Nalbuphine
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NALBUPHINE (NALBUPHIN)
Composition:
Active substance: nalbuphine;
1 ml of solution contains 10 mg of nalbuphine hydrochloride, calculated as anhydrous substance;
Excipients: sodium chloride, sodium citrate, citric acid monohydrate, water for injections.
Pharmaceutical form. Injection solution.
Main physicochemical properties: a clear, colorless or almost colorless solution, practically free from particles.
Pharmacotherapeutic group. Analgesics. Opioids. Morphinan derivatives.
ATC code N02AF02.
Pharmacological Properties
Pharmacodynamics
Nalbuphine hydrochloride is a kappa-opioid receptor agonist and a mu-opioid receptor antagonist. Nalbuphine hydrochloride is also a potent analgesic. Its analgesic activity is essentially equivalent to that of morphine on a milligram basis 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 the same degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling effect, meaning that increasing the dose above 30 mg does not result in further respiratory depression, provided no other central nervous system (CNS) active agents affecting respiration are present.
Nalbuphine hydrochloride itself has potent opioid antagonist activity at doses equal to or less than its analgesic dose. When administered after or concurrently with mu-opioid agonist analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reduce or eliminate respiratory depression caused by mu-opioid agonist analgesics. Nalbuphine hydrochloride may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine hydrochloride should be used with caution in patients who are regularly receiving 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 being classified as an agonist-antagonist, the respiratory depressant effects of nalbuphine hydrochloride may 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 bladder lesions may present with similar symptoms). In cases of overdose, marked mydriasis may occur due to hypoxia.
Effects on the Gastrointestinal Tract and Other Smooth Muscles
Nalbuphine hydrochloride causes decreased 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 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
A higher incidence of bradycardia has been observed in patients receiving nalbuphine hydrochloride during anesthesia, particularly in those who did not receive atropine prior to surgery.
Opioids cause peripheral vasodilation, which may lead to orthostatic hypotension or syncope. Signs of histamine release and/or peripheral vasodilation may include itching, flushing, redness of the eyes, 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 — somatotropic hormone), and pancreatic hormones—insulin and glucagon.
Chronic use of opioids 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, opioid effects are moderately immunosuppressive.
Concentration–Effect Relationship
The minimum effective analgesic concentration varies widely among patients, particularly in those previously treated with strong opioid agonists. The minimum effective analgesic concentration of nalbuphine hydrochloride in an individual patient may increase over time due to increasing pain, development of new pain syndromes, 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 5 hours. The duration of analgesic effect in clinical studies ranged from 3 to 6 hours.
The primary metabolic pathway for nalbuphine hydrochloride has not been definitively established—likely hepatic.
Clinical Characteristics.
Indications.
For the treatment of pain of sufficient intensity requiring opioid analgesics and for which alternative treatment options are inadequate. The medicinal product may also be used as an adjunct in anesthesia, for reduction of pain in pre- and postoperative periods, as well as for analgesia during labor and delivery.
Warning
Due to the risk of dependence, abuse, and misuse of opioids, even at recommended doses, nalbuphine hydrochloride should be used only in patients for whom alternative pain treatments (e.g., non-opioid analgesics):
- were not tolerated or cannot be tolerated;
- did not provide adequate analgesia or cannot provide adequate analgesia.
Contraindications.
The medicinal product is contraindicated in patients with:
- respiratory depression or marked CNS depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcohol psychosis, significant impairment of liver or kidney function;
- 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 medicinal product.
Not recommended:
- concomitant use of the drug with pure morphine-like agonists;
- use of the drug without appropriate diagnostic evaluation in surgical abdominal conditions, as nalbuphine may mask their clinical presentation.
Special safety precautions.
Nalbuphine as an adjunct to general anesthesia should be administered only by personnel specifically trained in the use of intravenous anesthetics and management of respiratory effects associated with potent opioids.
Naloxone, resuscitation and intubation equipment, and oxygen must be immediately available.
Interaction with other medicinal products and other forms of interaction.
