Bridex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRIDEX (BRIDEX)

Composition:

Active substance: sugammadex;

1 ml of solution contains 100 mg of sugammadex (as sugammadex sodium);

Excipients: 1 M sodium hydroxide solution or hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear solution.

Pharmacotherapeutic group. Antidotes. ATC code V03A B35.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Sugammadex is a modified gamma-cyclodextrin that selectively binds neuromuscular blocking agents. It forms a plasma complex with the neuromuscular blocking agents rocuronium and vecuronium, thereby reducing the amount of neuromuscular blocker available to bind to nicotinic receptors at the neuromuscular junction. This results in reversal of neuromuscular blockade induced by rocuronium or vecuronium.

Pharmacodynamic Effects

In dose-effect relationship studies, sugammadex was administered at doses ranging from 0.5 mg/kg to 16 mg/kg during neuromuscular blockade induced by rocuronium (0.6, 0.9, 1.0, and 1.2 mg/kg rocuronium bromide with or without maintenance dosing) or vecuronium (0.1 mg/kg vecuronium bromide with or without maintenance dosing). Sugammadex was administered at various time points and at different depths of blockade. In these studies, a clear dose-response relationship was observed.

Clinical Efficacy and Safety

Sugammadex can be administered at various time points after administration of rocuronium or vecuronium bromide.

Standard Reversal — Deep Neuromuscular Blockade

In the main study, patients were randomized into groups receiving either rocuronium or vecuronium. After the last dose of rocuronium or vecuronium, when 1–2 post-tetanic counts were observed, sugammadex 4 mg/kg or neostigmine 70 μg/kg was administered. The time from initiation of sugammadex or neostigmine administration to recovery of the T4/T1 ratio to 0.9 was:

Time (min) from administration of sugammadex or neostigmine during deep neuromuscular blockade (1–2 post-tetanic counts) induced by rocuronium or vecuronium to recovery of T4/T1 ratio to 0.9

Standard reversal — moderate neuromuscular blockade

In another main study, patients were randomized into groups receiving either rocuronium or vecuronium. After the last dose of rocuronium or vecuronium, upon reappearance of T2, patients were assigned to receive either sugammadex 2 mg/kg or neostigmine 50 mcg/kg. The time from initiation of sugammadex or neostigmine administration to recovery of the T4/T1 ratio to 0.9 was:

Time (min) from administration of sugammadex or neostigmine upon reappearance of T2 after rocuronium or vecuronium to recovery of T4/T1 ratio to 0.9

Reversal of rocuronium-induced neuromuscular blockade with sugammadex was compared to reversal of cisatracurium-induced neuromuscular blockade with neostigmine. Upon reappearance of T2, 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered. Administration of sugammadex resulted in faster reversal of rocuronium-induced neuromuscular blockade compared to reversal of cisatracurium-induced neuromuscular blockade with neostigmine.

Time (min) from administration of sugammadex or neostigmine at reappearance of T2 following rocuronium or cisatracurium administration to recovery of T4/T1 ratio to 0.9

Immediate reversal

Time to recovery from neuromuscular blockade induced by succinylcholine (1 mg/kg) was compared to recovery with sugammadex (16 mg/kg, administered 3 minutes later) following neuromuscular blockade induced by rocuronium (1.2 mg/kg).

Time (min) from administration of rocuronium and sugammadex or succinylcholine to recovery of T1 to 10 %

In the pooled analysis, the following data were obtained regarding recovery time after administration of 16 mg/kg sugammadex following 1.2 mg/kg rocuronium bromide:

Time (min) from sugammadex administration (3 min after rocuronium administration) to recovery of T4/T1 ratio to 0.9, 0.8, or 0.7

Renal impairment

The efficacy and safety of sugammadex use during surgery in patients with severe renal impairment compared to those without were evaluated in two open-label studies. In one study, sugammadex was administered following rocuronium-induced neuromuscular blockade at a post-tetanic count of 1–2 (4 mg/kg; N = 68); in another study, sugammadex was given at reappearance of T2 (2 mg/kg; N = 30). Recovery from neuromuscular blockade was slightly prolonged in patients with severe renal impairment compared to those without renal impairment. In these studies, residual or recurrent neuromuscular blockade was not observed in patients with severe renal impairment.

Effect on QTc interval

In three dedicated clinical studies (N = 287), administration of sugammadex alone, sugammadex in combination with rocuronium or vecuronium, and sugammadex combined with propofol or sevoflurane was not associated with clinically significant QT/QTc prolongation. This conclusion is supported by integrated ECG data and adverse reaction reports from phase 2–3 studies.

Patients with pathological obesity

In a clinical study involving 188 patients diagnosed with pathological obesity, the time to recovery from moderate or deep neuromuscular blockade induced by rocuronium or vecuronium was investigated. Patients received either 2 mg/kg or 4 mg/kg sugammadex, depending on the depth of blockade, dosed based on actual body weight or ideal body weight randomly, in a double-blind study. According to pooled data across all depths of blockade and neuromuscular blocking agents, the mean recovery time to a train-of-four (TOF) ratio ≥ 0.9 was statistically significantly shorter (p < 0.0001) in patients dosed based on actual body weight (1.8 min) compared to those dosed based on ideal body weight (3.3 min).

Children

In a study involving 288 patients aged 2 to < 17 years, the safety and efficacy of sugammadex was compared to neostigmine for reversal of neuromuscular blockade induced by rocuronium or vecuronium. Recovery from moderate blockade to a TOF ratio ≥ 0.9 was significantly faster in the sugammadex 2 mg/kg group compared to the neostigmine group (geometric mean 1.6 minutes for sugammadex 2 mg/kg and 7.5 minutes for neostigmine; ratio of geometric means 0.22, 95% CI (0.16, 0.32), p < 0.0001). Sugammadex 4 mg/kg resulted in reversal of deep blockade with a geometric mean time of 2.0 minutes, similar to results observed in adults. These effects were consistent across all age cohorts (2 to < 6; 6 to < 12; 12 to < 17 years) and for both rocuronium and vecuronium (see section "Posology and method of administration").

Patients with severe systemic diseases

In a study involving 331 patients classified as ASA class 3 or 4, the incidence of treatment-emergent arrhythmias (sinus bradycardia, sinus tachycardia, or other cardiac arrhythmias) following sugammadex administration was evaluated.

In patients receiving sugammadex (2 mg/kg, 4 mg/kg, or 16 mg/kg), the incidence of treatment-emergent arrhythmias was generally similar to that observed with neostigmine (50 mcg/kg up to a maximum dose of 5 mg) + glycopyrrolate (10 mcg/kg up to a maximum dose of 1 mg). The safety profile in ASA class 3 and 4 patients was generally similar to that in adult patients from pooled phase 1–3 studies; therefore, dose adjustment is not required (see section "Undesirable effects").

Pharmacokinetics

Pharmacokinetic parameters of sugammadex were determined based on total concentrations of both free and complex-bound drug. In anesthetized patients, pharmacokinetic parameters such as clearance and volume of distribution are similar for free and complex-bound sugammadex.

Distribution

The steady-state volume of distribution of sugammadex is approximately 11–14 L in adult patients with normal renal function (based on standard non-compartmental pharmacokinetic analysis). Neither sugammadex nor the sugammadex–rocuronium complex binds to plasma proteins or erythrocytes, as demonstrated in vitro using human (male) plasma and whole blood. Following intravenous bolus administration at doses ranging from 1 to 16 mg/kg, sugammadex exhibits linear kinetics.

Metabolism

Metabolites of sugammadex were not detected in preclinical and clinical studies; only renal excretion of unchanged drug was observed as the elimination pathway.

Elimination

In adult patients with normal renal function undergoing anesthesia, the elimination half-life (t½) of sugammadex is approximately 2 hours, and the calculated plasma clearance is approximately 88 mL/min. Mass balance studies showed that more than 90% of the dose is excreted within 24 hours. Of the administered dose, 96% is excreted in urine, of which at least 95% is unchanged sugammadex. Less than 0.02% of sugammadex is excreted in feces and exhaled air. Enhanced renal excretion of rocuronium as part of the complex was observed following sugammadex administration in healthy volunteers.

Special patient groups

Renal function and age

In a pharmacokinetic study comparing patients with severe renal impairment to those with normal renal function, plasma concentrations of sugammadex were similar during at least the first hour after administration, then declined more rapidly in the control group. Total exposure to sugammadex was prolonged, resulting in approximately a 17-fold increase in exposure in patients with severe renal impairment. Low concentrations of sugammadex were detectable for at least 48 hours after administration in patients with severe renal impairment.

In a second study comparing drug effects in patients with moderate or severe renal impairment to those with normal renal function, elimination of sugammadex progressively decreased and t½ progressively increased with decreasing renal function. Exposure was 2-fold and 5-fold higher in patients with moderate and severe renal impairment, respectively. Sugammadex concentrations were not detectable beyond 7 days after dose administration in patients with severe renal impairment.

Pharmacokinetic parameters of sugammadex according to age group and renal function are presented in the table below.

* CV — coefficient of variation.

Sex

No differences depending on sex were observed.

Race

In a study involving healthy volunteers of Japanese and European origin, no clinically significant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in individuals of Black race.

Body Weight

Population pharmacokinetic analysis in adult and elderly patients showed no clinically significant relationship between clearance, volume of distribution, and body weight.

Obesity

In one clinical study involving patients with pathological obesity, sugammadex 2 mg/kg and 4 mg/kg was dosed according to actual body weight (n = 76) or ideal body weight (n = 74). Sugammadex exposure increased linearly with dose when administered based on actual body weight or ideal body weight. No clinically significant differences in pharmacokinetic parameters were observed between patients with pathological obesity and the general population.

Clinical Characteristics

Indications

Adults: for reversal of neuromuscular blockade induced by rocuronium or vecuronium.

Children: sugammadex is recommended for use in children and adolescents aged 2 to 17 years only for standard reversal of neuromuscular blockade induced by rocuronium.

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction

The information presented in this section is based on data regarding binding affinity between sugammadex and other medicinal products, preclinical and clinical studies, modeling using a model that accounts for the pharmacodynamic effects of neuromuscular blockers and sugammadex, as well as pharmacokinetic interaction data between neuromuscular blockers and sugammadex. Based on these data, clinically significant pharmacodynamic interactions with other drugs are not expected, except as outlined below:

• Displacement-type interaction with toremifene and fusidic acid cannot be excluded (capture-type interaction is not expected to be clinically significant);
• Capture-type interaction with hormonal contraceptives cannot be excluded (displacement-type interaction is not expected).

Interactions potentially affecting the efficacy of sugammadex (displacement-type interactions)

Since certain drugs may be administered after sugammadex administration, rocuronium or vecuronium could theoretically be displaced from the sugammadex complex. As a result, recurrence of neuromuscular blockade may occur. In such cases, artificial ventilation of the lungs must be maintained. If the drug causing displacement is being administered by infusion, the infusion should be discontinued. In situations where displacement-type interactions may occur, patients should be closely monitored for signs of recurrent neuromuscular blockade (approximately for 15 minutes) after parenteral administration of other drugs given within 7.5 hours after sugammadex administration.

Toremifene

Toremifene has relatively high binding affinity to sugammadex and may reach relatively high plasma concentrations, thereby increasing the likelihood of displacing vecuronium or rocuronium from the sugammadex complex. Physicians should be aware that recovery of the T4/T1 ratio to 0.9 may be delayed in patients who have received toremifene on the day of surgery.

Intravenous fusidic acid

Preoperative administration of fusidic acid may result in some delay in recovery of the T4/T1 ratio to 0.9. Recurrence of neuromuscular blockade in the postoperative period is not expected, as fusidic acid is administered over several hours and its blood levels persist for 2–3 days.

Interactions potentially affecting the efficacy of other drugs (capture-type interactions)

Following sugammadex administration, certain medicinal products may become less effective due to reduced (free) plasma concentration. If such a situation occurs, physicians are advised to consider re-administering the same drug, a therapeutically equivalent drug (preferably of a different chemical class), and/or, where appropriate, non-pharmacological procedures.

Hormonal contraceptives

An interaction between sugammadex at a dose of 4 mg/kg and progesterone may lead to reduced progesterone activity (34% reduction in AUC), similar to the reduction observed when a daily oral contraceptive dose is taken 12 hours late, potentially resulting in reduced contraceptive efficacy. A reduction in estrogen effect is also expected. Therefore, administration of a bolus dose of sugammadex is considered equivalent to missing one daily dose of an oral steroid contraceptive (combined or progestogen-only). If the oral contraceptive was taken on the day of sugammadex administration, refer to the section in the oral contraceptive’s instruction leaflet describing actions to be taken in case of a missed dose.

In case of using non-oral hormonal contraceptives, the patient should use an additional non-hormonal contraceptive method for the next 7 days and follow the recommendations provided in the contraceptive’s instruction leaflet.

Interactions caused by prolonged effect of rocuronium or vecuronium

When administering drugs in the postoperative period that potentiate neuromuscular blockade, particular attention should be paid to the potential recurrence of neuromuscular blockade. Refer to the medical instructions for rocuronium or vecuronium for a list of specific medicinal products that enhance neuromuscular blockade. If neuromuscular blockade recurs, the patient may require mechanical ventilation or re-administration of sugammadex.

