Nalbaxon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NALBAXON (NALBAXON)

Composition:

Active substance: nalbuphine;

1 ml of injection solution contains 10 mg of nalbuphine hydrochloride, calculated as 100% substance;

Excipients: citric acid anhydrous, sodium citrate, sodium metabisulfite (E 223), sodium chloride, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Analgesics. Opioids. Morphine 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, the analgesic effect of which is equivalent to that of morphine on a milligram-for-milligram basis at doses of approximately 30 mg.

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

Nalbuphine may cause respiratory depression similar to that caused by equianalgesic doses of morphine.

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

Nalbuphine 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 caused 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 CNS.

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

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 present with similar symptoms). Marked mydriasis, rather than miosis, may be observed due to hypoxia following overdose.

Effects on the gastrointestinal tract and other smooth muscles.

Nalbuphine causes reduced motility associated with increased tone of smooth muscles in the antral region 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 reduced secretion from the biliary and pancreatic ducts, spasm of the sphincter of Oddi, and transient elevation of serum amylase levels.

Effects on the cardiovascular system.

During anesthesia, a higher incidence of bradycardia has been reported in patients receiving nalbuphine who did not receive atropine prior to surgery.

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

Manifestations 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. They also stimulate the secretion of prolactin, growth hormone (GH – somatotropic hormone), and insulin and glucagon from the pancreas.

Chronic opioid use 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 not known, as various medical, physical, and psychological stress factors and lifestyle influences that may affect gonadal hormone levels have not been adequately controlled in studies conducted to date.

Effects on the immune system.

In vitro and animal models have shown that opioids have variable 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 varies widely among patients, particularly in those previously treated with strong opioid agonists. The minimum effective analgesic concentration of nalbuphine hydrochloride in an individual patient may increase over time due to increasing pain, development of a new pain syndrome, and/or development of tolerance.

Pharmacokinetics.

The onset of action of nalbuphine occurs within 2–3 minutes after intravenous administration and in less than 15 minutes after subcutaneous or intramuscular injection. The plasma 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 has not been fully elucidated, but metabolism is likely to occur in the liver.

Clinical characteristics.

Indications.

Nalbuphine is indicated for the treatment of moderate to severe pain, for which opioid analgesics are justified, and for which alternative treatment methods do not provide the expected results. The medicinal product Nalbuphine is also recommended as an adjunctive therapy during mixed anesthesia for preoperative and postoperative analgesia, as well as for pain relief during labor and delivery.

Contraindications.

• Hypersensitivity to nalbuphine hydrochloride or any of the excipients of the medicinal product.
• Known or potential gastrointestinal obstruction, including paralytic ileus.
• Use of the medicinal product in acute inflammatory conditions of the abdominal organs (e.g., acute appendicitis or pancreatitis), as this may complicate diagnosis.
• Mild pain, which can be relieved by other analgesic medicinal products.
• Acute or severe bronchial asthma, chronic obstructive airway disease, or status asthmaticus.
• Marked respiratory depression, elevated carbon dioxide levels in the blood, or cor pulmonale.
• Acute alcohol intoxication, delirium, or seizures.
• Marked central nervous system (CNS) depression, increased intracranial pressure, or head injury.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuation of MAOI therapy.
• Pregnancy or breastfeeding (except for use during labor and delivery).

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other CNS depressants.

Although the medicinal product Nalbuphine exhibits opioid receptor antagonistic activity, data indicate that in patients without opioid dependence, it does not antagonize the analgesic effect of an opioid analgesic administered immediately before, simultaneously with, or immediately after Nalbuphine. Therefore, due to additive pharmacological effects, concomitant use of nalbuphine hydrochloride with other opioid analgesics, benzodiazepines, or other CNS depressants (e.g., alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, neuroleptics, and other opioids) may increase the risk of respiratory depression, profound sedation, coma, and fatal outcomes.

Concomitant use of such agents should be limited to patients for whom alternative therapies are ineffective. Doses and duration of treatment should be minimized. Patients should be closely monitored for signs of respiratory depression and sedation.

Serotonergic agents.

