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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
NUBAIN (NDA-018024)
(NALBUPHINE HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/22/2025 (SUPPL-44)
5 Warnings and Precautions
WARNINGS
Additions and/or revisions underlined:
NUBAIN contains nalbuphine. As an opioid, nalbuphine exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE]. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see ADVERSE REACTIONS].
. . .
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 overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO) retention from opioid- induced respiratory depression can exacerbate the sedating effects of opioids.
. . .
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from concomitant use of NUBAIN with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepines sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
. . .
Risks of Gastrointestinal Complications
. . .
Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see CLINICAL PHARMACOLOGY].
. . .
Withdrawal
. . .
When discontinuing NUBAIN in a physically-dependent patient, gradually taper the dosage (see DOSAGE AND ADMINISTRATION). Do not rapidly reduce or abruptly discontinue NUBAIN in these patients (see DRUG ABUSE AND DEPENDENCE).
. . .
PRECAUTIONS
Additions and/or revisions underlined:
. . .
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome 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 after discharge from the hospital. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see PRECAUTIONS; Drug Interactions]
. . .
6 Adverse Reactions
Additions and/or revisions underlined:
. . .
Postmarketing Experience
. . .
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.
7 Drug Interactions
Additions and/or revisions underlined:
Benzodiazepines and other Central Nervous System (CNS) Depressants
Although NUBAIN possesses opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after an injection of NUBAIN. Therefore, due to additive pharmacologic effects, the concomitant use of other opioid analgesics, benzodiazepines or other CNS depressants such as alcohol, other 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.
. . .
Muscle Relaxants
Nalbuphine may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression.
. . .
8 Use in Specific Populations
Additions and/or revisions underlined:
Pregnancy
. . .
Clinical Considerations
. . .
Labor and Delivery
. . .
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. NUBAIN is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including NUBAIN, 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.
. . .
Lactation
Limited data suggest that NUBAIN (nalbuphine hydrochloride) is excreted in maternal milk but only in a small amount (less than 1% of the administered dose) and with a clinically insignificant effect.
Monitor infants exposed to NUBAIN through breast milk 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.
. . .
12/15/2023 (SUPPL-43)
5 Warnings and Precautions
WARNINGS
(Additions and/or revisions underlined)
Addiction, Abuse, and Misuse
NUBAIN contains nalbuphine. As an opioid, nalbuphine exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].
Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling NUBAIN. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. 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.
…
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUBAIN with benzodiazepines and/or other CNS depressants, including alcohol (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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
…
Opioid-Induced Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DRUG ABUSE AND DEPENDENCE; Dependence]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non- painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.
Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE AND ADMINISTRATION, WARNINGS].
…
PRECAUTIONS
…
Information for Patients
Patients should be advised of the following information:
Addiction, Abuse, and Misuse
Inform patients that the use of NUBAIN, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNING]. Instruct patients not to share NUBAIN with others and to take steps to protect NUBAIN 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 Morphine Sulfate Injection or when the dosage is increased, and that it can occur even at recommended dosages.
Hyperalgesia and Allodynia
Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS, ADVERSE REACTIONS].
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 after discharge from the hospital. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see PRECAUTIONS; Drug Interactions]
…
Geriatric Use
Elderly patients (aged 65 years or older) may have increased sensitivity to NUBAIN. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co- administered with other agents that depress respiration. Titrate the dosage of NUBAIN slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see WARNINGS].
6 Adverse Reactions
(Additions and/or revisions underlined)
Postmarketing Experience
The following adverse reactions have been identified during post approval use of nalbuphine. 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.
Abdominal pain, pyrexia, depressed level or loss of consciousness, somnolence, tremor, anxiety, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and hot sensations. Death has been reported from severe allergic reactions to NUBAIN treatment. Fetal death has been reported where mothers received NUBAIN during labor and delivery.
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).
10/07/2019 (SUPPL-42)
5 Warnings and Precautions
PRECAUTIONSDrug Interactions
Serotonergic Drugs
Additions and/or revisions underlined:
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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., 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.
Life-Threatening Respiratory Depression
Newly added information to the end of this titled subsection:
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.
12/16/2016 (SUPPL-41)
Boxed Warning
(Newly added subsection)
WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of NUBAIN, particularly when used concomitantly with other opioids or central nervous system depressants. Monitor for respiratory depression, especially during initiation of NUBAIN or following a dose increase
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.
- Reserve concomitant prescribing of NUBAIN 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.
4 Contraindications
(Additions and/or revisions are underlined)
NUBAIN is contraindicated in patients with:
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
- Known or suspected gastrointestinal obstruction, including paralytic ileus
5 Warnings and Precautions
PRECAUTIONS(Additions and/or revisions are underlined)
Information for Patients
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 physicians if they are taking, or plan to take serotonergic medications.
Monoamine Oxidase Inhibitor (MAOI) Interaction
Inform patients to avoid taking NUBAIN while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking NUBAIN.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There was no evidence of carcinogenicity in long term animal studies were performed in rats (24 months) and mice (19 months) by oral administration at doses up to 200 mg/kg [12 times the maximum recommended human daily dose (MRHD)] and 200 mg/ per day (6 times the MRDH), respectively.
Impairment of Fertility
Female rats were treated with nalbuphine hydrochloride beginning 15 days prior to mating through Lactation Day 20 via subcutaneous doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD of 160 mg/day based on body surface area, respectively). Male rats were treated via oral gavage with the same oxymorphone hydrochloride doses beginning 60 days prior to and throughout mating. There were no adverse effects on either male or female fertility.
(Additions and/or revisions are underlined)
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. Carbon dioxide (CO) 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 NUBAIN, 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 NUBAIN.
