Sufentanil-3n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUFENTANIL-ZN (SUFENTANIL-ZN)

Composition:

Active substance: sufentanil;

1 ml of injection solution contains 5 mcg or 50 mcg of sufentanil citrate calculated as sufentanil;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Nervous system. Anesthetics. General anesthetics. Opioid anesthetics. ATC code N01AH03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sufentanil is a synthetic opioid acting as a μ-agonist.

Pharmacodynamic properties. Sufentanil is a highly potent narcotic analgesic (approximately 10 times more potent than fentanyl), used for epidural and intravenous administration. In rats, a wide therapeutic range of sufentanil has been demonstrated: the minimum LD50/ED50 ratio is 25,211 (fentanyl: 277; morphine: 69.5).

Intravenous administration. The effect of intravenously administered sufentanil occurs rapidly. With short-term use, rapid elimination allows for quick recovery. The degree of analgesia is dose-dependent and also depends on the duration of administration. It can be adjusted according to the level of surgical pain.

Like all opioid analgesics, sufentanil may cause muscle rigidity, depending on the dose and rate of administration.

Studies have shown that sufentanil does not cause significant histamine release.

All effects of sufentanil can be reversed by a specific opioid antagonist (e.g., naloxone).

Epidural administration. When administered epidurally, sufentanil is used for the treatment of postoperative pain and as an adjunct analgesic. It produces deep spinal anesthesia of intermediate duration (usually 4–6 hours), with onset within 5–10 minutes.

Children. After epidural administration of 0.75 mcg/kg sufentanil in 15 children aged 4 to 12 years, the mean time to onset of analgesia was 3 ± 0.3 minutes, and the mean duration of analgesia was 198 ± 19 minutes.

Epidural sufentanil has been used only in a limited number of children aged 3 months to 1 year as a single bolus dose of 0.25–0.75 mcg/kg for postoperative pain control.

In children aged 3 months and older, an epidural bolus dose of 0.1 mcg/kg sufentanil followed by an epidural infusion of 0.03–0.3 mcg/kg/hour in combination with an amide-type local anesthetic provided effective postoperative analgesia for up to 72 hours after lower abdominal surgery.

Pharmacokinetics.

Absorption. After epidural administration, maximum plasma concentration is reached within 10 minutes after injection; it is 4–6 times lower than after intravenous administration. Addition of epinephrine (50–75 mcg) reduces the initial rapid absorption by 25–50%.

After intravenous administration of 5 mcg/kg, plasma levels are approximately 28 ng/mL. Sufentanil is extensively distributed into tissues. Due to its high lipophilicity, it rapidly crosses cell membranes and penetrates the blood-brain barrier.

Distribution. Studies with intravenous doses of 250–1500 mcg sufentanil, with serum concentration measurements over prolonged periods, yielded the following results: the distribution phase half-lives were 2.3–4.5 minutes and 35–73 minutes. The volume of distribution in the central compartment was 14.2 L, and the volume of distribution at steady state was 344 L.

The decline in plasma concentration from the therapeutic level to the awakening level is determined by the distribution phase half-lives, not the terminal half-life (4.1 hours after 250 mcg administration, increasing to 10–16 hours after 500–1500 mcg). Sufentanil pharmacokinetics are linear within the studied dose range.

Sufentanil is highly bound to plasma proteins (92.5%). Compared to adults, protein binding in children is lower and increases with age. In neonates, about 80.5% of sufentanil is protein-bound, compared to 88.5% in infants and 91.9% in children.

Secondary plasma concentration peaks may occur due to redistribution from tissues.

Metabolism. The liver and small intestine are the primary sites of biotransformation. Cytochrome P450 3A4 (CYP3A4) is the main enzyme involved.

