Source: Health Products and Food Branch (CA) Revision Year: 2018
NUBAIN (nalbuphine hydrochloride) should not be administered to:
Patients should be instructed not to give NUBAIN (nalbuphine hydrochloride) to anyone other than for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. NUBAIN should be stored securely to avoid theft or misuse.
NUBAIN should only be administered by persons knowledgeable in the continuous delivery of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.
NUBAIN should be administered as a supplement to surgical anesthesia only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.
Naloxone, resuscitative and intubation equipment and oxygen should be readily available.
Patients should be cautioned not to consume alcohol while taking NUBAIN as it may increase the chance of experiencing serious adverse events, including death.
Hyperalgesia that will not respond to a further dose increase of nalbuphine can occur at particularly high doses. A nalbuphine dose reduction or change in opioid may be required.
Like all opioids, NUBAIN is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, NUBAIN should be prescribed and handled with caution.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.
Opioids, such as NUBAIN, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
See TOXICOLOGY section.
NUBAIN administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of NUBAIN.
The use of NUBAIN in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.
Rapid intravenous injection of opioid analgesics increases the possibility of hypotension and respiratory depression and should be avoided (see DOSAGE AND ADMINISTRATION).
Myocardial Infarction: As with all potent analgesics, NUBAIN should be used with caution in patients with myocardial infarction who have nausea or vomiting. Hemodynamic studies in patients with severe arteriosclerotic heart changes reveal that NUBAIN has circulatory effects similar to those of morphine, i.e., a minimal decrease in oxygen consumption, cardiac index, left ventricular end-diastolic pressure and cardiac work.
As with other opioids, tolerance and physical dependence may develop upon repeated administration of NUBAIN and there is a potential for development of psychological dependence.
Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).
Use in Drug and Alcohol Addiction: NUBAIN is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to NUBAIN; extreme caution and awareness is warranted to mitigate the risk.
Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one 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.
NUBAIN and other morphine-like opioids have been shown to decrease bowel motility. Nalbuphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see CONTRAINDICATIONS).
Biliary Tract Surgery: NUBAIN may cause spasm of the sphincter of Oddi. It is not recommended to be used for analgesia in patients with acute abdominal conditions. It should only be used for anesthesia in these patients when its benefits outweigh its potential risks.
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.
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.
Use of NUBAIN is contraindicated in pregnant women (see CONTRAINDICATIONS).
Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol): NUBAIN should be used with caution and in a reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result.
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 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 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 (see DRUG INTERACTIONS).
NUBAIN should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see CONTRAINDICATIONS and ADVERSE REACTIONS, Sedation, and DRUG INTERACTIONS).
Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.
Head Injury: The respiratory depressant effects of nalbuphine, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, nalbuphine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, nalbuphine must be used with extreme caution and only if it is judged essential (see CONTRAINDICATIONS).
Use in Patients with Convulsive or Seizure Disorders: The nalbuphine hydrochloride in NUBAIN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Therefore, NUBAIN should not be used in these patients (see CONTRAINDICATIONS).
Serotonin syndrome: NUBAIN could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g. antidepressants, migraine medications). Treatment with the serotonergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. NUBAIN should not be used in combination with MAO inhibitors or serotoninprecursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see DRUG INTERACTIONS).
The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist).
In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with NUBAIN for at least 24 hours before the operation and NUBAIN should not be used in the immediate post-operative period.
Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated.
Nalbuphine and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving opioids. Standard supportive therapy should be implemented.
NUBAIN may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of nalbuphine with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.
Impaired Renal or Hepatic Function: Because NUBAIN is metabolized in the liver and excreted by the kidneys, patients with renal or liver dysfunction may show an exaggerated response to customary doses. In these individuals, NUBAIN should be used with caution and administered in reduced amounts.
Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, 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. Nalbuphine should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see CONTRAINDICATIONS).
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 dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with NUBAIN and following dose increases.
Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
To reduce the risk of respiratory depression, proper dosing and titration of NUBAIN are essential. Overestimating the NUBAIN dose when converting patients from another opioid product can result in a fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see WARNINGS AND PRECAUTIONS, Special Populations, Special Risk Groups, and DOSAGE AND ADMINISTRATION).
Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with NUBAIN, as in these patients, even usual therapeutic doses of NUBAIN may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of NUBAIN is contraindicated in Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).
Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).
Special Risk Groups: Nalbuphine should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison’s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture
Pregnant Women: Studies in humans have not been conducted. NUBAIN crosses the placental barrier and is contraindicated in pregnant women.
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS), ADVERSE REACTIONS, PostMarketing Experience).
Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.
Labour, Delivery and Nursing Women: Since opioids can cross the placental barrier and are excreted in breast milk, NUBAIN is contraindicated in nursing women and is not recommended to be used during labour and delivery unless, in the judgement of the physician, the potential benefits outweigh the risks. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opiates, should be readily available if NUBAIN is used in this population.
The placental transfer of nalbuphine is high, relatively rapid and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6.03. Fetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labour include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. 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.
Pediatrics (<18 years of age): The safety and efficacy of NUBAIN have not been studied in the pediatric population. Therefore, use of NUBAIN is not recommended in patients under 18 years of age.
Geriatrics (>65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).
Adverse effects of NUBAIN (nalbuphine hydrochloride) injection are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.
The following adverse effects occur less frequently with opioid analgesics and include those reported in NUBAIN clinical trials, whether related or not to nalbuphine hydrochloride.
In clinical trials with NUBAIN (nalbuphine hydrochloride) the most frequently reported side effects were: sedation (36% of 1066), sweating or clammy (9%), nausea or vomiting (6%), dizziness or vertigo (5%), dry mouth (4%) and headache (3%).
Central Nervous System: nervousness, crying, depression, restlessness, euphoria, hostility, confusion, faintness, floating, unusual dreams, numbness, feeling of heaviness, and psychotomimetic effects such as hallucinations, feeling of unreality and dysphoria. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine.
Cardiovascular: Hypertension, hypotension, bradycardia, tachycardia.
Gastrointestinal: Cramps, dyspepsia, bitter taste. Respiration: Depression, dyspnea, asthma.
Dermatological: Itching, burning, urticaria.
Miscellaneous: Speech difficulty, urinary urgency, blurred vision, flushing and warmth.
Allergic Reactions: Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. These reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Other allergic-type reactions reported with patients using NUBAIN include stridor, bronchospasm, wheezing, edema, rash, pruritis, nausea, vomiting, diaphoresis, weakness, and shakiness.
Post-marketing: Other reports include pulmonary edema, agitation and injection site reactions such as pain, swelling, redness, burning and hot sensations.
Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitarygonadal 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants (including alcohol): Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases 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 (see WARNINGS AND PRECAUTIONS, Neurologic, Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol) and Psychomotor Impairment). NUBAIN should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.
Central Nervous System (CNS) Depressants: Both magnitude and duration of CNS and cardiovascular effects may be enhanced when NUBAIN is administered to patients receiving barbiturates, benzodiazepines, neuroleptics, halogenic gases and other nonselective CNS depressants (e.g. alcohol). When patients have received such drugs, the dose of NUBAIN required will be less than usual. Likewise, following the administration of NUBAIN the dose of other CNS-depressant drugs should be reduced.
MAO Inhibitors: It is usually recommended to discontinue MAO inhibitors 2 weeks prior to any surgical or anesthetic procedure.
Serotonergic Agents: Coadministration of nalbuphine with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may increase the risk of serotonin syndrome, a potentially life-threatening condition (see WARNINGS AND PRECAUTIONS, Neurologic).
The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS, General).
Monitoring and Laboratory Tests: NUBAIN may interfere with enzymatic methods for the detection of opioids depending on the specificity and sensitivity of the laboratory tests. Please consult the test manufacturer for specific details.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
