Nalben

INSTRUCTION for medical use of the medicinal product NALBEN

Composition:

Active substance: nalbuphine;

1 ml of solution contains 10 mg of nalbuphine hydrochloride;

Excipients: sodium chloride, sodium citrate, citric acid anhydrous, sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, colorless solution, free from visible particles.

Pharmacotherapeutic group. Analgesics. Opioids. Morphinan derivatives.

ATC code N02A F02.

Pharmacological properties.

Pharmacodynamics.

Nalbuphine hydrochloride is a kappa-opioid receptor agonist and a mu-opioid receptor antagonist. Nalbuphine is a potent analgesic, and its analgesic effect is essentially equivalent to that of morphine on a milligram basis at doses of approximately 30 mg.

The opioid antagonist activity of nalbuphine is one-quarter that of nalorphine and 10 times greater than that of pentazocine.

Nalbuphine may cause respiratory depression to the same extent as equianalgesic doses of morphine.

However, nalbuphine exhibits a ceiling effect; thus, increasing the dose above 30 mg does not result in further respiratory depression in the absence of other central nervous system (CNS) active agents that affect respiration.

Nalbuphine itself has potent opioid antagonist activity at doses equal to or less than its analgesic dose.

When administered after or concurrently with mu-opioid receptor agonists (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reduce or reverse the respiratory depression induced by these agents. Nalbuphine may precipitate withdrawal syndrome in patients dependent on opioid drugs. Nalbuphine should be used with caution in patients who have regularly received mu-opioid analgesics.

Effects on the central nervous system

Nalbuphine causes respiratory depression by direct action on respiratory centers in the brainstem. Respiratory depression involves reduced sensitivity of the brainstem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. However, a ceiling effect may be observed for respiratory depression caused by nalbuphine. Although nalbuphine is a mixed agonist/antagonist, naloxone can reverse its respiratory depressant effects.

Nalbuphine causes miosis even in complete darkness. Pinpoint pupils are a sign of opioid overdose, but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar symptoms). Marked mydriasis, rather than miosis, may be observed due to hypoxia resulting from overdose.

Effects on the gastrointestinal tract and other smooth muscles

Nalbuphine causes decreased motility associated with increased tone of the smooth muscles of the antrum of the stomach and duodenum. Digestion in the small intestine is delayed, and propulsive contractions are reduced. Propulsive peristaltic waves in the large intestine are diminished, and tone may increase to the point of spasm, leading to constipation. Other opioid effects may include decreased secretion from the biliary tract and pancreas, spasm of the sphincter of Oddi, and transient elevation of serum amylase levels.

Effects on the cardiovascular system

When nalbuphine is used during anesthesia, a higher incidence of bradycardia has been reported in patients who did not receive atropine prior to surgery.

Opioids cause peripheral vasodilation, which may lead to orthostatic hypotension or syncope.

Signs of histamine release and/or peripheral vasodilation may include itching, flushing, redness of the eyes, sweating, and/or orthostatic hypotension.

Effects on the endocrine system

Opioids suppress the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans (see section "Adverse reactions"). They also stimulate the secretion of prolactin, growth hormone (GH—somatotropic hormone), and insulin and glucagon secretion by the pancreas.

Chronic use of opioids may affect the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency, which may manifest as decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown, as various medical, physical, and psychological stress factors and lifestyle factors that may influence gonadal hormone levels have not been adequately controlled in studies conducted to date (see section "Adverse reactions").

Effects on the immune system

In in vitro models and in animals, opioids have been shown to have varying effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids are moderately immunosuppressive.

Concentration-effect relationship

The minimum effective analgesic concentration will vary widely among patients, especially in those who have previously received potent opioid agonists. The minimum effective analgesic concentration of nalbuphine for any individual patient may increase over time due to increasing pain, the emergence of a new pain syndrome, and/or the development of analgesic tolerance.

Pharmacokinetics.

The effect of nalbuphine begins within 2–3 minutes after intravenous administration and within less than 15 minutes after subcutaneous or intramuscular injection. The plasma elimination half-life of nalbuphine is 5 hours. In clinical studies, the duration of analgesic effect ranged from 3 to 6 hours.

The metabolic pathway of nalbuphine is not fully defined, but metabolism is likely to occur in the liver.

Clinical characteristics.

Indications.

Pain of sufficient intensity requiring the use of an opioid analgesic when alternative treatment methods do not provide the expected effect.