Excretion. The mean elimination half-life of sufentanil is 784 (656–938) minutes. Due to the limit of detection of the assay, the half-life after a 250 mcg dose was significantly shorter (240 minutes) than after a 1500 mcg dose. Plasma clearance is 917 mL/min. Nearly 80% of the administered dose is excreted within the next 24 hours, and only 2% of the administered dose is excreted unchanged.

Pharmacokinetics in special patient populations.

Patients with hepatic impairment. In patients with liver cirrhosis, the volume of distribution is slightly increased and total clearance slightly reduced compared to healthy subjects. This results in a significant prolongation (by almost 30%) of the elimination half-life, necessitating prolonged postoperative monitoring.

Patients with renal impairment. The volume of distribution at steady state, total clearance, and terminal elimination half-life in dialysis patients and patients after kidney transplantation do not differ from those in healthy subjects. The unbound fraction of sufentanil in this population is the same as in healthy individuals.

Children. Pharmacokinetic data in children are limited.

Intravenous administration. Plasma protein binding in children is lower than in adults and increases with age. In neonates, sufentanil is approximately 80.5% bound to plasma proteins, compared to 88.5% in infants, 91.9% in children, and 92.5% in adults.

After intravenous bolus administration of 10–15 mcg/kg sufentanil to children undergoing cardiac surgery, sufentanil pharmacokinetics, as in adults, exhibited a triexponential curve. Body weight-normalized clearance was found to be higher in infants and children than in adolescents, in whom clearance was comparable to that in adults. Neonates showed significantly lower clearance with high variability (range 1.2–8.8 mL/min/kg, and one individual outlier value of 21.4 mL/min/kg). Neonates also exhibited a larger volume of distribution at steady state and a longer elimination half-life. Pharmacodynamic differences due to variations in pharmacokinetic parameters may be even greater when considering the unbound fraction.

Epidural administration. After epidural administration of 0.75 mcg/kg sufentanil to 15 children aged 4 to 12 years, plasma concentrations measured at 30, 60, 120, and 240 minutes after injection ranged between 0.08 ± 0.01 and 0.1 ± 0.01 ng/mL.

In 6 children aged 5 to 12 years who received a bolus dose of 0.6 mcg/kg sufentanil followed by continuous epidural infusion of 0.08 mcg/kg/h sufentanil and 0.2 mg/kg/h bupivacaine for 48 hours, maximum plasma concentration was reached approximately 20 minutes after the bolus injection and ranged from below the limit of quantification (< 0.02 ng/mL) to 0.074 ng/mL.

Clinical Characteristics.

Indications.

The medicinal product to be administered epidurally to adults:

• For postoperative pain management following general surgical procedures, thoracic surgery, orthopedic procedures, and cesarean section.
• As an adjunct analgesic in combination with epidural administration of bupivacaine during labor and normal delivery.

The medicinal product to be administered intravenously to adults:

• As a primary analgesic agent during induction and maintenance phases of combined anesthesia in general surgical, gynecological, or orthopedic procedures.
• As the sole general anesthetic agent for induction and maintenance of anesthesia during major cardiac and neurosurgical procedures.

Use in children:

• The medicinal product to be administered intravenously to children aged 1 month and older as an additional analgesic agent during the induction and/or maintenance phase of balanced general anesthesia.
• The medicinal product to be administered epidurally to children aged 1 year and older for postoperative pain management following general surgical procedures, thoracic surgery, and orthopedic procedures.

Contraindications.

Hypersensitivity to sufentanil or other opioids.

Sufentanil, like other opioids for epidural administration, should not be used in the following conditions: severe bleeding or shock, sepsis, infection at the injection site, coagulation disorders such as thrombocytopenia and coagulopathy, anticoagulant therapy, or any medical condition or concomitant treatment contraindicating epidural administration.

Intravenous administration is contraindicated during labor or, in the case of cesarean section, prior to clamping of the umbilical cord due to the risk of respiratory depression in the newborn. On the other hand, epidural administration of doses not exceeding 30 mcg during labor does not affect the condition of the mother or the newborn.

