Estesia®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESTESIA®

Composition:

Active substance: dinalbuphine sebacate;

1 ml of solution contains 75 mg of dinalbuphine sebacate;

Excipients: benzyl benzoate, sesame oil.

Pharmaceutical form. Prolonged-release injectable solution.

Main physicochemical properties: clear, light yellow, oily solution.

Pharmacotherapeutic group. Analgesics. Opioids. Morphinan derivatives. ATC code N02AF.

Pharmacological Properties

Dynalbuphone sebacate belongs to nalbuphine prodrugs. The medicinal formulation is a sterile oily solution suitable for intramuscular administration. Dynalbuphone sebacate contains two molecules of nalbuphine linked by a sebacoyl ester bridge, which is rapidly hydrolyzed to nalbuphine by esterases. Nalbuphine is the active component.

Nalbuphine is a potent analgesic, with analgesic activity equivalent to that of morphine when comparing equal milligram doses. Receptor studies indicate that nalbuphine binds to mu, kappa, and delta receptors, but not to sigma receptors. It acts primarily as a kappa-receptor agonist and a partial mu-receptor antagonist.

Pharmacodynamics

The pharmacodynamics of dynalbuphone sebacate differ from those of nalbuphine. Nalbuphine may produce a degree of respiratory depression similar to that of equivalent doses of morphine. However, in the absence of other central nervous system (CNS) depressants that suppress respiration, the medicinal product does not increase the level of respiratory depression within the therapeutic dose range.

Nalbuphine exhibits potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered after or concurrently with mu-receptor agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reverse or block opioid-induced respiratory depression. Nalbuphine may precipitate withdrawal symptoms in patients dependent on opioid drugs; therefore, the medicinal product should be used with caution in patients who have regularly received opioid analgesics, particularly mu-receptor agonists.

Pharmacokinetics

Absorption

After intramuscular administration, the medicinal product is slowly and continuously absorbed, followed by rapid conversion into nalbuphine. Peak plasma concentration (Cmax) is reached at 64.0 ± 9.3 hours. The mean Cmax is 15.4 ± 6.4 ng/mL.

A single injection of the oily solution provides sustained plasma levels of nalbuphine over several days. Clinical study results indicate that the medicinal product may effectively relieve pain and maintain a sustained analgesic effect for up to 7 days following a single injection.

Metabolism

Once dynalbuphone sebacate reaches systemic circulation, it is rapidly and extensively hydrolyzed by esterases into the active substance—nalbuphine. In vitro biotransformation studies have shown that over 90% of nalbuphine sebacate prodrug is converted into nalbuphine within 30 minutes in whole blood.

Nalbuphine is metabolized by cytochrome P450 enzymes and phase II UGTs (uridine diphosphate glucuronosyltransferases), resulting in the formation of glucuronide metabolites.

Distribution

Approximately 90% of dynalbuphone sebacate is plasma protein-bound. The mean volume of distribution of dynalbuphone sebacate is approximately 10,628 ± 4,403 L following a 150 mg dose.

Dynalbuphone sebacate and nalbuphine penetrate into erythrocytes, but not to a greater extent than into plasma.

Elimination

Nalbuphine is primarily eliminated via the kidneys.

Elimination half-life is 83.2 ± 46.4 hours. Mean nalbuphine clearance is 100 ± 11 L/hour.

Clinical characteristics.

Indications.

Moderate to severe pain in the postoperative period.

Contraindications.

Intravenous administration is prohibited.

The medicinal product is contraindicated in patients with:

• respiratory depression;
• acute or severe bronchial asthma in the absence of appropriate monitoring or resuscitation equipment;
• existing or suspected intestinal obstruction, including paralytic ileus;
• hypersensitivity to nalbuphine, sesame oil, or benzyl benzoate.

Interaction with other medicinal products and other forms of interactions.