NALBEN may also be used as an adjunctive agent in balanced anesthesia; for pre- and postoperative analgesia, and for labor analgesia.

Limitations of use

Due to the risk of dependence, abuse, and misuse of opioids, even at recommended doses (see section "Special precautions"), nalbuphine should be used only in patients for whom alternative treatments (e.g., non-opioid analgesics):

• were not tolerated or tolerance is not expected;
• did not provide adequate analgesia or such is not expected.

Contraindications.

Hypersensitivity to nalbuphine hydrochloride or to any component of the medicinal product.

Known or potential gastrointestinal obstruction, including paralytic ileus.

Acute abdominal pain suspected to be due to appendicitis or pancreatitis.

Severe respiratory depression or marked central nervous system (CNS) depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcoholic delirium, seizures.

Acute or severe bronchial asthma, chronic respiratory obstruction, or status asthmaticus.

Acute respiratory failure, elevated blood carbon dioxide levels, cor pulmonale.

Concomitant use of monoamine oxidase inhibitors (MAOIs), or use of nalbuphine within 14 days after discontinuation of MAOIs.

Do not use for mild pain that can be managed with other analgesic agents.

Contraindicated in women during pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other central nervous system (CNS) depressants

Although nalbuphine exhibits opioid antagonist activity, evidence suggests that in patients without opioid dependence, it will not antagonize opioid analgesics administered immediately before, concurrently, or immediately after nalbuphine injection. Therefore, due to additive pharmacological effects, concomitant use of other opioid analgesics, benzodiazepines, or other CNS depressants such as alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, neuroleptics, and other opioids increases the risk of respiratory depression, profound sedation, coma, and death.

Caution should be exercised when co-prescribing these agents to patients for whom alternative treatment options do not provide the expected benefit. The lowest effective dose should be used for the shortest possible duration, with careful monitoring for signs of respiratory depression and sedative effects.

Serotonergic drugs

Concomitant use of opioids with other drugs affecting the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, triptans, 5-HT3 serotonin-receptor antagonists, and other drugs affecting serotonergic neurotransmission (e.g., mirtazapine, trazodone, tramadol), MAO inhibitors (used to treat psychiatric disorders), as well as other agents such as linezolid and intravenous methylene blue, may result in serotonin syndrome.

If concomitant use cannot be avoided, close monitoring of patients is required, especially at the initiation of therapy and during dose adjustments. If serotonin syndrome is suspected, the drug should be discontinued.

Muscle relaxants

Nalbuphine may enhance the neuromuscular blockade of muscle relaxants and increase the degree of respiratory depression.

Patients should be monitored for signs of respiratory depression, which may be more severe than expected, and the dose of nalbuphine and/or the muscle relaxant should be reduced as necessary.

Diuretics

Opioids may reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Patients should be monitored for signs of reduced diuresis and/or effects on blood pressure, and the diuretic dose may need to be increased if necessary.

Anticholinergic drugs

Concomitant use of anticholinergic drugs increases the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Patients should be monitored for signs of urinary retention or decreased gastric motility when nalbuphine is used concomitantly with anticholinergic drugs.

MAO inhibitors

Interaction between MAO inhibitors (e.g., phenelzine, tranylcypromine, linezolid) and opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Nalbuphine should not be administered to patients taking MAO inhibitors or within 14 days after discontinuation of such agents.

If urgent opioid use is necessary, an initial test dose followed by incremental small doses should be administered until adequate pain control is achieved, with careful monitoring of blood pressure, CNS symptoms, and respiration.

Special precautions for use.

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 promptly recognized and treated, may lead to respiratory arrest and death. Preventive measures for respiratory depression may include close monitoring, supportive interventions, and the use of opioid antagonists, depending on the patient's clinical condition. Carbon dioxide (CO2) retention due to opioid-induced respiratory depression may exacerbate the sedative effects of opioids.

Although serious, life-threatening, or fatal respiratory depression may occur at any time during nalbuphine administration, the risk is greatest at the beginning of therapy or following a dose increase. Patients should be closely monitored for respiratory depression, particularly during the first 24–72 hours after initiation of therapy and after any dose increase.

To reduce the risk of respiratory depression, nalbuphine dosage must be properly selected and titrated. Overdosing nalbuphine when switching patients from another opioid may result in fatal overdose with the first dose.

Opioids may cause sleep-related respiratory depression, including central sleep apnea (CSA), and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. For patients with CSA, opioid dosage should be reduced to the extent possible, following clinical guidelines for gradual opioid tapering.

