Nalbuphine-mikrokhim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NALBUPHINE-MICROKHIM (NALBUPHINE-MICROKHIM)

Composition:

Active substance: nalbuphine;

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

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colourless or pale yellow solution.

Pharmacotherapeutic group.

Analgesics. Opioids. Morphine derivatives. Nalbuphine. ATC code N02AF02.

Pharmacological Properties.

Pharmacodynamics.

Nalbuphine hydrochloride is a kappa-opioid receptor agonist and a mu-opioid receptor antagonist. Nalbuphine hydrochloride is also a potent analgesic. Its analgesic activity is essentially equivalent to that of morphine in milligrams up to a dosage of approximately 30 mg.

The opioid antagonist activity of nalbuphine hydrochloride is 4 times lower than that of nalorphine and 10 times greater than that of pentazocine.

Nalbuphine hydrochloride may produce respiratory depression to the same extent as equianalgesic doses of morphine. However, nalbuphine hydrochloride demonstrates a ceiling effect – increasing the dose above 30 mg does not result in further respiratory depression, provided there is no influence from other central nervous system (CNS) depressant drugs.

Nalbuphine hydrochloride itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered after or concurrently with mu-opioid receptor agonist opioids (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block mu-opioid agonist-induced respiratory depression. Nalbuphine hydrochloride may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine hydrochloride should be used with caution in patients who are regularly receiving mu-agonist opioid analgesics.

Effects on the CNS

Nalbuphine hydrochloride causes respiratory depression by direct action on the respiratory centers in the brainstem. Respiratory depression refers to reduced responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Respiratory depression caused by nalbuphine hydrochloride may exhibit a ceiling effect. Despite nalbuphine hydrochloride being classified as a mixed agonist-antagonist, its respiratory depressant effects can be reversed with the administration of naloxone.

Nalbuphine hydrochloride causes miosis even in complete darkness. Pinpoint pupils are a sign of opioid overdose, but are not pathognomonic (e.g., hemorrhagic or ischemic brainstem lesions may present with similar symptoms). However, in hypoxia caused by overdose, marked mydriasis rather than miosis may be observed.

Effects on the gastrointestinal tract and other smooth muscles

Nalbuphine hydrochloride causes reduced motility due to 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 increased tone may lead to spasm, resulting in constipation. Other opioid-induced effects may include reduced secretion of bile and pancreatic juice, spasm of the sphincter of Oddi, and transient elevation of serum amylase levels.

Effects on the cardiovascular system

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

Opioids cause peripheral vasodilation, which may lead to orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include itching, flushing, conjunctival hyperemia, increased sweating, and/or orthostatic hypotension.

Effects on the endocrine system

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH). They also stimulate the secretion of prolactin, growth hormone (GH), and insulin and glucagon from the pancreas.

Chronic opioid use may affect the hypothalamic-pituitary-gonadal system, leading to androgen deficiency, which may manifest as decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is not fully established, as various medical, physical, psychological stressors, and lifestyle factors that may influence gonadal hormone levels have not been adequately controlled in studies conducted to date.

Effects on the immune system

Opioids have varying effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids are generally considered to be moderately immunosuppressive.

Concentration-effect relationship

The minimum effective analgesic concentration of nalbuphine hydrochloride 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 hydrochloride occurs within 2–3 minutes after intravenous administration and within less than 15 minutes after subcutaneous or intramuscular injection. The plasma half-life of nalbuphine hydrochloride is approximately 5 hours, and in clinical studies, the duration of analgesic effect ranges from 3 to 6 hours.

The primary metabolic pathway for nalbuphine hydrochloride has not been fully established, but it is likely hepatic.

Clinical characteristics.

Indications.

The medicinal product NALBUPHINE-MIKROKHIM is indicated for the treatment of moderate to severe pain requiring opioid analgesics and for which alternative treatment options are inadequate. The drug may also be used as an adjunct in anesthesia, for reduction of pre- and postoperative pain, as well as analgesia during labor and delivery.

Warnings for use

Due to the risks of dependence, abuse, and misuse of opioids, even at recommended doses, nalbuphine hydrochloride should be used in patients for whom alternative treatments (e.g., non-opioid analgesics):

• are not tolerated or cannot be tolerated;
• have not provided or cannot provide adequate analgesia.

Nalbuphine hydrochloride injections should not be used for prolonged periods, except when pain remains severe enough to require an opioid analgesic and alternative treatment options are insufficient.

Contraindications.

The medicinal product is contraindicated in patients with:

• respiratory depression;
• acute or severe bronchial asthma in the absence of appropriate monitoring or resuscitation equipment;
• known or suspected intestinal obstruction, including paralytic ileus;
• hypersensitivity to nalbuphine hydrochloride or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other CNS depressants

Although nalbuphine hydrochloride has opioid antagonist activity, evidence shows that in patients without opioid dependence, it will not antagonize the opioid analgesic administered immediately before, simultaneously with, or immediately after nalbuphine hydrochloride. Therefore, due to additive pharmacological effects, concomitant use of other opioid analgesics, benzodiazepines, or other CNS depressants (alcohol, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, anesthetics, antipsychotics, and other opioids) may increase the risk of respiratory depression, profound sedation, coma, and death.

These drugs may be used concomitantly in patients for whom alternative treatment options are inadequate. The lowest effective doses should be used for the shortest possible duration. Patients must be closely monitored for signs of respiratory depression and sedation.

Serotonergic drugs

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

Patients should be informed that opioids, when used concomitantly with serotonergic drugs, may cause serotonin syndrome, a rare but potentially life-threatening condition. Patients must be warned about the symptoms of serotonin syndrome and the importance of seeking immediate medical attention if these symptoms occur. Patients who are taking or plan to take serotonergic drugs should inform their physician.

If concomitant use is justified, continuous monitoring of patients—especially at the start of therapy—is required, along with dose adjustments. If serotonin syndrome is suspected, nalbuphine hydrochloride should be discontinued.

Muscle relaxants

Nalbuphine hydrochloride may enhance the neuromuscular blockade of muscle relaxants and increase the degree of respiratory depression. Patients should be monitored for signs of respiratory depression, and the dosage of nalbuphine hydrochloride and/or the muscle relaxant should be reduced if necessary.

Diuretics

Opioids 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 the diuretic dose may need to be increased if necessary.

Anticholinergic drugs

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

When nalbuphine hydrochloride is used concomitantly with anticholinergic drugs, patients should be monitored for signs of urinary retention or decreased gastrointestinal motility.

MAO inhibitors

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

The use of nalbuphine hydrochloride is not recommended in patients receiving MAO inhibitors, as well as within 14 days after discontinuation of such therapy. In case of emergency opioid use, dose selection with frequent titration of small doses should be performed to manage pain, with careful monitoring of blood pressure and signs and symptoms of CNS effects and respiratory depression.