Dynalbuphine sebacate is rapidly converted by carboxylesterase into the active substance—nalbuphine—after intramuscular administration, entering the bloodstream. Therefore, the clinical pharmacokinetic and pharmacodynamic characteristics of dynalbuphine sebacate are similar to those of nalbuphine.

Central nervous system (CNS) depressants

Studies on the concomitant use of dynalbuphine sebacate with general anesthetics have not been conducted.

Although nalbuphine has opioid antagonist activity, data indicate that in patients without opioid dependence, it will not exhibit antagonism toward an opioid analgesic administered immediately before, simultaneously with, or immediately after nalbuphine injection. Therefore, in patients receiving concomitantly an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol), additive effects may occur, increasing the risk of respiratory depression. If such combination therapy is anticipated, the dose of one or both agents should be reduced. Combination with phenothiazine derivatives and penicillin preparations may intensify nausea and vomiting.

In a phase III study of dynalbuphine sebacate, all subjects received the local anesthetic bupivacaine (99%) prior to surgery. Bupivacaine was combined with the local anesthetic lidocaine in 94% of cases, and midazolam was used in 2%. Regarding overall adverse reactions, the use of local anesthetics bupivacaine, lidocaine, propofol, and midazolam in combination with dynalbuphine sebacate in phase III studies did not lead to clinically significant adverse reactions.

Opioids

Studies on the concomitant use of dynalbuphine sebacate with opioids have not been conducted. Since dynalbuphine sebacate is a prodrug of nalbuphine, concomitant use with opioids will be accompanied by interactions similar to those characteristic of nalbuphine.

When dynalbuphine sebacate is used in combination with nalbuphine, the nalbuphine dose should not exceed 80 mg per day, or 20 mg every 6 hours.

General anesthesia

Studies on the concomitant use of dynalbuphine sebacate with general anesthetics, including inhalational anesthetics and intravenous anesthetics such as opioids and benzodiazepines, have not been conducted. Since dynalbuphine sebacate is a prodrug of nalbuphine, interactions during concomitant use with general anesthetics may be similar to those of nalbuphine. Data indicate no clinically significant safety issues with the concomitant use of dynalbuphine sebacate and anesthetics at usual doses.

Cytochrome P450 3A4 inhibitors or inducers

Concomitant use of dynalbuphine sebacate with cytochrome P450 3A4 inhibitors or discontinuation of P450 3A4 inducers may result in overdose with fatal outcome.

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, metaxalone), and monoamine oxidase inhibitors (MAOIs) (used to treat psychiatric disorders, as well as others such as linezolid and intravenous methylene blue)—has led to the development of serotonin syndrome.

If concomitant use of such agents is justified, continuous monitoring of patients is required, especially at the beginning of therapy, due to the potential risk of serotonin syndrome.

Muscle relaxants

Nalbuphine 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 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 development of severe constipation, which may lead to paralytic bowel disease.

When dynalbuphine sebacate is used concomitantly with anticholinergic drugs, patients should be monitored for signs of urinary retention or reduced gastric 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 the medicinal product Estesia® is not recommended in patients taking MAO inhibitors, or within 14 days after discontinuation of such treatment. If urgent opioid use is necessary, careful monitoring of blood pressure, central nervous system symptoms, and respiration is required.

Special precautions for use.

Head injury and increased intracranial pressure

The potential for respiratory depression and the property of potent analgesics to increase cerebrospinal fluid pressure (due to vasodilation following CO2 retention) may be significantly enhanced in the presence of head trauma, intracranial lesions, or pre-existing increased intracranial pressure. In addition, potent analgesics may produce effects that mask the clinical picture in patients with head injury. Therefore, dynalbufine sebacate should be used under such conditions only when the benefit outweighs the potential risk, and the drug should be administered with particular caution.

Renal and hepatic impairment

Since dynalbufine sebacate is metabolized in the liver and excreted by the kidneys, the drug should be used with caution in patients with renal or hepatic insufficiency.