Benzodiazepines and other CNS depressants
Concomitant use of nalbuphine hydrochloride with benzodiazepines or other CNS depressants (alcohol, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, anesthetics, antipsychotics, and other opioids) increases the risk of respiratory depression, profound sedation, coma, and death. Concomitant use should be reserved for patients for whom alternative treatment options are inadequate and applied with caution. Doses should be limited and duration of use as short as 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—namely: 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 for psychiatric disorders, as well as others such as linezolid and intravenous methylene blue)—has led to the development of serotonin syndrome.
If concomitant use is justified, continuous monitoring of patients—especially at the beginning 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 dose 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 increases 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 gastric motility.
MAO inhibitors
Interaction between MAO inhibitors (e.g., phenelzine, tranylcypromine, linezolid) and opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
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 urgent need for opioid administration, dose selection should be performed with frequent titration of small doses for pain management, with careful monitoring of blood pressure, CNS symptoms, and respiration.
Special precautions for use.
Life-threatening respiratory depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including when used according to recommended guidelines. Untreated 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 initiation of therapy and following dose increases. Patients must be closely monitored for respiratory depression, particularly during the first 24–72 hours after starting therapy or after a dose increase of nalbuphine hydrochloride.
To reduce the risk of respiratory depression, appropriate dosing of nalbuphine hydrochloride should be achieved through titration (see section "Dosage and administration"). Higher doses of nalbuphine hydrochloride when switching patients from another opioid may result in fatal overdose, even with 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. For 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, alcohol). Such 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 death 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. Patients already receiving an opioid analgesic should be started on a lower initial dose of benzodiazepine or another CNS depressant than doses used without opioid therapy, with gradual dose titration according to the patient's condition. 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 advised about the risk of respiratory depression and sedation.
Patients should not drive or operate machinery until the effects of concomitant use of benzodiazepines or other CNS depressants with nalbuphine hydrochloride are known. Patients should be assessed for risk of substance abuse, including opioid misuse, and warned about the risk of overdose and death associated with use of CNS depressants, including alcohol and illicit drugs.
Life-threatening respiratory depression in patients with chronic lung disease, elderly, cachectic, or debilitated patients
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 reduced respiratory reserve, hypoxia, hypercapnia, or prior 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. Such patients should be closely monitored, especially when nalbuphine hydrochloride is administered or when the drug is used concomitantly with other medications that depress respiration. Non-opioid analgesics may be considered as an alternative.
Adrenal insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more commonly after use exceeding one month. Adrenal insufficiency may present with nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. If adrenal insufficiency is suspected, diagnosis should be established as quickly as possible. For diagnosed adrenal insufficiency, physiological replacement doses of corticosteroids are required. Opioid use should be discontinued until adrenal function recovers. Other opioids may be used, as recurrence of adrenal insufficiency has not been reported in some cases.
Severe arterial hypotension
Nalbuphine hydrochloride may cause severe arterial hypotension, including orthostatic hypotension and syncope in ambulatory patients. Patients whose blood pressure regulation is compromised due to reduced blood volume or concomitant administration of CNS depressants (e.g., phenothiazines or anesthetics) are at increased risk of severe arterial hypotension. Patients should be monitored for signs of hypotension after initiation and titration of nalbuphine hydrochloride. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, leading to reduced cardiac output and blood pressure. The use of 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 during nalbuphine hydrochloride therapy.
Opioids may also mask clinical signs in patients with head injury. The use of 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.
The drug should not be used without appropriate diagnostic evaluation in surgical abdomen, as nalbuphine may mask its clinical presentation.
When administering nalbuphine to patients undergoing surgery for hepatobiliary disease, the high risk of developing Oddi's sphincter spasm should be considered.
Opioids may increase serum amylase levels. Patients with hepatobiliary disorders, including acute pancreatitis, should be monitored for worsening of disease symptoms.
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 (abstinence syndrome)
The use of nalbuphine hydrochloride, a mixed opioid receptor agonist-antagonist, in patients receiving opioid receptor agonists may reduce analgesic efficacy and/or precipitate withdrawal symptoms. Concomitant use of nalbuphine hydrochloride with opioid receptor agonists 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 mixed opioid receptor agonist-antagonist. As an opioid, its use exposes patients to the risks of dependence, abuse, and misuse.
Dependence may occur with use at recommended doses as well as with abuse or misuse.
