Nalbuphine

INSTRUCTIONS for medical use of the medicinal product NALBUPHINE (NALBUPHINE)

Composition:

Active substance: nalbuphine hydrochloride;

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

Excipients: sodium citrate; citric acid, monohydrate; sodium chloride; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or almost colorless solution.

Pharmacotherapeutic group. Analgesics. Opioids. Morphine derivatives. ATC code N02A F02.

Pharmacological properties.

Pharmacodynamics.

Nalbuphine is a kappa-receptor agonist and a mu-receptor antagonist.

Nalbuphine, solution for injection, is a potent analgesic. Its analgesic effect is practically equivalent to that of morphine on a milligram-to-milligram basis up to a maximum dose of approximately 30 mg.

The opioid receptor antagonist activity of nalbuphine hydrochloride is ¼ that of nalorphine and 10 times greater than that of pentazocine.

Nalbuphine hydrochloride may cause a similar degree of respiratory depression as equianalgesic doses of morphine. However, the medicinal product Nalbuphine, solution for injection, has a ceiling effect, whereby further dose increases beyond 30 mg do not cause greater respiratory depression without concomitant administration of other central nervous system (CNS)-active drugs affecting respiratory function.

Alone, nalbuphine hydrochloride has strong antagonist activity at opioid receptors at doses less than or equal to its analgesic dose. When administered after or in combination with mu-receptor agonist analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially neutralize or block respiratory depression caused by mu-receptor agonist opioid analgesics. Nalbuphine hydrochloride may alleviate withdrawal symptoms in patients dependent on opioids. This medicinal product should be used with caution in patients who have regularly used mu-receptor agonist analgesics.

Effects on the CNS. Nalbuphine causes respiratory depression by direct action on respiratory centers in the brainstem. Respiratory depression includes reduced responsiveness of brainstem respiratory centers to both increased carbon dioxide tension and electrical stimulation. However, nalbuphine-induced respiratory depression exhibits a ceiling effect. Although the drug is an agonist/antagonist, the respiratory depression caused by nalbuphine can be reversed by naloxone.

Nalbuphine causes miosis, even under conditions of complete darkness. Pupillary constriction is a sign of opioid analgesic overdose, although it is not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic etiology may produce similar symptoms). In hypoxia caused by overdose, marked mydriasis rather than miosis may occur.

Effects on the gastrointestinal tract and other smooth muscle. Nalbuphine reduces gastrointestinal motility by increasing smooth muscle tone in the antral portion of the stomach and duodenum. Digestion in the small intestine is slowed, and propulsive contractions are reduced. Propulsive peristaltic waves in the colon are diminished, and tone may increase to the point of spasm, leading to constipation. Other effects caused by opioid analgesics may include reduced secretion of bile and pancreatic juice, spasm of the sphincter of Oddi, and transient elevation of serum amylase.

Effects on the cardiovascular system. When nalbuphine is used during induction of anesthesia, increased incidence of bradycardia has been reported in patients who did not receive atropine prior to surgery.

Opioid analgesics 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, increased sweating, and/or orthostatic hypotension.

Effects on the endocrine system. Opioid analgesics inhibit the secretion of adrenocorticotropic hormone (cortisol) and luteinizing hormone in humans (see section "Adverse reactions"). They also stimulate the secretion of prolactin, growth hormone, and insulin and glucagon from the pancreas.

With prolonged use, opioid analgesics 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 relationship between opioid analgesic use and the clinical syndrome of hypogonadism is unknown, as controlled studies accounting for various medical, physical, lifestyle, and physiological stress factors that may influence gonadal hormone levels have not been conducted to date (see section "Adverse reactions").

Effects on the immune system. In vitro studies in animal models have shown that opioid analgesics exert diverse effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effect of opioid analgesics is somewhat immunosuppressive.

Dose-effect relationship. The minimum effective analgesic concentration varies among patients, particularly in those previously treated with potent opioid receptor agonists. The minimum effective analgesic concentration of nalbuphine for an individual patient may increase over time due to intensification of pain, development of new pain syndromes, and/or development of analgesic tolerance (see section "Dosage and administration").

Pharmacokinetics.

Nalbuphine begins to act within 2–3 minutes after intravenous administration and within less than 15 minutes after subcutaneous or intramuscular administration. The plasma half-life of nalbuphine is 5 hours, and the duration of analgesic activity, according to clinical studies, ranges from 3 to 6 hours.

