Butorphanol Tartrate

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 spray. 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 with butorphanol tartrate injection and butorphanol tartrate nasal spray were somnolence (43%), dizziness (19%), nausea and/or vomiting (13%). 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

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 spray 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 spray and butorphanol tartrate injection 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 spray or butorphanol tartrate injection 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 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.

Clinical Trial Experience

In all clinical trials, less than 1% of patients using butorphanol tartrate nasal spray 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 spray. However, in one controlled clinical trial where patients with chronic pain from nonmalignant disease were treated with butorphanol tartrate nasal spray (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 spray and no patients receiving placebo. Probable withdrawal symptoms were reported in eight (2.6%) patients using butorphanol tartrate nasal spray and no patients receiving placebo in the chronic nonmalignant pain study. Most of these patients abruptly discontinued butorphanol tartrate nasal spray 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 spray formulation than with the injectable formulation.

Butorphanol
Tartrate Nasal Spray USP CIV
(buoo TORE fa nole TAR trate)

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

What is the most important information I should know about butorphanol tartrate nasal spray?

• Your doctor has prescribed butorphanol tartrate nasal spray to treat your pain. The medication in butorphanol tartrate nasal spray belongs to a group of medicines that is known to cause dependence and abuse. Butorphanol tartrate nasal spray causes these effects only in a small number of patients. However, because it can have these effects, it is VERY IMPORTANT that you not use butorphanol tartrate nasal spray more often or in larger doses than your doctor has instructed. Also, it is important to have regular checkups with your doctor to ensure that you're using butorphanol tartrate nasal spray correctly. The longer you use butorphanol tartrate nasal spray, the greater your risk of getting dependent on it.
• Because butorphanol tartrate nasal spray may make you feel sleepy or dizzy, do not drive or operate dangerous machinery, e.g., automobiles until you can no longer feel the effects of the drug. Also, do not drink alcohol while using butorphanol tartrate nasal spray because it may worsen any side effects.

What is butorphanol tartrate nasal spray?

Butorphanol tartrate nasal spray is an opioid narcotic pain reliever that is used for the relief of pain when the use of an opioid pain medication is appropriate. Butorphanol tartrate nasal spray comes in the form of a nasal spray. One spray of butorphanol tartrate nasal spray is quickly absorbed in the nasal passages.

What do I need to know about using a strong opioid narcotic pain reliever such as butorphanol tartrate nasal spray?

Butorphanol tartrate nasal spray has been reported to be abused. Do not use butorphanol tartrate nasal spray more often or in larger doses than instructed by your doctor. Follow your doctor’s instructions exactly and have regular checkups with your doctor when using butorphanol tartrate nasal spray to ensure you are using butorphanol tartrate nasal spray properly.

Who should not take butorphanol tartrate nasal spray?

Butorphanol tartrate nasal spray should not be used if you have ever had an allergic reaction to the active ingredient, butorphanol, or if you are allergic to benzethonium chloride, a preservative in butorphanol tartrate nasal spray. Butorphanol tartrate nasal spray should not be used by patients less than 18 years old. Butorphanol has been found in the breast milk of women who are using butorphanol tartrate nasal spray. Therefore, butorphanol tartrate nasal spray should not be used by patients who are breastfeeding. Patients over the age of 65 years may need less butorphanol tartrate nasal spray than younger patients.

You should not use butorphanol tartrate nasal spray if you are dependent on another narcotic medicine. Dependence is when you need the medicine and you can’t perform normally unless you are taking it.

How should I take butorphanol tartrate nasal spray?

Use butorphanol tartrate nasal spray only as directed by your doctor. Never use butorphanol tartrate nasal spray more often or in larger doses than instructed by your doctor. Since you may experience sleepiness or dizziness, use butorphanol tartrate nasal spray in a comfortable location where you can lie down if necessary.

Usual Dosing

If your doctor prescribed a 1 mg dose of butorphanol tartrate nasal spray for relief of pain:

• Spray ones pray into one nostril – one spray is a 1 mg dose. This is the most common initial dose.

If prescribed by your doctor, a second spray may be taken 60 to 90 minutes after the first if needed for pain relief. If instructed by your doctor, the above sequence may be repeated every 3 to 4 hours as needed for pain relief. If your pain hasn’t lessened or it becomes worse, please contact your doctor immediately.

If your doctor prescribed a 2 mg dose of butorphanol tartrate nasal spray for relief of pain:

• Spray one spray in each nostril – two sprays equal a 2 mg dose. If instructed by your doctor, this dose of butorphanol tartrate nasal spray may be repeated every 3 to 4 hours as needed for pain relief. If your pain hasn't lessened or it becomes worse, please contact your doctor immediately.

If you have liver or kidney disease, you may need to take butorphanol tartrate nasal spray less often or in a lower dose. Elderly patients may also need to take a lower dose of butorphanol tartrate nasal spray.

