Nalbuphine-darnitsa

INSTRUCTIONS for medical use of the medicinal product Nalbuphine-Darnitsa (Nalbuphine-Darnitsa)

Composition:

active substance: nalbuphine hydrochloride;

1 ml of solution contains nalbuphine hydrochloride 10 mg;

excipients: sodium citrate, citric acid monohydrate, sodium chloride, sodium hydroxide or hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: transparent, colorless or almost colorless liquid.

Pharmacotherapeutic group. Analgesics. Opioids. Morphinan derivatives.

ATC code N02AF02.

Pharmacological Properties.

Pharmacodynamics.

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

Nalbuphine is a potent analgesic, with analgesic potency equivalent to that of morphine on a milligram basis at approximately 30 mg dosing.

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

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

However, nalbuphine exhibits a ceiling effect; thus, increasing the dose above 30 mg does not result in further respiratory depression, provided there are no other centrally acting (CNS) drugs affecting respiration.

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

When administered after or concurrently with mu-opioid receptor agonists (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reduce or reverse the respiratory depression induced by these agents. Nalbuphine may precipitate withdrawal symptoms 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 a reduced responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. However, a ceiling effect for respiratory depression caused by nalbuphine may occur. Although nalbuphine is a mixed agonist/antagonist, naloxone can reverse its respiratory depressant effects.

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

Effects on the gastrointestinal tract and other smooth muscles.

Nalbuphine causes decreased 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 colon 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 pruritus, flushing, conjunctival redness, 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 secretion by the pancreas.

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

The causal role of opioids in the clinical syndrome of hypogonadism is unknown, as various medical, physical, and psychological stress factors and lifestyle influences that may affect gonadal hormone levels have not been adequately controlled in studies conducted to date.

Effects on the immune system.

In vitro models and animal studies have shown that opioids have variable effects on components of the immune system. The clinical significance of these findings is unknown. Overall, opioid effects 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 for 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 within less than 15 minutes after subcutaneous or intramuscular injection. The plasma elimination half-life of nalbuphine is 5 hours. In clinical studies, the duration of analgesic effect ranged from 3 to 6 hours.

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

Clinical characteristics.

Indications.

Nalbuphine-Darnytsia is indicated for the treatment of moderate to severe pain, for which opioid analgesics are justified and for which alternative pain management approaches are ineffective. The medicinal product Nalbuphine-Darnytsia is also recommended as an adjunctive therapy during balanced anesthesia for preoperative and postoperative analgesia, as well as for obstetric analgesia during labor.

Limitations of use

Due to the risk of dependence, abuse, and misuse associated with opioid analgesics, even when used at recommended doses (see section "Special precautions for use"), the use of Nalbuphine-Darnytsia should be restricted to patients for whom alternative treatment options (e.g., non-opioid analgesics):

• are associated with intolerance or suspected intolerance;
• are ineffective or are not expected to provide adequate analgesia.

Contraindications.

• Hypersensitivity to nalbuphine hydrochloride or to any other component of the medicinal product.
• Known or suspected gastrointestinal obstruction, including paralytic ileus.
• Use in acute inflammatory conditions of the abdominal organs (e.g., acute appendicitis or pancreatitis), as it may complicate diagnosis.
• Mild pain that can be managed with other analgesic agents.
• Acute or severe bronchial asthma, chronic respiratory obstruction, or status asthmaticus.
• Severe respiratory depression, hypercapnia, or pulmonary heart disease.
• Acute alcohol intoxication, delirium, or convulsions.
• Marked central nervous system (CNS) depression, increased intracranial pressure, or head injury.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of MAOI therapy.
• Pregnancy or breastfeeding (except for use during labor).

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other CNS depressants.

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

Concomitant use of such agents should be limited to patients for whom alternative therapies are inadequate. 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, metaxalone), and MAOIs (including drugs used to treat psychiatric disorders, as well as others such as linezolid and intravenous methylene blue) may result in serotonin syndrome.

If concomitant use is clinically warranted, patients should be closely observed, particularly at the initiation of therapy and during dose adjustments. If serotonin syndrome is suspected, Nalbuphine-Darnytsia should be discontinued.

Muscle relaxants.

Nalbuphine-Darnytsia 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 doses may need to be increased if necessary.

Anticholinergic agents.

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

When Nalbuphine-Darnytsia is used concomitantly with anticholinergic agents, patients should be closely monitored for symptoms of urinary retention or decreased gastrointestinal motility.

MAO inhibitors.

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

In cases of urgent need for opioid analgesia, it is recommended to initiate treatment with test doses and gradually increase small doses while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Special precautions for use.

Respiratory depression that may be life-threatening.

Serious, life-threatening, or even fatal cases of respiratory depression have been reported with opioid use, even when used as recommended. Respiratory depression, if not promptly recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close monitoring, supportive measures, and administration of opioid receptor antagonists, depending on the patient's clinical status. Carbon dioxide (CO₂) retention due to opioid-induced respiratory depression may exacerbate the sedative effects of these analgesics.

Although potentially life-threatening respiratory depression may occur at any time during treatment with Nalbuphine-Darnitsia, the highest risk occurs at the beginning of therapy or following a dose increase. Patients should be closely monitored for respiratory depression, particularly during the first 24–72 hours after initiation of therapy and after any dose increase of nalbuphine.

Proper dosing and dilution of Nalbuphine-Darnitsia are critical to minimize the risk of respiratory depression. Incorrect dose calculation of nalbuphine when switching a patient from another opioid may result in overdose of the first dose with fatal consequences.

Opioid analgesics may cause respiratory dysfunction during sleep, including central sleep apnea and nocturnal hypoxemia. Opioid analgesics increase the risk of central sleep apnea in a dose-dependent manner. For patients with symptoms of central sleep apnea, consideration should be given to reducing the dose of opioid analgesics using best practices for gradual dose tapering.

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

Concomitant use of Nalbuphine-Darnitsia with benzodiazepines or other central nervous system (CNS) depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, neuroleptics, other opioid analgesics, alcohol) may result in profound sedation, respiratory depression, and death. Due to these risks, the use of nalbuphine hydrochloride in combination with such 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. Patients already receiving an opioid analgesic should be prescribed a lower initial dose of benzodiazepine or another CNS depressant than would be used without an opioid analgesic, with gradual dose titration according to clinical response. When initiating an opioid analgesic in a patient already taking a benzodiazepine or another CNS depressant, a lower initial dose of the opioid analgesic should be prescribed, with gradual dose titration according to clinical response. Patients should be closely monitored for signs of respiratory depression and sedation.

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

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

The use of Nalbuphine-Darnitsia 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 reserve, hypoxia, hypercapnia, or existing respiratory depression, are at increased risk of respiratory center depression, including apnea, even when Nalbuphine-Darnitsia is used at recommended doses.

Elderly, cachectic, or debilitated patients

Life-threatening respiratory depression is most likely in elderly patients, patients with cachexia, 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 Nalbuphine-Darnitsia, and when used concomitantly with other drugs causing respiratory depression. As an alternative, non-opioid analgesics should be considered for such patients.

Adrenal insufficiency.

Cases of adrenal insufficiency have been reported with opioid analgesics, most commonly after use exceeding one month. Symptoms of adrenal insufficiency may include non-specific 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 include physiological replacement doses of corticosteroids. Patients should be gradually weaned off opioid analgesics to allow recovery of adrenal function, and corticosteroid therapy should be continued until full adrenal function recovery. Switching to another opioid analgesic may be attempted, as there have been reports of successful transition to another opioid 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 hypotension.

Nalbuphine-Darnitsia 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, tricyclic antidepressants, hypnotics, sedatives, or general anesthetics. These patients should be monitored for signs of low blood pressure after initiation or dose increase of Nalbuphine-Darnitsia. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, potentially leading to reduced cardiac output and decreased blood pressure. The use of Nalbuphine-Darnitsia should be avoided in patients with circulatory shock.

