DESCRIPTION

Butorphanol tartrate is a synthetically derived opioid agonist-antagonist analgesic of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol D-(-)- tartrate (1:1) (salt). The molecular formula is C21H29NO2 • C4H6O6, which corresponds to a molecular weight of 477.56 and the following structural formula:

Butorphanol tartrate is a white crystalline substance. The dose is expressed as the tartrate salt. One milligram of the salt is equivalent to 0.68 mg of the free base. The n-octanol/aqueous buffer partition coefficient of butorphanol is 180:1 at pH 7.5.

Butorphanol tartrate injection is a sterile, nonpyrogenic parenteral aqueous solution of butorphanol tartrate for intravenous or intramuscular administration.

Each milliliter (mL) contains butorphanol tartrate 1 or 2 mg; sodium citrate, dihydrate, 6.4 mg; citric acid hydrous 3.3 mg; sodium chloride 6.4 mg. The pH is 4.5 (3.0 to 5.5).

CLINICAL PHARMACOLOGY

General Pharmacology and Mechanism of Action

Butorphanol is a mixed agonist-antagonist  with low intrinsic activity at receptors of the 11-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 the 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 kappa 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 butorphanoiiV  and 10 mg of morphine  sulfate  IV depressed respiration to a comparable  degree. At higher dose s, 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 section). 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, increase s in left ventricular end diastolic pressure and in systemic artenal 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 and within  15 minutes for intramuscular  injection.

Peak analgesic activity occurs within 30 to 60 minutes following intravenous and intramuscular 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).

Pharmacokinetics

Butorphanol tartrate injection is rapidly absorbed after IM injection and peak plasma levels are reached in 20 to 40 minutes.

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

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 1541iters/hr (see Table 1)..

The drug is transported across the blood-brain  and placental barriers and into human milk (see PRECAUTIONS: Labor and Delivery and Nursing Mothers sections).

Butorphanol is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively similar following intravenous or intramuscular 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.

Elimination occurs by urine and fecal excretion. When 3H labeled 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)

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 Tma x 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 hepatic ally impaired patients to butorphanol was significantly greater (about 2-fold) than that in healthy subjects.

For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, Drug Interactions  and Geriatric Use sections and to the CLINICAL PHARMACOLOGY: Individualization of Dosage section below.

Clinical Trials

The effectiveness of opioid analgesics varies in different pain syndromes. Studies with butorphanol tartrate injection have been performed in postoperative (primarily abdominal and orthopedic) pain and pain during labor and delivery, as preoperative  and preanesthetic medication, and as a supplement to balanced anesthesia (see below).

Use in the Management of Pain-Postoperative Pain

The analgesic efficacy  of butorphanol tartrate injection in postoperative pain was investigated in several double-blind active-controlled  studies involving 958 butorphanol-treated  patients. The following doses were found to have approxim ately equivalent ana lge sic effect:  2 mg butorphanol, 10 mg morphine, 40 mg pentazocine  and 80 mg meperidine.

After intravenous administration of butorphanol tartrate, onset and peak analgesic effect occurred by the time of first observation (30 minutes). After intramuscular administration, pain relief onset occurred  at 30 minutes or le ss, and peak effect occurred between 30 minutes  and one hour. The duration of action  of butorphanol tartrate injection was 3 to 4 hours when defined as the time necessary  for pain intensity to return to pretreatment level or the time to retreatment.

Preanesthetic Medication

Butorphanol  tartrate  injection, (2 mg and 4 mg) and meperidine  (80 mg) were studied fo r use as preanesthetic  medication  in hospitalized surgical patients. Patients received a single intramuscular  dose of either butorphanol or meperidine approximately  90 minutes prior to anesthesia. The anesthesia regimen included barbiturate induction, followed by nitrous oxide and oxygen with halothane or enflurane, with or without a muscle relaxant.