The metabolic pathway of nalbuphine has not been fully elucidated, but the drug is likely metabolized by the liver.

Clinical characteristics.

Indications.

Nalbuphine, injection solution, is indicated for the management of pain severe enough to require opioid analgesics and for which alternative treatment options are inadequate. Nalbuphine is also recommended as adjunctive therapy in balanced anesthesia for preoperative and postoperative analgesia, as well as for obstetrical analgesia during labor and delivery.

Limitations of use

Due to the risks of addiction, abuse, and misuse associated with opioid analgesics, even at recommended dosages (see section "Special precautions"), the use of Nalbuphine, injection solution, should be reserved for patients for whom alternative treatment options (e.g., non-opioid analgesics):

• are not tolerated or are suspected to be intolerable;
• are ineffective or are not expected to provide adequate analgesia.

Contraindications.

The medicinal product Nalbuphine is contraindicated in patients with:

• hypersensitivity to nalbuphine hydrochloride or to any of the excipients of the medicinal product;
• known or suspected gastrointestinal obstruction, including paralytic ileus (see section "Special precautions");
• acute abdominal pain where appendicitis or pancreatitis is suspected;
• pronounced respiratory depression or pronounced central nervous system (CNS) depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcoholic delirium, seizures (see section "Special precautions");
• acute or severe bronchial asthma, chronic obstructive airway disease, or status asthmaticus (see section "Special precautions");
• acute respiratory failure, elevated blood carbon dioxide levels (hypercapnia), or cor pulmonale;
• concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of MAOIs.

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

Nalbuphine is contraindicated in women during pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other CNS depressants. Although the medicinal product Nalbuphine has opioid receptor antagonist activity, data indicate that in opioid-naïve patients it does not antagonize the analgesic effect of opioids administered immediately before, concurrently 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 death.

Concomitant use of such agents should be reserved for patients for whom alternative treatment options are ineffective. Dosages and duration of treatment should be minimized. Patients should be closely monitored for signs of respiratory depression and sedation (see section "Special precautions").

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 (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (e.g., cyclobenzaprine, metaxalone), and monoamine oxidase inhibitors (MAOIs) (medicinal products indicated for psychiatric disorders and others, e.g., linezolid and intravenous methylene blue)) may result in serotonin syndrome (see section "Special precautions").

If concomitant use of such agents is warranted, close observation of the patient is required, particularly during initiation of therapy and dose adjustments. If serotonin syndrome is suspected, administration of Nalbuphine should be discontinued.

Neuromuscular blockers. Nalbuphine may enhance the neuromuscular blockade of skeletal muscle relaxants and lead to profound respiratory depression.

Patients should be monitored for signs of respiratory depression, which may be more pronounced 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 promoting the release of antidiuretic hormone.

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

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 Nalbuphine is used concomitantly with anticholinergic agents, patients should be closely monitored for signs of urinary retention or decreased gastrointestinal 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) (see section "Special precautions").

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

If urgent opioid analgesia is required, it is recommended to use test doses and titrate small doses frequently while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Special precautions for use.

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

Myocardial infarction. The medicinal product Nalbuphine, like other potent analgesics, should be used with caution in patients with myocardial infarction who experience nausea and vomiting.

Cardiovascular system. When assessing the use of Nalbuphine during induction of anesthesia, an increased incidence of bradycardia has been reported in patients who did not receive atropine prior to surgery.

Head injury. The respiratory depressant effect 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. In addition, nalbuphine may cause confusion, miosis, vomiting, and other adverse 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 truly necessary.

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 dosing range, as this population has a higher prevalence of decreased hepatic, renal, or cardiac function, concomitant diseases, or use of other medicinal products.

Respiratory depression is a major risk for elderly patients taking opioids and occurs after administration of large initial doses to opioid-naïve patients or when opioids are co-administered with other respiratory depressants. Dosage in elderly patients should be increased very slowly.

Nalbuphine is substantially excreted by the kidneys, and the risk of adverse reactions is higher in patients with impaired renal function. Since reduced renal function is more likely in elderly patients, caution should be exercised in dose selection and, whenever possible, renal function should be monitored.

Laboratory tests. Nalbuphine hydrochloride may affect the results of enzymatic methods for opioid detection, depending on the specificity/sensitivity of the test system. For more detailed information, consult the test system manufacturer.