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

In patients predisposed to intracranial effects of CO₂ retention (e.g., patients with signs of or increased intracranial pressure, or brain tumors), Nalbuphine-Darnitsia may reduce respiratory center activity, and the associated CO₂ retention may further increase intracranial pressure. Such 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 adverse effects that may mask the clinical course in patients with head injury.

The use of Nalbuphine-Darnitsia should be avoided in patients with impaired consciousness or coma.

Risks of use in patients with gastrointestinal disorders.

Nalbuphine-Darnitsia 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.

Nalbuphine-Darnitsia 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).

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

When discontinuing Nalbuphine-Darnitsia in physically dependent patients, the dose should be gradually reduced. Abrupt discontinuation of this medication should be avoided 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 use of the drug at recommended doses as well as in cases of abuse or misuse.

The risk of opioid dependence, abuse, or misuse should be assessed for each patient. The risk is increased in patients with a personal or family history of substance abuse (including prescription drug or alcohol abuse or dependence) and in patients with psychiatric disorders (e.g., major depression). The existence of these risks should not preclude appropriate pain management in individual patients.

Opioids used by patients with substance dependence may be diverted 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 close monitoring for signs of abuse and dependence, as the use of such substances carries a risk of dependence even with appropriate medical use.

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

Medication 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 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 or tests, "losing" prescriptions, forging prescriptions, unwillingness to provide previous medical records or contact information for other healthcare providers. Frequent visits to multiple doctors to obtain additional prescriptions are common among individuals with untreated substance dependence. 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 exhibit tolerance or physical dependence symptoms. Furthermore, opioid analgesic abuse is possible even in the absence of true dependence.

Nalbuphine-Darnitsia, 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 prescribing practices, periodic therapy evaluation, and proper dispensing and storage. Nalbuphine abuse may lead to overdose and death. Risks are increased with concomitant use of nalbuphine with other CNS depressants and alcohol. Parenteral drug abuse is commonly 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 drug effects and may vary for different effects.

Physical dependence leads to 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, nalorphine), opioid receptor agonist-antagonist analgesics (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. If a physically dependent patient abruptly stops using Nalbuphine-Darnitsia, 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 spasms, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or pulse.

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

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.

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

Cardiovascular system.

During evaluation of Nalbuphine-Darnitsia use during anesthesia induction, increased incidence of bradycardia has been reported in patients who did not receive atropine prior to surgery.

Laboratory tests.

Nalbuphine-Darnitsia may interfere with enzymatic methods for detecting opioids, depending on the specificity/sensitivity of the test. For more detailed information, refer to the test kit manufacturer.

Serotonin syndrome.

Opioid analgesics rarely may cause a potentially life-threatening condition due to concomitant use with serotonergic drugs. Immediate medical attention should be sought 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.

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

Interaction with MAO inhibitors.

Concomitant use of Nalbuphine-Darnitsia with any MAO-inhibiting drugs should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

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. Caution should generally be exercised when selecting dosing for elderly patients, usually starting at the lowest end of the dosing range, due to the higher frequency of decreased hepatic, renal, or cardiac function, concomitant disease, or other drug use in this population.

Respiratory depression is the primary risk for elderly patients taking opioids, occurring after administration of large initial doses to opioid-naive patients or when opioids are used concomitantly with other respiratory depressants. Dosing for elderly patients should be increased very slowly.

Nalbuphine is known to be substantially excreted by the kidneys, and the risk of adverse reactions is higher in patients with impaired renal function. Since such patients are more likely to have decreased renal function, caution should be exercised in dose selection and, if possible, renal function should be monitored.

Carcinogenesis.

Long-term studies in rats (24 months) and mice (19 months) with oral administration at doses of 200 µg/mL (12 times the maximum recommended human daily dose, MRHD) and 200 mg/day (6 times the MRHD), respectively, showed no evidence of carcinogenicity.