Life-threatening respiratory depression

Serious, life-threatening, or fatal respiratory depression has been reported with opioid use, 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 the use of opioid antagonists, depending on the patient's condition. Retention of carbon dioxide (CO2) during opioid-induced respiratory depression may intensify the sedative effect of opioids.

Although serious, life-threatening, or fatal respiratory depression may occur at any time during administration of the medicinal product Estesia®, the risk is greatest at the beginning of therapy and after dose escalation. Patients must be closely monitored for respiratory depression, especially during the first 24–72 hours after initiation of therapy.

Switching patients to the medicinal product Estesia® from another opioid may result in overdose, potentially leading to fatal outcomes.

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.

Cytochrome P450 3A4 inhibitors or inducers

The medicinal product Estesia® is metabolized via the cytochrome P450 3A4 system; therefore, medicinal products that inhibit or induce this enzyme system may alter the clearance of dynalbufine sebacate.

Caution is advised in patients who have discontinued a cytochrome P450 3A4 inducer or who are taking moderate or strong P450 3A4 inhibitors due to the risk of increased plasma concentrations of dynalbufine sebacate. Such patients require close monitoring for signs of respiratory depression and sedation.

A risk of low plasma concentrations of dynalbufine sebacate may occur in patients receiving concomitant therapy with Estesia® and P450 3A4 inducers or in those who discontinue a moderate or strong P450 3A4 inhibitor. In some patients, additional or alternative analgesic agents may be required.

Concomitant therapy with benzodiazepines and other CNS depressants

Profound sedation, respiratory depression, coma, and death may occur with concomitant use of the medicinal product Estesia® with benzodiazepines or other 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 not suitable.

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 and opioid analgesics.

If co-administration of benzodiazepines or other CNS depressants with an opioid analgesic is necessary, 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 titration according to the patient's condition. Patients must be closely observed for signs and symptoms of respiratory depression and sedation.

When Estesia® is used concomitantly with benzodiazepines or other CNS depressants (including alcohol and illicit drugs), both patients and caregivers should be counseled about the risks 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 dynalbufine sebacate 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

Administration of the medicinal product Estesia® 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 dynalbufine sebacate.

Elderly, cachectic, or debilitated patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients, as they may exhibit altered pharmacokinetic parameters or clearance compared to younger, healthier patients. Such patients require close monitoring, especially when receiving Estesia®, and particularly when the drug is used concomitantly with other respiratory depressants. Non-opioid analgesics may be considered as an alternative.

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use, particularly 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 soon as possible. In diagnosed cases of adrenal insufficiency, physiological replacement doses of corticosteroids are required. Opioid use should be discontinued until adrenal function recovers. Other opioids may be used, as in some cases, recurrence of adrenal insufficiency has not been reported.

Severe arterial hypotension

Nalbuphine may cause severe arterial 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 anesthetics) are at increased risk of severe arterial hypotension. Patients should be monitored for signs of arterial hypotension following initiation and titration of dynalbufine sebacate. In patients with circulatory shock, nalbuphine may cause vasodilation, leading to reduced cardiac output and arterial pressure. Administration of the medicinal product Estesia® should be avoided in patients with circulatory shock.

Use in patients with gastrointestinal disorders

The medicinal product Estesia® is contraindicated in patients with known or suspected intestinal obstruction, including paralytic ileus.

When administering dynalbufine sebacate to patients undergoing surgical procedures for hepatobiliary pathology, 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 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 treatment with Estesia®.

Dependence, abuse, and misuse

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

Dependence may occur with use of the drug both at recommended doses and in cases of abuse or misuse.

The risk of opioid dependence, abuse, or misuse should be assessed for each patient. Risk increases in patients with a 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 presence of these risk factors should not preclude appropriate pain management in individual patients.

Opioids prescribed to patients with opioid dependence may be diverted for illicit use. These risks should be considered when prescribing Estesia®. To reduce these risks, the drug should be prescribed at the lowest effective dose.

