de injection. to reduce the risk of respiratory depression, proper dosing and titration of nalbuphine hydrochloride injection is essential [see dosage and administration]. overestimating the nalbuphine hydrochloride injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. opioids can cause sleep-related breathing disorders including central sleep apnea (csa) and sleep-related hypoxemia. opioid use increases the risk of csa in a dose-dependent fashion. in patients who present with csa, consider decreasing the opioid dosage using best practices for opioid taper [see dosage and administration]. risks from concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of nalbuphine hydrochloride injection with benzodiazepines or other cns depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other cns depressant drugs with opioid analgesics [see precautions; drug interactions]. if the decision is made to prescribe a benzodiazepine or other cns depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other cns depressant than indicated in the absence of an opioid, and titrate based on clinical response. if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other cns depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. follow patients closely for signs and symptoms of respiratory depression and sedation. advise both patients and caregivers about the risks of respiratory depression and sedation when nalbuphine hydrochloride injection is used with benzodiazepines or other cns depressants (including alcohol and illicit drugs). advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other cns depressant have been determined. screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional cns depressants including alcohol and illicit drugs [see precautions; drug interactions and information for patients]. life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients the use of nalbuphine hydrochloride injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. patients with chronic pulmonary disease nalbuphine hydrochloride injection-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of use of nalbuphine hydrochloride injection [see warnings]. elderly, cachectic, or debilitated patients life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see warnings]. monitor such patients closely, particularly when initiating and titrating nalbuphine hydrochloride injection and when nalbuphine hydrochloride injection is given concomitantly with other drugs that depress respiration [see warnings]. alternatively, consider the use of non-opioid analgesics in these patients. adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. if adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. the information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. severe hypotension nalbuphine hydrochloride injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain cns depressant drugs (e.g., phenothiazines or general anesthetics) [see precautions; drug interactions]. monitor these patients for signs of hypotension after initiating or titrating the dosage of nalbuphine hydrochloride injection. in patients with circulatory shock, nalbuphine hydrochloride injection may cause vasodilation that can further reduce cardiac output and blood pressure. avoid the use of nalbuphine hydrochloride injection in patients with circulatory shock. risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness in patients who may be susceptible to the intracranial effects of co2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), nalbuphine hydrochloride injection may reduce respiratory drive, and the resultant co2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with nalbuphine hydrochloride injection. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of nalbuphine hydrochloride injection in patients with impaired consciousness or coma. risks of use in patients with gastrointestinal conditions nalbuphine hydrochloride injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. the nalbuphine in nalbuphine hydrochloride injection may cause spasm of the sphincter of oddi. opioids may cause increases in serum amylase. monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. increased risk of seizures in patients with seizure disorders the nalbuphine in nalbuphine hydrochloride injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. monitor patients with a history of seizure disorders for worsened seizure control during nalbuphine hydrochloride injection therapy. withdrawal the use of nalbuphine hydrochloride injection, a mixed agonist/antagonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. avoid concomitant use of nalbuphine hydrochloride injection with a full opioid agonist analgesic. when discontinuing nalbuphine hydrochloride injection, in a physically-dependent patient, gradually taper the dosage [see dosage and administration]. do not abruptly discontinue nalbuphine hydrochloride injection in these patients [see drug abuse and dependence]. risks of driving and operating machinery nalbuphine hydrochloride injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of nalbuphine hydrochloride injection and know how they will react to the medication [see precautions; information for patients]. maintain patient under observation until recovered from nalbuphine hydrochloride injection effects that would affect driving or other potentially dangerous tasks. use in pregnancy (other than labor) severe fetal bradycardia has been reported when nalbuphine hydrochloride injection is administered during labor. naloxone may reverse these effects. although there are no reports of fetal bradycardia earlier in pregnancy, it is possible that this may occur. avoid the use of nalbuphine hydrochloride injection in pregnant women unless the potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring are taken to detect and manage any potential adverse effect on the fetus. use during labor and delivery the placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6. fetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. some of these events have been life-threatening. maternal administration of naloxone during labor has normalized these effects in some cases. severe and prolonged fetal bradycardia has been reported. permanent neurological damage attributed to fetal bradycardia has occurred. a sinusoidal fetal heart rate pattern associated with the use of nalbuphine has also been reported. nalbuphine should be used during labor and delivery only if clearly indicated and only if the potential benefit outweighs the risk to the infant. newborns should be monitored for respiratory depression, apnea, bradycardia and arrhythmias if nalbuphine has been used. addiction, abuse, and misuse nalbuphine hydrochloride is a synthetic opioid agonist-antagonist analgesic. as an opioid, nalbuphine hydrochloride injection exposes users to the risks of addiction, abuse, and misuse [see drug abuse and dependence]. although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed nalbuphine hydrochloride injection. addiction can occur at recommended dosages and if the drug is misused or abused. assess each patient's risk for opioid addiction, abuse, or misuse. risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). the potential for these risks should not, however, prevent the proper management of pain in any given patient. opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. consider these risks when prescribing or dispensing nalbuphine hydrochloride injection. strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

