FDA Label for Butorphanol Tartrate
View Indications, Usage & Precautions
- WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
- DESCRIPTION
- MECHANISM OF ACTION
- PHARMACODYNAMICS
- PHARMACOKINETICS
- DRUG INTERACTIONS
- CLINICAL TRIALS
- INDIVIDUALIZATION OF DOSAGE
- INDICATIONS AND USAGE
- CONTRAINDICATIONS
- ADDICTION, ABUSE, AND MISUSE
- LIFE-THREATENING RESPIRATORY DEPRESSION
- NEONATAL OPIOID WITHDRAWAL SYNDROME
- RISKS OF CONCOMITANT USE OR DISCONTINUATION OF CYTOCHROME P450 3A4 INHIBITORS AND INDUCERS
- RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
- LIFE-THREATENING RESPIRATORY DEPRESSION IN PATIENTS WITH CHRONIC PULMONARY DISEASE OR IN ELDERLY, CACHECTIC, OR DEBILITATED PATIENTS
- ADRENAL INSUFFICIENCY
- RISKS OF USE IN PATIENTS WITH INCREASED INTRACRANIAL PRESSURE, BRAIN TUMORS, HEAD INJURY, OR IMPAIRED CONSCIOUSNESS
- RISKS OF USE IN PATIENTS WITH GASTROINTESTINAL CONDITIONS
- INCREASED RISK OF SEIZURES IN PATIENTS WITH SEIZURE DISORDERS
- WITHDRAWAL
- CARDIOVASCULAR EFFECTS
- GENERAL
- RISKS OF DRIVING AND OPERATING MACHINERY
- DISORDERS OF RESPIRATORY FUNCTION OR CONTROL
- HEPATIC AND RENAL DISEASE
- INFORMATION FOR PATIENTS
- CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
- PREGNANCY
- LABOR AND DELIVERY
- NURSING MOTHERS
- PEDIATRIC USE
- GERIATRIC USE
- CLINICAL TRIAL EXPERIENCE
- POSTMARKETING EXPERIENCE
- CONTROLLED SUBSTANCE
- ABUSE
- DEPENDENCE
- CLINICAL PRESENTATION
- TREATMENT OF OVERDOSE
- IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS
- INITIAL DOSAGE
- DOSAGE MODIFICATIONS IN ELDERLY PATIENTS AND PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT
- TITRATION AND MAINTENANCE OF THERAPY
- DISCONTINUATION OF BUTORPHANOL TARTRATE
- SAFETY AND HANDLING
- HOW SUPPLIED
- STORAGE CONDITIONS
- PHARMACIST ASSEMBLY INSTRUCTIONS FOR BUTORPHANOL TARTRATE NASAL SPRAY USP
- PATIENT INSTRUCTIONS
- MEDICATION GUIDE
Butorphanol Tartrate Product Label
The following document was submitted to the FDA by the labeler of this product Hikma Pharmaceuticals Usa Inc.. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.
Warning: Addiction, Abuse, And Misuse; Life-Threatening Respiratory Depression; Accidental Ingestion; Neonatal Opioid Withdrawal Syndrome; Cytochrome P450 3A4 Interaction; And Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants
Addiction, Abuse, and Misuse
Butorphanol Tartrate Nasal Spray exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Butorphanol Tartrate Nasal Spray, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Butorphanol Tartrate Nasal Spray. Monitor for respiratory depression, especially during initiation of Butorphanol Tartrate Nasal Spray or following a dose increase [see WARNINGS].
Accidental Exposure
Accidental exposure of butorphanol, especially by children, can result in a fatal overdose of butorphanol [see WARNINGS].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Butorphanol Tartrate Nasal Spray during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see
WARNINGS].
Cytochrome P450 3A4 Interaction
The concomitant use of Butorphanol Tartrate Nasal Spray with all cytochrome P450 3A4 inhibitors may result in an increase in butorphanol plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in butorphanol plasma concentration. Monitor patients receiving Butorphanol Tartrate Nasal Spray and any CYP3A4 inhibitor or inducer [see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see WARNINGS, PRECAUTIONS; Drug Interactions]
• Reserve concomitant prescribing of Butorphanol Tartrate Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.• Limit dosages and durations to the minimum required.• Follow patients for signs and symptoms of respiratory depression and sedation.