Risks associated with concomitant use of benzodiazepines or other CNS depressants

Profound sedation, respiratory depression, coma, and death may occur when nalbuphine is used concomitantly with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, neuroleptics, other opioids, alcohol). Because of these risks, co-prescribing these medications should be avoided in patients for whom alternative treatment options are ineffective.

Review studies have shown that concomitant use of opioid analgesics and benzodiazepines increases the risk of death associated with combination therapy compared to opioid analgesics alone. Due to similar pharmacological properties, a comparable risk is expected with concomitant use of other CNS depressants and opioid analgesics (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

If a decision is made to prescribe a benzodiazepine or another CNS depressant concomitantly with an opioid analgesic, the lowest effective doses and the shortest possible duration of concomitant use should be prescribed. Patients already receiving an opioid analgesic should be started on a lower initial dose of benzodiazepine or another CNS depressant than would be used in the absence of opioid use, and the dose should be titrated according to clinical response. If an opioid analgesic is prescribed to a patient already taking a benzodiazepine or another CNS depressant, a lower initial dose of the opioid analgesic should be used, with dose escalation based on clinical response. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation.

Patients and/or caregivers should be informed about the risks of respiratory depression and sedation when nalbuphine is used concomitantly with benzodiazepines or other CNS depressants (including alcohol and illicit substances). Patients should refrain from driving or operating heavy machinery until the effects of combining benzodiazepines or other CNS depressants with opioids are known. Patients should be monitored for substance use disorders, including opioid misuse and abuse, and should be warned about the risk of overdose and death associated with additional use of CNS depressants, including alcohol and illicit substances, during opioid therapy (see section "Interaction with other medicinal products and other forms of interaction").

Life-threatening respiratory depression in patients with chronic lung disease, elderly, debilitated, or compromised patients

The use of nalbuphine in patients with acute or severe bronchial asthma in the absence of appropriate monitoring or resuscitation equipment is contraindicated.

Patients with chronic lung disease: Patients with serious chronic obstructive lung disease or cor pulmonale, as well as those with significantly decreased respiratory function, hypoxia, hypercapnia, or a history of respiratory depression, are at increased risk of respiratory center depression, including apnea, even when nalbuphine is used at recommended doses.

Elderly, debilitated, or compromised patients: Life-threatening respiratory depression occurs more frequently in elderly, debilitated, or compromised patients, as pharmacokinetics or clearance may be altered compared to younger, healthier individuals. Close monitoring of such patients is essential, particularly at the start of therapy, during dose escalation, and when nalbuphine is used concomitantly with other respiratory depressants. Non-opioid analgesics may be considered as an alternative for these patients.

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more commonly after use exceeding one month. Clinical manifestations of adrenal insufficiency may include nonspecific symptoms such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. If adrenal insufficiency is suspected, diagnosis should be established as quickly as possible. If adrenal insufficiency is diagnosed, treatment with physiological replacement doses of corticosteroids should be initiated. Opioid therapy should be gradually discontinued, and corticosteroid treatment continued until adrenal function recovers. Reintroduction of other opioids may be attempted, as recurrence of adrenal insufficiency has not always been reported with other opioids. Available data do not indicate that any specific opioid is more likely to be associated with adrenal insufficiency.

Severe hypotension

Nalbuphine may cause severe hypotension, including orthostatic hypotension and syncope, particularly in patients with hypovolemia. The risk is increased in patients with impaired ability to maintain blood pressure due to reduced blood volume or concomitant use of certain CNS depressants (e.g., phenothiazines or general anesthetics). These patients should be monitored for signs of hypotension after initiation or dose adjustment of nalbuphine. In patients with circulatory shock, nalbuphine may cause vasodilation, leading to reduced cardiac output and arterial pressure. Nalbuphine should be avoided 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 signs of increased intracranial pressure or brain tumors), nalbuphine may reduce respiratory center activity, and CO2 retention may further increase intracranial pressure. Such patients should be monitored for sedation and respiratory depression, particularly at the beginning of nalbuphine therapy.

Opioids may also mask symptoms in patients with head injury. Nalbuphine should be avoided in patients with impaired consciousness or coma.

Risks of use in patients with gastrointestinal disorders

Nalbuphine is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

Nalbuphine may cause spasm of the sphincter of Oddi. Opioids may increase serum amylase levels. Patients with biliary tract disorders, including acute pancreatitis, should be monitored for worsening of symptoms.

Increased risk of seizures in patients with seizure disorders

Nalbuphine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings. Patients with a history of seizure disorders should be monitored for seizure control during nalbuphine therapy.

Renal or hepatic impairment

Since nalbuphine is metabolized in the liver and excreted by the kidneys, it should be used with caution in patients with renal or hepatic impairment, and lower doses should be administered.

Myocardial infarction

Like all potent analgesics, nalbuphine should be used with caution in patients with myocardial infarction who experience nausea or vomiting.

Cardiovascular system

During anesthesia studies with nalbuphine, a higher incidence of bradycardia was reported in patients who did not receive atropine preoperatively.

Use in elderly patients

Elderly patients (aged 65 years and older) may have increased sensitivity to nalbuphine. Caution should generally be exercised in dose selection for elderly patients, starting at the lower end of the dosing range, due to higher prevalence of decreased hepatic, renal, or cardiac function, concomitant diseases, or other drug therapies in this population.

Respiratory depression is the primary risk for elderly patients receiving opioids, particularly after administration of high initial doses in opioid-naïve patients or when opioids are used concomitantly with other respiratory depressants. Dose escalation in elderly patients should be very gradual.

Nalbuphine is primarily excreted by the kidneys, and the risk of adverse reactions is higher in patients with renal impairment. Since elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and renal function should be monitored when possible.

Laboratory tests

Nalbuphine may interfere with enzymatic methods for opioid detection, depending on the specificity/sensitivity of the test.

Abuse and dependence

Abuse

Nalbuphine has potential for abuse, misuse, addiction, and illegal diversion.

All patients receiving opioids should be closely monitored for signs of abuse and dependence, as opioid analgesic use carries a risk of dependence, even with appropriate medical use.

Like other opioids, nalbuphine may be used for non-medical purposes and diverted into illegal distribution channels.

Measures to reduce opioid abuse include proper patient assessment, appropriate prescribing practices, and periodic re-evaluation of therapy.

Abuse of nalbuphine may lead to overdose and death. Risks are increased with concomitant use of nalbuphine and other CNS depressants or alcohol.

Dependence

Both tolerance and physical dependence may develop during prolonged opioid therapy. Tolerance may develop to both desired and undesired effects of the drug and may progress at different rates for different effects.

Physical dependence leads to withdrawal symptoms following abrupt discontinuation or significant dose reduction. Withdrawal syndrome may also be precipitated by administration of opioid antagonists (e.g., naloxone, nalorphine), analgesics, opioid receptor agonist-antagonists (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine).

Discontinuation (withdrawal syndrome)

Nalbuphine should not be abruptly discontinued (see section "Dosage and administration"), as this may precipitate withdrawal syndrome in physically dependent patients. Withdrawal syndrome may be characterized by restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, and miosis. Other signs and symptoms may also occur, including irritability, restlessness, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or pulse.

Infants born to mothers physically dependent on opioids will also be physically dependent and may experience respiratory problems and withdrawal symptoms.

Use in opioid- or alcohol-dependent patients

Nalbuphine hydrochloride is an opioid not approved for use in the treatment of dependence. Its use in patients with opioid or alcohol dependence (active or in remission) is primarily indicated for the management of pain requiring opioid analgesia. Patients with a history of opioid or alcohol dependence are at higher risk of becoming dependent on nalbuphine.

Head injury

The respiratory depressant effects of nalbuphine and its ability to increase cerebrospinal fluid pressure may be significantly intensified in the presence of already elevated intracranial pressure due to trauma. Additionally, nalbuphine may cause confusion, miosis, vomiting, and other side effects that may mask the clinical course in patients with head injury. Nalbuphine should be used with particular caution in such patients and only when deemed absolutely necessary.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Studies in humans have not been conducted. Nalbuphine crosses the placental barrier and is contraindicated in pregnant women.

Prolonged use of opioid analgesics during pregnancy may lead to neonatal opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome may be life-threatening.

The potential risk of serious congenital malformations and miscarriage in this population is unknown. There is a potential risk of congenital malformations, miscarriage, or other adverse outcomes at all stages of pregnancy. Pregnant women taking opioids should not abruptly discontinue medication, as this may lead to pregnancy complications such as miscarriage or stillbirth. Dose reduction should be gradual and under medical supervision to avoid serious adverse effects on the fetus.