Concomitant use of opioid analgesics with other medicinal products affecting the serotonergic neurotransmission system (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans, 5-HT3 receptor antagonists, other serotonergic agents such as mirtazapine, trazodone, tramadol), certain muscle relaxants (e.g., cyclobenzaprine, methocarbamol), and MAOIs (medicinal products used to treat psychiatric disorders and others, e.g., linezolid and intravenous methylene blue) may result in serotonin syndrome.

If concomitant use of these agents is justified, close monitoring of the patient is required, particularly at the beginning of treatment and during dose adjustments. If serotonin syndrome is suspected, treatment with Nalbuphine should be discontinued.

Muscle relaxants.

The medicinal product Nalbuphine may enhance the neuromuscular blockade of skeletal muscle relaxants and lead to severe respiratory depression.

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

Diuretics.

Opioid analgesics may reduce the efficacy of diuretics by stimulating the release of antidiuretic hormone.

Patients should be monitored for signs of reduced diuresis and/or effects on blood pressure, and the dose of diuretics should be increased as needed.

Anticholinergic agents.

Concomitant use of nalbuphine hydrochloride with anticholinergic agents may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

When using Nalbuphine concomitantly with anticholinergic agents, patients should be closely monitored for signs of urinary retention or decreased gastric motility.

MAO inhibitors.

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

The use of Nalbuphine is not recommended in patients receiving MAO inhibitors or within 14 days after discontinuation of such therapy.

In cases of urgent need for opioid analgesics, it is recommended to use test doses and gradually increase small doses for pain management, with careful monitoring of blood pressure, and signs and symptoms of CNS and respiratory depression.

Special precautions for use.

Nalbaxon contains nalbuphine. As an opioid, nalbuphine exposes users to the risks of dependence, abuse, and misuse.

Lifethreatening respiratory depression.

Serious, lifethreatening, or even fatal cases of respiratory depression have been reported with opioid use, even when used according to recommendations. If not promptly recognized and treated, respiratory depression can lead to respiratory arrest and fatal outcomes. Treatment of respiratory depression may include careful monitoring, supportive measures, and administration of opioid receptor antagonists, depending on the patient's clinical condition. Retention of carbon dioxide (CO2) due to opioid-induced respiratory depression may exacerbate the sedative effects of these analgesics.

Although lifethreatening respiratory depression may occur at any time during Nalbaxon treatment, the highest risk is observed at the beginning of therapy or after dose escalation. Patients should be closely monitored for respiratory depression, particularly during the first 24–72 hours after initiation of therapy and following any increase in nalbuphine dosage.

Proper dosing and dilution of Nalbaxon are crucial to minimize the risk of respiratory depression. Incorrect calculation of nalbuphine dosage when switching a patient from another opioid may result in overdose with potentially fatal consequences.

Opioid analgesics may impair respiratory function during sleep, including central sleep apnea and nocturnal hypoxemia. The use of opioid analgesics in a dose-dependent manner increases the risk of central sleep apnea. For patients with complaints of central sleep apnea, consideration should be given to reducing the dose of opioid analgesics, using best practices for gradual dose reduction.

Risks associated with concomitant use of benzodiazepines or other CNS depressants.

Concomitant use of Nalbaxon with benzodiazepines or other central nervous system (CNS) depressants (e.g., sedatives/non-benzodiazepine hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioid analgesics, alcohol) may result in profound sedation, respiratory depression, and fatal outcomes. Due to these risks, prescribing nalbuphine hydrochloride for concomitant use with these agents should be limited to patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to opioid analgesics alone. Given the similar pharmacological properties, similar risks are expected with concomitant use of other CNS depressants and opioid analgesics.

If a decision is made to prescribe a benzodiazepine or another CNS depressant alongside an opioid analgesic, the lowest effective dose should be prescribed for the shortest duration of concomitant use. For patients already receiving an opioid analgesic, a lower initial dose of the benzodiazepine or other CNS depressant should be prescribed compared to the dose used without an opioid analgesic, with gradual dose titration based on clinical response. When prescribing an opioid analgesic to a patient already taking a benzodiazepine or another CNS depressant, a lower initial dose of the opioid analgesic should be used, with gradual dose escalation based on clinical response. Patients should be closely monitored for symptoms of respiratory depression and sedation.