Patients must be informed to avoid taking nalbuphine hydrochloride while receiving any drugs that inhibit monoamine oxidase.

Special precautions for use.

Respiratory depression that may be life-threatening

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including when used according to recommended guidelines. Failure to diagnose and treat respiratory depression may lead to respiratory arrest and death. Management of respiratory depression may include careful monitoring, supportive measures, and administration of opioid antagonists, depending on the patient's condition. Retention of carbon dioxide (CO2) due to opioid-induced respiratory depression may exacerbate the sedative effects of opioids.

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

To reduce the risk of respiratory depression, appropriate dosage selection and titration of nalbuphine hydrochloride are essential (see section "Dosage and administration"). Higher doses of nalbuphine hydrochloride when switching patients from another opioid may result in fatal overdose upon administration of the first dose.

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. The use of opioids increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the opioid dose (see section "Dosage and administration").

Concomitant use with benzodiazepines and other CNS depressants

Profound sedation, respiratory depression, coma, and death may occur when nalbuphine hydrochloride is used concomitantly with benzodiazepines or other central nervous system (CNS) depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, anesthetics, antipsychotics, other opioids). Concomitant use of these agents should be reserved for patients for whom alternative treatment options are inadequate.

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

If benzodiazepines or other CNS depressants must be prescribed alongside an opioid analgesic, the lowest effective dose should be used for the shortest duration possible. For patients already receiving an opioid analgesic, a lower initial dose of the benzodiazepine or other CNS depressant should be prescribed compared to doses used without opioid therapy, with gradual dose titration based on clinical response. If an opioid analgesic is prescribed for a patient already taking a benzodiazepine or another CNS depressant, a lower initial dose of the opioid analgesic should be prescribed, with gradual titration based on clinical response. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation.

When nalbuphine hydrochloride is used concomitantly with benzodiazepines or other CNS depressants (including alcohol and illicit drugs), both patients and caregivers should be counseled about the risk of respiratory depression and sedation.

Patients should not drive or operate heavy machinery until the effects of concomitant use of benzodiazepines or other CNS depressants with nalbuphine hydrochloride have resolved. Patients should be assessed for risk of substance abuse, including opioid misuse, and warned about the risks of overdose and death associated with the use of CNS depressants, including alcohol and illicit drugs.

Opioid-induced hyperalgesia and allodynia

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically increases pain sensitivity or causes heightened pain perception. This condition differs from tolerance, which requires increasing opioid doses to maintain analgesic effect. Symptoms of OIH include (but are not limited to): increased pain levels with higher opioid doses, reduced pain with lower opioid doses, or pain from stimuli that normally do not cause pain (allodynia). These symptoms suggest OIH only if there is no evidence of disease progression, opioid tolerance, opioid withdrawal, or aberrant drug-seeking behavior.

Cases of OIH have been reported with both short-term and long-term use of opioid analgesics. Although the mechanism of OIH is not fully understood, several biochemical pathways are involved. Medical literature supports a biological link between opioid analgesic use and OIH and allodynia. If OIH is suspected, consideration should be given to reducing the opioid analgesic dose or switching to another opioid analgesic.

Patients and caregivers should be informed about the need to consult a physician before increasing opioid doses. Patients should also be advised to seek medical help if they experience symptoms such as hyperalgesia, including increased pain, heightened pain sensitivity, or new pain.

Respiratory depression in patients with chronic lung disease, elderly, cachectic, or debilitated patients, which may be life-threatening

The use of nalbuphine hydrochloride 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 substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, are at increased risk of respiratory depression, including apnea, even at recommended doses of nalbuphine hydrochloride.

Elderly, cachectic, or debilitated patients

Life-threatening respiratory depression is more likely in elderly, cachectic, or debilitated patients due to altered pharmacokinetic parameters or clearance compared to younger, healthier patients. These patients should be closely monitored, especially at the beginning of nalbuphine hydrochloride therapy and when the drug is used concomitantly with other respiratory depressants. Alternative use of non-opioid analgesics may be considered in these patients.

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more commonly with use exceeding one month. Adrenal insufficiency may present with nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, diagnosis should be confirmed promptly. Diagnosed adrenal insufficiency requires treatment with physiological replacement doses of corticosteroids. Opioid use should be discontinued until adrenal function recovers. Reinitiation of other opioids may be possible, as some cases have reported use of other opioids without recurrence of adrenal insufficiency. Available data do not identify any specific opioids more likely to be associated with adrenal insufficiency.

Severe hypotension

Nalbuphine hydrochloride may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Patients whose blood pressure maintenance is compromised by reduced blood volume or concomitant administration of CNS depressants (e.g., phenothiazines or general anesthetics) are at increased risk of severe hypotension. Patients should be monitored for signs of hypotension after initiation and dose increases of nalbuphine hydrochloride. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, leading to reduced cardiac output and blood pressure. Nalbuphine hydrochloride should be avoided in patients with circulatory shock.

Use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with signs of increased intracranial pressure or brain tumors), nalbuphine hydrochloride may reduce respiratory center activity; CO2 retention may further increase intracranial pressure. Such patients should be monitored for signs of sedation and respiratory depression, especially at the beginning of nalbuphine hydrochloride therapy.

Opioids may also mask clinical signs in patients with head injuries. Nalbuphine hydrochloride should be avoided in patients with impaired consciousness or coma.

Use in patients with gastrointestinal disorders

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

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

Patients should be informed about the possibility of developing severe constipation during nalbuphine use and when to seek medical help.

Increased risk of seizures in patients with epilepsy

Nalbuphine hydrochloride may increase the frequency of seizures in patients with epilepsy and may increase the risk of seizures in other clinical situations associated with epilepsy. Patients with a history of epilepsy should be monitored for seizure control during nalbuphine hydrochloride use.

Withdrawal syndrome

The use of nalbuphine hydrochloride, a mixed opioid receptor agonist/antagonist, in patients receiving opioid agonist analgesics may reduce analgesic efficacy and/or precipitate withdrawal symptoms. Concomitant use of nalbuphine hydrochloride with opioid agonist analgesics should be avoided.

Discontinuation of nalbuphine hydrochloride in dependent patients should be done gradually by tapering the dose (see section "Dosage and administration"). Abrupt discontinuation of nalbuphine hydrochloride is not recommended in such patients.

Dependence, abuse, and misuse

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

Although the risk of dependence in any individual is unknown, it may occur in patients using nalbuphine hydrochloride. Dependence may develop with use at recommended doses as well as with abuse or misuse.

Each patient should be assessed for the risk of opioid dependence, abuse, or misuse. Risk is increased in patients with personal or family history of substance abuse (including prescription drug abuse, drug or alcohol dependence) or psychiatric disorders (e.g., major depression). The possibility of these risks should not prevent appropriate pain management in individual patients. Opioids may be prescribed to patients at increased risk of dependence and misuse, but their use requires careful monitoring for signs of dependence, abuse, and misuse.

