Nalbuphine hydrochloride

Indications and Usage Nalbuphine hydrochloride injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Nalbuphine hydrochloride injection can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. 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]: 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.

Dosage and Administration 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 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. Saf …

CONTRAINDICATIONS Nalbuphine hydrochloride injection is contraindicated in patients with: Significant respiratory depression [see WARNINGS ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] Hypersensitivity to nalbuphine to any of the other ingredients in nalbuphine hydrochloride injection. WARNINGS 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 (9)]. 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 (CO) 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 minimu …

Adverse Reactions The most frequent adverse reaction in 1066 patients treated in clinical studies with nalbuphine hydrochloride injection was sedation 381 (36%). Less frequent reactions were: sweaty/clammy 99 (9%), nausea/vomiting 68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache 27 (3%). Other adverse reactions which occurred (reported incidence of 1% or less) were: CNS Effects : Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine. Cardiovascular : Hypertension, hypotension, bradycardia, tachycardia. Gastrointestinal : Cramps, dyspepsia, bitter taste. Respiratory : Depression, dyspnea, asthma. Dermatologic: Itching, burning, urticaria. Miscellaneous: Speech difficulty, urinary urgency, blurred vision, flushing and warmth. Allergic Reactions : Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. These reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. 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. To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at +1 800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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).

Description Nalbuphine hydrochloride injection is a synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It is chemically related to both the widely used opioid antagonist, naloxone, and the potent opioid analgesic, oxymorphone. Chemically nalbuphine hydrochloride is 17-(cyclobutylmethyl)- 4,5α-epoxymorphinan-3,6α,14-triol hydrochloride. Nalbuphine hydrochloride molecular weight is 393.91 and is soluble in H 2 O (35.5 mg/mL @ 25oC) and ethanol (0.8%); insoluble in CHCl 3 and ether. Nalbuphine hydrochloride has pKa values of 8.71 and 9.96. The molecular formula is C 21 H 27 NO 4 · HCl. The structural formula is: Nalbuphine hydrochloride injection is a sterile solution suitable for subcutaneous, intramuscular, or intravenous injection. Nalbuphine hydrochloride injection is available in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride injection per mL. Both strengths in 10 mL vials contain 0.94% sodium citrate dihydrate, 1.26% citric acid anhydrous, and 0.2% of a 9:1 mixture of methylparaben and propylparaben as preservatives; pH is adjusted, if necessary, to 3.0 to 4.5 with hydrochloric acid. The 10 mg/mL strength contains 0.2% sodium chloride. Nalbuphine hydrochloride injection is also available in ampuls in a sterile, paraben-free formulation in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. One mL of each strength contains 0.94% sodium citrate dihydrate, and 1.26% citric acid anhydrous; pH is adjusted, if necessary, to 3.0 to 4.5 with hydrochloric acid. The 10 mg/mL strength contains 0.2% sodium chloride. Formula1.jpg

OVERDOSAGE 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.

How Supplied Nalbuphine Hydrochloride Injection is supplied as a clear colorless, essentially free from visible extraneous matter sterile solution in single-dose ampuls (scoring and blue band) and multiple‐dose flip-off vials for intramuscular, subcutaneous, or intravenous administration, and available as follows: NDC 70069- 661 -01 (sulfite-free) 10 mg/mL, 10 mL multiple dose vials (box of 1) NDC 70069- 661 -10 (sulfite-free) 10 mg/mL, 10 mL multiple dose vials (box of 10) NDC 70069- 671 -10 (sulfite/paraben-free) 10 mg/mL, 1 mL ampuls (box of 10) NDC 70069- 662 -01 (sulfite-free) 20 mg/mL, 10 mL multiple dose vials (box of 1) NDC 70069- 662 -10 (sulfite-free) 20 mg/mL, 10 mL multiple dose vials (box of 10) NDC 70069- 672 -10 (sulfite/paraben-free) 20 mg/mL, 1 mL ampuls (box of 10) Discard unused portion of Single-Dose Formulations. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Protect from excessive light. Store in carton until contents have been used. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 70069-662-10 Box of 10 NDC 0404-9767-10 1 10 mL Multiple-dose Vial in a bag (Vial bears 70069-662-01) 20 mg/mL NDC 70069-661-10 Box of 10 NDC 0404-9766-10 1 10 mL Multiple-dose Vial in a bag (Vial bears 70069-661-01) 10 mg/mL