Interaction with other medicinal products and other forms of interaction.

Central nervous system (CNS) depressants. Medicinal products acting on the CNS, such as barbiturates, benzodiazepines or related agents, neuroleptics, general anesthetics, and other non-specific CNS depressants (e.g., alcohol), may enhance opioid-induced respiratory depression. The required dose of sufentanil will be lower than usual in patients who have received such depressants. Concomitant use of these types of medicinal products with sufentanil in patients with spontaneous respiration may increase the risk of respiratory depression, deep sedation, coma, and death.

Effect of sufentanil on other medicinal products. The dose of other CNS depressants should be reduced after administration of sufentanil. This is particularly important after surgical procedures, as profound analgesia is associated with marked respiratory depression, which may persist or recur in the postoperative period. Administration of a CNS depressant, such as a benzodiazepine or related agent, during this phase may disproportionately increase the risk of respiratory depression.

Monoamine oxidase inhibitors (MAOIs). Patients receiving MAOIs (including selegiline) should discontinue treatment at least 2 weeks prior to surgery.

CYP3A4 inhibitors. Sufentanil is primarily metabolized by CYP3A4. However, in vivo, erythromycin (which also inhibits CYP3A4) does not inhibit the metabolism of a single intravenous dose of sufentanil. Although clinical data on this phenomenon are lacking, in vitro data indicate that erythromycin, as well as other potent inhibitors of this isoenzyme (such as ketoconazole, itraconazole, and ritonavir), may inhibit the metabolism of sufentanil, potentially increasing the risk of delayed or prolonged respiratory depression. Special patient monitoring is required if the medicinal product is used concomitantly with CYP3A4 inhibitors such as macrolides, imidazole antifungals, or protease inhibitors. In particular, a reduced dosage of the medicinal product may be necessary.

Serotonergic agents. Concomitant use of sufentanil and serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or MAOIs, may increase the risk of developing serotonin syndrome, which may be fatal.

Special precautions for use.

Respiratory depression. The occurrence of respiratory depression is dose-dependent and duration-dependent, and can be reversed by specific opioid antagonists such as naloxone. Repeated administration of an antagonist may be required, as its duration of action may be shorter than that of respiratory depression.

Like all potent opioids, sufentanil causes profound analgesia when administered intravenously, accompanied by respiratory depression that may persist into or recur during the early postoperative period. Before transferring a patient who has received sufentanil via infusion or in high doses from the recovery room, it is essential to ensure that the patient is breathing spontaneously, adequately, and regularly. Hyperventilation during anesthesia may alter the patient's response to carbon dioxide and thus affect postoperative respiration. Therefore, it is important to have resuscitation equipment readily available, including equipment for lung ventilation, as well as opioid antagonists.

Risk of concomitant use with CNS depressants, including benzodiazepines or related agents. Concomitant use of sufentanil and CNS depressants, including benzodiazepines or related agents, in patients with spontaneous respiration is associated with an increased risk of respiratory depression, profound sedation, coma, and death. If a decision is made to use the drug concomitantly with a CNS depressant, including a benzodiazepine or related agent, the lowest effective doses of both drugs should be used for the shortest possible duration. Patients should be closely monitored for signs of respiratory depression and profound sedation. Due to this risk, patients and caregivers should be strongly advised about the potential for these symptoms.

Dependence and abuse potential. Repeated administration of opioids may lead to tolerance and physical and psychological dependence. The risk is increased in patients with a personal or family history of substance abuse (including drugs, alcohol, or narcotics) or psychiatric disorders (e.g., severe depression). Therefore, higher doses of the drug may be required to achieve the desired clinical response.

Physical dependence may lead to acute withdrawal symptoms following abrupt discontinuation or significant dose reduction of opioids.

Sufentanil has an abuse potential similar to other opioid receptor agonists. Misuse and intentional inappropriate use of the drug may result in overdose and/or death. Individuals at increased risk of opioid abuse may still receive appropriate treatment with sufentanil.