Serotonin syndrome. Opioid analgesics rarely may lead to a potentially life-threatening condition when used concomitantly with serotonergic agents. Immediate medical attention should be sought if symptoms of serotonin syndrome occur. Inform your physician about taking or planning to take serotonergic agents (see sections **"**Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with MAO inhibitors. The use of the medicinal product Nalbuphine should be avoided when any MAO-inhibiting agents are being used. When using Nalbuphine injection solution, MAO inhibitors should not be initiated (see section "Interaction with other medicinal products and other forms of interaction").

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

Life-threatening respiratory depression. Serious, life-threatening, or even fatal cases of respiratory depression have been reported with opioid use, even when used according to recommendations. If respiratory depression is not promptly recognized and appropriate therapy initiated, it may lead to respiratory arrest and death. Management of respiratory depression may include careful monitoring, supportive measures, and administration of opioid receptor antagonists, depending on the patient's clinical condition (see section "Overdose"). Retention of carbon dioxide (CO₂) due to opioid-induced respiratory depression may exacerbate the sedative effect of opioid analgesics.

Although serious, life-threatening respiratory depression, which may also lead to fatal outcomes, may occur at any time during Nalbuphine use, the highest risk is observed at the beginning of therapy or after dose escalation. Patients should be carefully monitored for respiratory depression, especially during the first 24–72 hours after initiation of therapy and after dose increases of Nalbuphine.

Proper dosing and dilution of Nalbuphine are crucial to minimize the risk of respiratory depression (see section "Method of administration and dosage"). Incorrect dose calculation of nalbuphine when switching a patient from another opioid may lead to overdose of the first dose with fatal consequences.

Opioid analgesics may cause respiratory dysfunction 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 reporting central sleep apnea, consider dose reduction of opioid analgesics using best practices for gradual tapering (see section "Method of administration and dosage").

Risks associated with concomitant use of nalbuphine hydrochloride with benzodiazepines or other CNS depressants. Concomitant use of the medicinal product Nalbuphine with benzodiazepines or other central nervous system (CNS) depressants (e.g., sedatives/non-benzodiazepine hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, neuroleptics, other opioid analgesics, alcohol) may result in profound sedation, respiratory depression, and fatal outcomes. Due to these risks, the prescription of 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 the use of opioid analgesics alone. Due to similar pharmacological properties, similar risks are expected with concomitant use of other CNS depressants with opioid analgesics (see section "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 dose should be prescribed for the shortest duration of concomitant use. For patients already receiving an opioid analgesic, it is recommended to initiate a lower starting dose of the benzodiazepine or other CNS depressant than would be prescribed without an opioid analgesic, and gradually increase the dose according to clinical response. When prescribing an opioid analgesic to a patient already taking a benzodiazepine or another CNS depressant, initiate a lower starting dose of the opioid analgesic and gradually increase it according to clinical response. Patients should be carefully monitored for signs of respiratory depression and sedation.

Patients and caregivers should be informed about the risk of respiratory depression and sedation when using the medicinal product Nalbuphine 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 concomitant use of nalbuphine hydrochloride with benzodiazepines or other CNS depressants are known. Patients should be screened for risk of substance use disorders, including misuse and abuse of opioid analgesics, and informed about the risk of overdose and death from additional intake of CNS depressants, including alcohol and illicit drugs (see section "Interaction with other medicinal products and other forms of interaction").

Life-threatening respiratory depression in patients with chronic lung disease or elderly patients (aged 65 years and older), cachectic or debilitated patients. The use of Nalbuphine injection solution in patients with acute or severe bronchial asthma under uncontrolled conditions or in the absence of 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, have an increased risk of reduced respiratory center activity, including apnea, even when Nalbuphine is used at recommended doses.

Elderly, cachectic, or debilitated patients. Life-threatening 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 and healthier patients. These patients should be carefully monitored, especially at the beginning of treatment, during dose escalation of Nalbuphine, and during concomitant use with other drugs causing respiratory depression. As an alternative for such patients, consider the use of non-opioid analgesics.

Increased sensitivity to nalbuphine hydrochloride may be observed in elderly patients. In general, careful dose selection is recommended for elderly patients, usually starting with the lowest dose, due to the higher frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and use of other medications.

Nalbuphine is primarily excreted by the kidneys, and the risk of adverse reactions to this drug may be higher in patients with renal impairment. Since reduced renal function is more likely in elderly individuals, careful dose selection is necessary, and monitoring of renal function may be required.