Anesthetic preparation was rated as satisfactory in all 42 butorphanol  injection patients regardle ss of the typ e of surgery.

Balanced Anesthesia

Butorphanol  tartrate  administered  intravenously  (mean dose 2 mg) was compared to intravenous  morphine  sulfate (mean dose 10 mg) as premedication shortly before thiopental induction, followed by balanced anesthesia in 50 ASA Class 1 and 2 patients. Anesthesia was then maintained by repeated intravenous  doses, averaging  4.6 mg butorphanol  and 22.8 mg morphine  per patient.

Anesthetic induction and maintenance were generally rated as satisfactory with both butorphanol injection (25 patients) and morphine (25 patients) regardless of the type of surgery performed. Emergence from anesthesia was comparable with both agents.

Labor (see PRECAUTIONS)

The analgesic efficacy of intravenous butorphanol tartrate injection was studied in pain during labor. In a total of 145 patients butorphanol  (1 mg and 2 mg) was as effective  as 40 mg and 80 mg of meperidine  (144 patients)  in the relief of pain in labor with no effect on the duration or progress of labor. Both drugs readily crossed the placenta and entered fetal circulation. The condition of the infants in these studies, determined by Apgar scores at 1 and 5 minutes (8 or above) and time to sustained respiration, showed that butorphanol had the same effects on the infants as meperidine.

In these studies neurobehavioral testing in infants exposed to butorphanol injection at a mean  of 18.6 hours after delivery, showed no significant difference s between treatment groups.

Individualization of Dosage

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

For pain relief the recommended initial dosage regimen of butorphanol tartrate injection is 1 mg IV or 2 mg IM with repeated doses every three to tour hours as necessary. This dosage regimen is likely to be effective for the majority of patients. Dosage adjustments of butorphanol injection should be based on observations of its beneficial and adverse effects. The initial dose in the elderly and in patients with renal or hepatic impairment should generally be half the recommended  adult dose (0.5 mg IV and 1 mg IM). Repeat doses in these patients should be determined by the patient's response rather than at fixed intervals but will generally be no less than 6 hours (see PRECAUTIONS).

The usual preoperative dose is 2 mg IM given 60 to 90 minutes before surgery or 2 mg IV shortly before induction.  This is approximately equivalent in sedative effect to 10 mg morphine  or 80 mg of meperidine. This single preoperative dose should be individualized based on age, body weight, physical status, underlying pathological c ondition, use of other drugs, type of anesthesia to be used and the surgical procedure involved.

During maintenance in balanced anesthesia the usual incremental dose of butorphanol tartrate is 0.5 to 1 mg IV. The incremental dose may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of butorphanol injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately  0.06 to 0.18 mg/kg).

As with other opioids of this class, butorphanol injection may not provide adequate intraoperative analge sia in every patient or under all conditions. A failure to achieve successful analgesia during balanced anesthesia is commonly reflected by increases in general sympathetic tone. Consequently, if blood pressure or heart rate continue to rise, consideration should be given to adding a potent volatile liquid inhalation anesthetic or another intravenous medication.

In labor, the recommended initial dose of butorphanol tartrate is 1 or 2 mg IM or IV in mothers with fetuses of 37 weeks gestation or beyond and without signs of fetal distress. Dosage adjustments of butorphanol in labor should be based on initial response with consideration given to concomitant analgesic or sedative drugs and the expected time of delivery. A dose should not be repeated in less than four hours nor administered less than four hours prior to the anticipated delivery (see PRECAUTIONS).

INDICATIONS AND USAGE

Butorphanol tartrate injection is indicated  as a preoperative  or preanesthetic medication,  as a supplement to balanced anesthesia, for the relief of pain during labor, and for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations  of Use

Because of the risks of addiction, abuse, 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 injection is contraindicated in patients hypersensitive to butorphanol tartrate.

