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Nubain

Generic Name: Nalbuphine Hydrochloride
Class: Opiate Partial Agonists
VA Class: CN101
CAS Number: 23277-43-2

The Nubain brand name has been discontinued in the U.S. If generic versions of this product have been approved by the FDA, there may be generic equivalents available.

Introduction

Analgesic; opiate partial agonist.a b

Uses for Nubain

Pain

Relief of moderate to severe paina b such as that associated with acute and chronic medical disorders including cancer, orthopedic problems, renal or biliary colic, migraine or vascular headaches, and surgery.b

Preoperative and postoperative sedation and analgesia.a b

Supplement to balanced surgical anesthesia.a b

Obstetric analgesia during labor and delivery.106 a b

Nubain Dosage and Administration

General

  • Avoid increases in dose or frequency of administration which in susceptible individuals might result in physical dependence.b

Administration

Administer by sub-Q, IM, or IV injection.a b

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Rate of Administration

For induction of anesthesia: Administer IV over 10–15 minutes.a b

Dosage

Available as nalbuphine hydrochloride; dosage expressed in terms of the salt.a

Adjust dosage according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving.a b

Adults

Pain
Patients Not Tolerant to Opiate Agonists
IV, IM, or Sub-Q

10 mg in a 70-kg patient (about 0.14 mg/kg).a b Repeat every 3–6 hours as necessary.a b

Patients Tolerant to Opiate Agonists
IV, IM, or Sub-Q

Initially, administer 25% of the usual dose of nalbuphine in patients chronically receiving morphine, meperidine, codeine, or other opiate agonists with a similar duration of action.b

Observe the patient for signs or symptoms of withdrawal (e.g., abdominal cramps, nausea, vomiting, lacrimation, rhinorrhea, anxiety, restlessness, increased temperature, piloerection).b If symptoms are troublesome, give IV morphine slowly in small increments until withdrawal symptoms are relieved.b However, waiting until the abstinence syndrome abates is probably preferred.b If withdrawal symptoms do not occur, increase dosage progressively until the desired level of analgesia is obtained.b

Supplement to Balanced Anesthesia
IV

0.3–3 mg/kg for induction of anesthesia.a b For maintenance, 0.25–0.5 mg/kg as necessary.a b

Prescribing Limits

Adults

Pain
Patients Not Tolerant to Opiate Agonists
IV, IM, or Sub-Q

Maximum 20 mg as a single dose; maximum 160 mg daily.a b

Special Populations

Hepatic Impairment

Dosage reduction is recommended.a b

Renal Impairment

Dosage reduction is recommended.a b

Cautions for Nubain

Contraindications

  • Known hypersensitivity to nalbuphine or any ingredient in the formulation.a

Warnings/Precautions

Warnings

Respiratory Effects

Possible respiratory depression.a Administer with caution and in low doses in patients with impaired respiration caused by other drugs, uremia, bronchial asthma, severe infection, cyanosis, or respiratory obstruction.a

Should be administered as a supplement to general anesthesia only by individuals who are experienced in the use of parenteral anesthetics and in the maintenance of an adequate airway and respiratory support.a

Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be readily available; an opiate antagonist (e.g., naloxone) should also be readily available.a

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence.a

Prescribe cautiously for patients who are emotionally unstable or have a history of opiate abuse; closely supervise these patients when long-term therapy is contemplated.a Avoid unnecessary increases in dose or frequency of administration; avoid use in anticipation of pain.a

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.a b When used in emergency procedures, keep the patient under observation until recovery from the drug’s effects that would affect driving or other potentially hazardous tasks has occurred.a b

Concurrent use of other CNS depressants may potentiate CNS depression.a b (See Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Head Injury and Increased Intracranial Pressure

Potential for elevation of CSF pressure as a result of vasodilation following carbon dioxide retention.a b Opiate effects may obscure the existence, extent, or course of intracranial pathology.a b Use in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure only if the potential benefits justify the possible risks.a b

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactic or anaphylactoid and other serious hypersensitivity reactions, including shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, and laryngeal edema, reported.106

Sulfite Sensitivity

Some formulations contain sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.105

General Precautions

Patients Dependent on Opiates

Use with caution in patients who have been chronically receiving opiate agonists; nalbuphine does not suppress the abstinence syndrome in these patients; high doses may precipitate withdrawal symptoms (e.g., abdominal cramps, nausea, vomiting, lacrimation, rhinorrhea, anxiety, restlessness, increased temperature, piloerection) as a result of opiate antagonist effect.a b (See Patients Tolerant to Opiate Agonists under Dosage and Administration.)

