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    Mixed Opiate Agonist-Antagonist

    BOXED WARNING

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, infection, pulmonary disease, respiratory depression, respiratory insufficiency, uremia

    Avoid nalbuphine coadministration with other CNS depressants unless no other alternatives are available, as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death. If nalbuphine must be administered to patients with pulmonary disease (i.e.,  asthma, chronic obstructive pulmonary disease (COPD), respiratory insufficiency), use extreme caution and initiate treatment at the lowest effective dose. Caution is also recommended for use in patients with impaired respiration from uremia, severe infection, cyanosis, or respiratory obstructions. Nalbuphine may produce respiratory depression similar to the effect from equianalgesic doses of morphine. Nalbuphine, however, has a 'ceiling effect' for respiratory depression, where doses greater than 30 mg do not produce further respiratory depression in the absence of other CNS depressant agents.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic opiate agonist/antagonist; chemically related to naloxone and oxymorphone; used to treat moderate to severe pain; equianalgesic with morphine on a mg-per-mg basis; respiratory depressant ceiling effect at doses > 30 mg in the absence of other CNS depressants.

    COMMON BRAND NAMES

    Nubain

    HOW SUPPLIED

    Nalbuphine Hydrochloride/Nubain Intramuscular Inj Sol: 1mL, 10mg, 20mg
    Nalbuphine Hydrochloride/Nubain Intramuscular Sol: 1mL, 10mg
    Nalbuphine Hydrochloride/Nubain Intravenous Inj Sol: 1mL, 10mg, 20mg
    Nalbuphine Hydrochloride/Nubain Intravenous Sol: 1mL, 10mg
    Nalbuphine Hydrochloride/Nubain Subcutaneous Inj Sol: 1mL, 10mg, 20mg
    Nalbuphine Hydrochloride/Nubain Subcutaneous Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the relief of moderate pain to severe pain and for pain associated with obstetric labor and delivery.
    NOTE: For pain, doses should be titrated to the desired analgesic effect. Reduced initial dosages should be considered for geriatric patients and for patients at increased risk for respiratory depression, including patients receiving other CNS depressants.
    NOTE: Nalbuphine 10 mg IV is considered equianalgesic to morphine 10 mg IV.
    NOTE: Nalbuphine is not the analgesic of choice for opiate-tolerant patients because of the risk of withdrawal. If the previous analgesic was morphine, meperidine, codeine, or other opioid with similar duration of activity, administer 25% of the anticipated nalbuphine dose and closely observe the patient for withdrawal symptoms (e.g., abdominal cramps, nausea, vomiting, rhinorrhea, anxiety, piloerection). If the patient tolerates the reduced dosage, the nalbuphine dose may be slowly increased until the desired level of analgesia is achieved. If an opioid-tolerant patient has unduly troublesome opioid withdrawal symptoms upon nalbuphine administration, slow intravenous administration of small increments of morphine may be used as needed for symptom relief.
    Intramuscular, Intravenous, or Subcutaneous dosage
    Adults

    10 mg IM, IV, or subcutaneously every 3—6 hours as needed (NOTE: dosage is based on 70 kg body weight).

    Children†

    Safety and efficacy have not been established; 0.1 mg/kg IM, IV, or subcutaenously every 3—6 hours as needed has been suggested.

    For preanesthesia and adjunctive use in general anesthesia induction and general anesthesia maintenance.
    NOTE: Only persons specifically trained in the use of intravenous anesthetics and in the management of the respiratory effects of potent opioids should administer nalbuphine.
    Intravenous dosage
    Adults

    0.3—3 mg/kg IV over 10—15 minutes. Subsequent doses as required are 0.25—0.5 mg/kg IV.

    MAXIMUM DOSAGE

    Adults

    For opiate naive patients, 20 mg/dose IV, IM, or SC and 160 mg/day IV, IM, or SC.

    Children

    Not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.