Description
Butorphanol tartrate is a synthetically derived opioid agonist-antagonist analgesic of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl)morphinan-3,14-diol [S-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (salt). The molecular formula is C21H29NO2•C4H6O6, which corresponds to a molecular weight of 477.55 and the following structural formula:
Mechanism Of Action
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.
Pharmacodynamics
The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is within 15 minutes for the nasal administration doses. Peak analgesic activity occurs within 1 to 2 hours following nasal spray administration.
The duration of analgesia varies depending on the pain model as well as the route of administration. Compared to the injectable form and other drugs in this class, Butorphanol Tartrate Nasal Spray has a longer duration of action (4 to 5 hours) [see CLINICAL PHARMACOLOGY; Clinical Trials].
Effects on the Central Nervous System
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Effects on the Cardiovascular System
Hemodynamic changes noted during cardiac catheterization in patients receiving single 0.025 mg/kg intravenous doses of butorphanol have included increases in pulmonary artery pressure, wedge pressure and vascular resistance, increases in left ventricular end diastolic pressure, and in systemic arterial pressure.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone
(LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of butorphanol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing butorphanol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].
Pharmacokinetics
1. Young subjects (n=24) are from 20 to 40 years old and elderly (n=24) are greater than 65 years of age.2. Time to peak plasma concentration.3. Mean (1 S.D.)4. (range of observed values)5. Peak plasma concentration normalized to 1 mg dose.6. Area under the plasma concentration-time curve after a 1 mg dose.7. Derived from IV data.
Intravenous | Nasal | |||
Young Elderly | ||||
0.62 (0.32)3 | ||||
Drug Interactions
Sumatriptan
Cimetidine
Oxymetazoline
Benzodiazepine and Other Central Nervous System (CNS) Depressants
Serotonergic Drugs
Cytochrome P450 (CYP 450) Interactions
Monoamine Oxidase Inhibitors (MAOIs)
No information is available about the use of butorphanol concurrently with MAO inhibitors.
Advise patient to avoid concomitant use of these drugs.
Clinical Trials
The effectiveness of opioid analgesics varies in different pain syndromes.
Studies with Butorphanol Tartrate Nasal Spray have been performed in postoperative (general, orthopedic, oral, cesarean section) pain, in postepisiotomy pain, in pain of musculoskeletal origin, and in migraine headache pain (see below).
Use in the Management of Pain
Individualization Of Dosage
Indications And Usage
Butorphanol Tartrate Nasal Spray is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of Use
• Have not been tolerated, or are not expected to be tolerated,• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
Contraindications
Butorphanol Tartrate Nasal Spray is contraindicated in:
• Patients with significant respiratory depression [see WARNINGS].• Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS].• Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS].• Patients with hypersensitivity to butorphanol tartrate, the preservative benzethonium chloride, or any of the formulation excipients (e.g., anaphylaxis) [see WARNINGS].
Addiction, Abuse, And Misuse
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butorphanol Tartrate Nasal Spray, 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.
Neonatal Opioid Withdrawal Syndrome
Risks Of Concomitant Use Or Discontinuation Of Cytochrome P450 3A4 Inhibitors And Inducers
Concomitant use of Butorphanol Tartrate Nasal Spray with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of butorphanol and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS; Life-Threatening Respiratory Depression], particularly when an inhibitor is added after a stable dose of Butorphanol Tartrate Nasal Spray is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Butorphanol Tartrate Nasal Spray-treated patients may increase butorphanol plasma concentrations and prolong opioid adverse reactions. When using Butorphanol Tartrate Nasal Spray with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Butorphanol Tartrate Nasal Spray-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Butorphanol Tartrate Nasal Spray until stable drug effects are achieved [See PRECAUTIONS;Drug Interactions].
Concomitant use of Butorphanol Tartrate Nasal Spray with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease butorphanol plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to butorphanol. When using Butorphanol Tartrate Nasal Spray with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS; Drug Interactions].
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 Nasal Spray with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine 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 Nasal Spray 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; Information for Patients, Drug Interactions].
Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of Butorphanol Tartrate Nasal Spray 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
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 Nasal Spray 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 Nasal Spray.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use ofButorphanol Tartrate Nasal Spray in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
Butorphanol Tartrate Nasal Spray is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
Butorphanol in Butorphanol Tartrate Nasal Spray 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 Nasal Spray 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 Nasal Spray therapy.
Withdrawal
The use of Butorphanol Tartrate Nasal Spray, 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 Nasal Spray with a full opioid agonist analgesic.
When discontinuing Butorphanol Tartrate Nasal Spray, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue Butorphanol Tartrate Nasal Spray [see DRUG ABUSE AND DEPENDENCE].
Cardiovascular Effects
Because butorphanol may increase the work of the heart, especially the pulmonary circuit, the use of Butorphanol Tartrate Nasal Spray 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 Tartrate Nasal Spray therapy. In such cases, Butorphanol Tartrate Nasal Spray 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.
General
Hypotension associated with syncope during the first hour of dosing with Butorphanol Tartrate Nasal Spray has been reported rarely, particularly in patients with past history of similar reactions to opioid analgesics. Therefore, patients should be advised to avoid activities with potential risks.
Risks Of Driving And Operating Machinery
Butorphanol Tartrate Nasal Spray may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butorphanol Tartrate Nasal Spray and know how they will react to the medication [see PRECAUTIONS; Information for Patients].
Disorders Of Respiratory Function Or Control
Butorphanol may produce respiratory depression, especially in patients receiving other CNS active agents, or patients suffering from CNS diseases or respiratory impairment.
Hepatic And Renal Disease
In patients with hepatic or renal impairment, the initial dose sequence of Butorphanol Tartrate Nasal Spray should be limited to 1 mg followed, if needed, by 1 mg in 90 to 120 minutes. The repeat dose sequence in these patients should be determined by the patient’s response rather than at fixed times but will generally be at intervals of no less than at 6 hours [see CLINICAL PHARMACOLOGY: Pharmacokineticsand Individualization of Dosage].
Information For Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Life-Threatening Respiratory Depression
Accidental Exposure
Interactions with Benzodiazepines and Other CNS Depressants
Serotonin Syndrome
Adrenal Insufficiency
Important Administration Instructions
Anaphylaxis
Pregnancy
Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of Butorphanol Tartrate Nasal Spray during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy].
Embryo-Fetal Toxicity:Inform female patients of reproductive potential that Butorphanol
Tartrate Nasal Spray can cause fetalharm and to inform the healthcare provider of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].
Lactation
Infertility
Driving or Operating Heavy Machinery
Constipation
Disposal of Unused Butorphanol Tartrate
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
Mutagenesis
Impairment of Fertility
Pregnancy
Fetal/Neonatal Adverse Reactions
Labor And Delivery
Nursing Mothers
Although there is no clinical experience with the use of Butorphanol Tartrate Nasal Spray in nursing mothers, butorphanol has been detected in milk following administration of butorphanol tartrate injection to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4 mcg/L of milk in a mother receiving 2 mg IM four times a day). It should be assumed that butorphanol will appear in the milk in similar amounts following the nasal route of administration.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Butorphanol Tartrate Nasal Spray and any potential adverse effects on the breastfed infant from butorphanol or from the underlying maternal condition.
Infants exposed to Butorphanol Tartrate Nasal Spray 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
Geriatric Use
Elderly patients (aged 65 years or older) may have increased sensitivity to Butorphanol Tartrate Nasal Spray.
Of the approximately 1700 patients treated with Butorphanol Tartrate Nasal Spray in clinical studies, 8% were 65 years of age or older and 2% were 75 years or older.
Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6 hours) in patients over the age of 65 years [see CLINICAL PHARMACOLOGY: Pharmacokinetics]. Elderly patients may be more sensitive to the side effects of butorphanol. In clinical studies of Butorphanol Tartrate Nasal Spray, elderly patients had an increased frequency of headache, dizziness, drowsiness, vertigo, constipation, nausea and/or vomiting, and nasal congestion compared with younger patients. There are insufficient efficacy data for patients ≥65 years to determine whether they respond differently from younger patients.
Initially a 1 mg dose of Butorphanol Tartrate Nasal Spray should be generally used in geriatric patients and 90 to 120 minutes should elapse before administering a second 1 mg does, if needed [see CLINICAL PHARMACOLOGY: Individualization of Dosage].