Neonatal abstinence syndrome. Chronic use of opioids during pregnancy may lead to the development of neonatal abstinence syndrome.

Muscle rigidity. The drug may cause muscle rigidity, primarily in the chest area, when administered intravenously. This effect can usually be avoided by slow intravenous administration (usually sufficient for low doses), premedication with a benzodiazepine, and administration of muscle relaxants.

Non-epileptic myoclonic movements may occur.

Cardiac disorders. Bradycardia (or occasionally cardiac arrest) may occur when the patient has not received adequate anticholinergic agents or when the drug is combined with a non-depolarizing muscle relaxant. Atropine may be used to treat bradycardia.

Opioids may cause hypotension, especially in the presence of hypovolemia. Appropriate measures should be taken to stabilize blood pressure.

Dosing considerations. Rapid bolus administration should be avoided in patients with reduced cerebral vascular compliance. In such patients, transient hypotension usually leads to a short-term reduction in cerebral perfusion pressure.

Higher doses may be required in patients who have previously received chronic opioid therapy or who have abused opioids.

Dosage reduction is recommended in elderly or sensitive patients.

Caution is required when increasing the dose in patients with uncontrolled hyperthyroidism, pneumonia, reduced respiratory reserve, alcoholism, or hepatic and renal insufficiency. These patients also require prolonged monitoring.

Epidural administration requires caution in the presence of existing respiratory depression or functional respiratory discomfort, as well as in cases of fetopathy. Due to the early onset of respiratory depression, careful monitoring of the patient is required for at least 1 hour after each dose.

Opioid-induced hyperalgesia. Opioid-induced hyperalgesia is a paradoxical response to opioids, in which pain perception increases despite stable or increased opioid exposure. This is a distinct phenomenon from tolerance, which requires higher opioid doses to achieve the same analgesic effect or to manage breakthrough pain. Hyperalgesia may manifest as more intense, more generalized (i.e., less localized) pain or pain in response to normally non-painful stimuli (allodynia), without signs of disease progression. If opioid-induced hyperalgesia is suspected, the opioid dose should be reduced, if possible, or gradually discontinued.

Children. Due to high variability in pharmacokinetic parameters in neonates, there is a risk of overdose or underdosing when administering the drug intravenously during the neonatal period.

The safety and efficacy of the drug for epidural administration in children under 1 year of age have not been established.

Excipients. The medicinal product contains 1.08 mmol (or 24.78 mg) of sodium per 7 ml dose. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Sufentanil showed no teratogenic effects in reproductive studies in animals. However, controlled studies in pregnant women have not been conducted; therefore, the drug should not be used during pregnancy except in cases of clear necessity.

Sufentanil rapidly crosses the human placenta with a linear dependence on maternal concentration. The umbilical vein to maternal vein concentration ratio has been determined to have a coefficient of 0.81.

Chronic use of opioids during pregnancy may lead to neonatal dependence, potentially resulting in abstinence syndrome. If prolonged opioid use is necessary in a pregnant woman, she should be informed of the risk of neonatal abstinence syndrome.

Controlled clinical studies have shown that sufentanil administered during labor as an epidural dose of up to 30 mcg with bupivacaine has no negative impact on maternal or neonatal outcomes. However, intravenous administration of the drug during labor should be avoided. After epidural administration of the maximum total dose of 30 mcg, mean plasma concentrations in the umbilical vein were 0.016 ng/mL. An opioid antagonist should always be readily available for neonatal treatment.

Breastfeeding. Sufentanil is excreted in breast milk. The drug should not be used during breastfeeding due to the potential for analgesic effects in the newborn.

Ability to affect reaction speed when driving or operating machinery. Driving or operating machinery should only be undertaken after sufficient time has elapsed since administration of the drug.