WARNINGS

Addiction, Abuse, and Misuse

Butorphanol tartrate injection 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. 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 injection, and monitor all patients receiving butorphanol tartrate 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 tor 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 suc h patients necessitates intensive counseling about the risks and proper use of butorphanol tartrate along with intensive monitoring tor 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. Strategies to reduce these risks include prescribing the drug in the sma lle st appropriate quantity. 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 ha s been reported with the use of opioids, even when used as recommended.  Respiratory depression, if not immediately recognized and treated, may lead to re spiratory arrest and death. Management of respiratory  depre ssion may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status  [see OVERDOSAGE]. Carbon dioxide (C02 ) 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, the risk is greatest during the initiation  of therapy or following a dosage increase. Monitor patients closely for re spiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of butorphanol tartrate.

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

Neonatal Opioid Withdrawal Syndrome

Prolonged use of butorphanol  tartrate 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. It 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 due to Interactions with Central Nervous System Depressants

Hypotension, profound sedation, respiratory depression, coma, and death may result if butorphanol tartrate 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 anestheti cs, antipsychotics, other opioids).

When considering the use of butorphanol tartrate 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 is made, start with a lower dosage of butorphanol tartrate, 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 of butorphanol tartrate 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-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 [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 and when butorphanol tartrate 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.

PRECAUTIONS

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.

Hepatic and Renal Disease

In patients with hepatic or renal impairment, the initial dose of butorphanol tartrate injection should generally be half the recommended adult dose (0.5 mg IV and 1 mg IM). Repeat doses in these patients should be determined by the patient's response rather than at fixed intervals but will generally be no less than 6 hours apart (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization of Dosage sections).

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 section).

Information for Patients

Addiction, Abuse, and Misuse

Inform patients that the use of butorphanol tartrate, 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 with others and to take steps to protect butorphanol tartrate from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening  respiratory depression, including information that the risk is greatest when starting butorphanol tartrate 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.

Interactions  with CNS Depressants

Inform patients that potentially serious additive effects may occur if butorphanol tartrate is used with CNS depressants  and to seek medical attention if they experience increased sedation or difficulty breathing [see WARNINGS, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome

Inform patients that butorphanol tartrate 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]

Pregnancy

Neonatal Opioid Withdrawal  Syndrome

Inform patients that prolonged use of butorphanol tartrate 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 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].

Drug Interactions

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.

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 ISSRis). serotonin and norepinephrine reuptake inhibitors ISNRis), tricyclic antidepressants ITCAs), 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 if serotonin syndrome is suspected.

Carcinogenesis,Mutagenesis,Impairment of Fertility

lnfertilitv

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

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

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 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, 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

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for butorphanol tartrate and any potential adverse effects on the breastfed infant from butorphanol tartrate or from the underlying maternal condition.

Infants exposed to butorphanol tartrate through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

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

Elderly patients (aged 65 years or older) may have increased sensitivity to butorphanol tartrate. 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 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 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- 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 nasal spray were somnolence (43%), dizziness (19%). nausea and/or vomiting (13%). In long-term trials with nasal butorphanol 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 sprays trials and under circumstances where the association between these events and butorphanol administration is unknown. They are being listed as alerting information for the physician:

Body as a Whole:Edema

Cardiovascular: Chest Pain, Hypertension, Tachycardia

Nervous: Depression Respiratory: Shallow Breathing Postmarketing Experience

Postmarketing experience with 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 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.

• serotonin syndrome
• adrenal insufficiency

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 tor in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

DRUG ABUSE AND DEPENDENCE

Butorphanol tartrate  injection  is a Schedule IV Controlled Substance.

Abuse

Butorphanol tartrate is a substance with a high potential for abuse similar to other opioids including. Butorphanol tartrate injection 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, tor 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 tor 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.

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 lin 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 tor 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, nalmetene). 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 should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If butorphanol tartrate 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].

DRUG ABUSE AND DEPENDENCE

Clinical Presentation

Acute overdose with butorphanol tartrate can be manifested by respiratory depression, somnolence progressing to stupor or  coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, 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 antagonist, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to butorphanol tartrate 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 overdose.