tion and container permit. initial dosage the usual recommended adult dose is 10 mg for a 70 kg individual administered subcutaneously, intramuscularly, or intravenously; this dose may be repeated every 3 to 6 hours as necessary. dosage should be adjusted according to the severity of the pain, physical status of the patient, and other medications which the patient may be receiving [see warnings; risks from concomitant use with benzodiazepines or other cns depressants]. in nontolerant individuals, the recommended single maximum dose is 20 mg with a maximum total daily dose of 160 mg. the use of nalbuphine hydrochloride injection as a supplement to balanced anesthesia requires larger doses than those recommended for analgesia. induction doses of nalbuphine hydrochloride range from 0.3 mg/kg to 3 mg/kg intravenously to be administered over a 10 to 15 minute period with maintenance doses of 0.25 to 0.5 mg/kg in single intravenous administrations as required. the use of nalbuphine hydrochloride injection may be followed by respiratory depression which can be reversed with the opioid antagonist naloxone hydrochloride. titration and maintenance of therapy individually titrate nalbuphine hydrochloride injection to a dose that provides adequate analgesia and minimizes adverse reactions. continually reevaluate patients receiving nalbuphine hydrochloride to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see warnings]. frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. if the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the nalbuphine hydrochloride dosage. if unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse events. discontinuation of nalbuphine hydrochloride injection when a patient who has been taking nalbuphine hydrochloride injection regularly and may be physically dependent no longer requires therapy with nalbuphine hydrochloride injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. if the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. do not abruptly discontinue nalbuphine hydrochloride injection in a physically-dependent patient [see warnings, drug abuse and dependence].

us: speech difficulty, urinary urgency, blurred vision, flushing and warmth. allergic reactions: anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. these reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. some of these allergic reactions may be life-threatening. other allergic-type reactions reported include stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting, diaphoresis, weakness, and shakiness. postmarketing experience the following adverse reactions have been identified during post approval use of nalbuphine. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. abdominal pain, pyrexia, depressed level or loss of consciousness, somnolence, tremor, anxiety, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and hot sensations. death has been reported from severe allergic reactions to nalbuphine hydrochloride injection treatment. fetal death has been reported where mothers received nalbuphine hydrochloride injection during labor and delivery. serotonin syndrome cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

onist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block opioid-induced respiratory depression from the mµ agonist analgesic. nalbuphine hydrochloride injection may precipitate withdrawal in patients dependent on opioid drugs. nalbuphine hydrochloride injection should be used with caution in patients who have been receiving mµ opioid analgesics on a regular basis. effects on the central nervous system nalbuphine produces respiratory depression by direct action on brain stem respiratory centers. the respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. however, there may be a ceiling effect for the respiratory depression caused by nalbuphine. although a mixed agonist/antagonist, the respiratory depressant effects of nalbuphine can be reversed by naloxone. nalbuphine causes miosis, even in total darkness. pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. effects on the gastrointestinal tract and other smooth muscle nalbuphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. digestion of food in the small intestine is delayed and propulsive contractions are decreased. propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of oddi, and transient elevations in serum amylase. effects on the cardiovascular system during use of nalbuphine during anesthesia, a higher incidence of bradycardia has been reported in patients who did not receive atropine pre-operatively. opioids produce peripheral vasodilation, which may result in orthostatic hypotension or syncope. manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. effects on the endocrine system opioids inhibit the secretion of adrenocorticotropic hormone (acth), cortisol, and luteinizing hormone (lh) in humans [see adverse reactions]. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon. chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. the causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see adverse reactions]. effects on the immune system opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. the clinical significance of these findings is unknown. overall, the effects of opioids appear to be modestly immunosuppressive. concentration–efficacy relationships the minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. the minimum effective analgesic concentration of nalbuphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see dosage and administration]. pharmacokinetics the onset of action of nalbuphine hydrochloride injection occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. the plasma half-life of nalbuphine is 5 hours, and in clinical studies the duration of analgesic activity has been reported to range from 3 to 6 hours. the metabolic pathway for nalbuphine has not been defined, but is likely hepatic.