Biliary Tract Surgery

Possible spasm of Oddi’s sphincter; use with caution in patients about to undergo biliary tract surgery.a

MI

Use with caution in patients with MI who exhibit nausea and vomiting.a

Bradycardia

During studies evaluating nalbuphine as a supplement to balanced anesthesia, increased incidence of bradycardia reported in patients who did not receive atropine preoperatively.a b

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400

Specific Populations

Pregnancy

Category B.a

Safe use during pregnancy (except during labor and delivery) not established.a b

Administration during labor and delivery may result in fetal bradycardia or respiratory depression, apnea, cyanosis, and hypotonia in neonates at birth.a b Adverse effects may resolve in some cases following maternal administration of naloxone during labor.106 Fetal bradycardia may be severe and prolonged; permanent neurological damage associated with fetal bradycardia reported.106 In addition, a sinusoidal fetal heart rate pattern associated with maternal use of nalbuphine.106

Use with caution in women during labor and delivery, especially in those delivering premature infants; monitor neonates for respiratory depression, apnea, bradycardia, and cardiac arrhythmias.106

Lactation

Distributed into milk.a Caution if used in nursing women.a

Pediatric Use

Safety and efficacy not established in children <18 years of age.a

Hepatic Impairment

Use with caution and in reduced dosage.a b

Renal Impairment

Use with caution and in reduced dosage.a b

Common Adverse Effects

Sedation, sweatiness, clamminess, nausea, vomiting, dizziness, vertigo, dry mouth, headache.a

Interactions for Nubain

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs.400 May occur at usual dosages.400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.400

If serotonin syndrome is suspected, discontinue nalbuphine, other opiate therapy, and/or any concurrently administered serotonergic agents.400

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, the antidepressant, and/or any concurrently administered opiates or serotonergic agents400

Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents400

Buspirone

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, buspirone, and/or any concurrently administered opiates or serotonergic agents400

CNS depressants (general anesthetics, phenothiazines, tranquilizers, sedatives, hypnotics, alcohol)

Additive CNS depressant effectsa

Reduce dosage of one or both drugsa

Cyclobenzaprine

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents400

Dextromethorphan

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents400

5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, the triptan, and/or any concurrently administered opiates or serotonergic agents400

Lithium

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, lithium, and/or any concurrently administered opiates or serotonergic agents400

MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, the MAO inhibitor, and/or any concurrently administered opiates or serotonergic agents400

Opiate agonists

Usual doses do not antagonize the effects of an opiate agonist administered immediately before, concurrently with, or just after nalbuphine is given inpatients who are not dependent on opiate agonistsa b

St. John’s wort (Hypericum perforatum)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, St. John’s wort, and/or any concurrently administered opiates or serotonergic agents400

Tests for detection of opiates

Possible interference with enzymatic methods for detection of opiatesa

Consult test manufacturer for specific detailsa

Tryptophan

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue nalbuphine, tryptophan, and/or any concurrently administered opiates or serotonergic agents400

Nubain Pharmacokinetics

Absorption

Bioavailability

Undergoes first-pass metabolism in the GI mucosa and/or liver following oral administration; only about 1/5 as effective for pain relief when given orally as when given IM.b

Onset

Following IV administration, onset of action occurs within 2–3 minutes; peak effects occur in about 30 minutes.a b

Following IM or sub-Q administration, onset of analgesia occurs within 15 minutes.a b

Duration

After IV, IM, or sub-Q administration, duration of analgesia is usually 3–6 hours.a b