The risk of opioid dependence, abuse, or misuse should be assessed for each patient. Risk increases in patients with personal or family history of substance abuse (including drug or alcohol abuse or dependence) and in patients with psychiatric disorders (e.g., major depression). The existence of these risks should not prevent appropriate pain management in individual patients.
Opioids prescribed to patients with substance dependence may be used for criminal purposes. These risks should be considered when prescribing nalbuphine hydrochloride. To reduce these risks, the drug should be prescribed at the lowest effective dose.
Renal and hepatic impairment
Since nalbuphine hydrochloride is likely metabolized in the liver and excreted by the kidneys (see section "Pharmacokinetics"), 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 during anesthesia with nalbuphine hydrochloride in patients who did not receive atropine prior to surgery.
Laboratory tests
Nalbuphine hydrochloride may interfere with enzymatic tests for opioids, depending on the specificity/sensitivity of the test. Consultation with the test manufacturer is recommended for appropriate information.
Warnings
Due to the risks of dependence, abuse, and misuse of opioids, even at recommended doses, nalbuphine hydrochloride should be used only in patients for whom alternative treatments (e.g., non-opioid analgesics):
- were not tolerated or cannot be tolerated;
- did not provide adequate analgesia or cannot provide adequate analgesia.
Elderly patients
Elderly patients (aged 65 years and older) may have increased sensitivity to nalbuphine hydrochloride due to frequent reduction in liver, kidney, or cardiac function, concomitant diseases, or other concomitant therapies. Caution should be exercised when selecting dosage. Therapy is generally initiated at the lowest effective dose.
The primary risk for elderly patients using opioids is respiratory depression, resulting from high initial doses in opioid-naïve patients or from concomitant use of opioids with other respiratory depressants. For elderly patients, nalbuphine hydrochloride therapy should be initiated at the lowest dose and titrated slowly to achieve therapeutic effect.
Nalbuphine hydrochloride is substantially excreted by the kidneys, and the risk of adverse reactions is higher in patients with impaired renal function. Since elderly patients more frequently have reduced renal function, caution should be exercised in dose selection with mandatory monitoring of renal function.
Carcinogenesis
Animal studies with oral doses of 200 mcg/kg (12 times the maximum recommended human daily dose [MRHD]) and 200 mg/kg (6 times the MRHD) showed no evidence of carcinogenicity.
Mutagenesis
Nalbuphine hydrochloride increased the frequency of mutations in the animal lymphoma assay. The drug did not show mutagenic activity in the Ames test with four bacterial strains, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test in Chinese hamster ovary cells, or in the sister chromatid exchange test. Clastogenic activity was not observed in the mouse micronucleus test or in the bone marrow cytogenetic analysis in rats.
Nalbuphine contains: 0.13 mmol (or 3 mg) of sodium per 10 mg dose and 0.26 mmol (or 6 mg) of sodium per 20 mg dose, i.e., nearly sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
Prolonged use of opioid analgesics during pregnancy may result in neonatal withdrawal syndrome. There are insufficient data on the use of nalbuphine hydrochloride in pregnant women to determine the risk of serious congenital malformations and miscarriage.
In reproductive animal studies, nalbuphine hydrochloride reduced survival and body weight in rat offspring when administered to pregnant females during late gestation and throughout lactation at doses 1.7 times the MRHD, as well as when administered to male and female rats 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 in humans is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Adverse effects in fetus/newborn
Severe fetal bradycardia has been reported with nalbuphine hydrochloride use during labor. These effects may be reversed with naloxone. There are no reports of fetal bradycardia in early pregnancy, but this risk exists. The drug should be used during pregnancy only if necessary, when potential benefit outweighs risks to the fetus, and with fetal monitoring for any adverse effects.
Labour and delivery
Nalbuphine hydrochloride rapidly and significantly crosses the placenta.
Fetal and neonatal adverse effects 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. Permanent neurological damage associated with fetal bradycardia has been observed. Sinusoidal fetal heart rate patterns associated with nalbuphine hydrochloride use have also been reported. Nalbuphine hydrochloride should be used during labor only if necessary and only 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, administration of the opioid antagonist naloxone is required. When alternative analgesic methods are available, nalbuphine hydrochloride is not recommended for use in pregnant women during or immediately before delivery. Opioid analgesics, including nalbuphine hydrochloride, may prolong labor, as they 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.
