated with butorphanol tartrate nasal solution in clinical studies, 8% were 65 years of age or older and 2% were 75 years or older.

Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6 hours) in patients over the age of 65 years (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Elderly patients may be more sensitive to the side effects of butorphanol. In clinical studies of butorphanol tartrate nasal solution, elderly patients had an increased frequency of headache, dizziness, drowsiness, vertigo, constipation, nausea and/or vomiting, and nasal congestion compared with younger patients. There are insufficient efficacy data for patients ≥ 65 years to determine whether they respond differently from younger patients.

Initially a 1 mg dose of butorphanol tartrate nasal solution should generally be used in geriatric patients and 90 to 120 minutes should elapse before administering a second 1 mg dose, if needed (see CLINICAL PHARMACOLOGY: Individualization of Dosage).

Butorphanol and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

Elderly patients (aged 65 years or older) may have increased sensitivity to butorphanol tartrate nasal solution. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of butorphanol tartrate nasal solution slowly in geriatric patients [see WARNINGS].

Adverse Reactions

Clinical Trial Experience

A total of 2446 patients were studied in premarketing clinical trials of butorphanol. Approximately half received butorphanol tartrate injection with the remainder receiving butorphanol tartrate nasal solution. In nearly all cases the type and incidence of side effects with butorphanol by any route 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 by any route. 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 were somnolence (43%), dizziness (19%), nausea and/or vomiting (13%). In long-term trials with butorphanol tartrate nasal solution 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: bronchitis, cough, dyspnea, epistaxis, nasal congestion, nasal irritation, pharyngitis, rhinitis, sinus congestion, sinusitis, upper respiratory infection

Skin and Appendages: sweating/clammy, 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 solution 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.

Body as a Whole: edema

Cardiovascular: chest pain, hypertension, tachycardia

Nervous: depression

Respiratory: shallow breathing

Postmarketing Experience

Postmarketing experience with butorphanol tartrate nasal solution has shown an adverse event profile similar to that seen during the premarketing evaluation of butorphanol by all routes of administration. Adverse experiences that were associated with the use of butorphanol tartrate nasal solution and that are not listed above have been chosen for inclusion below because of their seriousness, frequency of reporting, or probable relationship to butorphanol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These adverse experiences include serotonin syndrome, adrenal insufficiency, apnea, convulsion, delusion, drug dependence, excessive drug effect associated with transient difficulty speaking and/or executing purposeful movements, overdose, and vertigo. Reports of butorphanol overdose with a fatal outcome have usually but not always been associated with ingestion of multiple drugs.

Androgen deficiency

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms of hypogonadism, such as impotence, erectile dysfunction, or amenorrhea. The causal role of opioids in the 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Drug Abuse and Dependence

Controlled Substance

Butorphanol tartrate nasal solution is a Schedule IV controlled substances.

Abuse

Butorphanol tartrate is a substance with a high potential for abuse similar to other opioids including: alfentanil, buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, remifentanil, sufentanil, tapentadol, and tramadol. Butorphanol tartrate can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Butorphanol tartrate, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Butorphanol Tartrate Nasal Solution

Dependence
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Butorphanol tartrate nasal solution should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If butorphanol tartrate nasal solution is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and physical dependence with butorphanol tartrate. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a continuous basis for an extended period.

Clinical Trial Experience

In all clinical trials, less than 1% of patients using butorphanol tartrate nasal solution had experiences that suggested the development of physical dependence or tolerance. Much of this information is based on experience with patients who did not have prolonged continuous exposure to butorphanol tartrate nasal solution. However, in one controlled clinical trial where patients with chronic pain from nonmalignant disease were treated with butorphanol tartrate nasal solution (n=303) or placebo (n=99) for up to 6 months, overuse (which may suggest the development of tolerance) was reported in nine (2.9%) patients receiving butorphanol tartrate nasal solution and no patients receiving placebo. Probable withdrawal symptoms were reported in eight (2.6%) patients using butorphanol tartrate nasal solution and no patients receiving placebo in the chronic nonmalignant pain study. Most of these patients abruptly discontinued butorphanol tartrate nasal solution after extended use or high doses. Symptoms suggestive of withdrawal included anxiety, agitation, tremulousness, diarrhea, chills, sweats, insomnia, confusion, incoordination, and hallucinations.

Postmarketing Experience

Butorphanol tartrate has been associated with episodes of abuse and dependence. Of the cases received, there were more reports of abuse with the nasal solution formulation than with the injectable formulation.