Patients and caregivers should be informed about the risks of respiratory depression and sedation when using Nalbaxon with benzodiazepines or other CNS depressants, including alcohol and illicit drugs. Patients should be advised to refrain from driving or operating complex machinery until the effects of combining nalbuphine hydrochloride with benzodiazepines or other CNS depressants are known. Patients should be screened for the risk of substance use disorders, including opioid analgesic abuse and misuse, and informed about the risk of overdose and fatal outcomes from additional use of CNS depressants, including alcohol and illicit drugs.

Opioid-induced hyperalgesia and allodynia.

Opioid-induced hyperalgesia occurs when an opioid analgesic paradoxically causes increased pain or heightened sensitivity to pain. This condition differs from tolerance, which refers to the need for increasing opioid doses to maintain a certain effect. Symptoms of opioid-induced hyperalgesia include (but are not limited to) increased pain levels with higher opioid doses, reduced pain with lower opioid doses, or pain from normally non-painful stimuli (allodynia). These symptoms may indicate opioid-induced hyperalgesia only if there is no evidence of progression of the underlying disease, opioid tolerance, opioid withdrawal, or dependence. Cases of opioid-induced hyperalgesia have been reported with both short-term and long-term use of opioid analgesics. Although the mechanism of this condition is not fully understood, several biochemical pathways have been identified. Strong biological plausibility between opioid analgesics, opioid-induced hyperalgesia, and allodynia has been described in the medical literature. If a patient is suspected of experiencing opioid-induced hyperalgesia, appropriate dose reduction of the current opioid analgesic or opioid rotation (safe switching to another opioid analgesic) should be carefully considered.

Patients and caregivers should not increase the opioid dose without prior consultation with a physician. Patients should inform their healthcare provider if they experience symptoms of hyperalgesia, including increased pain, heightened sensitivity to pain, or new pain.

Lifethreatening respiratory depression in patients with chronic lung disease, elderly patients, cachectic patients, or debilitated patients.

The use of Nalbaxon 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 significant chronic obstructive pulmonary disease or cor pulmonale, as well as those with markedly reduced lung capacity, hypoxia, hypercapnia, or existing respiratory depression, are at increased risk of reduced respiratory center activity, including apnea, even when Nalbaxon is used at recommended doses.

Elderly, cachectic, or debilitated patients.

Lifethreatening respiratory depression is most likely in elderly patients, cachectic patients, or debilitated patients due to possible changes in pharmacokinetic parameters or clearance compared to younger, healthier patients. These patients should be closely monitored, especially at the beginning of treatment, during dose escalation of Nalbaxon, and during concomitant use with other drugs that cause respiratory depression. As an alternative for these patients, non-opioid analgesics should be considered.

Adrenal insufficiency.

Adrenal insufficiency has been reported with the use of opioid analgesics, most commonly when used for more than one month. Symptoms of adrenal insufficiency may include nonspecific signs and symptoms such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, diagnosis should be confirmed as soon as possible through diagnostic testing. If adrenal insufficiency is diagnosed, treatment should be initiated with physiological replacement doses of corticosteroids. Opioid analgesics should be gradually discontinued to allow recovery of adrenal function, and corticosteroid therapy should continue until full recovery of adrenal function. Switching to another opioid analgesic may be attempted, as there have been reports of successful transitions without recurrence of adrenal insufficiency. Based on available data, it is unknown which specific opioid analgesics are more likely to be associated with adrenal insufficiency.

Severe arterial hypotension.

Nalbaxon may cause severe arterial hypotension, including orthostatic hypotension and syncope, in ambulatory patients. The risk is increased in patients whose ability to maintain blood pressure is already compromised due to reduced blood volume or concomitant use of certain CNS depressants, such as phenothiazines, tricyclic antidepressants, hypnotics, sedatives, or general anesthetics. These patients should be monitored for signs of low blood pressure after initiation or dose escalation of Nalbaxon. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, which may further lead to reduced cardiac output and decreased blood pressure. The use of Nalbaxon should be avoided in patients with circulatory shock.

Risks of use in patients with increased intracranial pressure, brain tumors, head injuries, or impaired consciousness.