Withdrawal (abstinence syndrome)

Administration of dynalbufine sebacate, a mixed opioid receptor agonist-antagonist, to patients receiving opioid receptor agonists may reduce analgesic efficacy and/or precipitate withdrawal symptoms. Concomitant use of Estesia® with opioid receptor agonists should be avoided.

Use in geriatric population

No dose adjustment is necessary.

Important information on excipients.

Sesame oil may rarely cause severe allergic reactions.

Use during pregnancy or breastfeeding.

Fetal bradycardia has been reported with nalbuphine use during labor. Although reproductive toxicity studies did not show embryotoxic or fetotoxic effects, this drug should be used during pregnancy only if clearly necessary and if the potential benefit outweighs the risk to the fetus.

Use during labor

Placental transfer of nalbuphine is high, rapid, and variable, with maternal-to-fetal ratios ranging from 1:0.37 to 1:6. Adverse reactions in fetuses and newborns whose mothers received nalbuphine during labor include fetal bradycardia, respiratory depression in the newborn, apnea, cyanosis, and hypotonia, which may be life-threatening. Administration of naloxone to the mother has in some cases normalized these effects. Severe and prolonged fetal bradycardia and neurological injury associated with fetal bradycardia have been reported. Sinusoidal fetal heart rate patterns associated with nalbuphine use have also been reported. Estesia® should be used during labor only if absolutely necessary and only when the potential benefit outweighs the risk to the neonate. Newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Pregnancy

Prolonged use of opioid analgesics during pregnancy may result in neonatal opioid withdrawal syndrome, which may be life-threatening. Therefore, careful monitoring of the newborn is required. If pregnant women require prolonged opioid therapy, they should be informed about the risk of neonatal opioid withdrawal syndrome, and appropriate treatment should be ensured.

Teratogenic effects. Animal studies did not show evidence of developmental toxicity, including teratogenicity, or fetal harm. There are insufficient data on the safety of the drug in pregnant women. The drug should not be used during pregnancy except in exceptional cases where benefit to the pregnant woman outweighs the potential risk to the fetus.

Non-teratogenic effects. Subcutaneous administration of nalbuphine to male and female rats before mating, throughout pregnancy and lactation, or to pregnant rats during the last third of gestation and throughout lactation at doses approximately four times the maximum recommended human dose reduced body weight and survival of offspring.

Lactation period

Nalbuphine passes into breast milk in small amounts (less than 1% of the administered dose), resulting in clinically insignificant effects. Caution should be exercised when administering dynalbufine sebacate to a nursing woman.

Fertility

Carcinogenesis. In long-term carcinogenicity studies in rats (24 months) and mice (19 months), no evidence of increased tumor incidence was observed with oral administration of nalbuphine at doses up to 200 mg/kg (1180 mg/m²) and 200 mg/kg (600 mg/m²) per day, respectively.

Genotoxicity. Dynalbufine sebacate did not show genotoxic activity in the in vivo micronucleus test in mouse peripheral blood.

Nalbuphine showed no mutagenic activity in the Ames test with four bacterial strains, in the Chinese hamster ovary HGPRT assay, or in the sister chromatid exchange assay. However, nalbuphine increased mutation frequency in the mouse lymphoma assay. No clastogenic activity was observed in the micronucleus test in mice or in the bone marrow cytogenetic assay in rats.

Impairment of fertility. In reproductive toxicity studies in rats, nalbuphine did not affect fertility at subcutaneous doses up to 56 mg/kg/day or 330 mg/m²/day.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Estesia**®** 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 machinery during treatment.

Patients should be monitored until their condition fully recovers after administration of dynalbufine sebacate, which may affect the ability to drive or operate potentially dangerous machinery.

Dosage and Administration

Dosing

Administer the medicinal product only intramuscularly at a single dose of 150 mg. Dose adjustment based on body weight is not required.