Overdosage

Clinical Presentation

Acute overdose with butorphanol tartrate nasal solution 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

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 techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to butorphanol tartrate nasal solution overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to butorphanol tartrate nasal solution overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of butorphanol tartrate in butorphanol tartrate nasal solution, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. The use of a specific opioid antagonist such as naloxone should be considered. As the duration of butorphanol action usually exceeds the duration of action of naloxone, repeated dosing with naloxone may be required. In managing cases of suspected butorphanol overdosage, the possibility of multiple drug ingestion should always be considered.

Butorphanol Nasal Spray Dosage and Administration

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.

Important Dosage and Administration Instructions

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 nasal solution and adjust the dosage accordingly [see WARNINGS].

Initial Dosage

Initiating Treatment with Butorphanol Tartrate Nasal Solution
The usual recommended dose for initial nasal administration of butorphanol tartrate nasal solution 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 solution is not recommended because it has not been studied in induction or maintenance of anesthesia.

Labor

The use of butorphanol tartrate nasal solution is not recommended as it has not been studied in labor.

Safety and Handling

Butorphanol tartrate nasal solution 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.

Titration and Maintenance of Therapy

Individually titrate butorphanol tartrate nasal solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving butorphanol tartrate nasal solution 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 nasal solution 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 Nasal Solution

When a patient who has been taking butorphanol tartrate nasal solution regularly and may be physically dependent no longer requires therapy with butorphanol tartrate nasal solution, use a gradual downward titration of the dosage to prevent signs and symptoms of withdrawal. Do not stop butorphanol tartrate nasal solution abruptly [see WARNINGS, DRUG ABUSE AND DEPENDENCE].

How is Butorphanol Nasal Spray Supplied

Butorphanol Tartrate Nasal Solution, USP, 10 mg/ mL is supplied in a child-resistant plastic container containing a 2.5 mL bottle nasal solution and a metered-dose spray pump with protective clip and dust cover. A patient instruction leaflet and a medication guide are enclosed. On average, one bottle will deliver 14 to 15 doses if no repriming is necessary.

NDC 60505-0813-1 - 10 mg per mL, 2.5 mL bottle.

Storage Conditions

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

PHARMACIST ASSEMBLY INSTRUCTIONS FOR BUTORPHANOL TARTRATE NASAL SOLUTION USP
The pharmacist will assemble Butorphanol Tartrate Nasal Solution USP prior to dispensing to the patient, according to the following instructions:

1) Open the child-resistant plastic container and remove the spray pump and solution bottle.

2) Assemble Butorphanol Tartrate Nasal Solution by first unscrewing the white cap from the solution bottle and screwing the pump unit tightly onto the bottle. Make sure the clear dust cover is on the pump unit.

3) Return the Butorphanol Tartrate Nasal Solution USP bottle to the child-resistant plastic container for dispensing to the patient with the patient instruction leaflet and a medication guide for patients.

IMITREX® is the registered trademark of Glaxo Wellcome, Inc.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

APOTEX INC.
BUTORPHANOL TARTRATE NASAL SOLUTION USP,
10 mg/mL

Manufactured by Manufactured for
Apotex Inc.   Apotex Corp.
Toronto, Ontario Weston, FL
Canada M9L 1T9 33326

April 2016

PHARMACIST - DETACH HERE AND DISPENSE TO PATIENT

MEDICATION GUIDE FOR PATIENTS

Butorphanol Tartrate Nasal Solution USP, 10 mg/mL 

(bue-TOR-fa-nol TAR-trate)

Caution: Federal law prohibits the transfer of this drug to any person other than the patient for whom it was prescribed.

Butorphanol tartrate nasal solution is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage [insert indication], when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Butorphanol tartrate nasal solution:

  • Get emergency help right away if you take too much Butorphanol tartrate nasal solution (overdose). When you first start taking butorphanol tartrate nasal solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Never give anyone else your butorphanol tartrate nasal solution. They could die from taking it. Store butorphanol tartrate nasal solution away from children and in a safe place to prevent stealing or abuse. Selling or giving away butorphanol tartrate nasal solution is against the law.

Do not take butorphanol tartrate nasal solution if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.
  • [insert other product-specific information in order of importance]

Before taking butorphanol tartrate nasal solution, tell your healthcare provider if you have a history of:

  • head injury, seizures
  • liver, kidney, thyroid problems
  • problems urinating
  • pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of butorphanol tartrate nasal solution during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. butorphanol tartrate passes into breast milk and may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking butorphanol tartrate nasal solution with certain other medicines can cause serious side effects that could lead to death.

