INDICATIONS AND USAGE Butorphanol Tartrate Injection is indicated: as a preoperative or pre-anesthetic 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 Injection for use in patients for whom alternative treatment options [e.g.

non-opioid analgesics] Have not been tolerated, or are not expected to be tolerated Have not provided adequate analgesia, or are not expected to provide adequate analgesia

WARNINGS Addiction, Abuse, and Misuse Butorphanol Tartrate Injection contains butorphanol, a Schedule IV controlled substance.

As an opioid, Butorphanol Tartrate Injection 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 Injection.

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 Injection for the development of these behaviors or conditions.

Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as Butorphanol Tartrate Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Butorphanol Tartrate Injection along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Consider these risks when prescribing or dispensing Butorphanol Tartrate Injection.

Strategies to reduce these risks include prescribing the drug in the smallest 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 has been reported with the use of opioids, even when used as recommended.

Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ].

Carbon dioxide (CO 2 ) 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 Injection, the risk is greatest during the initiation of therapy or following a dosage increase.

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Butorphanol Tartrate Injection.

To reduce the risk of respiratory depression, proper dosing and titration of Butorphanol Tartrate Injection are essential [see DOSAGE AND ADMINISTRATION ].

Overestimating the Butorphanol Tartrate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.

Opioid use increases the risk of CSA in a dose-dependent fashion.

In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ].

Neonatal Opioid Withdrawal Syndrome Prolonged use of Butorphanol Tartrate Injection 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.

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients , Pregnancy ].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Butorphanol Tartrate Injection with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).

Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.

Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions ].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.

In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.

If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Butorphanol Tartrate Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).

Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.

Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS; Drug Interactions and PRECAUTIONS; Information for Patients ].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Butorphanol Tartrate Injection 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 Injection-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 Injection [see WARNINGS ].

Elderly, Cachectic, 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 Injection and when Butorphanol Tartrate Injection 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.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Butorphanol Tartrate Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Butorphanol Tartrate Injection.

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of Butorphanol Tartrate Injection in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions Butorphanol Tartrate Injection is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

Butorphanol in Butorphanol Tartrate Injection may cause spasm of the sphincter of Oddi.

Opioids may cause increases in serum amylase.

Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders The butorphanol in Butorphanol Tartrate Injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.

Monitor patients with a history of seizure disorders for worsened seizure control during Butorphanol Tartrate Injection therapy.

Withdrawal The use of Butorphanol Tartrate Injection, a mixed agonist/antagonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms.

Avoid concomitant use of Butorphanol Tartrate Injection with a full opioid agonist analgesic.

When discontinuing Butorphanol Tartrate Injection, gradually taper the dosage (see DOSAGE AND ADMINISTRATION ).

Do not abruptly discontinue Butorphanol Tartrate Injection (see DRUG ABUSE AND DEPENDENCE ).

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.

ADVERSE REACTIONS Clinical Trial Experience 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-term 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%).

In long-term trials with the 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: 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 Spray trials or trials of Butorphanol Tartrate Injection and under circumstances where the association between these events and butorphanol administration is unknown.

They are being listed as alerting information for the physician physician due to their clinical significance..

Body as a Whole: Edema Cardiovascular: Chest pain, hypertension, tachycardia Nervous: Depression Respiratory: Shallow breathing Postmarketing Experience 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 chronic use of opioids (see CLINICAL PHARMACOLOGY ).

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp.

at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .