Apein

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT APAIN® (APAIN)

Composition:

Active substance: nalbuphine;

One 2.4 ml vial (24 doses) containing powder and solvent separated by a partition contains 84 mg of nalbuphine hydrochloride, calculated as 100% dry substance;

One 3.6 ml vial (36 doses) containing powder and solvent separated by a partition contains 126 mg of nalbuphine hydrochloride, calculated as 100% dry substance;

One dose (0.1 ml) of the prepared medicinal product contains 3.5 mg of nalbuphine hydrochloride, calculated as 100% dry substance;

Excipients:

Powder: colloidal anhydrous silicon dioxide, diamond green;

Solvent: povidone, propylene glycol, benzalkonium chloride, glutamic acid, chitosan, purified water.

Pharmaceutical form. Powder and solvent for preparation of nasal spray.

Main physicochemical properties:

Powder: light, fluffy powder of greenish hue; presence of green specks is acceptable.

Solvent: liquid from colorless to beige with opalescence.

Prepared medicinal product ready for use: solution of light blue color with greenish tint and opalescence.

Pharmacotherapeutic group. Analgesics. Opioids. Morphinan derivatives. Nalbuphine.

ATC code N02A F02.

Pharmacological Properties

Pharmacodynamics

Nalbuphine hydrochloride is a kappa-opioid receptor agonist and a mu-opioid receptor antagonist. Nalbuphine hydrochloride is also a potent analgesic. The analgesic activity of parenteral nalbuphine is approximately equivalent to morphine on a milligram-to-milligram basis at doses around 30 mg.

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

Nalbuphine hydrochloride may cause a similar degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling effect—doses above 30 mg do not lead to further respiratory depression in the absence of concomitant administration of other central nervous system (CNS)-depressant drugs.

Alone, nalbuphine hydrochloride at doses equal to or lower than its analgesic dose demonstrates strong opioid antagonist activity. When administered after or concurrently with mu-opioid receptor agonists (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reduce or block respiratory depression induced by mu-opioid receptor agonists. 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 receptor agonist analgesics.

Effects on the CNS

Nalbuphine hydrochloride causes respiratory depression by direct action on respiratory centers in the brainstem. Respiratory depression refers to decreased sensitivity of brainstem respiratory centers to increased carbon dioxide tension and electrical stimulation. A ceiling effect may occur with respiratory depression caused by nalbuphine hydrochloride. Despite nalbuphine hydrochloride being classified as a mixed agonist-antagonist, its respiratory depressant effects may be reversed by 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 produce similar symptoms). However, in hypoxia caused by overdose, marked mydriasis rather than miosis may occur.

Effects on the gastrointestinal tract and smooth muscles

Nalbuphine hydrochloride reduces gastrointestinal motility due to increased tone of smooth muscles in the gastric antrum and duodenum. Digestion in the small intestine is delayed, and propulsive contractions are reduced. Propulsive peristaltic waves in the large intestine are diminished, and increased tone may lead to spasm, resulting in constipation. Other opioid-induced effects may include reduced bile and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevation of serum amylase levels.

Effects on the cardiovascular system

When nalbuphine hydrochloride is administered 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 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 animal studies. 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 varies widely among patients, especially 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.

Clinical efficacy and safety

The clinical efficacy and tolerability of intranasal nalbuphine were evaluated in a multicenter, double-blind, randomized, parallel-group comparative study assessing the efficacy and tolerability of the medicinal product “APEYN®” (Microhim LLC, Ukraine) compared to 10 mg nalbuphine administered by intramuscular injection in patients after orthopedic or trauma surgery. The study included 90 patients who underwent orthopedic or trauma surgical procedures (45 patients per group). The mean age of all patients was 52.07 ± 13.07 years. Their height ranged from 152 cm to 193 cm (mean 172.26 ± 8.57 cm), and body weight ranged from 56.00 to 120.00 kg (mean 83.39 ± 14.11 kg). Body mass index (mean 28.04 ± 3.86 kg/m²) was within accepted normal limits and met the inclusion criteria (≥18.5 kg/m² and ≤30 kg/m²).