Labour and delivery

Placental transfer of nalbuphine is high, rapid, and variable, with maternal-to-fetal ratios ranging from 1:0.37 to 1:6. Adverse effects in the fetus and newborn reported after maternal administration of nalbuphine during labour include fetal bradycardia, neonatal respiratory depression, apnea, cyanosis, and hypotonia. Some of these effects have been life-threatening. In some cases, administration of naloxone to the mother during labour has normalized the situation. Severe and prolonged fetal bradycardia has been reported. Cases of persistent neurological injury associated with fetal bradycardia have also been reported.

Changes in fetal heart rate patterns have also been reported with nalbuphine use. Nalbuphine should be used during labour and delivery only if clearly necessary and only if the potential benefit to the mother outweighs the risk to the infant. If nalbuphine is used during labour, newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Nalbuphine is not recommended for use in pregnant women during or immediately before labour if alternative analgesic methods are available. Opioid analgesics, including nalbuphine, may prolong the duration of labour due to their ability to temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which typically shortens labour.

Breastfeeding

Since opioids can cross the placental barrier and are excreted in breast milk, NALBEN is contraindicated in breastfeeding women and is not recommended during labour and delivery unless, in the physician’s opinion, the potential benefit outweighs the risks. Life-threatening respiratory depression may occur in infants if mothers are administered opioids. Naloxone must be readily available. Infants whose mothers are taking nalbuphine during breastfeeding should be monitored for excessive sedation and respiratory depression.

If a woman discontinues opioid analgesics during breastfeeding or stops breastfeeding while taking opioid analgesics, infants may experience withdrawal symptoms.

Reproductive function

Prolonged use of opioids may cause decreased levels of sex hormones, with symptoms such as low libido, erectile dysfunction, or infertility.

Ability to affect reaction speed when driving or operating machinery.

Nalbuphine may impair mental or physical abilities required for potentially hazardous activities such as driving or operating machinery. Patients should refrain from driving or operating dangerous machinery until tolerance to nalbuphine is established and until individual response to the drug is known.

Patient monitoring is necessary until the effects of nalbuphine that may affect the ability to drive, operate machinery, or perform other activities requiring heightened attention are resolved.

Administration and Dosage

The medicinal product should be administered only by healthcare professionals who have completed specialized training in the use of intravenous anesthetics and in managing respiratory effects of potent opioids. Naloxone, appropriate resuscitation and intubation equipment, and oxygen must be readily available.

Before administration, visually inspect the ampoules for the presence of particulate matter and discoloration of the solution.

The medicinal product is intended for intravenous, intramuscular, and subcutaneous administration.

Caution should be exercised when administering nalbuphine within 12 hours before and 12–24 hours after surgical intervention.

Rapid intravenous administration of opioid analgesics increases the risk of hypotension and respiratory depression.

For acute pain, nalbuphine is recommended for use for a maximum of 7 days at the lowest dose providing adequate analgesia.

All opioid doses carry a risk of fatal or non-fatal adverse events. This risk increases with higher doses. If nalbuphine is used for more than 7 days to treat chronic non-cancer, non-palliative pain, it is recommended not to exceed 90 mg of nalbuphine per day. The risk should be assessed for each patient prior to prescribing nalbuphine, as the likelihood of serious adverse effects depends on the duration of treatment, pain severity, and the patient's tolerance level. In addition, pain levels should be monitored regularly to confirm the optimal dose and the continued need for nalbuphine.

Dosage

Dosage must be individually calculated for each patient, taking into account pain intensity, response to the drug, prior experience with analgesic treatment, and risk factors for dependence, abuse, and misuse (see section "Special Warnings and Precautions for Use").

Dosage depends on the patient's body weight. Exercise caution to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose (see Table 1).

Table 1: Dosage for adult patients:

**The information provided refers to the dosage form – injection solution 10 mg/mL

Patients must be carefully monitored for respiratory depression, especially during the first 24–72 hours after initiation of nalbuphine therapy and following dose increases, and appropriate dose adjustments should be made.

Analgesia

The usual recommended dose of nalbuphine for adults weighing 70 kg is 10 mg; the dose may be repeated every 3–6 hours as needed. Dosage should be adjusted according to the severity of pain, the patient's physical condition, and concomitant use of other medicinal products (see section "Special precautions for use"). The maximum single dose is 20 mg, and the maximum daily dose is 160 mg.

Use in special patient populations (patients with renal or hepatic impairment, elderly patients) – see section "Special precautions for use".