    ADMINISTRATION

    Injectable Administration

    Nalbuphine is administered intramuscularly, intravenously, or subcutaneously.
    No dilution necessary. 
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Direct intravenous injection
    Prior to administration, an opiate antagonist (e.g., naloxone) and facilities for administration of oxygen and control of respiration (e.g., intubation equipment) should be readily available.

    Intramuscular Administration

    Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Nubain:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until contents are used

    CONTRAINDICATIONS / PRECAUTIONS

    Opiate agonist hypersensitivity, paraben hypersensitivity

    Nalbuphine is contraindicated in patients who are hypersensitive to nalbuphine chloride or any components of the product. Use with caution in patients who have demonstrated a prior opiate agonist hypersensitivity; these patients may be at increased risk of developing reactions to nalbuphine. Patients with paraben hypersensitivity should not receive nalbuphine from the 10 ml vials. Both the 10 mg/ml and 20 mg/ml vials contain methylparaben and propylparaben. In contrast, the 1 ml ampules of each concentration do not contain parabens.

    Constipation, diarrhea, GI disease, GI obstruction, inflammatory bowel disease, ulcerative colitis

    Due to the effects of opiate agonists on the gastrointestinal tract, nalbuphine should be used cautiously in patients with GI disease including GI obstruction, ulcerative colitis, or pre-existing constipation. Patients with acute ulcerative colitis (UC) or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists are usually contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, nalbuphine should not be given until the toxic substance has been eliminated.

    Acute myocardial infarction, angina, cardiac disease, heart failure, ventricular dysfunction

    Patients with cardiac disease should be treated with caution. Nalbuphine can increase blood pressure and cardiac workload, so its use in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency (e.g., angina, heart failure) must be carefully evaluated.

    Biliary tract disease

    Nalbuphine can potentially increase the tone of the biliary tract causing spasms (especially in the sphincter of Oddi) increasing biliary tract pressure. Nalbuphine can cause biliary tract spasm and should be used cautiously in patients with biliary tract disease or those who are undergoing biliary tract surgery.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, infection, pulmonary disease, respiratory depression, respiratory insufficiency, uremia

    Avoid nalbuphine coadministration with other CNS depressants unless no other alternatives are available, as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death. If nalbuphine must be administered to patients with pulmonary disease (i.e.,  asthma, chronic obstructive pulmonary disease (COPD), respiratory insufficiency), use extreme caution and initiate treatment at the lowest effective dose. Caution is also recommended for use in patients with impaired respiration from uremia, severe infection, cyanosis, or respiratory obstructions. Nalbuphine may produce respiratory depression similar to the effect from equianalgesic doses of morphine. Nalbuphine, however, has a 'ceiling effect' for respiratory depression, where doses greater than 30 mg do not produce further respiratory depression in the absence of other CNS depressant agents.

    Head trauma, increased intracranial pressure, intracranial mass

    Patients with head trauma, intracranial mass, or increased intracranial pressure should only be given nalbuphine if the benefits outweigh the risks. The effects of nalbuphine can compromise the evaluation of neurologic parameters. Also, respiratory depression and increased CO2 retention leads to vasodilation and may further raise CSF pressure and, thus, exaggerate the injury. If nalbuphine is deemed essential for use, extreme caution is recommended.

    Children

    The safety and efficacy of nalbuphine in adolescents and children < 18 years have not been established.

    Geriatric

    Nalbuphine should be used with caution, if at all, in geriatric patients because they may be more prone to adverse effects, especially respiratory depression. Elderly patients are more likely to experience opiate-induced urinary retention. Due to decreased metabolism, elderly patients usually require longer dosing intervals or lower doses.

    Infants, labor, obstetric delivery, pregnancy

    Nalbuphine is classified in FDA pregnancy risk category B, but there are no adequate and well-controlled studies in pregnant women. During animal studies no teratogenic effects were noted; however, decreased birth weight was observed. Use of nalbuphine during labor has been associated with fetal adverse effects, including fetal bradycardia (see Adverse Reactions). Although fetal bradycardia has not been reported when nalbuphine is administered earlier in pregnancy, it is possible that it may occur. Nalbuphine should only be used during pregnancy, labor, and obstetric delivery if clearly indicated, if the potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring are undertaken to detect and manage any potential adverse reactions to the fetus. Newborn infants should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias if nalbuphine has been used.