Administration and Dosage

General recommendations. Dosage should be individually determined based on age, body weight, general condition of the patient, concomitant use of other medicinal products, and the type of surgical procedure and anesthesia.

If additional doses are required, the effect of the initial dose should be taken into account.

Epidural administration. Prior to injecting the medicinal product into the epidural space, correct placement of the needle or catheter should be confirmed.

Use for postoperative pain relief: an initial dose of 30–50 mcg usually provides adequate analgesia for 4–6 hours. Additional bolus doses of 25 mcg may be administered if signs of diminishing analgesic effect occur.

The duration of use for postoperative analgesia is limited to a maximum of 24 hours.

Use as an adjunct analgesic during labor: adding 10 mcg of the drug to bupivacaine for epidural administration (0.125–0.25%) provides longer and higher-quality analgesia. If necessary, two repeat injections of the combination may be given. A maximum of 30 mcg of sufentanil may be administered during labor.

Special patient groups.

Elderly patients (aged 65 years and older). Dosage should be reduced in elderly and debilitated patients. Although no increase in plasma elimination half-life has been observed in elderly patients, a higher incidence of cardiovascular changes has been noted.

Children. Epidural administration in children should only be performed by anesthesiologists trained in pediatric epidural anesthesia and management of opioid-induced respiratory depression. Appropriate resuscitation equipment, including airway support devices, and an opioid antagonist must be readily available.

Children should be monitored for signs of respiratory depression for at least 2 hours following epidural administration. Available data on epidural use of the drug in children are limited.

Children <1 year of age. There are no data on epidural administration of sufentanil in neonates and infants under 3 months of age, and only limited data in children aged 3 months to 1 year. The safety and efficacy of sufentanil in children under 1 year of age have not been established. Therefore, dosage recommendations cannot be provided for this age group.

Children ≥1 year of age. In clinical studies, a single intraoperative bolus dose of 0.25–0.75 mcg/kg of sufentanil provided analgesia lasting 1–12 hours. The duration of effective analgesia is influenced by the surgical procedure and concomitant epidural administration of amide local anesthetics.

Intravenous administration. To avoid bradycardia, it is recommended to administer low doses of intravenous anticholinergic agents immediately before sufentanil injection.

Use as an adjunct analgesic: in patients undergoing general surgery, initial doses of 0.5–5 mcg/kg of the drug produce profound analgesia. Sympathetic and hormonal responses to surgical stimuli are reduced, resulting in adequate cardiovascular stability. Duration of action is dose-dependent. A dose of 0.5 mcg/kg is usually effective for approximately 50 minutes. Additional doses of 10–25 mcg should be administered according to individual patient needs and expected duration of surgery.

Use as the sole general anesthetic: doses exceeding 5 mcg/kg produce sedation and prolonged, dose-dependent analgesia without the use of additional anesthetics. Furthermore, sympathetic and hormonal responses to surgical stimuli are further reduced. Additional injections of 25–50 mcg are usually sufficient to maintain cardiovascular stability during anesthesia.

Special patient groups.

Elderly patients (aged 65 years and older). Dosage should be reduced in elderly and debilitated patients. Although no increase in plasma elimination half-life has been observed in elderly patients, a higher frequency of cardiovascular changes has been reported.

Children.

Children ≤1 month of age (neonates). Due to high variability in pharmacokinetic parameters in neonates, dosage recommendations cannot be provided.

Children >1 month of age. Premedication with an anticholinergic agent such as atropine is recommended for all doses (unless anticholinergics are contraindicated).

Anesthesia induction. The drug may be administered as a slow bolus injection of 0.2–0.5 mcg/kg over 30 seconds or longer, in combination with an induction anesthetic agent. In major surgical procedures (e.g., cardiac surgery), doses up to 1 mcg/kg may be administered.