Opioids used by dependent patients or individuals with substance use disorder may be diverted for illicit purposes. These risks should be considered when prescribing nalbuphine hydrochloride. Risk mitigation strategies include prescribing the lowest effective dose.

Renal and hepatic impairment

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

Myocardial infarction

Like all potent analgesics, nalbuphine hydrochloride should be used cautiously in patients with myocardial infarction and associated nausea or vomiting.

Cardiovascular system

A high incidence of bradycardia has been observed in patients not receiving atropine prior to surgery during anesthesia with nalbuphine hydrochloride.

Laboratory tests

Nalbuphine hydrochloride may interfere with enzymatic methods for opioid detection, depending on the specificity/sensitivity of the test. Consultation with the test manufacturer is recommended for appropriate information.

Elderly patients

Elderly patients (aged 65 years and older) may have increased sensitivity to nalbuphine hydrochloride. Caution should be exercised in dosage selection. Therapy is generally initiated with the lowest effective dose due to frequent reduction in hepatic, renal, or cardiac function, concomitant diseases, or other concomitant therapies.

The primary risk for elderly patients using opioids is respiratory depression, which may result from high initial doses in opioid-naïve patients or from concomitant use of other respiratory depressants. For elderly patients, nalbuphine hydrochloride therapy should be initiated at the lowest dose with gradual titration to achieve therapeutic effect.

Nalbuphine hydrochloride is substantially eliminated by the kidneys, and the risk of adverse reactions may be greater in patients with impaired renal function. Since elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection with mandatory monitoring of renal function.

Carcinogenesis

In 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, no evidence of carcinogenicity was observed.

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 Chinese hamster ovary HGPRT assay, or in the sister chromatid exchange assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenetic analysis of rat bone marrow.

Use during pregnancy or breastfeeding.

Pregnancy

Prolonged use of opioid analgesics during pregnancy may result in neonatal withdrawal syndrome. Available data on the use of nalbuphine hydrochloride in pregnant women are insufficient to inform about associated risks of major congenital malformations and miscarriage.

In reproductive animal studies, nalbuphine hydrochloride reduced survival and body weight of offspring when pregnant rats were treated during late gestation and throughout lactation at doses 1.7 times the MRHD, as well as when male and female rats were treated before mating or throughout gestation and lactation. No developmental abnormalities were observed in rats or rabbits at doses 6.1 and 3.9 times the MRHD, respectively.

The background risk of major congenital malformations and miscarriage for the indicated population is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general U.S. 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 nalbuphine hydrochloride use 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 clearly needed, when potential benefit outweighs the existing risks to the fetus, and with appropriate measures such as fetal monitoring to detect and address any potential adverse effects.

Labour and delivery

Placental transfer of nalbuphine hydrochloride is high, rapid, and variable, with maternal-to-fetal ratios ranging from 1:0.37 to 1:6. Fetal and neonatal adverse outcomes reported after maternal administration of nalbuphine hydrochloride during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotension. Some of these events were life-threatening. Administration of naloxone to the mother during labor has in some cases reversed these effects. Severe and prolonged fetal bradycardia has been reported. Persistent neurological injury associated with fetal bradycardia has been observed. Sinusoidal fetal heart rate patterns have also been reported with nalbuphine hydrochloride use. Nalbuphine hydrochloride should be used during labor only if clearly needed and when potential benefit outweighs risks to the child. If nalbuphine hydrochloride is used, newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Opioids cross the placenta and may cause respiratory depression and psychophysiological effects in newborns. To reverse opioid-induced respiratory depression in the newborn, an opioid antagonist (naloxone) must be administered. If alternative analgesic methods are available, nalbuphine hydrochloride is not recommended for use in pregnant women during or immediately before labor. Opioid analgesics, including nalbuphine hydrochloride, may prolong labor duration, as they can 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, leading to shortened labor duration. Newborns exposed to opioid analgesics during labor should be monitored for signs of excessive sedation and respiratory depression.

Animal experience

Pregnant rats were administered nalbuphine hydrochloride subcutaneously from day 6 to day 15 of gestation 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 gestation 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 nalbuphine hydrochloride subcutaneously from day 15 of gestation 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 groups receiving medium and high doses, and neonatal body weight was dose-dependent. Maternal toxicity was observed in all treatment groups (reduced body weight).

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

Lactation period

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Nalbuphine hydrochloride may impair mental or physical abilities required for potentially hazardous activities such as driving a car or operating dangerous machinery. Patients should refrain from driving and operating dangerous machinery when hypersensitive to nalbuphine hydrochloride or when an adequate response to the drug has not been established.

Patients should be monitored until full recovery after nalbuphine hydrochloride administration, which may affect driving or operation of other potentially hazardous machinery.

Administration and Dosage

The medicinal product NALBUPHINE-MICROCHEM should be administered as an adjunct to general anesthesia only by individuals specially trained in the use of intravenous anesthetics and management of respiratory effects associated with the use of potent opioids.

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

Use the lowest effective dose for the shortest duration consistent with individual patient needs. The risk of overdose increases with increasing doses of opioids. Therefore, dose escalation of nalbuphine hydrochloride is recommended only for patients in whom lower doses are insufficiently effective and for whom the expected benefits from higher opioid doses clearly outweigh the substantial risks.

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

The risk of respiratory depression must be considered, and patients should be closely monitored for respiratory depression, especially at the beginning of therapy and after dose increases.

Dosing

Dosing is based on patient weight. 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 (adults)).

Adults. 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 maximum single dose for adults should not exceed 20 mg.

The dose may be repeated every 3–6 hours as needed, with a maximum daily dose of 160 mg. Dosing should be adjusted according to the intensity of pain, the patient's physical condition, and potential interactions with other concurrently administered medicinal products.

The solution is administered subcutaneously, intramuscularly, or intravenously. Use the smallest dose necessary to achieve adequate analgesia. The recommended maximum single dose for opioid-naïve patients is 20 mg.

Table 1: Dosage table for adult patients:

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

When using the medicinal product NALBUPHINE-MICROCHEM 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.

Titrating and Maintaining Therapy

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

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

Discontinuation of NALBUPHINE-MICROCHEM

In patients who have been regularly receiving nalbuphine hydrochloride and may be physically dependent, discontinuation of therapy should be done gradually by reducing the dose by 25–50% every 2–4 days, with careful monitoring for signs and symptoms of withdrawal. If withdrawal symptoms occur, the dose should initially 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-MICROCHEM should not be performed in physically dependent patients (see section "Special precautions").

Children

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

Overdose

Symptoms

Acute overdose of nalbuphine hydrochloride alone may present with respiratory depression and dysphoria. Acute overdose of nalbuphine hydrochloride taken concomitantly with other opioids or CNS depressants may present with respiratory depression, drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, miosis, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. In overdose cases with hypoxia, marked mydriasis may be observed.