    Breast-feeding

    According to the manufacturer, caution should be exercised if nalbuphine is given to a mother who is breast-feeding due to the possibility of adverse reactions in the nursing infant. Limited data suggest that nalbuphine is excreted in breast milk, but only a small amount (< 1% of administered dose) appears in the breast milk, which is generally considered clinically insignificant.  Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.

    Abrupt discontinuation, alcoholism, substance abuse

    Abrupt discontinuation of prolonged nalbuphine therapy can result in withdrawal symptoms (see Adverse Reactions). Although the incidence is rare, nalbuphine may cause psychologic dependence, which may lead to substance abuse in some patients. Patients with a previous history of substance abuse may be at increased risk. The indication for use of nalbuphine in patients with a history of alcoholism or drug dependence is for the treatment of moderate to severe pain. Patients with active substance abuse or dependence upon opiate agonist should not receive nalbuphine. Nalbuphine may precipitate withdrawal symptoms in opiate-dependent patients due to its opiate antagonist effects (see Dosage).

    Hepatic disease, renal failure, renal impairment

    Because nalbuphine is metabolized in the liver and is excreted by the kidneys, nalbuphine should be used with caution in patients with hepatic disease, renal impairment, or renal failure. Reduced dosages are recommended.

    Driving or operating machinery

    Patients should be warned that nalbuphine can impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. These effects may persist for varying periods of time after dosing.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use nalbuphine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-1.0
    cardiac arrest / Early / 0-1.0
    laryngeal edema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    respiratory arrest / Rapid / 0-1.0
    bronchospasm / Rapid / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    seizures / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    apnea / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    fetal death / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    confusion / Early / 0-1.0
    dysphoria / Early / 0-1.0
    hallucinations / Early / 0-1.0
    depression / Delayed / 0-1.0
    hostility / Early / 0-1.0
    euphoria / Early / 0-1.0
    respiratory depression / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    hypertension / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    dysarthria / Delayed / 0-1.0
    blurred vision / Early / 0-1.0
    wheezing / Rapid / 0-1.0
    edema / Delayed / 0-1.0
    psychosis / Early / Incidence not known
    fetal distress / Delayed / Incidence not known
    fetal bradycardia / Delayed / Incidence not known
    hypotonia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    tolerance / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known