Use and Storage of Nasal Spray Unit

Your pharmacist will assemble the nasal spray unit. However, you must prime the unit before using it the first time and if it has not been used for 48 hours or longer. NOTE: VIALS DO NOT APPEAR “FULL.” THEY ARE PREFILLED TO DELIVER ON AVERAGE 14 TO 15 ONE (1) MG DOSES. If you only use butorphanol tartrate nasal spray occasionally and need to reprime it each time, the vial will deliver an average of 8 to 10 doses of butorphanol tartrate nasal spray. See additional instructions below for priming and using the spray unit.

What should I avoid while taking butorphanol tartrate nasal spray?

• Because butorphanol tartrate nasal spray may make you feel sleepy or dizzy, do not drive or operate dangerous machinery, e.g., automobiles until you no longer feel the effects of the drug.
• Do not drink alcohol while using butorphanol tartrate nasal spray because it may worsen drowsiness, dizziness and your general ability to function appropriately.
• Some medications cannot be taken with butorphanol tartrate nasal spray because of unwanted side effects. Before you begin using butorphanol tartrate nasal spray, as well as while you are using it, be sure to tell your doctor about any and all other drugs you are taking, including those sold without a prescription (over-the-counter). Do not take any other medicine, including any over-thecounter medicine, unless directed to do so by a doctor who knows you are using butorphanol tartrate nasal spray.
• Because butorphanol tartrate nasal spray may cause harm to an unborn child, tell your doctor if you are pregnant or planning to become pregnant.
• Because small amounts of butorphanol tartrate may appear in breast milk, be sure to consult with your doctor if you are nursing an infant.
• Because of butorphanol tartrate nasal spray's potential to cause dependence or abuse, be sure to tell your doctor if you ever had a problem with overuse of drugs or alcohol.

What are the possible side effects of butorphanol tartrate nasal spray?

The type and frequency of side effects experienced by patients taking butorphanol tartrate nasal spray are those commonly seen with opioid narcotic pain relievers. The most frequently reported side effects in studies with butorphanol tartrate were drowsiness, dizziness, nausea and/or vomiting. In studies where patients used butorphanol tartrate nasal spray for up to 6 months, nasal congestion and difficulty sleeping were frequently reported.

Butorphanol tartrate nasal spray may affect your breathing. This side effect is serious but unlikely if butorphanol tartrate nasal spray is taken as instructed. Notify your doctor immediately if you experience shortness of breath or other difficulty breathing.

Butorphanol tartrate nasal spray may affect your blood pressure or your heart rate. Notify your doctor immediately if you feel lightheaded, have an irregular heartbeat or have headaches that you did not have before you started taking butorphanol tartrate nasal spray.

Side effects other than those listed above have occurred in some patients. For example, the following side effects have been reported rarely, but may be disturbing if they do occur: visual blurring, dysphoria (feeling of sadness, unpleasantness, or discomfort), floating feeling, and hallucinations. Notify your doctor or pharmacist if any side effects persist or become troublesome.

What do I do if someone takes an overdosage of butorphanol tartrate nasal spray?

If you suspect that someone may have taken an overdosage of this medicine, contact your local poison control center or emergency room immediately.

This medication was prescribed for your current condition. Do not use butorphanol tartrate nasal spray for another condition or give the drug to others. Keep butorphanol tartrate nasal spray and all medicines out of the reach of children. Discard any unused portion of the medicine by removing the cap, rinsing the bottle and spray assembly under the water faucet, and disposing the parts in a waste can where children cannot easily get to them.

This summary does not include everything there is to know about butorphanol tartrate nasal spray. Medicines are sometimes prescribed for uses other than those listed. If you have questions or concerns, or want more information about butorphanol tartrate nasal spray, your doctor and pharmacist have the complete prescribing information upon which this guide is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace a careful discussion with your doctor. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.

PHARMACIST ASSEMBLY INSTRUCTIONS FOR BUTORPHANOL TARTRATE NASAL SPRAY USP

The pharmacist will assemble butorphanol tartrate nasal spray prior to dispensing to the patient, according to the following instructions:

1. Open the child-resistant prescription vial and remove the spray pump and solution bottle.
2. Assemble butorphanol tartrate nasal spray by first unscrewing the white cap from the solution bottle and screwing the pump unit tightly onto the bottle. Make sure the clear cover is on the pump unit.
3. Return the butorphanol tartrate nasal spray bottle to the child-resistant prescription vial for dispensing to the patient with patient instruction leaflet and medication guide.

KEEP OUT OF THE REACH OF CHILDREN.

PATIENT INSTRUCTIONS

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

NOTE: VIALS 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 spray.

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

Butorphanol tartrate nasal spray 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 spray 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.