Maintenance of anesthesia in patients on mechanical ventilation. The drug may be used as part of balanced general anesthesia. Dosage depends on the dose of concomitantly administered analgesics, as well as the type and duration of the surgical procedure. An initial dose of 0.3–2 mcg/kg administered as a slow bolus injection over 30 seconds may be followed, if necessary, by repeated doses of 0.1–1 mcg/kg, up to a maximum of 5 mcg/kg during cardiac procedures.

Children. The medicinal product is used in children according to the recommendations provided in the section "Administration and Dosage."

Overdose.

Symptoms. Overdose manifests as an intensification of the pharmacological effects of sufentanil. Respiratory depression of varying severity may occur, ranging from bradypnea to apnea.

Treatment. In case of hypoventilation or apnea, oxygenation with controlled ventilation should be performed. A specific opioid antagonist such as naloxone should be administered, bearing in mind that respiratory depression may outlast the effect of the antagonist. Therefore, repeated sequential doses of the antagonist may be required.

If respiratory depression is associated with muscle rigidity, an intravenous muscle relaxant should be administered to facilitate mechanical ventilation.

The patient must be closely monitored, with attention to maintaining adequate body temperature and fluid intake. If hypotension is severe or persistent, hypovolemia should be considered and corrected with parenteral hydration.

Adverse Reactions

Like all opioid analgesics, sufentanil causes miosis and dose-dependent respiratory depression (including fatal outcome). Respiratory depression may recur during the postoperative period. Sufentanil may cause muscle rigidity (including chest wall rigidity) and myoclonic movements.

Clinical study data. The safety of sufentanil was evaluated in 6 clinical studies involving 650 patients who received sufentanil. Of these 650 patients, 78 participated in 2 studies with sufentanil: in these studies, sufentanil was administered intravenously as an anesthetic agent for induction and maintenance of anesthesia in patients undergoing major surgery (coronary artery bypass grafting or open-heart surgery). The remaining 572 patients participated in 4 studies in which sufentanil was administered epidurally as a postoperative analgesic or as an adjunctive analgesic to epidural bupivacaine during labor and normal delivery. All patients received at least one dose of sufentanil, and safety data were collected. According to the pooled data from these clinical studies, the most frequently occurring adverse reactions (> 5 %) were sedation (19.5 %), pruritus (15.2 %), nausea (9.8 %), and vomiting (5.7 %). Table 1 below lists the adverse reactions of sufentanil reported in these studies.

The frequency of adverse reactions is defined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (≥ 1/10,000, including isolated cases).

Table 1. Adverse reactions observed in 6 clinical studies of sufentanil

* Adverse reactions observed only in studies where sufentanil was administered intravenously as an anesthetic agent.

Post-marketing data. Table 2 presents adverse reactions observed following the market release of sufentanil citrate in the context of post-marketing surveillance.

The frequency determined from these spontaneous reports does not reflect the actual frequency as observed in clinical or epidemiological studies due to limited information.

Table 2. Adverse reactions identified during post-marketing use of sufentanil based on spontaneous reports

The inferior vena cava syndrome (or supine hypotensive syndrome) is a common complication during pregnancy. In a placebo-controlled study of epidural sufentanil administration during childbirth, the inferior vena cava syndrome occurred in more than 1% of cases in patients who simultaneously received bupivacaine and epinephrine. Due to the concomitant administration of multiple drugs, it is not possible to clearly determine whether this syndrome is an adverse effect of sufentanil; however, it cannot be excluded that it may be contributed by, for example, the hypotensive properties of the drug.

Children. The frequency, type, and severity of adverse reactions in children are likely consistent with those observed in adults.

Shelf life. 2 years.

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

Incompatibilities. If necessary, the medicinal product may be mixed with the following infusion solutions: 0.9% sodium chloride solution, glucose solution, Ringer's lactate solution.

Packaging.

Injection solution 5 mcg/mL, 2 mL in a vial, 5 vials in a blister pack, 1 blister pack in a cardboard box.

Injection solution 50 mcg/mL, 5 mL in a vial, 5 vials in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity.

41 Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.