Concomitant anesthesia

The use of nalbuphine in concomitant anesthesia requires higher doses than those recommended for analgesia. The dose of nalbuphine for induction of anesthesia is 0.3 to 5 mg/kg intravenously over 10–15 minutes; supplemental doses of 0.25 to 0.5 mg/kg may be administered as needed. Nalbuphine use may be associated with respiratory depression, which can be reversed with the opioid antagonist naloxone.

As part of regional anesthesia, nalbuphine can be used in doses of 0.2 mg/kg to 0.5 mg/kg body weight. Nalbuphine provides sedation and additional analgesia during trigeminal nerve anesthesia, spinal anesthesia, regional nerve block, limb blockade, etc.

Dose titration

Appropriate optimization of doses calculated for pain relief should aim at administering the lowest dose that achieves an optimal balance between pain relief and opioid-related adverse effects.

Dose adjustments should be based on the patient's clinical response.

Dose adjustment or reduction

Physical dependence, with or without psychological dependence, usually develops with continuous use of opioids, including nalbuphine. Withdrawal symptoms may occur after abrupt discontinuation of therapy. These symptoms may include: body aches, diarrhea, paresthesia ("pins and needles"), loss of appetite, nausea, restlessness or agitation, runny nose, sneezing, tremor, stomach cramps, tachycardia, sleep problems, unusual sweating, palpitations, fever of unknown origin, weakness, and yawning.

After successful control of moderate to severe pain, gradual reduction of opioid doses should be attempted. Dose reduction or complete discontinuation may become possible if the patient's general or mental condition changes. Patients receiving long-term therapy should gradually discontinue the drug when it is no longer needed for pain control. Dose reduction must be individualized and conducted under medical supervision.

Patients should be informed that dose reduction or discontinuation of opioids reduces their tolerance to these drugs. If treatment needs to be resumed, the patient should start with the minimum dose and gradually increase it to avoid overdose.

Discontinuation

In patients who have received nalbuphine for a prolonged period and may have physical dependence, if nalbuphine therapy is no longer required, the dose should be gradually reduced by 25–50% every 2–4 days, with careful monitoring for signs and symptoms of withdrawal. If such signs or symptoms appear, the previous dose should be reinstated and the dose reduction should proceed more slowly, by increasing the interval between reductions or decreasing the amount of dose reduction, or both. Nalbuphine must not be abruptly discontinued in physically dependent patients (see section "Special precautions for use").

Missed dose

If a dose has been missed, the next dose should be administered at the next scheduled time and in the usual amount.

Children

The safety and efficacy of nalbuphine in children and adolescents (under 18 years of age) have not been established.

Overdose

Symptoms

Acute overdose of nalbuphine alone may manifest as respiratory depression and dysphoria. Acute overdose of nalbuphine with other opioids or CNS depressants may manifest as respiratory depression, drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, miosis, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis, rather than miosis, may be observed in cases of hypoxia due to overdose.

Treatment

In case of overdose, the primary measures are restoration of airway patency and protection of the airway, and, if necessary, application of assisted or controlled ventilation. In cases of circulatory shock and pulmonary edema, other supportive measures should be applied (including oxygen and vasopressors). In case of cardiac arrest or arrhythmias, modern life support techniques should be applied.

Opioid antagonists naloxone or nalmefene are specific antidotes in cases of respiratory depression caused by opioid overdose. In cases of clinically significant respiratory or circulatory depression due to nalbuphine overdose, an opioid antagonist should be administered. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression.

Since the duration of action of opioid antagonists is expected to be shorter than that of nalbuphine, patients must be monitored until complete recovery of respiration. If the response to an opioid antagonist is incomplete or transient, additional antagonist should be administered according to the recommended guidelines for its use.

In patients physically dependent on opioids, administration of the usual recommended dose of antagonist may precipitate acute withdrawal syndrome. The severity of withdrawal symptoms will depend on the degree of physical dependence and the dose of antagonist administered. If treatment of serious respiratory depression is required in a physically dependent patient, administration of the antagonist should begin cautiously, with doses smaller than usual.