Adrenal insufficiency. Adrenal insufficiency has been reported with the use of opioid analgesics, most commonly when used for more than 1 month. Symptoms of adrenal insufficiency may include nonspecific signs and symptoms such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. 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 be continued until full recovery of adrenal function. Switching to another opioid analgesic may be attempted, as several cases of switching to another opioid analgesic without recurrence of adrenal insufficiency have been reported. Based on available data, it is unknown which specific opioid analgesics are more likely associated with adrenal insufficiency.

Severe hypotension. Nalbuphine injection solution may cause severe 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 or general anesthetics (see section "Interaction with other medicinal products and other forms of interaction"). These patients should be monitored for signs of low blood pressure after initiation or dose escalation of Nalbuphine. 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 Nalbuphine should be avoided in patients with circulatory shock.

Risk of using nalbuphine hydrochloride in patients with increased intracranial pressure, brain tumors, head trauma, or altered consciousness. In patients predisposed to intracranial effects of CO₂ retention (e.g., patients with signs of or increased intracranial pressure or brain tumors), Nalbuphine may reduce respiratory center activity, and the associated CO₂ retention may further lead to increased intracranial pressure. Such patients should be monitored for signs of sedation and respiratory depression, especially at the beginning of drug use.

Opioid analgesics may also mask the clinical course of disease in patients with head trauma. The use of Nalbuphine should be avoided in cases of altered consciousness or coma.

Risk of using nalbuphine hydrochloride in patients with gastrointestinal disorders. Nalbuphine injection solution 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 cause an increase in 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 under other clinical conditions associated with seizures. Patients with a history of seizure disorders should be monitored for worsening seizure control during nalbuphine therapy.

Abuse of medicinal products and drug dependence.

Abuse. The medicinal product Nalbuphine contains nalbuphine hydrochloride, which is subject to abuse, misuse, dependence, and illegal resale.

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

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

Drug dependence is a cluster of behavioral, cognitive, and physiological phenomena developing after repeated substance use and includes 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 drug tolerance, and sometimes physical withdrawal symptoms.

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

Abuse and dependence are distinct concepts and differ from physical dependence and tolerance. Physicians should be aware that not all dependent individuals will exhibit tolerance or physical dependence symptoms. Moreover, opioid analgesic abuse is possible even in the absence of true dependence.

Nalbuphine hydrochloride injection solution, like other opioid analgesics, may enter illicit distribution channels for non-medical use.

Appropriate measures to help limit opioid analgesic abuse include proper patient assessment, appropriate prescribing practices, periodic therapy evaluation, and proper dispensing and storage.

Specific risks associated with nalbuphine hydrochloride abuse. Nalbuphine hydrochloride abuse carries a risk of overdose and death. The risk increases with abuse of nalbuphine hydrochloride together with alcohol or other CNS depressants.

Parenteral drug abuse is usually associated with transmission of infectious diseases, such as hepatitis and HIV.

Dependence. With prolonged opioid analgesic therapy, both tolerance and dependence may develop. Tolerance is the need to increase the dose of opioid analgesics to maintain a certain effect, such as analgesia (in the absence of disease progression or other external factors). Tolerance may develop to both desired and adverse effects of drugs and may vary 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 precipitated by drugs with opioid receptor antagonist activity (e.g., naloxone, nalmefene), opioid receptor agonist-antagonists (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Clinically significant physical dependence may only manifest after several days or even weeks of continuous opioid analgesic use.

Abrupt discontinuation of nalbuphine hydrochloride is not recommended (see section "Method of administration and dosage"). If a physically dependent patient abruptly stops using Nalbuphine, withdrawal syndrome may occur. Some or all of the following symptoms may characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, 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.

Discontinuation of the drug. The use of Nalbuphine injection solution, a mixed opioid analgesic of the opioid receptor agonist-antagonist class, in patients taking an analgesic that is a full opioid receptor agonist may result in reduced analgesic effect and/or precipitate withdrawal symptoms. Concomitant use of Nalbuphine with a full opioid receptor agonist analgesic should be avoided.

When discontinuing Nalbuphine in physically dependent patients, the dose should be gradually reduced (see section "Method of administration and dosage"). Such patients should not abruptly stop using this medicinal product.

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. Pregnant women taking opioids should not abruptly discontinue medication, as this may cause pregnancy complications such as miscarriage or stillbirth. Dose reduction should be gradual and under medical supervision to avoid serious adverse effects on the fetus.