To reduce the risk of respiratory depression, proper dosing and titration of NUBAIN are essential. Overestimating the NUBAIN dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUBAIN 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.
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 NUBAIN 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.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of NUBAIN 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: NUBAIN-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 use of NUBAIN.
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. Monitor such patients closely, particularly when initiating and titrating NUBAIN and when NUBAIN is given concomitantly with other drugs that depress respiration. 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.
Severe Hypotension
NUBAIN may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics. Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUBAIN. In patients with circulatory shock, NUBAIN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUBAIN in patients with circulatory shock.
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), NUBAIN 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 NUBAIN.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUBAIN in patients with impaired consciousness or coma.
Risks of Use in Patients with Gastrointestinal Conditions
NUBAIN is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The nalbuphine in NUBAIN 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 nalbuphine in NUBAIN 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 NUBAIN therapy.
Withdrawal
The use of NUBAIN, 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 NUBAIN with a full opioid agonist analgesic.
When discontinuing NUBAIN in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue NUBAIN in these patients.
Risks of Driving and Operating Machinery
NUBAIN 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 NUBAIN and know how they will react to the medication…
Use in Pregnancy (Other Than Labor)
… Avoid the use of NUBAIN in pregnant women unless the potential benefit outweighs the risk to the fetus…
Addiction, Abuse, and Misuse
Nalbuphine hydrochloride is a synthetic opioid agonist-antagonist analgesic. As an opioid, NUBAIN exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUBAIN. 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. 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.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUBAIN. 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.
6 Adverse Reactions
(Additions and/or revisions are underlined)
Postmarketing Experience
The following adverse reactions have been identified during post approval use of nalbuphine. 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.
7 Drug Interactions
(Additions and/or revisions are underlined)
Benzodiazepines and other Central Nervous System (CNS) Depressants
…Therefore, due to additive pharmacologic effects, the concomitant use of other opioid analgesics, benzodiazepines or other CNS depressants such as alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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. Follow patients closely for signs of respiratory depression and sedation
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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome.
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue NUBAIN if serotonin syndrome is suspected.
Muscle Relaxants
Nalbuphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUBAIN and/or the muscle relaxant as necessary.
Diuretics
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Monitor patients for signs of urinary retention or reduced gastric motility when NUBAIN is used concomitantly with anticholinergic drugs.
Monoamine Oxidase Inhibitors (MAOIs)
MAOI (e.g., phenelzine, tranylcypromine, linezolid) interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma. The use of NUBAIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
8 Use in Specific Populations
Geriatric Use(Newly added subsection)
Elderly patients (aged 65 years or older) may have increased sensitivity to NUBAIN. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co- administered with other agents that depress respiration. Titrate the dosage of NUBAIN slowly in geriatric patients.
Nalbuphine 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.
(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with NUBAIN in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies nalbuphine decreased pup survival and pup body weights when pregnant female rats were treated late in gestation and throughout lactation at 1.7 times the MRHD and when female and male rats treated either prior to mating and throughout gestation and lactation. No malformations were observed in either rats or rabbits at doses 6.1 and 3.9 times the MRHD, respectively
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Severe fetal bradycardia has been reported when NUBAIN is administered during labor. Naloxone may reverse these effects. Although there are no reports of fetal bradycardia earlier in pregnancy, it is possible that this may occur. This drug should be used in pregnancy only if clearly needed, if the potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring are taken to detect and manage any potential adverse effect on the fetus.
Labor and Delivery
The placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6. Fetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. Some of these events have been life-threatening. Maternal administration of naloxone during labor has normalized these effects in some cases. Severe and prolonged fetal bradycardia has been reported. Permanent neurological damage attributed to fetal bradycardia has occurred. A sinusoidal fetal heart rate pattern associated with the use of nalbuphine has also been reported. NUBAIN should be used during labor and delivery only if clearly indicated and only if the potential benefit outweighs the risk to the infant. Newborns should be monitored for respiratory depression, apnea, bradycardia and arrhythmias if NUBAIN has been used.
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. NUBAIN is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including NUBAIN, 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.
Data
Animal Data
Pregnant rats were treated with nalbuphine hydrochloride from Gestation Day 6 to 15 via subcutaneous doses of 7, 14, or 100 mg/kg/day (0.4, 0.85, or 6.1 times the MRHD of 160 mg/day based on body surface area, respectively). There was no evidence of malformations or embryotoxicity despite reductions in maternal weight gain in the mid- and high-dose groups.
Pregnant rabbits were treated with nalbuphine hydrochloride from Gestation Day 7 to 19 via intravenous doses of 4, 8, or 32 mg/kg/day (0.5, 1, or 3.9 times the MRHD based on body surface area, respectively). There was no evidence of malformations or embryotoxicity despite reductions in maternal weight gain in the high-dose group.
Pregnant rats were treated with nalbuphine hydrochloride from Gestation Day 15 to Lactation Day 20 via subcutaneous doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD based on body surface area, respectively). Pup survival was decreased in the mid- and high-dose groups and neonatal body weights were dose dependently reduced. Maternal toxicity was noted in all treatment groups (reduced body weights).
Female rats were treated with nalbuphine hydrochloride beginning 15 days prior to mating through Lactation Day 20 via subcutaneous doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD of 160 mg/day based on body surface area, respectively). Male rats were treated via oral gavage with the same oxymorphone hydrochloride doses beginning 60 days prior to and throughout mating. There was reduced pup survival in the high dose group animals and reduced pup body weights in the mid- and high- dose groups.
Lactation
…Infants exposed to NUBAIN 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.