Distribution

Extent

Crosses the placenta; fetal plasma concentrations are approximately equivalent to or higher than concurrent maternal plasma concentrations.104

Distributed into milk in small amounts (<1% of administered dose).a

Plasma Protein Binding

Not appreciably bound.b

Elimination

Metabolism

Metabolized in the liver.b

Elimination Route

Nalbuphine and its metabolites are excreted principally in feces via biliary secretion and to a lesser extent in urine.b

Half-life

Plasma half-life is 5 hours.a b Elimination half-life averaged 2.4 hours (range: 1.3–3.9 hours) following a single IV dose in pregnant women in active labor.104

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).a Protect from excessive light.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in sodium chloride 0.9%

Dextrose 10% in water

Ringer's injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Y-site CompatibilityHID

Compatible

Acyclovir sodium

Amifostine

Aztreonam

Bivalirudin

Cisatracurium besylate

Cladribine

Dexmedetomidine HCl

Etoposide phosphate

Fenoldopam mesylate

Filgrastim

Fludarabine phosphate

Gemcitabine HCl

Granisetron HCl

Hetastarch in lactated electrolyte injection (Hextend)

Linezolid

Melphalan HCl

Oxaliplatin

Paclitaxel

Propofol

Remifentanil HCl

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Allopurinol sodium

Amphotericin B cholesteryl sulfate complex

Docetaxel

Methotrexate sodium

Nafcillin sodium

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Sargramostim

Sodium bicarbonate

Actions

  • Analgesic effect may result from an interaction with an opiate receptor site in the CNS (probably in or associated with the limbic system); opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but other mechanisms are probably also involved.b

  • Believed to be a partial agonist at the κ opiate receptor100 101 102 103 107 and an antagonist or partial antagonist at the μ receptor100 102 107 and to have minimal agonist activity at the Σ receptor.100 103

  • Analgesic activity of IM, IV, or sub-Q nalbuphine is approximately equal to that of IM, IV, or sub-Q morphine on a weight basis.b

  • Produces respiratory depression, sedation, and miosis; however, respiratory depression in healthy adults plateaus with cumulative IV doses of 30 mg (given in doses of 10 mg/hour).b

Advice to Patients

  • Potential for nalbuphine to impair mental alertness or physical coordination; do not drive or operate machinery until effects on individual are known.a

  • Importance of taking exactly as prescribed; do not exceed the recommended dosage.a Do not abruptly discontinue the drug after prolonged usage.a

  • Potential risk of serotonin syndrome with concurrent use of nalbuphine and other serotonergic agents.400 Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.400

  • Potential risk of adrenal insufficiency.400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.400

  • Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption, as well as any concomitant illnesses.b

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.a

  • Importance of advising patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nalbuphine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion via compatible patient-controlled infusion device only

1.5 mg/mL*

Nalbuphine Hydrochloride Injection

Injection

10 mg/mL*

Nalbuphine Hydrochloride Injection

Nubain

Endo

20 mg/mL*

Nalbuphine Hydrochloride Injection

Nubain

Endo

AHFS DI Essentials. © Copyright 2017, Selected Revisions January 30, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

100. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:491-531.

101. Martin WR. Pharmacology of opioids. Pharmacol Rev. 1983; 35:283-323. [PubMed 6144112]

102. Zola EM, McLeod DC. Comparative effects and analgesic efficacy of the agonist-antagonist opioids. Drug Intell Clin Pharm. 1983; 17:411-7. [PubMed 6861632]

103. Schmidt WK, Tam SW, Shotzberger GS et al. Nalbuphine. Drug Alcohol Depend. 1985; 14:339-62. [PubMed 2986929]

104. Wilson SJ, Errick JK, Balkon J. Pharmacokinetics of nalbuphine during parturition. Am J Obstet Gynecol. 1986; 155:340-4. [PubMed 3740151]

105. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use; warning statement: final rule [21 CFR Part 201]. Fed Regist. 1986; 51:43900-5.

