Nalbuphine Hydrochloride

The most frequent adverse reaction in 1066 patients treated 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.

Events Observed During Post-marketing Surveillance Of Nalbuphine Hydrochloride Injection

Due to the nature and limitations of spontaneous reporting, causality has not been established for the following adverse events received for nalbuphine hydrochloride injection: 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 treatment. Fetal death has been reported where mothers received nalbuphine hydrochloride during labor and delivery.

Postmarketing Experience

• serotonin syndrome
• adrenal insufficiency

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms of hypogonadism, such as impotence, erectile dysfunction, or amenorrhea. The causal role of opioids in the 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Drug Abuse And Dependence

Nalbuphine hydrochloride is a substance with a high potential for abuse similar to other opioids. Nalbuphine hydrochloride can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“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 health care provider(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Nalbuphine hydrochloride, like other opioids, can be diverted for non-medical 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Both tolerance and physical dependence opioid therapy can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Nalbuphine hydrochloride should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If nalbuphine hydrochloride is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, 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 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

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 techniques.

The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to nalbuphine hydrochloride overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of nalbuphine hydrochloride in nalbuphine hydrochloride, 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 begun with care and by titration with smaller than usual doses of the antagonist.

Since nalbuphine is given by a healthcare professional, you are not likely to miss a dose.

Your doctor or pharmacist can provide more information about nalbuphine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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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.

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

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

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

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

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

Contraindications

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

Warnings/Precautions

Warnings

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

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

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 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

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

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

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

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.)

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

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

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 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

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

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

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

Use with caution and in reduced dosage.a b

Use with caution and in reduced dosage.a b

Common Adverse Effects

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

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

• 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.)