    Mild

    drowsiness / Early / 36.0-36.0
    diaphoresis / Early / 9.0-9.0
    vomiting / Early / 6.0-6.0
    nausea / Early / 6.0-6.0
    vertigo / Early / 5.0-5.0
    dizziness / Early / 5.0-5.0
    xerostomia / Early / 4.0-4.0
    headache / Early / 3.0-3.0
    restlessness / Early / 0-1.0
    dyspepsia / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    flushing / Rapid / 0-1.0
    urinary urgency / Early / 0-1.0
    rash (unspecified) / Early / 0-1.0
    weakness / Early / 0-1.0
    anxiety / Delayed / Incidence not known
    agitation / Early / Incidence not known
    tremor / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    fever / Early / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as dihydrocodeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce the analgesic effects of dihydrocodeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Oxycodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as oxycodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; oxycodone. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Pentazocine: (Major) Concomitant use of pentazocine and nalbuphine can potentiate respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. If these drugs are administered together, the dose of one or both drugs needs to be reduced.
    Acetaminophen; Propoxyphene: (Major) Nalbuphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists. Due to their antagonistic properties, nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists.
    Acetaminophen; Tramadol: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as tramadol. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. There is also a potential increased risk of seizures if tramadol is given with other opiates.
    Alfentanil: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as alfentanil. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Alprazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amitriptyline: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Amoxapine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, like amoxapine, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Aripiprazole: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Asenapine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as dihydrocodeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce the analgesic effects of dihydrocodeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Oxycodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as oxycodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; oxycodone. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Atracurium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Difenoxin: (Major) Concurrent administration of diphenoxylate/difenoxin with nalbuphine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Diphenoxylate: (Major) Concurrent administration of diphenoxylate/difenoxin with nalbuphine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Edrophonium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    atypical antipsychotic: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including nalbuphine.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including nalbuphine.
    Barbiturates: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with nalbuphine. Caution should be exercised during concomitant use of nalbuphine and any barbiturate. Dosage reduction of one or both agents may be necessary.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Belladonna; Opium: (Major) Nalbuphine concurrently used with some opiate agonists can cause additive CNS, respiratory, and hypotensive effects. If a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced. Due to opioid antagonistic properties, nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Brexpiprazole: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Buspirone: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as buspirone, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Butorphanol: (Major) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. Nalbuphine should be used cautiously in any patient receiving these agents. If a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Cariprazine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS including nalbuphine.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS including nalbuphine.
    Chloral Hydrate: (Moderate) Concomitant use of nalbuphine with other CNS depressants like chloral hydrate can potentiate the effects of nalbuphine on respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. If a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Chlordiazepoxide: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Chlorpheniramine; Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as dihydrocodeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce the analgesic effects of dihydrocodeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as dihydrocodeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce the analgesic effects of dihydrocodeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Cisatracurium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Clobazam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clomipramine: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Clonazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clorazepate: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clozapine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Codeine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Codeine; Guaifenesin: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    Codeine; Promethazine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Desipramine: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Deutetrabenazine: (Major) Concomitant use of mixed opiate agonists/antagonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dextromethorphan; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    Diazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as dihydrocodeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce the analgesic effects of dihydrocodeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Doxacurium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Doxepin: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Dronabinol, THC: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as dronabinol, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Droperidol: (Major) Mixed opiate agonists/antagonists have additive or potentiating effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
    Enflurane: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Entacapone: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Estazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Etomidate: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Ezogabine: (Moderate) Due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur during concurrent use of other centrally-acting medications such as nalbuphine. Patients should be monitored for excessive somnolence during concurrent therapy with this agent.
    Fentanyl: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as fentanyl. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as mixed opiate agonists/antagonists or their combinations (e.g., buprenorphine; naloxone), may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluoxetine; Olanzapine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Flurazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fospropofol: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    General anesthetics: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Guaifenesin; Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Haloperidol: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as haloperidol, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Halothane: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Homatropine; Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hydrocodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydrocodone; Ibuprofen: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydrocodone; Phenylephrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydrocodone; Pseudoephedrine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydrocodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hydromorphone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as hydromorphone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ibuprofen; Oxycodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as oxycodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; oxycodone. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Iloperidone: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Imipramine: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Isoflurane: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Ketamine: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS including nalbuphine.