When taking butorphanol tartrate nasal solution:

  • Do not change your dose. Take butorphanol tartrate nasal solution exactly as prescribed by your healthcare provider.
  • (for products with an IFU insert, add the following) See the detailed Instructions for Use for information about how to take butorphanol tartrate nasal solution.
  • (for oral solutions, insert the following) Always use the [insert type of dose delivery device] that comes with butorphanol tartrate nasal solution to correctly measure your dose.
  • Take your prescribed dose [insert frequency, e.g., every X hours at the same time every day]. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking butorphanol tartrate nasal solution regularly, do not stop taking butorphanol tartrate nasal solution without talking to your healthcare provider.
  • After you stop taking butorphanol tartrate nasal solution, [insert product-specific disposal information].

While taking butorphanol tartrate nasal solution DO NOT:

  • Drive or operate heavy machinery, until you know how butorphanol tartrate nasal solution affects you. butorphanol tartrate nasal solution can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with butorphanol tartrate may cause you to overdose and die.

The possible side effects of butorphanol tartrate nasal solution:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, (for oxymorphone add or hands, hives, itching, rash,) extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of butorphanol tartrate nasal solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

APOTEX INC.
BUTORPHANOL TARTRATE NASAL SOLUTION USP,
10 mg/mL

Manufactured by Manufactured for
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, FL
Canada M9L 1T9 33326

April 2016

PATIENT INSTRUCTIONS

Butorphanol Tartrate Nasal Solution USP, 10 mg/mL

(bue-TOR-fa-nol TAR-trate)

Take medication as directed by your doctor. For proper use of the nasal spray, read the following instructions carefully.

NOTE: BOTTLES DO NOT APPEAR “FULL”. THEY ARE PRE-FILLED TO DELIVER ON AVERAGE 14 to 15 ONE (1) mg DOSES. (THE USUAL DOSE IS 1 mg - ONE SPRAY IN ONE NOSTRIL.)

THE UNIT MUST BE PRIMED WITH ONE OR TWO STROKES IF NOT USED FOR 48 HOURS OR LONGER.

Note: 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 solution.

When not in use, store spray unit in the child-resistant plastic container.

Butorphanol tartrate nasal solution should not be used by anyone other than the person for whom it was prescribed. To prevent this and to reduce the chance of children taking the drug, it is important to dispose of any excess butorphanol tartrate nasal solution just as soon as it is no longer needed. 

The best way to safely dispose of the unit is to unscrew the cap, rinse the bottle and spray assembly under the water faucet, and dispose of the parts in a waste can where children cannot easily get to them.

 

KEEP OUT OF THE REACH OF CHILDREN

USUAL DOSE: ONE Spray. Spray ONLY ONCE into ONLY ONE nostril. DO NOT spray into both nostrils unless directed by your doctor. DO NOT repeat sooner than directed by your doctor.

APOTEX INC.
BUTORPHANOL TARTRATE NASAL SOLUTION USP,
10 mg/mL

Manufactured by                                         Manufactured for
Apotex Inc.                                                   Apotex Corp.
Toronto, Ontario                                            Weston, FL
Canada M9L 1T9                                           33326 

April 2016

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 2.5 ML LABEL

APOTEX CORP. NDC 60505-0813-1

CIV

Butorphanol Tartrate Nasal Solution USP - For Nasal Use Only

10mg/mL

Rx only

BUTORPHANOL TARTRATE 
butorphanol tartrate solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:60505-0813
Route of Administration NASAL DEA Schedule CIV    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
BUTORPHANOL TARTRATE (Butorphanol) BUTORPHANOL TARTRATE 10 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM CHLORIDE  
CITRIC ACID MONOHYDRATE  
benzethonium chloride  
WATER  
SODIUM HYDROXIDE  
hydrochloric acid  
Packaging
# Item Code Package Description
1 NDC:60505-0813-1 1 BOTTLE, SPRAY in 1 CONTAINER
1 2.5 mL in 1 BOTTLE, SPRAY
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075499 12/04/2002
Labeler - Apotex Corp. (845263701)
Registrant - Apotex Inc. (209429182)
Establishment
Name Address ID/FEI Operations
Apotex Inc. 255092496 manufacture(60505-0813), analysis(60505-0813)
Revised: 04/2016
 
Apotex Corp.
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