In patients predisposed to intracranial effects of CO2 retention (e.g., patients with signs of or increased intracranial pressure or brain tumors), Nalbaxon may reduce respiratory center activity, and the associated CO2 retention may further lead to increased intracranial pressure. These patients should be monitored for signs of sedation and respiratory depression, especially at the beginning of treatment. Additionally, nalbuphine may cause confusion, miosis, vomiting, and other side effects that may mask the clinical course in patients with head injuries.

The use of Nalbaxon should be avoided in patients with impaired consciousness or coma.

Risks of use in patients with gastrointestinal disorders.

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

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

Increased risk of seizures in patients with seizure disorders.

Nalbaxon may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures under other clinical conditions associated with seizures. Patients with a history of seizure disorders should be monitored for worsening seizure control during nalbuphine therapy.

Discontinuation (withdrawal syndrome).

The use of Nalbaxon, a mixed opioid analgesic and opioid receptor agonist-antagonist, in patients receiving an analgesic that is a full opioid receptor agonist may result in reduced analgesic effect and/or precipitated withdrawal symptoms. Concomitant use of Nalbaxon with a full opioid receptor agonist analgesic should be avoided.

When discontinuing Nalbaxon in physically dependent patients, the dose should be gradually reduced. Abrupt discontinuation of this medication should not be performed in such patients.

Dependence, abuse, and misuse.

Nalbuphine hydrochloride is a synthetic analgesic and an opioid receptor agonist-antagonist. The use of nalbuphine hydrochloride as an opioid exposes patients to the risks of dependence, abuse, and misuse.

Dependence may occur with the use of the drug both at recommended doses and in cases of abuse or misuse.

Each patient should be evaluated for the risk of opioid dependence, abuse, or misuse. The risk increases in patients with a personal or family history of substance abuse (including drug or alcohol abuse or dependence) and in patients with psychiatric disorders (e.g., severe depression). The existence of these risks should not prevent appropriate pain management in individual patients.

Opioids used by patients with substance dependence may be used for criminal purposes. These risks should be considered when prescribing nalbuphine hydrochloride. To reduce these risks, the drug should be prescribed at the lowest effective dose.

Abuse and dependence. Nalbuphine hydrochloride is subject to abuse, misuse, dependence, and illegal resale.

All patients receiving opioid analgesics require careful monitoring for signs of abuse and dependence, as the use of these substances carries a risk of dependence even with proper medical use.

Prescription drug abuse is intentional use not for therapeutic purposes, even if only once, to achieve psychological and physiological effects.

Drug dependence is a cluster of behavioral, cognitive, and physiological phenomena developing after repeated substance use and including a strong desire to take the drug, difficulty controlling its use, continued use despite harmful consequences, prioritizing drug use over other activities and obligations, increased tolerance, and sometimes physical withdrawal symptoms.

"Drug-seeking" behavior is typical for individuals with substance use disorders. "Drug-seeking" tactics include urgent calls or visits closer to the end of the working day, refusal to undergo necessary examinations, tests, or referrals to specialists, "loss" of prescriptions, prescription forgery, unwillingness to provide previous medical records or contact information for other healthcare providers. Among individuals suffering from drug dependence and those with untreated dependence, visiting multiple doctors to obtain additional prescriptions is common. Concern about achieving adequate pain relief may be appropriate behavior in patients with inadequate pain management.

Abuse and dependence are distinct concepts and differ from physical dependence and tolerance. Physicians should be aware that not all dependent individuals exhibit tolerance and physical dependence symptoms. Additionally, opioid analgesic abuse is possible without true dependence.

Nalbaxon, like other opioid analgesics, may enter illicit distribution channels for non-medical use.

Appropriate measures to limit opioid analgesic abuse include proper patient assessment, appropriate prescription practices, periodic therapy evaluation, and proper dispensing and storage. Abuse of nalbuphine may lead to overdose and fatal outcomes. Risks increase with concomitant use of nalbuphine with other CNS depressants and alcohol. Parenteral drug abuse is usually associated with transmission of infectious diseases, such as hepatitis and HIV.

Dependence. With prolonged therapy with opioid analgesics, both tolerance and dependence may develop. Tolerance is the need for increasing doses of opioid analgesics to maintain a certain effect, e.g., pain relief (in the absence of disease progression or other external factors). Tolerance may develop to both desired and adverse drug effects and develops differently for different effects.

Physical dependence leads to the development of withdrawal symptoms after abrupt discontinuation or significant dose reduction of the drug. Withdrawal syndrome may also be mitigated by drugs with antagonistic activity at opioid receptors (e.g., naloxone, nalorphine), analgesics belonging to the class of opioid receptor agonist-antagonists (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Clinically significant physical dependence may manifest only after several days or even weeks of continuous opioid analgesic use.

Abrupt discontinuation of nalbuphine hydrochloride is not recommended. If a physically dependent patient abruptly stops using Nalbaxon, withdrawal syndrome may occur. Some or all of the following symptoms may characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, excessive sweating, chills, muscle pain, and miosis. Other signs and symptoms may also develop, including irritability, anxiety, back pain, joint pain, weakness, abdominal muscle cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or pulse.

Infants born to women physically dependent on opioid analgesics will also experience physical dependence and may have respiratory complications and withdrawal symptoms.

Due to the risk of dependence, abuse, and misuse associated with opioid analgesics, even when used at recommended doses, the use of Nalbaxon should be limited to patients for whom alternative treatment methods (e.g., non-opioid analgesics):

• are associated with intolerance or suspected intolerance;
• do not provide adequate analgesia or adequate analgesic effect is not expected with their use.

Nalbaxon should not be used for prolonged periods unless pain remains so severe that opioid analgesic use is required and alternative treatment methods remain insufficiently effective.

Renal or hepatic impairment.

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

Myocardial infarction.

Nalbaxon, like other potent analgesics, should be used with caution in patients with myocardial infarction who experience nausea and vomiting.

Cardiovascular system.

In evaluations of Nalbaxon use during anesthesia induction, increased incidence of bradycardia has been reported in patients who did not receive atropine before surgery.

Laboratory tests.

Nalbaxon may interfere with enzymatic methods for detecting opioids, depending on the specificity/sensitivity of the test. For more detailed information, consult the test kit manufacturer.

Serotonin syndrome.

Opioid analgesics rarely may lead to a potentially life-threatening condition due to concomitant use of serotonergic drugs. Immediate medical attention is required if symptoms of serotonin syndrome occur. In such cases, the serotonergic agent should be discontinued and symptomatic treatment initiated. Physicians should be informed about the use or planned use of serotonergic drugs.

Nalbaxon should not be used concomitantly with MAO inhibitors, serotonin precursors, or other agents affecting the serotonergic neurotransmitter system.

Interaction with MAO inhibitors.

The use of Nalbaxon with any drugs that inhibit MAO should be avoided (see section "Interaction with other medicinal products and other types of interactions").

Constipation.

Severe constipation may occur (see sections "Pharmacological properties" and "Adverse reactions").

Use in elderly patients.

Elderly patients (aged 65 years and older) may have increased sensitivity to nalbuphine. In general, caution should be exercised when selecting dosage for elderly patients, usually starting at the lowest end of the dosage range, as this population has a higher frequency of reduced liver, kidney, or heart function, comorbid conditions, or concomitant medication use.

Respiratory depression is the primary risk for elderly patients taking opioids and occurs after administration of high initial doses to opioid-naive patients or concomitant administration of opioids with other respiratory depressants. Dosage for elderly patients should be increased very slowly.

Nalbuphine is primarily excreted by the kidneys, and the risk of adverse reactions is higher in patients with impaired renal function. Since renal function is more likely to be reduced in such patients, caution should be exercised when selecting dosage, and renal function should be monitored if possible.

Carcinogenesis.

In long-term studies conducted in rats (24 months) and mice (19 months) with oral administration at doses of 200 µg/mL (12 times the maximum recommended daily dose for humans [MRDH]) and 200 mg/day (6 times the MRDH), respectively, no evidence of carcinogenicity was found.

Mutagenesis.