    Levomethadyl: (Major) Nalbuphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists. Due to their antagonistic properties, nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists.
    Levorphanol: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as levorphanol. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Lorazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lurasidone: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists/antagonists. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Nalbuphine should be combined cautiously with maprotiline because it could cause additive depressant effects and possible respiratory depression or hypotension.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Meperidine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as meperidine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Meperidine; Promethazine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as meperidine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including nalbuphine.
    Methadone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as methadone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants. Dosage adjustments of either or both medications may be necessary.
    Methscopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Midazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as nalbuphine. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as mirtazapine, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Mivacurium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Molindone: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as molindone, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Monoamine oxidase inhibitors: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including nalbuphine. Use nalbuphine cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need reduced.
    Morphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as morphine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of morphine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Morphine; Naltrexone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as morphine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of morphine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Nabilone: (Moderate) Concomitant use of mixed opiate agonists-antagonists with nabilone can potentiate the effects of nabilone and may lead to additive CNS or respiratory depression. Prior to concurrent use of nabilone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, a reduced dosage nabilone and/or the opiate agonist-antagonist may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Nalmefene: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
    Naloxone: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Nefazodone: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Neuromuscular blockers: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Nortriptyline: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Olanzapine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Oxazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxybutynin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Oxycodone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as oxycodone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; oxycodone. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Oxymorphone: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as oxymorphone. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Paliperidone: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Pancuronium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Pentazocine: (Major) Concomitant use of pentazocine and nalbuphine can potentiate respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. If these drugs are administered together, the dose of one or both drugs needs to be reduced.
    Pentazocine; Naloxone: (Major) Concomitant use of pentazocine and nalbuphine can potentiate respiratory depression, CNS depression (e.g., dizziness, impaired mental function), and sedation. If these drugs are administered together, the dose of one or both drugs needs to be reduced. (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Perphenazine; Amitriptyline: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Phenothiazines: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as phenothiazines, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Phenylephrine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    Pimozide: (Moderate) Concomitant use of nalbuphine with other central nervous system (CNS) depressants, such as pimozide, can potentiate the effects of nalbuphine and may lead to additive CNS or respiratory depression. Prior to concurrent use of nalbuphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, a reduced dosage nalbuphine and/or pimozide may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Pramipexole: (Moderate) Concomitant use of nalbuphine with other CNS depressants, like pramipexole, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Pregabalin: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including nalbuphine. Respiratory depressant agents in combination with promethazine should be avoided in children and administered in reduced dosage with close monitoring to other patients receiving promethazine.
    Propantheline: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Propofol: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Propoxyphene: (Major) Nalbuphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists. Due to their antagonistic properties, nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists.
    Protriptyline: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Quazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Quetiapine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Rapacuronium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs, such as rasagiline, can be potentiated with concomitant administration of other drugs known to cause CNS depression including nalbuphine. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
    Remifentanil: (Major) Concurrent use of nalbuphine may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Risperidone: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Rocuronium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Rotigotine: (Moderate) Concomitant use of rotigotine with other CNS depressants, such as opiate agonists-antagonists, can potentiate the sedation effects of rotigotine.
    Scopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Sedating H1-blockers: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Sevoflurane: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Skeletal Muscle Relaxants: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as skeletal muscle relaxants, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Solifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Succinylcholine: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Sufentanil: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as sufentanil. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed. These agents include mixed opiate agonists/antagonists.