Lactation
Nalbuphine passes into breast milk; several cases of hypotonia and respiratory arrest in infants have been described after maternal use of morphine derivatives at doses exceeding therapeutic levels.
Therefore, breastfeeding is contraindicated during prolonged use of this medicinal product.
Breastfeeding may be possible when the drug is used in obstetric practice.
Fertility
No adverse effects on male or female fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery.
Nalbuphine is not recommended for outpatient use due to the risk of daytime drowsiness.
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 or 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 their condition fully recovers after nalbuphine hydrochloride administration, which may affect driving or operation of other potentially dangerous machinery.
Administration and Dosage
Nalbuphine is intended for intravenous, intramuscular, and subcutaneous administration.
Dosage for each patient should 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.
Patients must be closely monitored for respiratory depression, especially during the first 24–72 hours after initiation of therapy and following any dose increase, and dosage should be adjusted accordingly.
Dosage
Dosage depends on the patient's body weight.
Exercise caution to avoid dosage errors due to confusion between milligrams (mg) and milliliters (mL), as this may lead to accidental overdose (see dosage in Table 1 below).
The recommended single dose for adults is 10–20 mg of nalbuphine hydrochloride for patients weighing 70 kg, i.e., 0.1–0.3 mg/kg body weight, administered subcutaneously, intramuscularly, or intravenously. The single dose may be administered as needed every 3–6 hours. Dosage should be adjusted according to the severity of pain, the patient’s physical condition, and potential interactions with other concomitantly administered medicinal products. For opioid-naïve patients, the recommended maximum single dose is 20 mg. The maximum daily dose is 160 mg.
Table 1.
| Dose per administration |
Maximum single dose |
Maximum volume per administration |
Maximum daily dose |
Maximum daily volume |
| 0.1–0.3 mg/kg |
20 mg |
2 ml* |
160 mg |
16 ml* |
* Applies to the dosage form — injection solution 10 mg/mL.
When nalbupine is used as an adjunct to anesthesia, higher doses are required than for analgesia. Initial doses of nalbupine 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 nalbupine hydrochloride may be accompanied by respiratory depression, which can be reversed with the opioid antagonist naloxone hydrochloride.
For labor analgesia, the drug should be administered at a dose of 20 mg intramuscularly.
The drug should be used with caution in elderly patients, in patients with general debilitation, or with impaired respiratory function. In such cases, therapy should be initiated with the lowest effective doses due to the increased risk of adverse reactions.
Titration and Maintenance of Therapy
Titration of nalbupine should be performed by individualizing the dose to achieve adequate analgesia with minimal adverse effects. Patients receiving nalbupine hydrochloride must be continuously monitored to assess pain intensity and the relative frequency of adverse reactions, as well as to monitor for the development of dependence, abuse, or misuse. Frequent communication among the physician, other healthcare providers, the patient, and the caregiver is essential, especially 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 nalbupine hydrochloride. If opioid-related adverse effects occur, consideration should be given to reducing the dose. Dosage adjustments should be made to achieve an appropriate balance between pain relief and opioid-related side effects.
Discontinuation of Nalbupine
In patients who have been regularly receiving nalbupine hydrochloride and may have developed physical dependence, nalbupine therapy should be gradually discontinued by reducing the dose by 25–50% every 2–4 days, with careful monitoring for withdrawal symptoms. If withdrawal symptoms occur, the dose should first be increased back to the previous level, then gradually reduced by increasing the dosing interval, decreasing the dose amount, or both. Nalbupine should not be abruptly discontinued in patients with physical dependence (see section "Special Warnings and Precautions for Use").
Pediatric Patients
Safety and efficacy in pediatric patients (under 18 years of age) have not been established.
Overdose.
Overdose may result in respiratory depression, Cheyne-Stokes respiration; drowsiness, dysphoria, altered mental status up to coma; pallor, hypothermia, miosis; decreased arterial pressure, cardiovascular collapse; seizures; rhabdomyolysis progressing to renal failure.
Acute overdose when nalbupine hydrochloride is used concomitantly with other opioids or CNS depressants may manifest as respiratory depression, increasing drowsiness progressing to stupor or coma, skeletal muscle weakness, cold and clammy skin, pinpoint pupils, pulmonary edema, bradycardia, arterial hypotension, partial or complete airway obstruction, atypical snoring, and potentially fatal outcome. In cases of overdose with hypoxia, marked mydriasis may occur.