Treatment

In cases of overdose, priorities include restoration of airway patency, with assisted or controlled ventilation if necessary. Other supportive measures (including oxygen and vasopressors) may be used in treating circulatory shock and pulmonary edema. In cases of cardiac arrest or arrhythmias, advanced life support techniques are required.

Opioid antagonists such as naloxone or nalme­fene are specific antidotes for opioid-induced respiratory depression. In cases of clinically significant respiratory or circulatory depression caused by nalbuphine hydrochloride overdose, administration of an opioid antagonist is necessary. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression caused by nalbuphine hydrochloride overdose.

Since the duration of action of opioid antagonists is expected to be shorter than that of nalbuphine hydrochloride, patients must be carefully monitored until complete recovery of respiration. If the response to an opioid antagonist is suboptimal or transient, additional doses of the antagonist should be administered according to the instructions provided in the product’s labeling.

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

Adverse Reactions

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

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

Other adverse reactions reported (incidence of 1% or less):

Nervous system disorders: Euphoria, hostility, unusual dreams, weakness, heaviness sensation, numbness, tingling, dizziness, headache, muscle rigidity, increased intracranial pressure, loss of consciousness.

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

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

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

Hepatobiliary system 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.

Cardiovascular disorders: Hypertension, hypotension, bradycardia, tachycardia, orthostatic hypotension, palpitations.

Gastrointestinal disorders: Abdominal cramps, dyspepsia, bitter taste in mouth, nausea, vomiting, dry mouth, constipation.

Eye disorders: Blurred or disturbed vision, miosis.

Respiratory, thoracic and mediastinal disorders: Respiratory depression, dyspnea, asthma.

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

General disorders: Dysarthria, frequent urination, visual clouding, hyperemia and sensation of warmth, hypothermia, local pain, swelling, redness, burning, flushing, increased sweating. When used in obstetric practice – respiratory depression in newborns, which may be prolonged or delayed in onset.

Hypersensitivity reactions: Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following administration of nalbuphine hydrochloride, which may require immediate supportive medical treatment. These reactions may include shock, respiratory failure, apnea, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic reactions may be life-threatening. Other reports of allergic-type reactions include stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting, increased sweating, weakness, and tremors.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of nalbuphine hydrochloride. Because these reactions are reported voluntarily from an unknown population size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal pain, hyperthermia, depressed or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and sensation of warmth. Fatal cases due to severe allergic reactions have been reported with nalbuphine hydrochloride. Fetal death has been reported when nalbuphine hydrochloride was administered to mothers during labor and delivery.

Serotonin Syndrome

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

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more commonly after use exceeding one month.

Hyperalgesia and Allodynia

Cases of hyperalgesia and allodynia have been reported during opioid therapy of any duration.

Hypoglycemia

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

Drug Abuse and Dependence

Abuse

The medicinal product NALBUPHINE-MICROKHIM, solution for injection, contains nalbuphine, a substance that may be misused, and abuse of which may lead to dependence.

Abuse is the intentional use of a therapeutic agent by an individual in a manner different from that prescribed by a physician or use of a drug not prescribed to the individual. Abuse is intentional non-therapeutic use of the drug, even a single use, to achieve desired psychological or physiological effects.

Drug dependence is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing use despite harmful consequences, prioritizing drug use over other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of nalbuphine hydrochloride increases the risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concomitant abuse of nalbuphine with alcohol and other CNS depressants. Abuse and dependence on opioids in some individuals may occur without tolerance or physical dependence symptoms. Furthermore, opioid abuse may occur in the absence of dependence.

"Drug-seeking" behavior is very common among individuals with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate evaluation, testing, or referral, repeated "lost" prescriptions, prescription forgery, and unwillingness to provide prior medical records or contact information for other healthcare providers. "Doctor shopping" (visiting multiple physicians to obtain additional prescriptions) is a common practice among drug abusers and individuals with substance use disorders. Concern about achieving adequate pain relief may be appropriate behavior in a patient with inadequate pain control.

Appropriate patient assessment, proper prescribing practices, periodic re-evaluation of therapy, and proper dosing and storage are appropriate measures that can help limit opioid abuse.

Risks Specific to Injection Abuse of Nalbuphine Hydrochloride

Injection abuse of nalbuphine hydrochloride poses a risk of overdose and death. The risk is increased when nalbuphine hydrochloride for injection is used concomitantly with alcohol and/or other CNS depressants. Additionally, transmission of infectious diseases such as hepatitis and HIV is commonly associated with parenteral drug abuse.

Dependence

Both tolerance and physical dependence may develop during opioid therapy. Tolerance is a physiological state characterized by reduced responsiveness to a drug after repeated administration (i.e., a higher dose is required to achieve the same effect previously obtained with a lower dose).

Physical dependence is a state of physiological adaptation following repeated opioid use, manifested by signs and symptoms of withdrawal upon abrupt discontinuation or significant dose reduction.

Withdrawal may be precipitated by administration of opioid antagonists (e.g., naloxone), mixed agonist/antagonists (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine).

Physical dependence may develop to a clinically significant degree after several days to weeks of continuous use.

Nalbuphine hydrochloride injections should not be abruptly discontinued in physically dependent patients. Sudden cessation of nalbuphine injections in physically dependent patients may result in withdrawal syndrome, typically characterized by restlessness, lacrimation, rhinorrhea, sweating, chills, myalgia, and mydriasis. Other signs and symptoms may develop, including irritability, anxiety, back pain, joint pain, weakness, abdominal pain, seizures, insomnia, nausea, anorexia, vomiting, diarrhea, elevated blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory disturbances and withdrawal signs.

Shelf Life

2 years.

Storage Conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

1 ml in ampoules, 5 ampoules in a tray, 2 trays with the instruction for medical use in a cardboard box.

Or 2 ml in ampoules, 5 ampoules in a tray with the instruction for medical use in a cardboard box.

Prescription Status

Prescription only.

Manufacturer

MICROKHIM PHARMACEUTICAL R&D COMPANY LTD.

Manufacturer's Address

24-V Promyslova St., Severodonetsk, Luhansk Oblast, 93400, Ukraine.

Marketing Authorization Holder

MICROKHIM PHARMACEUTICAL R&D COMPANY LTD.

Address of Marketing Authorization Holder

5 Budyndustrії St., Kyiv, 01013, Ukraine.

Adverse events related to the use of this medicinal product should be reported via phone +38 (050) 309-83-54 (24/7).

INSTRUCTION

for medical use of the medicinal product

NALBUPHINE-MICROKHIM

(NALBUPHINE-MICROKHIM)

Composition:

Active ingredient: nalbuphine;

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

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or pale yellow solution.

Pharmacotherapeutic group.

Analgesics. Opioids. Morphinan derivatives. Nalbuphine. ATC code N02AF02.