For the treatment of moderate to severe pain, patients after orthopedic or trauma surgery received a single dose of 10.5 mg nalbuphine administered intranasally (medicinal product APEYN®) or 10 mg nalbuphine administered intramuscularly. Pain intensity was assessed using the visual analog scale (VAS). In the group receiving the injectable formulation, analgesic effect was achieved in 39 (86.67%) patients; in the intranasal group, in 40 (88.89%) patients. Significant reduction in pain intensity was observed within 15 minutes after nalbuphine administration in both study groups. The analgesic effect in both groups lasted for 6 hours.

The figure below shows the superimposed time-course curves of pain intensity for each group participating in the clinical efficacy study.

A – 10 mg nalbuphine by intramuscular injection
B – 10.5 mg medicinal product APEYN®

Statistical analysis confirmed the efficacy of the investigational drugs based on primary (sum of pain intensity differences over 6 hours post-dose) and secondary endpoints (onset of analgesia, duration of analgesia, sedation assessment using the RASS scale after emergence from anesthesia and after drug administration, number and percentage of patients achieving adequate analgesia throughout the treatment period, area under the pain intensity curve). Thus, the conducted clinical study demonstrated that intranasal and intramuscular administration of nalbuphine showed similar profiles in reducing pain intensity.

Pharmacokinetics.

A comparative pharmacokinetic, tolerability, and safety study was conducted using doses of 7 mg for the intranasal formulation and 10 mg for the injectable formulations.

The elimination half-lives of nalbuphine hydrochloride in plasma following intravenous, intramuscular, and intranasal administration are similar. Maximum plasma concentration is reached within 10 minutes and 15 minutes after intranasal and intramuscular administration, respectively.

Nalbuphine plasma concentrations are detectable for up to 12 hours after intranasal, intravenous, or intramuscular administration.

The bioavailability of nalbuphine after intranasal administration at a dose of 7 mg is approximately 65% (see Table 1).

Table 1. Pharmacokinetic parameters of nalbuphine hydrochloride after intranasal, intramuscular, and intravenous administration

Cmax – maximum concentration, Tmax – time to reach Cmax, AUC(0-∞) – area under the concentration-time curve extrapolated to infinity, T1/2 – elimination half-life. For Cmax and AUC(0-∞) parameters, arithmetic mean values ± standard deviations are presented in the table; for Tmax and T1/2 parameters, medians (minimum and maximum values) are presented.

Non-clinical safety data

In a study on local irritant effects following repeated intranasal administration of the medicinal product APEIN® to laboratory animals, no local irritant effect on nasal epithelium was observed in rabbits, and minimal local irritant effect on nasal epithelium, which was reversible, was observed in rats. Following intranasal administration of the test sample of the medicinal product APEIN®, female rabbits remained calm and showed no signs of pain. No itching of surrounding tissues at the site of administration was noted. Observations over 8 days revealed no behavioral abnormalities in the test animals. No toxic effects were recorded following repeated intranasal administration of nalbuphine to two species of laboratory animals.

Clinical Characteristics

Indications

The medicinal product APEIN® is indicated for the treatment of acute somatic pain of sufficient intensity to require opioid analgesics and for which alternative treatments are inadequate. The drug may also be used as an adjunctive agent for pain reduction in pre- and postoperative periods.

Warning for Use

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

• are contraindicated or may be contraindicated;
• have not provided or may not provide adequate analgesia.

Contraindications

The medicinal product APEIN® 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;
• suspected traumatic nasal cerebrospinal fluid leakage, ethmoiditis.

Interaction with Other Medicinal Products and Other Types of Interactions

Benzodiazepines and Other CNS Depressants

Although nalbupine hydrochloride has opioid antagonist activity, evidence suggests that in patients without opioid dependence, it will not antagonize the opioid analgesic administered immediately before, simultaneously with, or immediately 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 agents should be reserved for 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, serotonergic-acting 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) may result in serotonin syndrome.

Patients should be informed that concomitant use of opioids with serotonergic drugs may lead to serotonin syndrome, a rare but potentially life-threatening condition.

Patients must also be warned about the symptoms of serotonin syndrome and the importance of seeking immediate medical attention if such symptoms occur. Patients who are taking or plan to take serotonergic drugs should inform their physician.

If concomitant use of these drugs is justified, continuous monitoring of patients, especially at the beginning of therapy, is necessary, with dose adjustments as needed. 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. Monitoring for signs of respiratory depression is required, and dose reduction of nalbupine hydrochloride and/or the muscle relaxant may be necessary.

Diuretics

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

Patients should be monitored for 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

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, the dose should be carefully titrated using small, incremental doses (adjusting frequency of administration), with close monitoring of blood pressure and signs and symptoms of CNS and respiratory depression.

Patients must be informed of the need to avoid using nalbupine hydrochloride while taking any drugs that inhibit monoamine oxidase.

Special precautions for use

Respiratory depression, which may be life-threatening

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including when administered according to recommended guidelines. Failure to diagnose and treat respiratory depression may lead to respiratory arrest and death. Management of respiratory depression, depending on the patient's condition, may include careful monitoring, supportive measures, and administration of opioid antagonists. 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 a dose increase. Patients must be closely monitored for respiratory depression, particularly during the first 24–72 hours after initiation of therapy or after increasing the dose of nalbuphine hydrochloride.

To reduce the risk of respiratory depression, appropriate dose selection and dose titration of nalbuphine hydrochloride (achieved by adjusting the frequency of administration) are essential. 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. For patients with CSA, consideration should be given to reducing the opioid dose.

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 should be reserved for patients for whom alternative treatment options are inadequate and administered with caution.

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 opioid analgesics and other CNS depressants.

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 (achieved by adjusting the frequency of administration). Patients already receiving an opioid analgesic should be started on a lower initial dose of the benzodiazepine or other CNS depressant than doses typically used without opioid therapy, with gradual dose titration based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or another CNS depressant, a lower initial dose of the opioid analgesic should be used, with gradual titration (achieved by adjusting the frequency of administration) based on clinical response. Patients must be closely monitored for signs and symptoms of respiratory depression and sedation.

Patients and caregivers must be informed of the risks of respiratory depression and sedation when nalbuphine hydrochloride is used concomitantly with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).

Patients should be advised not to drive or operate complex 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, particularly opioids, 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 differs 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, reduced pain with dose reduction, or pain from 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 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 (by decreasing frequency of administration) or switching to another opioid analgesic.

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

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

Elderly, cachectic, or debilitated patients. Life-threatening respiratory depression occurs more frequently in elderly, cachectic, or debilitated patients due to altered pharmacokinetic parameters or clearance compared to younger, healthier patients. Close monitoring of such patients is required, 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 after use exceeding one month. Adrenal insufficiency may present with nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Diagnosis should be confirmed as soon as possible if adrenal insufficiency is suspected. 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 some cases report successful use of alternative opioids without recurrence of adrenal insufficiency. Available data do not identify any specific opioids more likely to cause adrenal insufficiency.

Severe hypotension

Nalbuphine hydrochloride may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients. Patients whose blood pressure regulation is compromised due to reduced blood volume or concomitant use 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 initiating nalbuphine hydrochloride and when increasing the dose. In patients with circulatory shock, nalbuphine hydrochloride may cause vasodilation, leading to reduced cardiac output and decreased 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, and the resulting 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 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 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 increase the risk of seizures in other clinical situations associated with epilepsy. Patients with a history of epilepsy should be monitored for seizure activity during nalbuphine hydrochloride use.

Withdrawal syndrome (discontinuation)

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 by gradual dose reduction (achieved by adjusting the frequency of 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 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 risk of opioid dependence, abuse, or misuse. Risk is increased in patients with personal or family history of substance abuse (including medication 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 dependence may be diverted for illicit purposes. These risks should be considered when prescribing nalbuphine hydrochloride. Risk mitigation strategies include prescribing the lowest effective dose and proper storage.

Patients should be informed that even at recommended doses, nalbuphine hydrochloride may lead to dependence, abuse, and misuse, potentially resulting in overdose and death (see section "Adverse reactions"). Patients should be warned not to share nalbuphine hydrochloride with others and to take measures to prevent theft or unauthorized use.

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 lower doses should be administered.

Myocardial infarction

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

Cardiovascular system

During anesthesia, a high incidence of bradycardia was observed in patients receiving nalbuphine hydrochloride who had not received atropine preoperatively.

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. Treatment is usually initiated with the lowest effective doses due to frequent reduction in liver, kidney, or heart function, concomitant diseases, or other concomitant therapies.

The main risk for elderly patients using opioids is respiratory depression, resulting from high initial doses in opioid-naïve patients or from concomitant use of other respiratory depressants. Nalbuphine hydrochloride therapy in elderly patients should be initiated at the lowest dose, with slow titration (achieved by adjusting the frequency of administration) to achieve therapeutic effect, and frequent monitoring for signs of CNS and respiratory depression.

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

Carcinogenesis

In long-term studies in rats (24 months) and mice (19 months), administered orally 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 increased the frequency of mutations in the mouse lymphoma assay. The drug did not show mutagenic activity in the Ames test with four bacterial strains, in the Chinese hamster ovary HGPRT test, 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.

Use during pregnancy or breastfeeding

Safety and efficacy studies of the medicinal product APEIN® during pregnancy or breastfeeding have not been conducted. This medicinal product should not be used during these periods.

The data below refer to the safety of nalbuphine use in parenteral formulations during pregnancy, labor, and breastfeeding.

Pregnancy

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

Adverse effects in fetus/newborn

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 reversed these effects in some cases. There are no reports of fetal bradycardia in early pregnancy, but this risk exists.

Breastfeeding period

Limited data indicate that nalbuphine hydrochloride passes into breast milk, but only in small amounts (less than 1% of the administered dose), with clinically insignificant effects. Withdrawal symptoms may occur in breastfed infants if the mother discontinues opioid analgesic use or stops breastfeeding.

Fertility

In rat studies, 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 tasks such as driving a vehicle or operating complex machinery. Patients should refrain from driving and operating complex machinery when hypersensitive to nalbuphine hydrochloride or when adequate response to the drug is not established.

Patients should be monitored until full recovery after nalbuphine hydrochloride administration.

Method of Administration and Dosage

The medicinal product APEIN® is intended for intranasal use only.

The lowest effective dose should be used (by adjusting the frequency of administration) for the shortest duration consistent with the individual patient's needs.

The risk of overdose increases with higher doses of opioids. Therefore, increasing the dose of nalbuphine hydrochloride is recommended only for patients in whom lower doses are not sufficiently effective and in whom the expected benefit from using higher opioid doses clearly outweighs the potential risks.

Dosage for each patient must be individualized (by adjusting the frequency of administration) and should take 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 should be considered, and patients should be closely monitored for respiratory depression, especially at the beginning of therapy and after dose increases.

Titrating and Maintaining Therapy

Dose titration of the medicinal product is recommended by individualizing the dose (through adjustment of administration frequency) to achieve adequate analgesia while minimizing adverse reactions. Patients receiving nalbuphine hydrochloride should be continuously monitored for pain intensity and the relative frequency of adverse reactions, as well as to monitor for the development of dependence, abuse, or misuse. Frequent communication among the physician, other healthcare providers, the patient, and the caregiver is essential during periods of analgesic dosage adjustment, 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 should be adjusted to achieve an appropriate balance between pain management and opioid-related side effects.

Dosing

The recommended dose of the medicinal product APEIN® is 10.5 mg of nalbuphine hydrochloride (3 sprays of 0.1 mL each, with each spray delivering 3.5 mg of nalbuphine hydrochloride). When administering the medicinal product, a 1-minute interval should be observed before the third spray to ensure better drug absorption.

If necessary, administration may be repeated every 6 hours. Use the lowest dose required to achieve adequate pain relief by adjusting the dosing frequency. Dosing should be adjusted according to pain severity, the patient's physical condition, and potential interactions with other concomitantly administered medicinal products. The maximum daily dose is 42 mg.

The medicinal product should be administered under the supervision of healthcare personnel.

The medicinal product APEIN® is not an inhalation drug. Do not inhale it during administration! The product should not be used simultaneously with other nalbuphine-containing medicinal formulations.

Instructions for Preparation and Administration of the Medicinal Product

Children

The safety and efficacy of APEN® in children (under 18 years of age) have not been established; therefore, it should not be used in pediatric patients.

Overdose

Data regarding overdose with intranasal formulations of nalbuphine are lacking; below are data on overdose with injectable formulations.

Symptoms

Acute overdose with nalbuphine hydrochloride alone may manifest as respiratory depression and dysphoria. Acute overdose occurring with concomitant use of nalbuphine hydrochloride and 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 associated with hypoxia, marked mydriasis rather than miosis may be observed.

Treatment

In cases of overdose, priorities include restoration of spontaneous respiration, using 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 techniques are required.