Nalbuphine hydrochloride caused an increased frequency of mutations in the mouse lymphoma assay. The drug did not show mutagenic activity in the Ames test with four bacterial strains, in the Chinese hamster ovary HGPRT assay, or in the sister chromatid exchange assay. Clastogenic activity was not observed in the micronucleus test in mice or in the bone marrow cytogenetic analysis in rats.

Important information about excipients.

Nalbaxon contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically 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 withdrawal syndrome. Neonatal opioid withdrawal syndrome may be life-threatening.

For humans, 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.

In reproductive animal studies, nalbuphine reduced survival and body weight of offspring when administered subcutaneously to pregnant rats during late pregnancy and lactation at 1.7 times the maximum recommended human dose, as well as when administered to male and female rats both before mating and during pregnancy and lactation. No developmental defects were observed in rats or rabbits when the drug was administered at 6.1- and 3.9-fold maximum recommended human doses, respectively. The predicted background risk of serious congenital defects and miscarriage in humans is unknown. All pregnancies have a background risk of congenital defects, miscarriage, or other adverse outcomes. In the general US population, the predicted background risk of major congenital defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Adverse reactions in the fetus/newborn.

Severe fetal bradycardia has been reported with the use of nalbuphine hydrochloride during labor. Reversal of these effects can be achieved with naloxone. Reports of fetal bradycardia in early pregnancy are lacking, but this risk exists. The drug should be used during pregnancy only if necessary, when potential benefit outweighs the risks to the fetus, and appropriate measures such as fetal monitoring for detection and correction of any potential adverse effects are applied.

Labour and delivery.

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

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

Nalbaxon is not recommended for use in pregnant women during or immediately before labor if alternative pain relief methods are available. Opioid analgesics, including nalbuphine, may prolong labor duration due to their properties of temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be compensated by increased cervical dilation rate, which usually shortens labor. Newborns exposed to opioid analgesics during labor should be monitored for signs of excessive sedation and respiratory depression.

Neonatal withdrawal syndrome.

Prolonged use of opioid analgesics during pregnancy may lead to neonatal withdrawal syndrome. Withdrawal syndrome in newborns manifests as irritability, hyperactivity, abnormal sleep patterns, high-pitched crying, tremors, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of opioid withdrawal syndrome in newborns vary depending on the specific opioid used, duration of use, timing and amount of the last maternal dose, and the rate of drug elimination by the newborn. Neonatal opioid withdrawal syndrome may be life-threatening.

Animal experience.

Pregnant rats were administered nalbuphine hydrochloride subcutaneously from day 6 to day 15 of pregnancy at doses of 7, 14, or 100 mg/kg/day (0.4, 0.85, or 6.1 times the MRDH of 160 mg/day based on body surface area, respectively). No signs of developmental abnormalities or embryotoxicity were observed, despite reduced maternal body weight gain at medium and high doses.

Pregnant rabbits were administered nalbuphine hydrochloride intravenously from day 7 to day 19 of pregnancy at doses of 4, 8, or 32 mg/kg/day (0.5, 1, or 3.9 times the MRDH based on body surface area, respectively). No signs of developmental abnormalities or embryotoxicity were observed, despite reduced maternal body weight gain in the high-dose group.

Pregnant rats were administered nalbuphine hydrochloride subcutaneously from day 15 of pregnancy to day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRDH based on body surface area, respectively). Offspring survival was reduced in groups receiving medium and high doses, and neonatal body weight was dose-dependent. Maternal toxicity was noted in all treatment groups (reduced body weight).

Female rats were administered nalbuphine hydrochloride subcutaneously from day 15 before mating to day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRDH of 160 mg/day based on body surface area, respectively). Male rats were treated via oral gavage with the same doses of nalbuphine hydrochloride starting from day 60 before and during mating. In the high-dose group, offspring survival was reduced, and in medium and high-dose groups, offspring body weight was reduced.

Breastfeeding.

According to limited data, nalbuphine hydrochloride passes into breast milk but only in small amounts (less than 1% of the administered dose) and with clinically insignificant effects. Infants exposed to nalbuphine hydrochloride through breast milk should be monitored for excessive sedation and respiratory depression. Withdrawal symptoms may occur in breastfed infants if the mother discontinues opioid analgesic use or stops breastfeeding.

Fertility.