Treatment.
In overdose, priority should be given to restoring airway patency, with assisted or controlled ventilation if necessary. Other supportive measures (including oxygen and vasopressor agents) may be used in the treatment of circulatory shock and pulmonary edema. In cases of cardiac arrest or arrhythmias, advanced life support measures are required.
Opioid antagonists, naloxone or nalmafene, are specific antidotes for opioid-induced respiratory depression. In cases of clinically significant respiratory or circulatory depression caused by nalbupine 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 nalbupine hydrochloride overdose.
Since the duration of action of opioid antagonists is expected to be shorter than the duration of action of nalbupine hydrochloride, careful monitoring of the patient is required 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 for use of the antidote.
In an opioid-dependent individual, administration of the usual recommended dose of an antagonist may precipitate acute withdrawal syndrome. The severity of withdrawal symptoms will depend on the degree of physical dependence and the dose of antagonist administered. If treatment of severe respiratory depression in a physically dependent patient is required, administration of the antagonist should be initiated cautiously, using smaller than usual doses titrated to effect.
Adverse Reactions
The most commonly observed adverse reactions were sedation and somnolence.
Less frequently reported reactions included: increased sweating/skin clamminess, nausea/vomiting, dizziness/vertigo, dry mouth, and headache.
Cardiovascular system: elevated or decreased blood pressure, orthostatic hypotension, bradycardia, tachycardia, palpitations.
Eye disorders: blurred or impaired vision, miosis.
Gastrointestinal disorders: constipation, nausea, vomiting, dry mouth, abdominal cramps, bitter taste in the mouth, dyspepsia.
Hepatobiliary disorders: impaired liver function tests, biliary tract spasm.
Immune system disorders: anaphylactic/anaphylactoid and other serious hypersensitivity reactions, which may require immediate supportive medical treatment. These reactions may include shock, respiratory distress syndrome, respiratory arrest, bradycardia, cardiac arrest, hypotension, and 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 tremor.
Respiratory, thoracic and mediastinal disorders: respiratory depression, dyspnea, asthma.
Nervous system disorders: euphoria, hostility, unusual dreams, weakness, heaviness, numbness, tingling, dizziness, headache, muscle rigidity, increased intracranial pressure.
Psychiatric disorders: drug dependence, psychomimetic reactions, neurotic reactions, somnolence, depression, confusion, dysphoria, speech disorders, mood changes, restlessness, nervousness (irritability), hallucinations, euphoria, feelings of unreality.
The potential for physical and psychological dependence, as well as tolerance during prolonged treatment, is the same as with other morphine derivatives.
It has been shown that the incidence of psychotomimetic effects such as feelings of unreality, depersonalization, delirium, dysphoria, and hallucinations is lower than with pentazocine.
Renal and urinary tract disorders: antidiuretic effect, urinary tract spasm.
Reproductive system and breast disorders: decreased libido or potency, amenorrhea or infertility.
When used in obstetric practice — respiratory depression in neonates, which may be prolonged or delayed in onset.
Skin and subcutaneous tissue disorders: urticaria, pruritus.
General disorders and administration site reactions: dysarthria, frequent micturition, blurred vision, hyperemia and sensation of warmth, local pain, swelling, redness, burning, hot flushes, increased sweating. When used in obstetric practice — respiratory depression in neonates, which may be prolonged or delayed in onset.
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 unknown 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 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 following use longer than one month.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse reactions via the national pharmacovigilance system.
Shelf life.
3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Incompatibilities.
Do not mix in the same syringe with other injectable solutions.
Nalbuphine is compatible with 0.9% sodium chloride solution, 5% glucose solution, and Hartmann's solution.
Packaging.
1 ml or 2 ml in a vial; 5 vials in a blister pack; 1 or 2 blisters in a carton.
1 ml or 2 ml in a vial; 5 or 10 vials in a cardboard box with cardboard dividers.
Prescription status.
Prescription only.
Manufacturer.
JSC "Lubnipharm".
Manufacturer's address and location of operations.
16 Barvinkova Street, Lubny, Poltava Oblast, 37500, Ukraine.