Mutagenesis.

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

Important information about excipients.

Nalbuphine-Darnitsia 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 result in neonatal withdrawal syndrome. Neonatal opioid withdrawal syndrome may be life-threatening.

The potential risk of major congenital malformations and miscarriage in this population is unknown. There is a potential risk of congenital malformations, miscarriage, or other adverse outcomes at any stage of pregnancy.

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 (MRHD). It also reduced survival and body weight when administered to both male and female rats before mating and during pregnancy and lactation. No developmental defects were observed in rats or rabbits at 6.1 and 3.9 times the MRHD, respectively. The background risk of major congenital malformations and miscarriage in humans is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Adverse effects in fetus/newborn.

Severe fetal bradycardia has been reported with the use of nalbuphine hydrochloride during labor. These effects may be reversed 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 implemented.

Labour and delivery.

Placental transfer of nalbuphine is high, rapid, and variable, with maternal-fetal ratios ranging 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. Cases of persistent neurological damage associated with fetal bradycardia have been reported.

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

Nalbuphine-Darnitsia is not recommended for use in pregnant women during or immediately before labor if alternative analgesic methods are available. Opioid analgesics, including nalbuphine, may prolong labor duration due to their ability to temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by increased cervical dilation rate, which generally 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 result in 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 newborn's drug elimination rate. Neonatal opioid withdrawal syndrome may be life-threatening.

Animal experience.

Pregnant rats were administered subcutaneous nalbuphine hydrochloride 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 MRHD 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 received intravenous nalbuphine hydrochloride 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 MRHD 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 subcutaneous nalbuphine hydrochloride 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 MRHD based on body surface area, respectively). Offspring survival was reduced in the medium- and high-dose groups, and neonatal body weight was dose-dependent. Maternal toxicity was observed in all treatment groups (reduced body weight).

Female rats were administered subcutaneous nalbuphine hydrochloride starting 15 days before mating until day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD of 160 mg/day based on body surface area, respectively). Male rats were dosed orally with equivalent doses of nalbuphine hydrochloride starting 60 days before and during mating. Offspring survival was reduced in the high-dose group, and offspring body weight was reduced in the medium- and high-dose groups.

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 the opioid analgesic or stops breastfeeding.

Fertility.

Female rats were administered subcutaneous nalbuphine hydrochloride starting 15 days before mating until day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD of 160 mg/day based on body surface area, respectively). Male rats were dosed orally with equivalent doses of nalbuphine hydrochloride starting 60 days before and during mating. No adverse effects on male or female fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

Nalbuphine-Darnitsia may impair mental or physical abilities required for potentially hazardous activities such as driving or operating machinery. Patients should refrain from driving or operating dangerous machinery until they are tolerant to nalbuphine and until their reaction to it is known.

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

Method of Administration and Dosage

The medicinal product must be administered only by healthcare professionals who have undergone special training in the use of intravenous anesthetics and in the management of respiratory effects of potent opioids.

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

Dosage for each patient must be individualized, taking into account the severity of pain, patient's 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, especially during the first 24–72 hours after initiation of therapy and after dose increases, with appropriate dosage adjustments.

Method of Administration

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

Before administration, the solution should be visually inspected for the presence of mechanical particles and discoloration.

Dosage

Dosage is based on patient weight. Exercise caution to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose (see dosage Table 1 (adults)). 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, patient's physical condition, and potential interactions with other concomitantly administered medicinal products. For non-tolerant patients, the recommended maximum single dose is 20 mg. The maximum daily dose is 160 mg.

Table 1: Dosage Table for Adult Patients:

Dose administered	Maximum single dose	Maximum volume administered	Maximum daily dose	Maximum daily volume
0.1-0.3 mg/kg	20 mg	2 ml	160 mg	16 ml

When using the medicinal product Nalbuphine-Darnitsia 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 accompanied by respiratory depression, which can be reversed with the opioid antagonist naloxone hydrochloride.