Opioid antagonists, naloxone or nalmefene, are specific antidotes for respiratory depression caused by opioid overdose. In cases of clinically significant respiratory or circulatory depression due to 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, 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 specified in the medicinal product's package insert.

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

Adverse Reactions

During clinical trials of the medicinal product APEIN®, only non-serious adverse reactions were observed, which are typical responses to intranasal administration of the drug, namely bitter taste in the mouth (30.0%), discomfort in the nasopharynx (23.2%), burning sensation (29.0%), numbness of the palate (2.9%), nausea (2.9%). These adverse reactions were generally transient and did not require medical treatment.

The data below refer to adverse reactions associated with injectable formulations of nalbuphine.

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

Less commonly observed 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 (frequency 1% or less):

Nervous system disorders: euphoria, hostility, unusual dreams, weakness, feeling of heaviness, 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 disturbances, mood changes, restlessness, nervousness (agitation), hallucinations, feelings of unreality.

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

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

Hepatobiliary system disorders: disturbances in liver function tests, biliary tract spasm.

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

Reproductive system and breast disorders: decreased libido or potency.

Cardiovascular system disorders: hypertension, hypotension, bradycardia, tachycardia, orthostatic hypotension, palpitations.

Gastrointestinal disorders: abdominal cramps, dyspepsia, bitter taste in the 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: dysarthria, frequent urination, visual blurring, flushing and sensation of warmth, hypothermia, local pain, swelling, redness, burning, hot flushes, increased sweating. When used in obstetric practice – respiratory depression in neonates, which may be prolonged; severe fetal bradycardia has also been reported.

Allergic reactions: following administration of nalbuphine hydrochloride, anaphylactic/anaphylactoid reactions and other serious hypersensitivity reactions have been reported, 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, itching, 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 reports are submitted 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, depressed or loss of consciousness, somnolence, tremor, restlessness, pulmonary edema, excitement, 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 pregnant women 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 APEIN® contains nalbuphine – a substance that may be misused, and abuse of which may lead to dependence.

Abuse is defined as intentional misuse of a medicinal product for therapeutic purposes by a person in a manner different from that prescribed by a physician, or use of a medicinal product not prescribed to that person. Abuse refers to intentional non-therapeutic use of the drug, even once, 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 drug use despite harmful consequences, prioritizing drug use over other activities and obligations), and possible tolerance or physical dependence. Inappropriate use 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 when nalbuphine is abused concomitantly with alcohol and other CNS depressants. Opioid abuse and opioid dependence in some individuals may occur without tolerance or symptoms of physical dependence. Furthermore, opioid abuse may occur in the absence of dependence.

"Drug-seeking" behavior is common among individuals with substance use disorders. Tactics include emergency calls to medical staff or visits at the end of office hours, refusal to undergo appropriate evaluation, testing, or referrals, repeated "loss" of prescriptions, prescription forgery, and unwillingness to provide prior medical records or contact information for other physicians. "Doctor shopping" (visiting multiple physicians to obtain additional prescriptions) is a common phenomenon among individuals who abuse drugs and those with substance use disorders. Concern about 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 help limit opioid abuse.

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.

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

Clinically significant physical dependence may develop only after several days to several weeks of continuous use.

Nalbuphine hydrochloride 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, increased blood pressure, respiratory rate, or heart rate. Neonates born to mothers who are physically dependent on opioids will also be physically dependent and may exhibit respiratory disorders and withdrawal symptoms.

Reporting of adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life

2 years.

Shelf life of the prepared medicinal product – 28 days.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging, protected from light. Do not refrigerate the prepared medicinal product.

Keep out of reach of children.

Packaging

Vial with powder and solvent separated by a partition, 2.4 mL (24 doses) or 3.6 mL (36 doses) with a mechanical metered-dose pump and nasal adapter. One vial per foil pouch or cardboard box.

Prescription status

Prescription only.

Manufacturer

MICROKHIM NPF LLC.

Manufacturer's address and location of operations

5 Budynstryi St., Kyiv, 01013, Ukraine.

Marketing authorization holder

MICROKHIM NPF LLC.

You can report an adverse event associated with the use of this medicinal product to the pharmacovigilance system of MICROKHIM NPF LLC by phone: +38(050) 309-83-54 or by email: [email protected].

Address of the marketing authorization holder

5 Budynstryi St., Kyiv, 01013, Ukraine.