Butorphanol Nasal Spray

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: Pharmacokinetics and Individualization of Dosage].

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse
Inform patients that the use of Butorphanol Tartrate Nasal Spray, 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 Nasal Spray with others and to take steps to protect Butorphanol Tartrate Nasal Spray 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 Nasal Spray 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.

Accidental Exposure
Inform patients that accidental exposure, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store Butorphanol Tartrate Nasal Spray securely and to dispose of unused Butorphanol Tartrate Nasal Spray by unscrewing the cap, rinsing the bottle, and placing the parts in the waste container.

Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Butorphanol Tartrate Nasal Spray is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome
Inform patients that opioids 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 healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].

Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS].

Important Administration Instructions
Inform patients of the proper use of Butorphanol Tartrate Nasal Spray [see PATIENT INSTRUCTIONS and MEDICATION GUIDE].

Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in Butorphanol Tartrate Nasal Spray. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications, Adverse Reactions].

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 fetal harm and to inform the healthcare provider 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].

Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Driving or Operating Heavy Machinery
Inform patients that Butorphanol Tartrate Nasal Spray may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery and to avoid such tasks while taking this product, until they know how they will react to the medication [see WARNINGS].

Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions].

Disposal of Unused Butorphanol Tartrate
Advise patients to dispose of butorphanol tartrate by unscrewing the cap, rinsing the bottle, and placing the parts in a waste container.

Drug Interactions

Benzodiazepine and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, such as alcohol, 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.

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. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS].

Serotonergic Drugs

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), 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 Nasal Spray if serotonin syndrome is suspected.

Cytochrome P450 (CYP 450) Interactions

It is not known if the effects of Butorphanol Tartrate Nasal Spray 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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies were conducted in mice and rats given butorphanol tartrate in the diet up to 60 mg/kg/day (24 and 48 times the human daily dose of 12 mg/day based on a body surface area comparison, respectively). There was no evidence of carcinogenicity in either species in these studies.

Mutagenesis

Butorphanol was not genotoxic in the in vitro bacterial reverse mutation assay (Ames) or in an in vitro unscheduled DNA synthesis and repair assay conducted in cultured human fibroblast cells.

Impairment of fertility

In a study where male rats were treated subcutaneously with 0.5 or 2.5 mg/kg butorphanol for 75 days prior to mating to female rats treated subcutaneously with 0.5 or 2.5 mg/kg butorphanol for 14-days prior to mating and throughout gestation and lactation, no adverse effects on fertility were noted (0.4- and 2-times the human daily dose of 12 mg based on body surface area).

In a study where male rats were treated orally with 10, 40, or 160 mg/kg for 63 days prior to mating to female rats treated orally with the same doses of butorphanol for 14 days prior to mating, reduced pregnancy rates were reported in the high dose group (130-times the human daily dose of 12 mg based on body surface area).

Pregnancy

Pregnancy Category C: Reproduction studies in mice, rats, and rabbits during organogenesis did not reveal any teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously with butorphanol at 1 mg/kg (5.9 mg/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m2) and 60 mg/kg/oral (720 mg/m2) also showed higher incidences of post-implantation loss in rabbits.

There are no adequate and well-controlled studies of Butorphanol Tartrate Nasal Spray in pregnant women before 37 weeks of gestation. Butorphanol Tartrate Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the infant.

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 Nasal Spray 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 Nasal Spray, 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.

Butorphanol Tartrate Nasal Spray is not recommended during labor or delivery because there is no clinical experience with its use in this setting.

Nursing Mothers

Although there is no clinical experience with the use of STADOL NS 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

Butorphanol Tartrate Nasal Spray 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 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 dose, 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 co-administered 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.

Butorphanol Tartrate Nasal Spray, USP 10 mg/mL 

(bue-TOR-fa-nol TAR-trate),

Butorphanol Tartrate Nasal Spray is:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
• An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Butorphanol Tartrate Nasal Spray:

• Get emergency help right away if you take too much Butorphanol Tartrate Nasal Spray (overdose). When you first start taking Butorphanol Tartrate Nasal Spray, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
• Taking Butorphanol Tartrate Nasal Spray with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma and death.
• Never give anyone else your Butorphanol Tartrate Nasal Spray. They could die from taking it. Store Butorphanol Tartrate Nasal Spray away from children and in a safe place to prevent stealing or abuse. Selling or giving away Butorphanol Tartrate Nasal Spray is against the law.

Do not take Butorphanol Tartrate Nasal Spray if you have:

• Severe asthma, trouble breathing, or other lung problems.
• A bowel blockage or have narrowing of the stomach or intestines.
• Previously had an allergic reaction to butorphanol or the preservative benzethonium chloride

Before taking Butorphanol Tartrate Nasal Spray, tell your healthcare provider if you have a history of:

• head injury, seizures
• liver, kidney, thyroid problems
• problems urinating
• pancreas or gallbladder problems
• abuse of street or prescription drugs, alcohol addiction, or mental health problems

Tell your healthcare provider if you are:

• Pregnant or planning to become pregnant. Prolonged use of Butorphanol Tartrate Nasal Spray during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
• Breastfeeding. Butorphanol Tartrate Nasal Spray passes into breast milk and may harm your baby.
• Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Butorphanol Tartrate Nasal Spray with certain other medicines can cause serious side effects that could lead to death.

When taking Butorphanol Tartrate Nasal Spray:

• Do not change your dose. Take Butorphanol Tartrate Nasal Spray exactly as prescribed by your healthcare provider.
• See the detailed Patient Instructions for information about how to take Butorphanol Tartrate Nasal Spray. Use the lowest dose possible for the shortest time needed.
• Take your prescribed dose as instructed by your healthcare provider. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. 
• Call your healthcare provider if the dose you are taking does not control your pain.
• If you have been taking Butorphanol Tartrate Nasal Spray regularly, do not stop taking Butorphanol Tartrate Nasal Spray without talking to your healthcare provider.
• After you stop taking Butorphanol Tartrate Nasal Spray, dispose of unused Butorphanol Tartrate Nasal Spray by unscrewing the cap, rinsing the bottle, and placing the parts in a waste container. 

While taking Butorphanol Tartrate Nasal Spray DO NOT:

• Drive or operate heavy machinery, until you know how Butorphanol Tartrate Nasal Spray affects you. Butorphanol Tartrate Nasal Spray can make you sleepy, dizzy, or lightheaded.
• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Butorphanol Tartrate Nasal Spray may cause you to overdose and die.

The possible side effects of Butorphanol Tartrate Nasal Spray:

• Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

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

This Medication Guide has been approved by the U.S. Food and Drug Administration.

KEEP OUT OF THE REACH OF CHILDREN.

APOTEX INC.
BUTORPHANOL TARTRATE NASAL SPRAY, USP
10 mg/mL

Revised January 2017

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 2.5 ML LABEL

APOTEX CORP. NDC 60505-0813-1

CIV

Butorphanol Tartrate Nasal Spray, USP - For Nasal Use Only

10mg/mL

Rx only