Pharmacological Properties.

Pharmacodynamics.

Nalbuphine hydrochloride is a kappa-opioid receptor agonist and a mu-opioid receptor antagonist. Nalbuphine hydrochloride is also a potent analgesic. Its analgesic activity is essentially equivalent to that of morphine on a milligram basis up to doses of approximately 30 mg.

The opioid antagonist activity of nalbuphine hydrochloride is 4 times lower than that of nalorphine and 10 times greater than that of pentazocine.

Nalbuphine hydrochloride may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling effect—increasing the dose above 30 mg does not result in further respiratory depression, provided there is no concomitant use of other central nervous system (CNS) depressants.

Nalbuphine hydrochloride itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered after or concurrently with mu-opioid receptor agonist opioids (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block mu-opioid agonist-induced respiratory depression. Nalbuphine hydrochloride may precipitate withdrawal symptoms in patients dependent on opioid drugs. Nalbuphine hydrochloride should be used with caution in patients who are regularly receiving mu-opioid agonist analgesics.

Effects on the CNS

Nalbuphine hydrochloride causes respiratory depression by direct action on respiratory centers in the brainstem. Respiratory depression refers to reduced responsiveness of brainstem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Respiratory depression caused by nalbuphine hydrochloride may exhibit a ceiling effect. Despite nalbuphine hydrochloride being classified as an agonist-antagonist, its respiratory depressant effects can be reversed with naloxone.

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

Effects on the gastrointestinal tract and other smooth muscles

Nalbuphine hydrochloride causes decreased gastrointestinal motility due to increased tone of smooth muscles in the antral portion 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 increased tone may lead to spasm, resulting in constipation. Other opioid-induced effects may include reduced secretion of bile and pancreatic juice, spasm of the sphincter of Oddi, and transient elevation of serum amylase levels.

Effects on the cardiovascular system

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

Opioids cause peripheral vasodilation, which may lead to orthostatic hypotension or syncope. Signs of histamine release and/or peripheral vasodilation may include itching, flushing, conjunctival hyperemia, increased sweating, and/or orthostatic hypotension.

Effects on the endocrine system

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH). They also stimulate the secretion of prolactin, growth hormone (GH), and insulin and glucagon from the pancreas.

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

Effects on the immune system

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

Concentration-effect relationship

The minimum effective analgesic concentration of nalbuphine hydrochloride 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 hydrochloride 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 hydrochloride is 5 hours, and in clinical studies, the duration of analgesic effect ranges from 3 to 6 hours.

The primary metabolic pathway for nalbuphine hydrochloride has not been definitively established, but hepatic metabolism is likely.

Clinical characteristics.

Indications.

The medicinal product NALOBUPHINE-MIKROKHEM is indicated for the treatment of moderate to severe pain requiring opioid analgesics and for which alternative treatment options are inadequate. The drug may also be used as an adjunctive agent during anesthesia, for pain reduction in pre- and postoperative periods, as well as for pain relief during labor and delivery.

Warnings for use

Due to the risks of dependence, abuse, and misuse of opioids, even at recommended doses, nalbupine hydrochloride should be used in patients for whom alternative treatments (e.g., non-opioid analgesics):

• were not tolerated or cannot be tolerated;
• did not provide or cannot provide adequate analgesia.

Nalbupine hydrochloride injections should not be used for prolonged periods, except when pain remains severe enough to require an opioid analgesic and when alternative treatment options are insufficient.

Contraindications.

The medicinal product is contraindicated in patients with:

• respiratory depression;
• acute or severe bronchial asthma in the absence of appropriate monitoring or resuscitation equipment;
• known or suspected intestinal obstruction, including paralytic ileus;
• hypersensitivity to nalbupine hydrochloride or to any component of the drug.

Interaction with other medicinal products and other types of interactions.

Benzodiazepines and other CNS depressants

Although nalbupine hydrochloride has opioid antagonist activity, evidence shows that in patients without opioid dependence, it will not antagonize the opioid analgesic administered immediately before, simultaneously with, or right after nalbupine hydrochloride. Therefore, due to additive pharmacological effects, concomitant use of other opioid analgesics, benzodiazepines, or other CNS depressants (alcohol, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, anesthetics, antipsychotics, and other opioids) may increase the risk of respiratory depression, profound sedation, coma, and death.

Concomitant use of these drugs may be considered in patients for whom alternative treatment options are inadequate. The lowest effective doses should be used for the shortest duration possible. Patients must be closely monitored for signs of respiratory depression and sedation.

Serotonergic drugs

Concomitant use of opioids with other medicinal products affecting the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, other serotonergic agents (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (cyclobenzaprine, metaxalone), and monoamine oxidase inhibitors (MAOIs) (used to treat psychiatric disorders, as well as others such as linezolid and intravenous methylene blue) may lead to the development of serotonin syndrome.

Patients should be informed that opioids, when used concomitantly with serotonergic drugs, may cause serotonin syndrome—a rare but potentially life-threatening condition. Patients must be warned about the symptoms of serotonin syndrome and the importance of seeking immediate medical help if these symptoms occur. Patients who are taking or plan to take serotonergic drugs should inform their physician.

If concomitant use of such drugs is justified, continuous monitoring of patients, especially at the beginning of therapy, and dose adjustments are required. If serotonin syndrome is suspected, nalbupine hydrochloride should be discontinued.

Muscle relaxants

Nalbupine hydrochloride may enhance the neuromuscular blockade of muscle relaxants and increase the degree of respiratory depression. Patients should be monitored for signs of respiratory depression, and the dosage of nalbupine hydrochloride and/or the muscle relaxant should be reduced if necessary.

Diuretics

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

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

Anticholinergic drugs

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

When nalbupine hydrochloride is used concomitantly with anticholinergic drugs, patients should be monitored for signs of urinary retention or decreased gastrointestinal motility.

MAO inhibitors

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

The use of nalbupine hydrochloride is not recommended in patients receiving MAO inhibitors, as well as within 14 days after discontinuation of such therapy. In cases where urgent opioid use is necessary, dose selection should be performed with frequent titration of small doses for pain management, while closely monitoring blood pressure, signs and symptoms of CNS effects, and respiratory depression.

Patients must be informed to avoid taking nalbupine hydrochloride while receiving any drugs that inhibit monoamine oxidase.

Special precautions for use.

Respiratory depression, life-threatening

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including when used according to recommended guidelines. Failure to diagnose and treat respiratory depression may lead to respiratory arrest and death. Management of respiratory depression may include careful monitoring, supportive measures, and administration of opioid antagonists, depending on the patient's condition. Retention of carbon dioxide (CO2) due to opioid-induced respiratory depression may exacerbate the sedative effect of opioids.

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

To reduce the risk of respiratory depression, appropriate selection and titration of nalbuphine hydrochloride dosage is essential (see section "Dosage and administration"). Higher doses of nalbuphine hydrochloride when switching patients from another opioid may result in fatal overdose upon administration of the first dose.