In reproductive animal studies, nalbuphine reduced survival and body weight of offspring when administered to female 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 before mating and throughout pregnancy and lactation. No developmental defects were observed in rats or rabbits when the drug was administered at 6.1 and 3.9 times the maximum recommended human doses, respectively (see Animal study data).

The estimated background risk of serious congenital malformations and miscarriage for this population is unknown. All pregnancies carry a background risk of congenital defects, miscarriage, or other adverse outcomes.

Adverse reactions in the fetus/newborn. Cases of severe fetal bradycardia have been reported with the use of nalbuphine hydrochloride during labor. Naloxone may neutralize these effects. Although data on fetal bradycardia at earlier stages of pregnancy are lacking, its occurrence is possible.

Use during labor. Nalbuphine crosses the placental barrier in significant amounts and rapidly, with fetal-to-maternal blood concentration ratios ranging from 1:0.37 to 1:6. Adverse effects on the fetus and newborn reported after administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. Some of these effects were life-threatening. Administration of naloxone to the mother during labor has normalized these drug effects in some cases. Severe and prolonged fetal bradycardia has been reported. Cases of irreversible neurological damage associated with fetal bradycardia have been documented. Sinusoidal fetal heart rate patterns associated with nalbuphine use have also been reported. Nalbuphine should be used during labor only when clearly indicated and only when the expected benefit to the mother outweighs the potential risk to the child. If nalbuphine is used in mothers, newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Opioid analgesics cross the placental barrier and may cause respiratory depression and psychophysiological effects in newborns. An opioid receptor antagonist, such as naloxone, should be available to counteract opioid-induced respiratory depression in newborns. The use of Nalbuphine injection solution in pregnant women during or immediately before labor is not recommended when other analgesic methods are more appropriate. Opioid analgesics, including Nalbuphine, may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be counteracted by increased cervical dilation, which may shorten labor duration. Newborns exposed to opioid analgesics during labor should be monitored for signs of profound sedation and respiratory depression.

Lactation period. Since opioids can cross the placental barrier and are excreted in breast milk, Nalbuphine injection solution is contraindicated in breastfeeding women and not recommended for use during weaning and labor unless, in the physician's opinion, the potential benefit outweighs the risks. Life-threatening respiratory depression may occur in the infant if the mother is administered opioids. Naloxone must be readily available. Infants whose mothers take nalbuphine during breastfeeding should be monitored for excessive sedative effects and respiratory depression.

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

Reproductive function. Long-term use of opioids may cause decreased sex hormone levels, with symptoms such as low libido, erectile dysfunction, or infertility.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Nalbuphine may affect mental or physical abilities required for performing potentially hazardous activities, such as driving or operating machinery. Abstaining from driving or operating dangerous machinery is necessary.

Patient monitoring should continue until all adverse effects of nalbuphine hydrochloride that may affect the ability to drive or operate potentially hazardous machinery have completely subsided.

Administration and Dosage

The medicinal product Nalbuphine, as an adjunct in the induction of general anesthesia, should be administered by specialists trained in intravenous administration of anesthetic agents and management of respiratory side effects associated with potent opioid analgesics.

Naloxone, resuscitation equipment, intubation instruments, and oxygen must be readily available.

The dosage regimen must be individualized for each patient based on the severity of pain, patient response to treatment, prior analgesic treatment experience, and risk factors for dependence, abuse, and misuse (see section "Special Precautions").

Close monitoring for respiratory depression is essential, particularly during the first 24–72 hours after initiation of therapy and following any dose increase of Nalbuphine injection solution. Dosage adjustments must be made appropriately (see section "Special Precautions").

Parenteral preparations should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Dosage is weight-based. Exercise caution to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may result in accidental overdose (see dosing Table 1).

Initial Dose

The recommended dose for adults is 10–20 mg of nalbuphine hydrochloride for patients with a body weight of 70 kg, equivalent to 0.1–0.3 mg/kg body weight. The drug may be administered subcutaneously, intramuscularly, or intravenously. If necessary, the dose may be repeated at intervals of 3–6 hours. The dose should be adjusted according to the intensity of pain, the patient's physical condition, and concomitant medications (see section "Special Precautions"). For patients without prior tolerance to the drug, the maximum recommended single dose is 20 mg. This dose may be repeated every 3–6 hours as needed, with a maximum daily dose of 160 mg. Dosing should be tailored to the intensity of pain and the patient's physical condition.

