Get your patient on Butorphanol Tartrate - Butorphanol Tartrate injection, Solution (Butorphanol Tartrate)

Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see WARNINGS ], reserve opioid analgesics, including butorphanol tartrate, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Butorphanol Tartrate Injection should be prescribed only by healthcare professionals who are ‎knowledgeable about the use of opioids and how to mitigate the ‎associated risks.‎

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS ]. Because the risk of overdose increases as opioid doses increase, reserve ‎titration to higher doses of Butorphanol Tartrate Injection for patients in whom lower ‎doses are insufficiently effective and in whom the expected benefits of ‎using a higher dose opioid clearly outweigh the substantial risks.‎

There is variability in the opioid analgesic dose and duration needed to ‎adequately manage pain due both to the cause of pain and to individual ‎patient factors. Initiate the dosing regimen for each patient individually, ‎taking into account the patient’s underlying cause and severity of pain, ‎prior analgesic treatment and response, and risk factors for addiction, ‎abuse, and misuse [see WARNINGS ].

Respiratory depression can occur at any time during opioid therapy, ‎especially when initiating and following dosage increases with Butorphanol Tartrate Injection. Consider this risk when selecting an initial dose and when ‎making dose adjustments [see WARNINGS ]‎.

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 ; 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.

The preoperative medication dosage of Butorphanol Tartrate Injection should be individualized [see CLINICAL PHARMACOLOGY: Individualization of Dosage ]. 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.

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).

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 ] the lowest effective dose should be employed.

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

Individually titrate Butorphanol Tartrate Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Butorphanol Tartrate Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as reassessing 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 Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage ‎[see WARNINGS ]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

When a patient who has been taking Butorphanol Tartrate Injection regularly and may be physically dependent no longer requires therapy with Butorphanol Tartrate Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not rapidly reduce or abruptly discontinue Butorphanol Tartrate Injection in patients who may be physically-dependent on opioids [see WARNINGS , DRUG ABUSE AND DEPENDENCE ].

Butorphanol Tartrate Injection is supplied in sealed delivery systems that have a low risk of accidental exposure to healthcare 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.

A total of 1658 patients were studied in premarketing clinical trials of Butorphanol Tartrate Injection. In nearly all cases the type and incidence of side effects with butorphanol were those commonly observed with opioid analgesics.

The adverse experiences described below are based on data from short- and long-term clinical trials in patients receiving Butorphanol Tartrate Injection.

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%). 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: Cough, Dyspnea

Skin and Appendages: Sweating, Pruritus

Special Senses: Blurred Vision, Ear Pain, Tinnitus, Unpleasant Taste

The following adverse experiences were reported with a frequency of less than 1% in clinical trials and were considered to be probably related to the use of butorphanol:

Cardiovascular: Hypotension, Syncope

Nervous: Abnormal Dreams, Agitation, Dysphoria, Hallucinations, Hostility, Withdrawal Symptoms

Skin and Appendages: Rash/Hives

Urogenital: Impaired Urination

The following infrequent additional adverse experiences were reported in a frequency of less than 1% of the patients studied in short-term butorphanol tartrate nasal 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 due to their clinical significance:

Body as a Whole: Edema

Cardiovascular: Chest Pain, Hypertension, Tachycardia

Nervous: Depression

Respiratory: Shallow Breathing

The following adverse reactions have been identified during post approval use of Butorphanol Tartrate Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Butorphanol Tartrate Injection.
• Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY ].
• Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of any duration [see WARNINGS ].‎
• Hypoglycemia: Cases of hypoglycemia have been reported in patients ‎taking opioids. Most reports were in patients with at least one ‎predisposing risk factor (e.g., diabetes).‎
• Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see WARNINGS ].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in DRUG ABUSE AND DEPENDENCE ], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants such as alcohol, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids, can increase the risk of respiratory depression, profound sedation, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation [see WARNINGS ]. If concomitant use is warranted, consider ‎prescribing naloxone for the emergency treatment of opioid overdose.

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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (eg., cyclobenzaprine, metaxalone), 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, regularly monitor the patient, particularly during treatment initiation and dose adjustment. Discontinue Butorphanol Tartrate Injection if serotonin syndrome is suspected.

It is not known if the effects of Butorphanol Tartrate Injection are altered by concomitant medications that affect hepatic metabolism of drugs (CYP 450 inhibitors or inducers) (e.g., erythromycin, theophylline, etc.), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

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

Advise patient to avoid concomitant use of these drugs.

Butorphanol is a partial opioid agonist at the mu opioid receptor and a full agonist at the kappa opioid receptor. The principal therapeutic action of butorphanol is analgesia. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is within 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 ].

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).

Figure 1—Butorphanol Plasma Levels After IV and IM Administration of 2 mg Dose

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

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

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

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 ³ H 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 C _max or T _max was observed after a single-dose.

After intravenous administration to patients with hepatic impairment, the elimination half-life of butorphanol was approximately tripled and total body clearance was approximately one half (half-life 16.8 hours, clearance 92 L/h) compared to healthy subjects (half-life 4.8 hours, clearance 175 L/h). The exposure of hepatically impaired patients to butorphanol was significantly greater (about 2-fold) than that in healthy subjects [see PRECAUTIONS: Hepatic and Renal Disease , Drug Interactions and Geriatric Use and CLINICAL PHARMACOLOGY: Individualization of Dosage ].

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 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 four 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 condition, 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 analgesia 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 ].

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

Protect from light.