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the opioid dose (see section "Dosage and administration").

Concomitant use with benzodiazepines and other CNS depressants

Profound sedation, respiratory depression, coma, and death may occur with concomitant use of nalbuphine hydrochloride with benzodiazepines or other central nervous system (CNS) depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, anesthetics, antipsychotics, other opioids). Concomitant therapy should be used with caution in patients for whom alternative treatment options are inadequate.

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

When concomitant prescribing of benzodiazepines or other CNS depressants with an opioid analgesic is necessary, the lowest effective dose should be used for the shortest duration possible. For patients already receiving an opioid analgesic, initiate benzodiazepines or other CNS depressants at lower initial doses than typically used without opioid therapy, with gradual dose titration based on clinical response. When initiating an opioid analgesic in a patient already taking a benzodiazepine or other CNS depressant, a lower initial opioid dose should be used, with gradual titration based on clinical response. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation.

When nalbuphine hydrochloride is used concomitantly with benzodiazepines or other CNS depressants (including alcohol and illicit drugs), both patients and caregivers should be counseled about the risk of respiratory depression and sedation.

Patients should not drive or operate heavy machinery until the effects of concomitant use of benzodiazepines or other CNS depressants with nalbuphine hydrochloride have resolved. Patients should be assessed for risk of substance abuse, including opioid abuse, and warned about the risks of overdose and death associated with use of CNS depressants, including alcohol and illicit drugs.

Opioid-induced hyperalgesia and allodynia

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically increases pain or sensitivity to pain. This condition is distinct from tolerance, which requires increasing opioid doses to maintain effect. Symptoms of OIH include (but are not limited to): increased pain intensity with dose escalation, decreased pain with dose reduction, or pain in response to stimuli that normally do not cause pain (allodynia). These symptoms suggest OIH only if there is no evidence of progression of the underlying disease, opioid tolerance, opioid withdrawal, or aberrant drug-related behavior.

Cases of OIH have been reported with both short-term and long-term use of opioid analgesics. Although the mechanism of OIH is not fully understood, several biochemical pathways are involved. Medical literature data support a biological link between opioid analgesic use and OIH and allodynia. If OIH is suspected, consideration should be given to reducing the opioid analgesic dose or switching to another opioid analgesic.

Patients and caregivers should be informed about the need to consult a physician before increasing the opioid dose. Patients should also be advised to seek medical attention if they experience symptoms such as hyperalgesia, including increased pain, heightened pain sensitivity, or new pain.

Respiratory depression in patients with chronic lung disease, elderly, cachectic, or debilitated patients, life-threatening

Administration of nalbuphine hydrochloride to 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 substantially reduced respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, are at increased risk of respiratory depression, including apnea, even at recommended doses of nalbuphine hydrochloride.

Elderly, cachectic, or debilitated patients

Life-threatening respiratory depression is more commonly observed in elderly, cachectic, or debilitated patients, due to altered pharmacokinetic parameters or clearance compared to younger, healthier patients. These patients should be closely monitored, especially at the beginning of nalbuphine hydrochloride therapy and when the drug is administered concomitantly with other respiratory depressants. Alternative use of non-opioid analgesics may be considered in these patients.

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more commonly with use exceeding one month. Adrenal insufficiency may present with nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, diagnosis should be confirmed promptly. Diagnosed adrenal insufficiency requires treatment with physiologic replacement doses of corticosteroids. Opioid use should be discontinued until adrenal function recovers. Use of other opioids may be possible, as there have been reports of using other opioids without recurrence of adrenal insufficiency. Available data do not identify any specific opioids more likely to be associated with adrenal insufficiency.

Severe hypotension

Nalbuphine hydrochloride may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Patients whose blood pressure maintenance is compromised by reduced blood volume or concomitant administration of CNS depressants (e.g., phenothiazines or general anesthetics) are at increased risk of severe hypotension. Patients should be monitored for signs of hypotension after initiation and dose increases of nalbuphine hydrochloride. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, leading to reduced cardiac output and blood pressure. Nalbuphine hydrochloride should be avoided in patients with circulatory shock.

Use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with signs of increased intracranial pressure or brain tumors), nalbuphine hydrochloride may reduce respiratory center activity; additionally, CO2 retention may further increase intracranial pressure. Such patients should be monitored for signs of sedation and respiratory depression, particularly at the beginning of nalbuphine hydrochloride therapy.

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

Use in patients with gastrointestinal disorders

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

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

Patients should be informed about the possibility of developing severe constipation during nalbuphine use and when to seek medical attention.

Increased risk of seizures in patients with epilepsy

Nalbuphine hydrochloride may increase the frequency of seizures in patients with epilepsy and may increase the risk of seizures in other clinical situations associated with epilepsy. Patients with a history of epilepsy should be monitored for seizure control during nalbuphine hydrochloride use.

Withdrawal syndrome

Administration of nalbuphine hydrochloride, a mixed opioid receptor agonist/antagonist, to patients receiving opioid agonist analgesics may reduce analgesic effect and/or precipitate withdrawal syndrome. Concomitant use of nalbuphine hydrochloride with opioid agonist analgesics should be avoided.

Discontinuation of nalbuphine hydrochloride in dependent patients should be achieved by gradual dose reduction (see section "Dosage and administration"). Abrupt discontinuation of nalbuphine hydrochloride is not recommended in such patients.

Dependence, abuse, and misuse

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

Although the risk of dependence in any individual is unknown, it may occur in patients using nalbuphine hydrochloride. Dependence may occur with use at recommended doses as well as with abuse or misuse.

Each patient should be assessed for risk of opioid dependence, abuse, or misuse. Risk is increased in patients with personal or family history of substance abuse (including prescription drug abuse, drug or alcohol dependence) or psychiatric disorders (e.g., major depression). The possibility of these risks should not prevent appropriate pain management in individual patients. Opioids may be prescribed to patients at increased risk of dependence and misuse, but their use requires careful monitoring with frequent assessment for signs of dependence, abuse, and misuse.

Opioids used by dependent patients and individuals with substance dependence may be used for criminal purposes. These risks should be considered when prescribing nalbuphine hydrochloride. Risk mitigation strategies include prescribing the lowest effective dose.

Renal and hepatic impairment

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

Myocardial infarction

Like all potent analgesics, nalbuphine hydrochloride should be used with caution in patients with myocardial infarction and associated nausea or vomiting.

Cardiovascular system

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

Laboratory tests

Nalbuphine hydrochloride may interfere with enzymatic methods for opioid detection depending on the specificity/sensitivity of the test. Consultation with the test manufacturer is recommended for appropriate information.

Elderly patients

Elderly patients (aged 65 years and older) may have increased sensitivity to nalbuphine hydrochloride. Caution should be exercised in dose selection. Therapy is generally initiated with the lowest effective dose due to frequent reduction in hepatic, renal, or cardiac function, concomitant diseases, or other concomitant therapies.