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.

OVERDOSAGE

Clinical Manifestations

The clinical manifestations of butorphanol overdose are those of opioid drugs in general. Consequences of overdose vary with the amount of butorphanol ingested and of individual response to the effects of opiates. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma and death. Butorphanol overdose may be associated with ingestion of multiple drugs (see ADVERSE REACTIONS:  Postmarketing Experience section).

Overdose can occur due to accidental or intentional misuse of butorphanol, especially in young children who may gain access to the drug in the home.

Treatment

The management of suspected butorphanol overdosage includes maintenance of adequate ventilation, peripheral perfusion, normal body temperature, and protection of the airway. Patients should be under continuous observation with adequate serial measures of mental state, responsiveness and vital signs. Oxygen and ventilatory assistance should be available with continual monitoring by pulse oximetry if indicated. In the presence of coma, placement of an artificial airway may be required. An adequate intravenous portal should be maintained to facilitate treatment of hypotension associated with vasodilation.

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.

DOSAGE AND ADMINISTRATION

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 and adjust the dosage accordingly [see WARNINGS].

InitialDosage

Factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly, patients with hepatic or renal disease, or in labor  requires  extra caution  (see PRECAUTIONS section and CLINICAL PHARMACOLOGY: Individualization  of Dosage section). The following doses are tor patients who do not have impaired hepatic or renal function and who are not on CNS active agents.

Use for Pain

Intravenous-The usual recommended single dose for IV administration is 1 mg repeated every three to tour hours as necessary. The effective dosage range, depending  on the severity  of pain, is 0.5 to 2 mg repeated  every three to tour hours.

Intramuscular-The usual recommended single dose for IM administration is 2 mg in patients  who  will be able to remain recumbent, in the event drowsiness or dizziness occurs. This may be repeated every three to tour hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4 mg repeated every three to tour hours. There are insufficient clinical data to recommend single doses above 4 mg.

Use as Preoperative/Preanesthetic Medication

The preoperative medication dosage of butorphanol tartrate injection should be individualized (see CLINICAL PHARMACOLOGY: Individualization  of Dosage section). The usual adult dose is 2 mg IM, administered  60 to 90 minutes before surgery. This is approximately equivalent in sedative effect to 10 mg morphine or 80 mg meperidine.

Use in Balanced Anesthesia

The usual dose of butorphanol tartrate injection is 2 mg IV shortly before induction and/or 0.5 to 1 mg IV in increments  during anesthesia. The increment may be higher, up to 0.06 mg/kg (4 mg/70 kg). depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of butorphanol injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 to 0.18 mg/kg).

Labor

In patients at full term in early labor a 1 to 2 mg dose of butorphanol tartrate IV or IM may be administered and repeated  after 4 hours. Alternative analgesia should be used for pain associated with delivery or if delivery is expected to occur within  4 hours.

If concomitant use of butorphanol with drugs that may potentiate its effects is deemed necessary (see PRECAUTIONS: Drug Interactions section) the lowest effective dose should be employed.

Safety and Handling

Butorphanol tartrate injection is supplied in sealed delivery systems that have a low risk of accidental exposure to health care workers. Ordinary care should be taken to avoid aerosol generation while preparing a syringe for use. Following skin contact, rinsing with cool water is recommended.

The disposal of Schedule IV controlled  substances must be consistent with State and Federal Regulations.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Titration and Maintenance  of Therapy

Individually titrate butorphanol tartrate to a dose that provides  adequate analgesia end minimizes adverse reactions. Continually reevaluate patients receiving butorphanol tartrate 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 [established name] 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

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

HOW SUPPLIED

Butorphanol Tartrate Injection, USP is supplied  as follows:

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

Protect from light.

Revised: 4/2016

SAMPLE PACKAGE LABEL