Estesia® is a prolonged-release medicinal product; therefore, it should be noted that 12–24 hours are needed to achieve therapeutic concentration. Dinabinfenum sebacate may be administered approximately 24 hours before the planned surgery to alleviate postoperative pain.

Estesia® should not be prescribed to patients requiring immediate analgesia.

Estesia® is a fixed-dose medicinal product intended for single use only. The safety and efficacy of repeated doses have not been established.

Clinical studies on the concomitant use of dinabinfenum sebacate with other analgesics, except ketorolac, have not been conducted.

The medicinal product Estesia® is contraindicated for intravenous administration.

Intramuscular administration should be performed slowly due to the viscous and oily nature of the solution. To prevent leakage of the solution, apply gentle pressure to the injection site; do not massage the injection site.

Children

The safety and efficacy of dinabinfenum sebacate in pediatric patients have not been established; therefore, the medicinal product should not be used in this age group.

Overdose.

Cases of overdose with dinabinfenum sebacate have not been observed in clinical trials. The product is supplied in a 2 mL single-use vial, which prevents overdose.

In the event of overdose, the following symptoms may occur: respiratory depression, arterial hypotension, circulatory insufficiency, deepening of coma, seizures, rhabdomyolysis progressing to renal failure.

Treatment of overdose includes:

• In conscious patients at an early stage – oral administration of activated charcoal;
• Supportive therapy (oxygen, intravenous fluid replacement, vasopressor agents);
• Intravenous administration of naloxone or nalmefene (specific antidotes).

Side effects

The most commonly observed adverse reactions during clinical trials were: injection site inflammation, fever, headache, dizziness, nausea, vomiting, and somnolence.

Reactions at the injection site usually resolved spontaneously by Day 8.

Respiratory, thoracic and mediastinal disorders: nasopharyngitis, cough, respiratory depression, decreased minute volume of respiration, dyspnea, asthmatic attacks.

Gastrointestinal disorders: dry mouth, abdominal discomfort, abdominal spasms and pain, gastrointestinal motility disorders including bloating, colic, flatulence, constipation, diarrhea, dyspepsia, bitter taste, toxic megacolon, fecaloma, intestinal obstruction, irritable bowel syndrome, nausea, vomiting, decreased appetite.

Hepatobiliary disorders: impaired liver function tests, biliary tract spasm.

Renal and urinary disorders: non-infectious cystitis, dysuria, urinary retention.

Nervous system disorders: dizziness, general weakness, headache, hypesthesia, sleep disturbances, somnolence, diplopia, excitement, tearfulness, hostility, night terrors, tinnitus, paresthesia, feelings of unreality, seizures, muscle rigidity, tremor, involuntary muscle contractions, increased intracranial pressure.

Psychiatric disorders: anxiety, insomnia, restlessness, neurotic reactions, depression, confusion, dysphoria, speech disturbances, mood changes, hallucinations, euphoria.

Cardiac and vascular disorders: decreased arterial and systolic pressure, increased blood pressure, tachycardia, palpitations.

Skin and subcutaneous tissue disorders: hyperhidrosis, rash, pruritus, urticaria, sensation of heat; scleral icterus and skin jaundice.

General disorders and administration site conditions: chills, fatigue, cold sensation, injection site swelling, increased body temperature.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at temperatures not exceeding 25 °C. Keep out of reach of children.

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

Packaging.

2 ml in a vial; 1 vial with a needle for intramuscular injection in a blister pack; 1 blister pack in a carton.

Prescription category. Prescription only.

Manufacturer.

Hsinchu Plant of UBI Pharma Inc.

Manufacturer's address and location.

No. 45, Guangfu N. Rd., Hukou Township, Hsinchu County 303036, Taiwan, R.O.C.

Marketing authorization holder.

JSC "Pharmaceutical Company "Darnitsya".

Address of the marketing authorization holder.

13 Borispilska St., Kyiv, 02093, Ukraine.