Adverse Reactions

Sedative Effect

Sedation is a common adverse effect of opioid analgesics, particularly in individuals who have not previously taken opioids. The sedative effect may also occur partly because patients typically regain strength from prolonged fatigue following relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within 3–5 days, and if sedation is not severe, no treatment other than reassurance is required. If excessive sedation persists for more than several days, the opioid dose should be reduced and alternative causes investigated. These may include concomitant use of CNS depressants, hepatic or renal dysfunction, brain metastases, hypercalcemia, and respiratory insufficiency. After dose reduction, the dose may be cautiously increased again after three or four days if inadequate pain control is evident. Dizziness and unsteadiness may be caused by postural hypotension, especially in elderly or debilitated patients. These symptoms may improve when the patient lies down.

Nausea and Vomiting

Nausea is a common adverse effect at the beginning of opioid analgesic therapy and is believed to result from stimulation of the chemoreceptor trigger zone, vestibular apparatus stimulation, and delayed gastric emptying. The frequency of nausea decreases with continued opioid therapy. When initiating opioid therapy for chronic pain, routine prescription of an antiemetic should also be considered. In cancer patients, evaluation of nausea should include possible causes such as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of the celiac plexus, and concomitant use of drugs with emetogenic properties. Persistent nausea not relieved by dose reduction may be due to opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting, and a sensation of gastric fullness. These symptoms may respond to chronic treatment with gastrointestinal prokinetic agents.

Constipation

Constipation occurs in virtually all patients receiving continuous opioid therapy. In some patients, particularly elderly or bedridden individuals, fecal impaction may occur. It is important to inform patients about this risk and to establish an appropriate bowel regimen at the initiation of long-term opioid therapy. Stimulant laxatives and other appropriate measures should be used as needed. Since fecal impaction may present as overflow diarrhea, constipation should be ruled out in patients receiving opioid therapy before initiating treatment for diarrhea.

In clinical trials of intravenous nalbuphine, the most common adverse reaction observed in 36% of 1055 patients was sedation. Less frequently observed reactions included: sweating and clammy skin (9%), nausea and vomiting (6%), dizziness and vertigo (5%), dry mouth (4%), and headache (3%).

Other adverse reactions occurring at a frequency of 1% or less were as follows:

CNS: nervousness, depression, restlessness, crying, euphoria, disorientation, hostility, unusual dreams, confusion, syncope, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, feeling of unreality. The incidence of psychotomimetic effects such as feeling of unreality, depersonalization, delirium, dysphoria, and hallucinations has been shown to be lower than with pentazocine.

Cardiovascular system: arterial hypertension, hypotension, bradycardia, tachycardia.

Gastrointestinal tract: cramps, dyspepsia, bitter taste in mouth.

Respiratory system: respiratory depression, dyspnea, asthma.

Skin and subcutaneous tissue: pruritus, burning, urticaria.

Other: dysarthria, urinary urgency, blurred vision, hyperemia, and flushing.

Allergic reactions: anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported after nalbuphine administration, which may require immediate supportive treatment. These reactions may include shock, respiratory distress syndrome, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic reactions may be life-threatening. Other allergic-type reactions have been reported, including stridor, bronchospasm, wheezing, swelling, rash, pruritus, nausea, vomiting, diaphoresis, weakness, and tremors.

Post-marketing Experience

The following adverse reactions have been identified during the post-marketing period. 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, hyperthermia, depression or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and sensation of warmth. Fatalities due to severe allergic reactions have been reported with nalbuphine use. Fetal death has been reported following nalbuphine administration to the mother during labor.

Androgen Deficiency

Chronic opioid use may affect the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency, which may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is not known, as in studies conducted to date, various medical, physical, lifestyle, and psychological stress factors that may influence gonadal hormone levels have not been adequately controlled. Patients with symptoms of androgen deficiency should undergo laboratory evaluation.

Serotonin syndrome: cases of serotonin syndrome, a potentially life-threatening condition, have been reported with concomitant use of opioids and serotonergic agents.

Adrenal insufficiency: cases of adrenal insufficiency have been reported with opioid use, more commonly after prolonged use (more than one month).

Reporting of Suspected Adverse Reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Incompatibility

Do not mix in the same syringe with other injectable solutions.

Nalbuphine is physically incompatible with nafcillin and ketorolac. Solutions of these drugs should not be mixed.

Nalbuphine is compatible with 0.9% sodium chloride solution, 5% glucose solution, and Hartmann's solution.

Packaging

1 ml in an ampoule, 5 ampoules in a blister pack, 1 blister pack in a cardboard box.

Prescription category

Prescription only.

Manufacturer

Steril-Jen Life Sciences (P) Ltd.

Manufacturer's address and place of business

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India.