WARNINGS

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.

Mangement 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 (CO 2 ) 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 are essential (see DOSAGE AND ADMINISTRATION ).

Overestimating the nalbuphine hydrochloride dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of 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 ].

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 ].

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 ].

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.

Head Injury and Increased Intracranial Pressure The possible respiratory depressant effects and the potential of potent analgesics to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure.

Furthermore, potent analgesics can produce effects which may obscure the clinical course of patients with head injuries.

Therefore, Nalbuphine Hydrochloride Injection should be used in these circumstances only when essential, and then should be administered with extreme caution.

Use in Ambulatory Patients Nalbuphine Hydrochloride Injection may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery.

Therefore, Nalbuphine Hydrochloride Injection should be administered with caution to ambulatory patients who should be warned to avoid such hazards.

Use in Emergency Procedures 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.