Mechanism of Action

Nalbuphine is an agonist at kappa opioid receptors and an antagonist at mu opioid receptors.

Pharmacodynamics

Nalbuphine Hydrochloride Injection is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis up to a dosage of approximately 30 mg.

The opioid antagonist activity of Nalbuphine Hydrochloride Injection is one-fourth as potent as nalorphine and 10 times that of pentazocine.

Nalbuphine Hydrochloride Injection may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, Nalbuphine Hydrochloride Injection exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression in the absence of other CNS active medications affecting respiration.

Nalbuphine Hydrochloride Injection by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block opioid-induced respiratory depression from the mu 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 mu opioid analgesics on a regular basis.

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.

Limitations of Use:

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see WARNINGS], reserve Nalbuphine Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics):

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Have not been tolerated, or are not expected to be tolerated,

•

Have not provided adequate analgesia or are not expected to provide adequate analgesia.

Nalbuphine Hydrochloride Injection should not be used for an extended period of time unless the pain ‎remains severe enough to require an opioid analgesic and for which ‎alternative treatment options continue to be inadequate.‎

Addiction, Abuse, and Misuse

Nalbuphine Hydrochloride Injection contains nalbuphine. As an opioid, nalbuphine exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE].

Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling Nalbuphine Hydrochloride Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Nalbuphine Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Nalbuphine Hydrochloride Injection.

To reduce the risk of respiratory depression, proper dosing and titration of Nalbuphine Hydrochloride Injection are 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 and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

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.

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.

General

Information for Patients

Patients should be advised of the following information:

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to Nalbuphine Hydrochloride Injection. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Nalbuphine Hydrochloride Injection slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system ‎and respiratory depression [see WARNINGS].

Nalbuphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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.

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of any duration [see WARNINGS]‎.

Hypoglycemia: Cases of hypoglycemia have been reported in patients ‎taking opioids. Most reports were in patients with at least one ‎predisposing risk factor (e.g., diabetes).‎

Abuse

Nalbuphine Hydrochloride Injection contains nalbuphine, a substance which is subject to misuse and abuse, which can lead to the ‎development of substance use disorder, including addiction [see WARNINGS].

Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than prescribed by a healthcare provider or for ‎whom it was not prescribed.‎

Abuse is the intentional, non-therapeutic use of a drug, even once, for its ‎desirable psychological or physiological effects.‎

Drug addiction is a cluster of behavioral, cognitive, and physiological ‎phenomena that may include a strong desire to take the drug, difficulties ‎in controlling drug use (e.g., continuing drug use despite harmful ‎consequences, giving a higher priority to drug use than other activities ‎and obligations), and possible tolerance or physical dependence.‎

Misuse and abuse of Nalbuphine Hydrochloride Injection ‎increases risk of overdose, which ‎may lead to central nervous system and respiratory depression, ‎hypotension, seizures, and death. The risk is increased with concurrent ‎abuse of Nalbuphine Hydrochloride Injection ‎with alcohol and other CNS ‎depressants. Abuse of and addiction to opioids in some individuals may ‎not be accompanied by concurrent tolerance and symptoms of physical ‎dependence. In addition, abuse of opioids can occur in the absence of ‎addiction.‎

All patients treated with opioids require careful and frequent reevaluation ‎for signs of misuse, abuse, and addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate medical use. ‎Patients at high risk of Nalbuphine Hydrochloride Injection ‎abuse include those with a history ‎of prolonged use of any opioid, including products containing nalbuphine, those with a history ‎of drug or alcohol abuse, or those who use Nalbuphine Hydrochloride Injection ‎in combination ‎with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Nalbuphine Hydrochloride Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Dependence

Both tolerance and physical dependence opioid therapy can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after ‎repeated administration (i.e., a higher dose of a drug is required to ‎produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response ‎to repeated drug use, manifested by withdrawal signs and symptoms after ‎abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with ‎opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist ‎analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists ‎‎(e.g., buprenorphine). Physical dependence may not occur to a clinically ‎significant degree until after several days to weeks of continued use.‎

Nalbuphine Hydrochloride Injection should not be abruptly discontinued in a physically-dependent patient [see DOSAGE AND ADMINISTRATION]. If Nalbuphine Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically‑dependent on opioids will also be physically‑dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

Clinical Presentation

Acute overdose with Nalbuphine Hydrochloride Injection alone can be manifested by respiratory depression and dysphoria. Acute overdose with Nalbuphine Hydrochloride Injection and other opioids or CNS depressants can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to nalbuphine hydrochloride overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of nalbuphine, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.

In an individual physically‑dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically‑dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Important Dosage and Administration Instructions

Nalbuphine Hydrochloride Injection should be administered as a supplement to general anesthesia only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

Naloxone, resuscitative and intubation equipment and oxygen should be readily available.

Use the lowest effective dosage for the shortest duration of time ‎consistent with individual patient treatment goals [see WARNINGS]. ‎Because the risk of overdose increases as opioid doses increase, reserve ‎titration to higher doses of Nalbuphine Hydrochloride Injection ‎for patients in whom lower ‎doses are insufficiently effective and in whom the expected benefits of ‎using a higher dose opioid clearly outweigh the substantial risks.‎

There is variability in the opioid analgesic dose and duration needed to ‎adequately manage pain due both to the cause of pain and to individual ‎patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS].

Respiratory depression can occur at any time during opioid therapy, ‎especially when initiating and following dosage increases with ‎Nalbuphine Hydrochloride Injection‎. Consider this risk when selecting an initial dose and when ‎making dose adjustments [see WARNINGS].‎

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution 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. Use the lowest dose necessary to achieve adequate analgesia. 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]. 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

Titrate the dose based upon the individual patient’s response to their initial dose of Nalbuphine Hydrochloride Injection. 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, signs and symptoms of opioid withdrawal,‎ and other adverse reactions, as well as to reassess 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 Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed ‎(including an increase in pain after a dosage increase)‎, consider reducing the dosage‎ [see WARNINGS]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse events.

Safe Reduction and 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 regularly evaluating 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].

Store at 20℃ to 25°C (68℉ to 77°F). [See USP Controlled Room Temperature.]

Protect from excessive light. Store in carton until contents have been used.