106. Du Pont Pharma. Nubain (nalbuphine hydrochloride) prescribing information. Manati, PR; 1994 Oct.

107. Nalbuphine. In: WHO Expert Committee on Drug Dependence. 25th report. Technical report series 775. Geneva: World Health Organization; 1989:30-2.

108. Errick JK, Heel RC. Nalbuphine: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs. 1983; 26:191-211. [PubMed 6137354]

109. Schmidt WK, Tam SW, Shotzberger GS et al. Nalbuphine. Drug Alcohol Depend. 1985; 14:339-62. [PubMed 2986929]

110. Hammond JE. Reversal of opioid-associated late-onset respiratory depression by nalbuphine hydrochloride. Lancet. 1984; 2:1208. [PubMed 6150248]

111. Latasch L, Probst S, Dudziak R. Reversal by nalbuphine of respiratory depression caused by fentanyl. Anesth Analg. 1984; 63:814-6. [PubMed 6465575]

112. Bailey PL, Clark HJ, Pace NL et al. Antagonism of postoperative opioid-induced respiratory depression: nalbuphine versus naloxone. Anesth Analg. 1987; 66:1109-14. [PubMed 3662056]

113. Baxter AD, Samson B, Penning J et al. Prevention of epidural morphine-induced respiratory depression with intravenous nalbuphine infusion in post-thoracotomy patients. Can J Anaesth. 1989; 39:503-9.

114. Latasch L, Teichmuller T, Dudziak R et al. Antagonisation of fentanyl-induced respiratory depression by nalbuphine. Acta Anaesthesiol Belg. 1989; 40:35-40. [PubMed 2499159]

115. Cheng EY, May J. Nalbuphine reversal of respiratory depression after epidural sufentanil. Crit Care Med. 1989; 17:378-9. [PubMed 2522870]

116. Penning JP, Samson B, Baxter AD. Reversal of epidural morphine-induced respiratory depression and pruritus with nalbuphine. Can J Anaesth. 1988; 35:599-604. [PubMed 3144443]

117. Jaffe RS, Moldenhauer CC, Hug CC Jr et al. Nalbuphine antagonism of fentanyl-induced ventilatory depression: a randomized trial. Anesthesiology. 1988; 68:254-60. [PubMed 3277486]

118. Bailey PL, Clark NJ, Pace NL et al. Failure of nalbuphine to antagonize morphine: a double-blind comparison with naloxone. Anesthe Analg. 186; 65:605-11.

119. Bailey PL, Clark NJ, Henderson C et al. Failure of nalbuphine to antagonize morphine-induced respiratory depression. Anesthesiology. 1985; 63(Suppl 3A):A370.

120. Moon RE, Camporesi EM. Pulmonary edema in a young, healthy woman. Chest. 1987; 92:385-6. [PubMed 3608619]

121. Stadnyk A, Grossman RF. Nalbuphine-induced pulmonary edema. Chest. 1986; 90:773-4. [PubMed 3769586]

122. DesMarteau JK, Cassot AL. Acute pulmonary edema resulting from nalbuphine reversal of fentanyl-induced respiratory depression. Anesthesiology. 1986; 65:237. [PubMed 3740525]

123. Stadnyk AN, Grossman RF. Pulmonary edema in a young, healthy woman. Chest. 1987; 92:386. [PubMed 3608620]

124. Guillonneau M, Jacqz-Aigrain E, de Crepy A et al. Perinatal adverse effects of nalbuphine given during parturition. Lancet. 1990; 1:1588.

400. US Food and Drug Administration. Drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Silver Spring, MD; 2016 Mar 22. From FDA website.

401. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009; 25:170-5. [PubMed 19333165]

402. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004; 100:851-8. [PubMed 14770444]

403. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000; 85:2215-22. [PubMed 10852454]

404. Fraser LA, Morrison D, Morley-Forster P et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009; 117:38-43. [PubMed 18523930]

a. Endo Pharmaceuticals Inc. Nubain (nalbuphine hydrochloride) prescribing information. Manati, PR; 2003 May

b. AHFS Drug Information 2004. McEvoy GK, ed. Nalbuphine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2078-9.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:841-845.

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