The primary risk for elderly patients using opioids is respiratory depression, which may occur with high initial doses in opioid-naïve patients or with concomitant administration of other respiratory depressants. For elderly patients, nalbuphine hydrochloride therapy should be initiated at the lowest dose with slow titration to achieve therapeutic effect.

Nalbuphine hydrochloride is primarily excreted by the kidneys, and the risk of adverse reactions may be higher in patients with renal impairment. Since elderly patients are more likely to have reduced renal function, caution should be exercised in dose selection with mandatory monitoring of renal function.

Carcinogenesis

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

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 CHL/HGPRT assay of Chinese hamster ovary cells, or in the sister chromatid exchange assay. Clastogenic activity was not observed in the mouse micronucleus test or in the bone marrow cytogenetic analysis in rats.

Use during pregnancy or breastfeeding.

Pregnancy

Prolonged use of opioid analgesics during pregnancy may result in neonatal withdrawal syndrome. Available data on the use of nalbuphine hydrochloride in pregnant women are insufficient to inform about associated risks of major congenital malformations and miscarriage.

In reproductive animal studies, nalbuphine hydrochloride reduced survival and body weight of offspring when administered to pregnant rats during late pregnancy and throughout lactation at doses 1.7 times the MRHD, as well as when administered to male and female rats either before mating or throughout pregnancy and lactation. No developmental abnormalities were observed in rats or rabbits at doses 6.1 and 3.9 times the MRHD, respectively.

The background risk of major congenital malformations and miscarriage in this population is unknown. All pregnancies carry a background risk of congenital 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 the fetus/newborn

Severe fetal bradycardia has been reported with nalbuphine hydrochloride use during labor. These effects may be reversed with naloxone administration. 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 existing risks to the fetus, and with appropriate measures such as fetal monitoring to detect and address any potential adverse effects.

Labour and delivery

Placental transfer of nalbuphine hydrochloride is high, rapid, and variable, with maternal-to-fetal ratios ranging from 1:0.37 to 1:6. Fetal and neonatal adverse outcomes reported after maternal administration of nalbuphine hydrochloride during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotension. Some of these events were life-threatening. Administration of naloxone to the mother during labor has in some cases reversed these effects. Severe and prolonged fetal bradycardia has been reported. Persistent neurological injury associated with fetal bradycardia has been observed. Sinusoidal fetal heart rate pattern has also been reported with nalbuphine hydrochloride use. Nalbuphine hydrochloride should be used during labor only if necessary and when potential benefit outweighs risks to the child. If nalbuphine hydrochloride is used, newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Opioids cross the placenta and may cause respiratory depression and psychophysiological effects in newborns. To reverse opioid-induced respiratory depression in a newborn, administration of the opioid antagonist naloxone is required. If alternative analgesic methods are available, nalbuphine hydrochloride is not recommended for use in pregnant women during or immediately before labor. Opioid analgesics, including nalbuphine hydrochloride, may prolong labor duration, as they have the property of temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by increased cervical dilation rate, leading to shortened labor duration. Newborns exposed to opioid analgesics during labor should be monitored for signs of excessive sedation and respiratory depression.

Animal experience

Pregnant rats were administered nalbuphine hydrochloride subcutaneously from day 6 to day 15 of gestation 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 were administered nalbuphine hydrochloride intravenously from day 7 to day 19 of gestation 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 nalbuphine hydrochloride subcutaneously from day 15 of gestation 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 groups receiving medium and high doses, and neonatal body weight was dose-dependent. Maternal toxicity was observed in all treatment groups (reduced body weight).

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

Lactation period

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

Fertility

Female rats were administered nalbuphine hydrochloride subcutaneously from day 15 before mating to day 20 of lactation at doses of 14, 28, or 56 mg/kg/day (0.85, 1.7, or 3.4 times the MRHD of 160 mg/day based on body surface area, respectively). Male rats were treated via oral gavage 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 influence reaction speed when driving or operating machinery.

Nalbuphine hydrochloride may impair mental or physical abilities required for potentially hazardous activities such as driving a car or operating dangerous machinery. Patients are advised to refrain from driving and operating dangerous machinery when hypersensitive to nalbuphine hydrochloride or lacking adequate response to the drug.

Patients should be monitored until full recovery after nalbuphine hydrochloride administration, which may affect driving or operation of other potentially hazardous machinery.

Administration and Dosage

The medicinal product NALBUPHINE-MICROCHEM should be administered as an adjunct to general anesthesia only by individuals specially trained in the use of intravenous anesthetics and management of respiratory effects associated with the use of potent opioids.

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

Use the lowest effective dose for the shortest duration consistent with individual patient needs. The risk of overdose increases with increasing doses of opioids. Therefore, dose escalation of nalbuphine hydrochloride is recommended only for patients in whom lower doses are not sufficiently effective and for whom the expected benefits of using higher opioid doses clearly outweigh the substantial risks.

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

The risk of respiratory depression must be considered, and patients should be closely monitored for respiratory depression, particularly at the beginning of therapy and following dose increases.

Dosing

Dosing is based on patient weight. 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 (adults)).

Adults. 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 maximum single dose for adults should not exceed 20 mg.

The dose may be repeated every 3–6 hours as needed, with a maximum daily dose of 160 mg. Dosing should be adjusted according to the intensity of pain, the patient's physical condition, and potential interactions with other concurrently administered medicinal products.

The solution is administered subcutaneously, intramuscularly, or intravenously. Use the smallest dose necessary to achieve adequate analgesia. For opioid-naïve patients, the recommended maximum single dose is 20 mg.

Table 1: Dosage table for adult patients:

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

When using the medicinal product NALBUPHINE-MIKROKHIM 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.

Titrating and Maintaining Therapy

Titrating the medicinal product NALBUPHINE-MIKROKHIM 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 frequency of adverse reactions, as well as to monitor for development of dependence, abuse, or misuse. Frequent communication is essential among the physician, other healthcare providers, the patient, and the caregiver 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. Dosage adjustments should be made to achieve an appropriate balance between pain control and opioid-related side effects.

Discontinuation of NALBUPHINE-MIKROKHIM

In patients who have been regularly receiving nalbuphine hydrochloride and may have developed physical dependence, nalbuphine hydrochloride therapy should be gradually discontinued by reducing the dose by 25–50% every 2–4 days, with careful monitoring for signs and symptoms of withdrawal. If such signs or symptoms occur, the dose should first be increased to the previous level and then gradually reduced by increasing the interval between dose reductions, reducing the amount of each dose, or both. Abrupt discontinuation of NALBUPHINE-MIKROKHIM should not be performed in patients with physical dependence (see section "Special precautions").