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 [see DOSAGE AND ADMINISTRATION].
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 coadministered with other agents that depress respiration. Titrate the dosage of Butorphanol Tartrate Nasal Spray slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see WARNINGS].
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Clinical Trial Experience
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.
Postmarketing Experience
• 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 Nasal Spray.• Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].
Controlled Substance
Abuse
Butorphanol Tartrate Nasal Spray contains butorphanol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Butorphanol Tartrate Nasal Spray 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, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Butorphanol Tartrate Nasal Spray, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of Butorphanol Tartrate Nasal Spray
Dependence
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine) [see WARNINGS]. Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Butorphanol Tartrate Nasal Spray should not be abruptly discontinued in a physically-dependent patient [see DOSAGE AND ADMINISTRATION]. If Butorphanol Tartrate Nasal Spray 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].
Clinical Presentation
Acute overdose with Butorphanol Tartrate Nasal Spray 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. As butorphanol is a mixed opioid agonist/antagonist, larger doses of naloxone or nalmefene may be needed to reverse the effects of an overdose.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to butorphanol tartrate overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of butorphanol in Butorphanol Tartrate Nasal Spray, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Important Dosage And Administration Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS].
Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS].
Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Butorphanol Tartrate Nasal Spray and adjust the dosage accordingly [see WARNINGS].
Initial Dosage
Use of Butorphanol Tartrate Nasal Spray as the first Opioid Analgesic
Factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly and in patients with hepatic or renal disease requires extra caution [see PRECAUTIONS and CLINICAL PHARMACOLOGY: Individualization of Dosage]. The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents.
Conversion from Other Opioids to Butorphanol Tartrate Nasal Spray
There is inter-patient variability in the potency of opioid drugs and opioid formulations.Therefore, a conservative approach is advised when determining the total daily dosage ofButorphanol Tartrate Nasal Spray. It is safer to underestimate a patient’s 24-hour Butorphanol Tartrate Nasal Spray dosage than to overestimate the 24-hour butorphanol dosage and manage an adverse reaction dueto overdose.
Dosage Modifications In Elderly Patients And Patients With Renal Or Hepatic Impairment
Titration And Maintenance Of Therapy
Discontinuation Of Butorphanol Tartrate
Safety And Handling
How Supplied
Butorphanol Tartrate Nasal Spray USP is supplied in a child-resistant vial containing a 2.5 mL bottle of nasal spray solution (10 mg/mL) and a metered-dose spray pump with protective clip and dust cover, a bottle of nasal spray solution, and a patient instruction leaflet and medication guide. On average, one bottle will deliver 14 to 15 doses if no repriming is necessary.
Butorphanol Tartrate Nasal Spray USP, 10 mg/mL
NDC 0054-3090-36: 2.5 mL Bottle.
Storage Conditions
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.
Distr. by: West-Ward
Pharmaceuticals Corp.
Eatontown, NJ 07724
10001972/07
Revised January 2017
Patient Instructions
1. Blow nose gently to clear both nostrils.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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.
DO NOT spray into both nostrils unless directed by your doctor.DO NOT repeat sooner than directed by your doctor.
Medication Guide
Butorphanol Tartrate Nasal Spray USP (bue tor’ fa nol tar’ trate) CIV Rx only |
Butorphanol Tartrate Nasal Spray is:
|
Important information about Butorphanol Tartrate Nasal Spray:
|
Do not take Butorphanol Tartrate Nasal Spray if you have:
|
Before taking Butorphanol Tartrate Nasal Spray, tell your healthcare provider if you have a history of: |
|
Tell your healthcare provider if you are:
|
When taking Butorphanol Tartrate Nasal Spray:
|
While taking Butorphanol Tartrate Nasal Spray DO NOT:
|
The possible side effects of Butorphanol Tartrate Nasal Spray: |
Get emergency medical help if you have:
These are not all the possible side effects of Butorphanol Tartrate Nasal Spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. |
Distr. by: West-Ward For more information, please call 1-800-962-8364. |
This Medication Guide has been approved by the U.S. Food and Drug Administration. |
KEEP OUT OF THE REACH OF CHILDREN.
10001972/07
Revised January 2017
* Please review the disclaimer below.