Female rats were administered nalbuphine hydrochloride subcutaneously from day 15 before mating to day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRDH of 160 mg/day based on body surface area, respectively). Male rats were treated via oral gavage with the same doses of nalbuphine hydrochloride starting from day 60 before and during mating. No adverse effects on male or female fertility were observed.

Ability to affect reaction speed when driving vehicles or operating machinery.

Nalbaxon may impair mental or physical abilities required for potentially hazardous activities such as driving vehicles or operating equipment. Patients should refrain from driving vehicles or operating dangerous machinery until tolerance to nalbuphine is established and until their reaction to it is known.

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

Administration and Dosage

The medicinal product must 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, resuscitation and intubation equipment, and oxygen must be readily available at all times.

Dosage for each patient must be individualized, taking into account the severity of pain, patient response to the drug, prior experience with analgesic therapy, and risk factors for dependence, abuse, and misuse.

Patients must be closely monitored for the development of respiratory depression, particularly during the first 24–72 hours after initiation of therapy and following any dose increase, with appropriate dosage adjustments made as necessary.

Administration method

Nalbuphine is compatible with 0.9% sodium chloride solution, 5% glucose solution, and Hartmann’s solution for up to 30 minutes after mixing, provided the solutions are stored in a place protected from direct sunlight.

Prior to administration, the solution should be inspected visually for particulate matter and discoloration.

Dosage

Dosage depends on the patient's body weight. Care must be taken to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may result in accidental overdose (see table below).

The recommended single dose for adults is 10 mg of nalbuphine hydrochloride for patients weighing 70 kg, administered subcutaneously, intramuscularly, or intravenously. The single dose may be administered as needed every 3–6 hours. Dosage should be adjusted according to the severity of pain, the patient’s physical condition, and potential interactions with other concurrently administered medicinal products. For non-tolerant patients, the recommended maximum single dose is 20 mg. The maximum daily dose is 160 mg.

Dosage table for adult patients

When nalbuphine hydrochloride is used as an adjunct to anesthesia, higher doses are required than for analgesia. Initial doses of nalbuphine hydrochloride range from 0.3 to 3 mg/kg intravenously over 10–15 minutes; maintenance doses are 0.25 to 0.5 mg/kg intravenously as needed. Administration of nalbuphine hydrochloride may be associated with respiratory depression, which can be reversed by the opioid antagonist naloxone hydrochloride.

Titration and Maintenance of Therapy

Titration of Nalbaxon should be performed by individualizing the dose to achieve adequate analgesia with minimal adverse reactions. Patients receiving nalbuphine hydrochloride must be continuously monitored for pain intensity, frequency of adverse reactions, and for signs of dependence, abuse, or misuse. Frequent communication among the physician, other healthcare providers, the patient, and the caregiver is essential during periods of changing analgesic requirements, including initial titration.

If pain intensity increases after dose stabilization, the source of pain should be evaluated before increasing the dose of nalbuphine hydrochloride. If opioid-related adverse reactions occur, dose reduction should be considered. Dosage adjustments should be made to achieve an appropriate balance between pain control and opioid-related side effects.

Discontinuation of Nalbaxon

In patients who have been regularly taking nalbuphine hydrochloride and may be physically dependent, if treatment with nalbuphine hydrochloride is no longer required, the dose should be gradually reduced by 25–50% every 2–4 days. Patients should be closely monitored for signs and symptoms of withdrawal. If such signs or symptoms appear, the dose should first be increased to the previous level, and then reduced more gradually by increasing the interval between dose reductions, reducing the amount of each dose, or both. Nalbaxon should not be abruptly discontinued in patients with physical dependence (see section "Special Precautions").

Children

The safety and efficacy of Nalbaxon in pediatric patients and adolescents (under 18 years of age) have not been established.

Overdose

Symptoms

Acute overdose of nalbuphine alone may present with respiratory depression and dysphoria. Acute overdose involving nalbuphine and other opioids or CNS depressants may result in 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 fatal outcomes. Marked mydriasis, rather than miosis, may be observed in cases of hypoxia due to overdose.