Children

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

Overdose

Symptoms

Acute overdose of nalbuphine hydrochloride alone may manifest as respiratory depression and dysphoria. Acute overdose of nalbuphine hydrochloride taken concomitantly with other opioids or CNS depressants may present as respiratory depression, drowsiness progressing to stupor or coma, skeletal muscle weakness, cold and clammy skin, miosis, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. In cases of overdose with hypoxia, marked mydriasis may occur.

Treatment

In overdose situations, priorities include restoration of airway patency, with assisted or controlled ventilation if necessary. Other supportive measures (including oxygen and vasopressor agents) may be used in treating circulatory shock and pulmonary edema. In cases of cardiac arrest or arrhythmias, advanced life support techniques are required.

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

Since the duration of action of opioid antagonists is expected to be shorter than that of nalbuphine hydrochloride, careful monitoring of the patient is required until complete recovery of respiration. If the response to an opioid antagonist is suboptimal or of short duration, additional antagonist should be administered according to the instructions specified in the drug's product information.

In an opioid-dependent individual, administration of a standard recommended dose of antagonist may precipitate acute withdrawal symptoms. 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 in a physically dependent patient is required, antagonist administration should be initiated cautiously and titrated using smaller-than-usual doses.

Adverse Reactions

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

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

Other adverse reactions reported (incidence of 1% or less):

Nervous system disorders: Euphoria, hostility, unusual dreams, weakness, heaviness sensation, numbness, tingling, dizziness, headache, muscle rigidity, increased intracranial pressure, loss of consciousness.

Psychiatric disorders: Drug dependence, psychomimetic reactions, neurotic reactions, somnolence, depression, confusion, dysphoria, speech disorder, mood changes, restlessness, nervousness (irritability), hallucinations, euphoria, feelings of unreality.

The incidence of psychomimetic effects such as feelings of unreality, 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 similar to that of other morphine derivatives.

Hepatobiliary system 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.

Cardiovascular disorders: Hypertension, hypotension, bradycardia, tachycardia, orthostatic hypotension, palpitations.

Gastrointestinal disorders: Abdominal cramps, dyspepsia, bitter taste in mouth, nausea, vomiting, dry mouth, constipation.

Eye disorders: Blurred or impaired vision, miosis.

Respiratory, thoracic and mediastinal disorders: Respiratory depression, dyspnea, asthma.

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

General disorders and administration site conditions: Speech difficulty, frequent urination, blurred vision, hyperemia and sensation of warmth, hypothermia, local pain, swelling, redness, burning, hot flushes, increased sweating. When used in obstetric practice – respiratory depression in newborns, which may be prolonged or delayed in onset.

Allergic reactions: Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following administration of nalbuphine hydrochloride, which may require immediate supportive medical treatment. These reactions may include shock, respiratory insufficiency, 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, pruritus, nausea, vomiting, increased sweating, weakness, and tremors.

Post-marketing experience

The following adverse reactions have been identified during post-approval use of nalbuphine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal pain, hyperthermia, depression or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and sensation of warmth. Fatal cases due to severe allergic reactions following administration of nalbuphine hydrochloride have been reported. Fetal death has been reported when nalbuphine hydrochloride was administered to mothers during labor and delivery.

Serotonin syndrome

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

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more commonly after use exceeding one month.

Hyperalgesia and allodynia

Cases of hyperalgesia and allodynia have been reported during opioid therapy of any duration.

Hypoglycemia

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

Drug abuse and dependence

Abuse

The medicinal product NALBUPHINE-MIKROKHEM, solution for injection, contains nalbuphine, a substance that may be misused, and abuse of which may lead to dependence.

Abuse is defined as the intentional non-therapeutic use of a drug by an individual in a way different from that prescribed by a physician or the use of a drug not prescribed to that individual. Abuse refers to the intentional non-therapeutic use of the drug, even a single use, to achieve a desired psychological or physiological effect.

Drug dependence is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling its use (e.g., continuing use despite harmful consequences, prioritizing drug use over other activities and obligations), and possibly tolerance or physical dependence. Misuse and abuse of nalbuphine hydrochloride increase the risk of overdose, which may result in central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased when nalbuphine is abused concomitantly with alcohol and other CNS depressants. Abuse and dependence on opioids in some individuals may occur without tolerance or signs of physical dependence. Furthermore, opioid abuse may occur in the absence of dependence.

"Doctor shopping" (visiting multiple physicians to obtain additional prescriptions) is a common behavior among individuals who abuse drugs and those with substance use disorders. Concern about achieving adequate pain relief may be appropriate behavior in a patient with inadequate pain control.

Proper patient assessment, appropriate prescribing practices, periodic re-evaluation of therapy, and proper dosing and storage are appropriate measures that can help limit abuse of opioid medications.

Risks associated with intravenous abuse of nalbuphine hydrochloride

Intravenous abuse of nalbuphine hydrochloride poses a risk of overdose and death. The risk is increased when nalbuphine hydrochloride for injection is used concomitantly with alcohol and/or other CNS depressants. Additionally, transmission of infectious diseases such as hepatitis and HIV is commonly associated with parenteral drug abuse.

Dependence

Both tolerance and physical dependence may develop during opioid therapy. Tolerance is a physiological state characterized by reduced response to the drug after repeated administration (i.e., a higher dose is required to achieve the same effect previously obtained with a lower dose).

Physical dependence is a state resulting from physiological adaptation in response to repeated use of opioid drugs, manifested by signs and symptoms of withdrawal upon abrupt discontinuation or significant dose reduction.

Withdrawal may be precipitated by administration of opioid antagonists (e.g., naloxone), mixed agonist/antagonists (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine).

Physical dependence may develop to a clinically significant degree after several days to weeks of continuous use.

Nalbuphine hydrochloride injections should not be abruptly discontinued in physically dependent patients. Sudden cessation of nalbuphine injections in physically dependent patients may lead to withdrawal syndrome, typically characterized by restlessness, lacrimation, rhinorrhea, sweating, chills, myalgia, and mydriasis. Other signs and symptoms may develop, including irritability, anxiety, back pain, joint pain, weakness, abdominal pain, seizures, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory disorders and withdrawal signs.

Shelf life.

2 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

1 ml in ampoules, 5 ampoules in a cassette, 2 cassettes together with the instructions for medical use in a cardboard box.

Or 2 ml in ampoules, 5 ampoules in a cassette together with the instructions for medical use in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MIKROKHEM PHARMACEUTICAL COMPANY LTD (responsible for batch release, excluding batch control/testing).

Manufacturer's address.

5 Budynstriji Street, Kyiv, 01013, Ukraine.

Marketing authorization holder.

MIKROKHEM PHARMACEUTICAL COMPANY LTD.

Address of the marketing authorization holder.

5 Budynstriji Street, Kyiv, 01013, Ukraine.

You can report adverse reactions associated with the use of this medicinal product by calling +38 (050) 309-83-54 (24/7).