    Tapentadol: (Major) Avoid the concomitant use of tapentadol and opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, or pentazocine). Opiate agonists/antagonists may partially block the analgesic, respiratory depressant, and CNS depressant effects of tapentadol. Due to their antagonistic properties, opiate agonists/antagonists may cause withdrawal symptoms in patients receiving chronic opiate agonists. These agents may also be used concurrently with some opiate agonists and cause additive CNS, respiratory, and hypotensive effects. Consider dose reduction of the opiate agonist in situations of concomitant prescription. The additive or antagonistic effects are dependent upon the dose of pure opiate agonist used; antagonistic effects are more common at low to moderate doses of the pure opiate agonist.
    Temazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tetrabenazine: (Moderate) Additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression, such as nalbuphine. Concurrent use of tetrabenazine and nalbuphine can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as nalbuphine due to the potential for additive sedative effects.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as nalbuphine. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like nalbuphine can cause additive CNS depression.
    Tolcapone: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Tolterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Tramadol: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as tramadol. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. There is also a potential increased risk of seizures if tramadol is given with other opiates.
    Trazodone: (Moderate) CNS depressants, such as nalbuphine, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Triazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tricyclic antidepressants: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Trihexyphenidyl: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like nalbuphine, may potentiate the effects of either trimethobenzamide or nalbuphine.
    Trimipramine: (Moderate) Pain medications such as nalbuphine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. In addition, if a CNS depressant needs to be used with nalbuphine, the dose of one or both drugs needs to be reduced.
    Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug, such as trospium. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Tubocurarine: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Vecuronium: (Minor) Concomitant use of nalbuphine with other CNS depressants like neuromuscular blockers can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with nalbuphine.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as nalbuphine.
    Zaleplon: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as zaleplon, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
    Ziprasidone: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Zolpidem: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as zolpidem, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, caution should be exercised if nalbuphine is given to a mother who is breast-feeding due to the possibility of adverse reactions in the nursing infant. Limited data suggest that nalbuphine is excreted in breast milk, but only a small amount (< 1% of administered dose) appears in the breast milk, which is generally considered clinically insignificant.  Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Nalbuphine has mixed opiate agonist and antagonist activity. Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Nalbuphine is a kappa agonist and a partial mu antagonist. The activity of nalbuphine at specific opiate-receptor subtypes more closely resembles pentazocine; however, nalbuphine is a more potent µ-antagonist and has less dysphoric effects than pentazocine. The opioid antagonist activity of nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine. The antagonistic activity of nalbuphine occurs at doses equal to or lower than its analgesic dose. The agonistic effects of nalbuphine at kappa1- and kappa3-receptors provide analgesia. Actions at the kappa-receptors are believed to produce alterations in the perception of pain as well as the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves sensitive to painful stimuli. On a milligram basis, the analgesic potency of nalbuphine and morphine is essentially equivalent. As an adjunct to anesthesia, nalbuphine is believed to protect against the hemodynamic responses to stress produced by surgery.Even though nalbuphine produces analgesia, it can paradoxically produce opiate withdrawal if administered to opiate-dependent patients. This effect is a function of antagonism at the µ-receptor. Withdrawal from nalbuphine is possible after long-term administration, although it is milder than withdrawal from morphine or other µ-receptor agonists.The pharmacologic effects observed after opiates bind to their receptors may involve a second messenger such as cyclic AMP, which is synthesized by adenylate cyclase. Opioid receptors are coupled to these second messenger systems through an inhibitory G-protein (guanine nucleotide-binding protein). G-proteins are located at the cell surface along with many other receptors, including opioid receptors. G-proteins are thought to interact with opiate receptors, giving the receptor a higher affinity for the opiate. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case the effector system is adenylate cyclase and cyclic AMP located at the inner surface of the plasma membrane. Opioid agonists effectively inhibit adenylate cyclase and cause a decrease in intracellular cyclic AMP levels. Other research has shown that µ, delta, and kappa receptors are associated with ion channels and control the influx of cations into the cell. Mu and delta agonists have been associated with increasing potassium influx and kappa receptors have been associated with reducing calcium influx in cells located in various human and animal nerve systems. All of these effects appear to ultimately reduce transmitter release, and may also be mediated through G-proteins.Nalbuphine shares some physiologic effects with opiate agonists, such as the increased smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Nalbuphine also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of nalbuphine on the GI tract results in constipation and delayed digestion. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor center in the medulla. This effect may be less pronounced during nalbuphine use when compared to other opiate agonists. Induction of nausea and vomiting possibly occurs from direct stimulation of the chemoreceptor trigger zone.

    PHARMACOKINETICS

    Nalbuphine must be administered parenterally due to extensive first-pass and GI mucosal metabolism. Nalbuphine exhibits low protein binding and crosses the placenta. The placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37—1.6. The half-life of the drug is approximately 3—6 hours in healthy subjects and about 2.4 hours in pregnant women in active labor. Metabolism of nalbuphine occurs in the liver with excretion of the drug and metabolites via the urine, bile, and feces.

    Oral Route

    The analgesic effects from oral administration of nalbuphine are roughly one-fifth of those from intramuscular administration.

    Intravenous Route

    Intravenous nalbuphine administration provides the most rapid onset of action (2—3 minutes), with peak effects seen within 30 minutes.

    Intramuscular Route

    After administration of a 10 mg IM nalbuphine dose to normal healthy subjects, peak serum concentrations occur within 30 minutes. The onset following IM injection occurs within 15 minutes, with a duration of 3—6 hours.

    Subcutaneous Route

    The onset following SC nalbuphine injection occurs within 15 minutes, with a duration of 3—6 hours.