Titration and maintenance of therapy.

Titration of the medicinal product Nalbuphine-Darnitsia is recommended by adjusting the individual dose to achieve adequate analgesic effect with minimal adverse reactions. Patients receiving nalbuphine hydrochloride must be continuously monitored to assess pain intensity and the relative frequency of adverse reactions, as well as to monitor for the development 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 determined before increasing the dose of nalbuphine hydrochloride. If opioid-related adverse reactions occur, dose reduction should be considered. Dose adjustments should be made to achieve an appropriate balance between pain control and opioid-related side effects.

Discontinuation of Nalbuphine-Darnitsia.

In patients who have been regularly taking nalbuphine hydrochloride and may have developed physical dependence, if further therapy with nalbuphine hydrochloride is no longer needed, it is recommended to gradually reduce the dose by 25–50% every 2–4 days, closely monitoring the patient for signs and symptoms of withdrawal. If such signs or symptoms appear, the dose should first be increased back to the previous level, then gradually reduced by increasing the interval between dose reductions, reducing the amount of each dose, or both. Abrupt discontinuation of Nalbuphine-Darnitsia in patients with physical dependence should not be performed (see section "Special precautions").

Children.

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

Overdose.

Symptoms

Acute overdose of nalbuphine alone may manifest as respiratory depression and dysphoria. Acute overdose of nalbuphine combined with other opioids or CNS depressants may present with respiratory depression, drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and fatal outcome. Marked mydriasis, but not miosis, may be observed in cases of hypoxia due to overdose.

Treatment

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

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

Since the duration of action of opioid antagonists is expected to be shorter than that of nalbuphine, the patient must be observed until complete recovery of respiration. If the response to an opioid antagonist is incomplete or short-lived, additional doses of the antagonist should be administered according to the recommended guidelines.

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

Adverse reactions.

Sedative effect.

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

Nausea and vomiting.

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

Constipation.

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

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

Less frequently reported reactions included: increased sweating/sticky skin 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, numbness, tingling, dizziness, headache, muscle rigidity, increased intracranial pressure.

Psychiatric disorders: drug dependence, psychomimetic reactions, neurotic reactions, somnolence, depression, crying, confusion, dysphoria, speech disorder, mood changes, restlessness, agitation (irritability), hallucinations, euphoria, depersonalization.

The incidence of psychotomimetic effects such as depersonalization, delirium, dysphoria, and hallucinations has been shown to be lower than with pentazocine.

The potential for physical and psychological dependence, as well as tolerance during prolonged treatment, is the same as for other morphine derivatives.

Eye disorders: blurred or impaired vision, miosis.

Respiratory, thoracic and mediastinal disorders: respiratory depression, dyspnea, asthma, pulmonary edema.

Cardiac disorders: bradycardia, tachycardia.

Vascular disorders: hypertension or hypotension, orthostatic hypotension, 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: itching, burning, urticaria.

General disorders and administration site conditions: dysarthria, urinary urgency, visual clouding, flushing and erythema, injection site reactions such as pain, swelling, redness, burning, and warmth.

Immune system disorders: anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following nalbuphine administration, which may require immediate supportive treatment. These reactions may include shock, respiratory distress syndrome, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic reactions may be life-threatening. Other allergic-type reactions have been reported, including stridor, bronchospasm, wheezing, 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 and the population size is unknown, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal pain, hyperthermia, lethargy or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and warmth. Fatal outcomes due to severe allergic reactions following nalbuphine administration have been reported. There have also been reports of fetal death following nalbuphine administration to the mother during labor.

Androgen deficiency.

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

Serotonin syndrome.

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

Adrenal insufficiency.

Cases of adrenal insufficiency have been reported with opioid use, more frequently after prolonged use (more than one month).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and/or lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibilities. Should not be mixed in the same syringe with other injectable solutions.

Nalbuphine should not be mixed with nafcillin and ketorolac due to physical incompatibility.

Packaging. 1 ml or 2 ml in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.