Table 1: Dosage Table for Adult Patients:

Dose per administration	Maximum single dose	Maximum volume per administration	Maximum daily dose	Maximum daily volume
0.1 – 0.3 mg/kg	20 mg	2 ml*	160 mg	16 ml*

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

The use of Nalbuphine injection solution as an adjunct in balanced anesthesia requires higher doses than those recommended for analgesia. Induction doses of nalbuphine hydrochloride range from 0.3 mg/kg to 3 mg/kg administered intravenously over 10–15 minutes, with maintenance doses of 0.25 mg/kg to 0.5 mg/kg given as separate intravenous injections. Administration of Nalbuphine may be associated with respiratory depression, which can be reversed by the opioid receptor antagonist naloxone hydrochloride.

Gradual dose escalation and maintenance therapy

In each individual case, the dose of Nalbuphine should be gradually increased to the dose providing adequate analgesia while minimizing adverse reactions. Continuous monitoring of patients receiving nalbuphine hydrochloride is recommended to assess maintenance of analgesic effect, relative frequency of adverse reactions, and to monitor for dependence, abuse, or misuse of the drug (see section "Special precautions"). Frequent communication between the prescribing physician, other members of the healthcare team, the patient, and caregiver/family during periods of changing analgesic requirements, including initial dose titration, is essential.

If pain intensity increases after dose stabilization, the source of increased pain should be identified before increasing the dose of nalbuphine hydrochloride. In the presence of unacceptable adverse reactions related to opioid analgesics, dose reduction should be considered. Dose adjustments should be made to achieve an appropriate balance between analgesia and opioid-induced adverse reactions.

Discontinuation of Nalbuphine. In patients who have been regularly taking Nalbuphine and who may have developed physical dependence, if the drug 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 syndrome. If withdrawal signs or symptoms occur, the dose should be increased to the previous level and tapering should proceed more slowly by increasing the interval between dose reductions, reducing the percentage of dose reduction, or using both approaches. Nalbuphine should not be abruptly discontinued in patients with physical dependence (see section "Special precautions").

Children.

Safety and efficacy of the drug in children under 18 years of age have not been established.

Overdose.

Clinical signs. Acute overdose with Nalbuphine injection solution may manifest as respiratory depression or dysphoria. Acute overdose with Nalbuphine, as with other opioid analgesics or CNS depressants, may present with respiratory depression, drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pinpoint pupils, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and fatal outcome. In cases of hypoxia due to overdose, marked mydriasis rather than miosis may be observed.

Treatment of overdose. In case of overdose, the primary step is to restore and protect airway patency and, if necessary, provide assisted or controlled ventilation. Other supportive measures (including oxygen and vasopressors) should be used in managing circulatory shock and pulmonary edema. Cardiac arrest or arrhythmia will require more advanced life support techniques.

Opioid receptor antagonists naloxone or nalmefone are specific antidotes for respiratory depression caused by opioid analgesic overdose. Opioid receptor antagonists should be used to treat clinically significant respiratory depression or circulatory insufficiency resulting from overdose with Nalbuphine injection solution. Opioid receptor antagonists should not be administered in the absence of clinically significant respiratory depression or circulatory insufficiency caused by overdose of Nalbuphine.

Since the duration of reversal of opioid analgesic effects is expected to be shorter than the duration of nalbuphine action, the patient must remain under close observation until spontaneous respiration is fully restored. If the response to the opioid receptor antagonist is suboptimal and of short duration, additional doses of the antagonist should be administered.

In a patient physically dependent on opioid analgesics, administration of a usual recommended dose of antagonist may precipitate acute withdrawal syndrome. The severity of withdrawal symptoms depends on the degree of physical dependence and the dose of antagonist administered. If treatment of serious respiratory depression in a physically dependent patient is required, administration of the antagonist should be done cautiously, starting with a lower dose than the usual dose of antagonist and gradually increasing it.

Adverse Reactions.

Sedative effect. Sedation is a common adverse effect of opioid analgesics, particularly in individuals who have not previously used opioids. The sedative effect may also occur partly because patients usually recover 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 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 it becomes evident that pain is poorly controlled. Dizziness and unsteadiness may be caused by postural hypotension, especially in elderly or debilitated patients. These symptoms may be reduced if the patient lies down.