Figure 1

1. Blow nose gently to clear both nostrils.

Figure 2

2. Pull clear cover off pump unit. Remove protective clip from neck of pump unit.

Figure 3

3. Prime butorphanol tartrate nasal spray by placing nozzle between first and second finger with thumb on the bottom of bottle. Pump sprayer unit FIRMLY and QUICKLY until a fine spray appears (up to 7 to 8 strokes).

Figure 4

4. Insert spray tip approximately 1 cm (width of small finger) into one nostril, pointing the tip toward the back of the nose.

Figure 5

5. Close other nostril with your forefinger and tilt head slightly forward.

Figure 6

6. Pump spray unit firmly and quickly by pushing down on the “finger grips” of the pump unit and against the thumb at the bottom of the bottle. Sniff gently with your mouth closed.

Figure 7

7. After spraying, remove pump unit from nose. Tilt your head backwards and sniff gently a few more seconds.

8. Your doctor will tell you whether a two spray dose is needed. If needed, administer a second spray in the other nostril, following steps 4 through 7. Replace protective clip and clear cover, respectively, (Fig. 2) after each dose.

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.

Opiate partial agonist; phenanthrene derivative.a b d

Absorption

Bioavailability

Rapidly absorbed following IM injection; peak plasma concentrations usually attained within 30–60 minutes.a d

Following nasal inhalation, peak blood concentrations are achieved in about 30–60 minutes.113 114 Absolute bioavailability of nasally administered butorphanol is 60–70% and appears to be unchanged in patients with allergic rhinitis.a

Completely absorbed from the GI tract following oral administration; however, after first-pass metabolism, bioavailability is only 5–17%.a b

Onset

Onset of analgesic activity occurs in a few minutes after IV administration or within 15 minutes after IM administration;a b peak analgesic effect achieved within 30–60 minutes after IV or IM administration.a

After nasal inhalation in postoperative patients, onset of analgesia occurs within 15 minutes;113 114 125 peak analgesic effect achieved within 1–2 hours.b

Duration

After IV or IM administration, duration of analgesia is 3–4 hours.a b

After nasal inhalation in postoperative patients, duration of analgesia is approximately 2.5–5 hours.113 114 125

Distribution

Extent

Highest concentrations of butorphanol and its metabolites in animals are found in the liver, kidneys, and intestine; drug concentrations are higher in the lungs, spleen, heart, endocrine tissues, blood cells, and fat tissue than in plasma; brain concentrations are lower than plasma concentrations.d

Rapidly crosses the placenta and is distributed into milk.a b

Plasma Protein Binding

About 80%.a b

Elimination

Metabolism

Extensively metabolized in the liver, principally by hydroxylation; N-dealkylation and conjugation of butorphanol and its metabolites also occur.a b d Metabolites have no analgesic activity.d

Elimination Route

Excreted principally in urine (70–80%) mainly as metabolites; also excreted in feces (15%).a b

Half-life

About 4.6–4.7 hours following intranasal or IV administration.113 114

Special Populations

In patients with hepatic impairment, elimination half-life of 16.8 hours reported.b

In patients with renal impairment (Clcr <30 mL/minute), elimination half-life of 10.5 hours reported.113

In geriatric individuals, elimination half-life reported to be about 5.6 hours (range 3.3–8.8 hours) or 6.6 hours (range: 3.8–9.2 hours) following IV or intranasal administration, respectively.113

Storage

Nasal

25°C.b

Parenteral

15–30°C; protect from light.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

• Analgesic effect is believed to result from an interaction with an opiate receptor site in the CNS (probably in or associated with the limbic system).a

• Opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but other mechanisms probably also are involved.d Butorphanol exerts antagonistic114 115 126 or partially antagonistic113 effects at μ opiate receptor sites; it appears to exerts agonistic effects principally at κ and Σ opiate receptors.101 102 103 104

• Produces respiratory depression, sedation, miosis and, in animals, antitussive effect.a

• Slightly increases pulmonary artery pressure, pulmonary wedge pressure, left ventricular end-diastolic pressure, systemic arterial pressure, pulmonary vascular resistance, and cardiac index.a

• In animals, inhibits GI motility slightly, causes little increase in duodenal smooth muscle activity, and has little or no effect on bile duct flow.d

• Potential for butorphanol to impair mental alertness or physical coordination; do not drive or operate machinery for ≥1 hour after receiving the drug or until effects on individual are known.a b

• Patients receiving the nasal solution should not perform activities that may pose risks if hypotension were to occur.113

• Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.a b

• Potential risk of serotonin syndrome with concurrent use of butorphanol and other serotonergic agents.400 Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.400

• Potential risk of adrenal insufficiency.400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.400

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.a b Importance of avoiding alcohol while receiving the drug.a b

• Importance of women informing their clinician if they are or plan to become pregnant or to breast-feed.a b

• Importance of advising patients of other important precautionary information.a b (See Cautions.)

Since butorphanol is often used as needed, you may not be on a dosing schedule. If you are using the medication regularly, use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.