Treatment

In cases of overdose, immediate measures include ensuring airway patency and protecting the airway, with assisted or controlled ventilation if necessary. In cases of circulatory shock and pulmonary edema, other supportive measures (including oxygen and vasopressors) should be applied. In cases of cardiac arrest or arrhythmias, current life-support techniques should be employed.

Opioid antagonists naloxone or nalmefene are specific antidotes for opioid-induced respiratory depression. 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 reversal by opioid antagonists is expected to be shorter than the duration of action of nalbuphine, patients must be closely observed until complete recovery of respiration is achieved. If the response to an opioid antagonist is incomplete or transient, additional doses of the 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 an opioid antagonist may precipitate an 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 significant respiratory depression is required in a physically dependent patient, the antagonist should be administered cautiously, starting with doses smaller than usual.

Adverse Reactions

The most common adverse reaction in 1066 patients treated with nalbuphine hydrochloride in clinical trials was sedation, occurring in 381 (36%) patients.

Less frequently reported reactions included: increased sweating/skin clamminess – 99 (9%), nausea/vomiting – 68 (6%), dizziness/vertigo – 58 (5%), dry mouth – 44 (4%), and headache – 27 (3%).

Other adverse reactions occurring at a frequency of 1% or less are listed below.

Nervous system disorders: nervousness, euphoria, hostility, unusual dreams, weakness, heaviness sensation, numbness, tingling, dizziness, headache, muscle rigidity, increased intracranial pressure.

Psychiatric disorders: drug dependence, psychomimetic reactions, neurotic reactions, somnolence, depression, crying, confusion, dysphoria, speech disturbance, mood changes, restlessness, agitation (inability to be comforted), hallucinations, euphoria, feelings of unreality.

It has been shown that the incidence of psychomimetic effects such as feelings of unreality, depersonalization, delirium, dysphoria, and hallucinations is lower than with pentazocine.

The potential for physical and psychological dependence, as well as tolerance during prolonged treatment, is similar to that of other morphine derivatives.

General disorders and administration site conditions: hypothermia; local pain, swelling, redness, burning, warmth sensation, hot flushes, and increased sweating may occur.

Eye disorders: blurred or impaired vision, miosis.

Respiratory system disorders: respiratory depression, dyspnea, asthma, pulmonary edema.

Cardiac disorders: increased or decreased blood pressure, orthostatic hypotension, bradycardia, tachycardia, palpitations.

Gastrointestinal disorders: constipation, nausea, vomiting, dry mouth, spasms, dyspepsia, bitter taste, abdominal pain.

Hepatobiliary disorders: liver function test abnormalities, biliary tract spasm.

Renal and urinary disorders: antidiuretic effect, urinary tract spasm.

Reproductive system and breast disorders: decreased libido or potency, amenorrhea or infertility.

Skin and subcutaneous tissue disorders: pruritus, burning sensation, urticaria.

Other: speech difficulty, urinary urgency, visual clouding, flushing and hot flushes, injection site reactions such as pain, swelling, redness, burning, and warmth sensation.

Allergic reactions: following nalbuphine administration, anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported, 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 reported include stridor, bronchospasm, wheezing, rales, edema, rash, pruritus, nausea, vomiting, sweating, 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 warmth sensation. A fatal outcome due to severe allergic reactions following nalbuphine administration has been reported. There have also been reports of fetal death when nalbuphine was administered to the mother during labor.

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).

Hyperalgesia and allodynia: cases of opioid-induced hyperalgesia and allodynia have been reported with opioid treatment of any duration.

Hypoglycemia: cases of hypoglycemia have been reported in patients receiving opioids. Most reports involved patients with at least one risk factor (e.g., diabetes).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life: 3 years.

Storage conditions: Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Incompatibilities

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

The product should not be mixed with nafcillin or ketorolac.

Packaging: 1 ml in an ampoule; 10 ampoules per cardboard pack.

Prescription status: Prescription only.

Manufacturer: Myungmoon Pharm. Co., Ltd.

Manufacturer's address and place of business:

26, Jeyakgongdan 2-gil, Hyangnam-eup, Hwaseong-si, Gyeonggi-do, Republic of Korea.

Marketing Authorization Holder: JSC "FITOFARM".

Address: 12 Almatinska Street, Kyiv, 02092, Ukraine.