Nausea and vomiting. Nausea is a common adverse effect at the beginning of opioid analgesic therapy and is thought to result from activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus, 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 causes such as constipation, intestinal obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of the celiac plexus, and concomitant use of drugs with emetogenic properties. Persistent nausea that does not improve with dose reduction may be caused by 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 warn patients about this and establish an appropriate bowel management regimen at the beginning 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 involving 1066 patients treated with nalbuphine hydrochloride, the most common adverse reaction was sedation, observed in 381 patients (36%).

Less frequent reactions include: increased sweating/sticky sweat – 99 patients (9%), nausea/vomiting – 66 patients (6%), dizziness/vertigo – 58 patients (5%), dry mouth – 44 patients (4%), headache – 27 patients (2%).

Other adverse reactions (frequency ≤ 1%) include:

CNS: restlessness, depression, anxiety, crying, euphoria, sensation of swaying, hostility, unusual dreams, confusion, loss of consciousness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, feelings of unreality. Psychotomimetic effects such as feelings of unreality, depersonalization, amnesia, dysphoria, and hallucinations occur less frequently than with pentazocine.

Cardiovascular system: hypertension, hypotension, bradycardia, tachycardia.

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

Respiratory system: depression, dyspnea, asthma.

Skin: itching, burning, urticaria.

Other: speech difficulties, imperative urges to urinate, blurred vision, flushing, and sensation of warmth.

Allergic reactions: anaphylactic/anaphylactoid reactions and other serious hypersensitivity reactions have been reported following nalbuphine administration, which may require immediate supportive medical treatment.

Such 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 reported allergic-type reactions include stridor, bronchospasm, wheezing, edema, rash, itching, nausea, vomiting, diaphoresis, weakness, and tremor.

Post-marketing experience

Adverse reactions observed during post-marketing use of nalbuphine include: abdominal pain, pyrexia, decreased or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, agitation, seizures, injection site reactions such as pain, swelling, redness, burning, and sensation of heat. A fatal case due to severe allergic reaction to nalbuphine hydrochloride has been reported. Fetal death has been reported following administration of nalbuphine hydrochloride to women during labor.

Since reports were voluntarily submitted from an undefined number of patients, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Androgen deficiency. Chronic use of opioids 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 unknown, as current studies have not adequately controlled for various medical, physical, lifestyle, and psychological stress factors that may influence gonadal hormone levels. Patients with symptoms of androgen deficiency should undergo laboratory evaluation.

Serotonin syndrome. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioid analgesics with serotonergic agents.

Adrenal insufficiency. Cases of adrenal insufficiency have been reported with opioid use, with increased frequency after administration of the drug for more than 1 month.

Carcinogenesis, mutagenesis, and effects on reproductive function

Carcinogenesis. Long-term studies in rats (24 months) and mice (19 months), administered oral nalbuphine hydrochloride at doses up to 200 mg/kg (12 times the maximum recommended human dose) and 200 mg/day (6 times the maximum recommended human dose), respectively, did not demonstrate carcinogenic potential of the drug.

Mutagenesis. Nalbuphine hydrochloride caused an increased frequency of mutations in the mouse lymphoma assay. Nalbuphine hydrochloride did not show mutagenic activity in the Ames test using four bacterial strains, in the Chinese hamster ovary cell assay using HPRT, or in the sister chromatid exchange assay. No clastogenic activity was observed in the micronucleus test in mice or in the cytogenetic study in rat bone marrow.

Effects on reproductive function. Female rats received nalbuphine hydrochloride subcutaneously starting 15 days before mating and continuing until day 20 of lactation at doses of 14 mg/kg/day, 28 mg/kg/day, or 56 mg/kg/day (0.85-, 1.7-, or 3.4-fold the maximum recommended human dose of 160 mg/day, respectively, based on body surface area). Male rats received nalbuphine hydrochloride via gastric intubation at the same doses starting 60 days before mating and throughout the mating period. No adverse effects on reproductive function in male or female rats were observed.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk ratio of the drug. Healthcare professionals should 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. Keep out of reach of children.

Incompatibility. See sections “Interaction with other medicinal products and other forms of interaction” and “Special precautions for use.”

Packaging. 1 ml or 2 ml in an ampoule, 5 ampoules in a blister, 1 or 2 blisters per carton, or 100 ampoules per carton.

Prescription category. Prescription only.

Manufacturer. Private Joint-Stock Company “Lekhym-Kharkiv”.

Manufacturer’s address and location of its business activity.
Ukraine, 61115, Kharkiv region, city of Kharkiv, 36 Severyn Pototskoho Street.