Effect on laboratory tests

Overall, sugammadex does not affect laboratory tests, except possibly for quantitative determination of progesterone in blood serum. An effect on this test was observed at a plasma concentration of sugammadex of 100 mcg/mL (maximum plasma level after a bolus injection of 8 mg/kg).

In a study involving healthy volunteers, administration of sugammadex at doses of 4 mg/kg and 16 mg/kg resulted in a maximum mean prolongation of aPTT (activated partial thromboplastin time) by 17% and 22%, respectively, and of PT (prothrombin time) (INR) (international normalized ratio) by 11% and 22%, respectively. These peak mean prolongations of aPTT and PT (INR) were observed for a short duration (≤ 30 minutes).

In vitro studies demonstrated a pharmacodynamic interaction (prolongation of aPTT and PT) when used with vitamin K antagonists, unfractionated heparin, low-molecular-weight heparinoids, rivaroxaban, and dabigatran.

Children

Formal interaction studies have not been conducted. When treating children, the interactions described above in adult patients should be taken into account, along with the warnings in the section "Special precautions for use".

Special precautions for use

According to standard practice in the post-anesthesia period following neuromuscular blockade, monitoring of the patient is recommended during the postoperative period to detect adverse complications, including recurrence of neuromuscular blockade.

Respiratory function monitoring during recovery

Mechanical ventilation is mandatory until adequate spontaneous respiration has been restored after reversal of neuromuscular blockade.

Even if neuromuscular transmission has been fully restored, other drugs administered during and after surgery may depress respiratory function; for this reason, continued mechanical ventilation may be required.

If neuromuscular blockade recurs after extubation, adequate pulmonary ventilation must be ensured.

Recurrence of neuromuscular blockade

In clinical studies involving patients who received rocuronium or vecuronium, with sugammadex administered at the standard recommended dose to reverse neuromuscular blockade, the incidence of recurrence of neuromuscular blockade based on neuromuscular monitoring or clinical evidence was 0.20%. Use at lower than recommended doses increases the risk of recurrence of neuromuscular blockade after the initial administration and is therefore not recommended.

Effect on hemostasis

In studies involving healthy volunteers, administration of sugammadex at doses of 4 mg/kg and 16 mg/kg resulted in a maximum mean prolongation of activated partial thromboplastin time (aPTT) by 17% and 22%, respectively, and of prothrombin time (international normalized ratio [INR]) by 11% and 22%, respectively. These peak mean prolongations of aPTT and PT (INR) were observed for a short duration (≤30 minutes). Based on clinical data (N = 3519) and a dedicated study involving 1184 patients undergoing hip fracture surgery/joint replacement surgery, no clinically significant effect of sugammadex alone at a dose of 4 mg/kg, or in combination with anticoagulants, on the incidence of bleeding complications during or after surgery was observed.

In vitro studies have shown a pharmacodynamic interaction (prolongation of aPTT and PT) when sugammadex is used concomitantly with vitamin K antagonists, unfractionated heparin, heparinoids with low molecular weight, rivaroxaban, and dabigatran. In patients receiving standard postoperative prophylactic anticoagulant therapy, this pharmacodynamic interaction was not clinically significant. Sugammadex should be used with caution in patients receiving anticoagulants for treatment of an existing or concomitant condition.

An increased risk of bleeding cannot be excluded in patients:

• with congenital deficiency of vitamin K-dependent clotting factors;
• with pre-existing coagulopathies;
• receiving coumarin derivatives, or when INR is above 3.5;
• receiving anticoagulants and sugammadex at a dose of 16 mg/kg.

If there is a medical indication for using sugammadex in such patients, the anesthesiologist should weigh the benefits of treatment against the potential risk of bleeding, taking into account the patient's history of bleeding and the type of planned surgical procedure. Monitoring of hemostasis and coagulation parameters is recommended when sugammadex is administered to such patients.

Recurrence of neuromuscular blockade

In clinical studies involving patients who received rocuronium or vecuronium, with sugammadex administered at the standard recommended dose to reverse neuromuscular blockade (N = 2022), the incidence of recurrence of neuromuscular blockade based on neuromuscular monitoring or clinical evidence was 0.20%. Use at lower than recommended doses increases the risk of recurrence of neuromuscular blockade after the initial administration and is therefore not recommended.

Waiting time before re-administration of neuromuscular blockers after reversal with sugammadex

Re-administration of rocuronium or vecuronium after standard reversal (up to 4 mg/kg sugammadex):

The onset of neuromuscular blockade may be prolonged by approximately 4 minutes, and the duration of neuromuscular blockade may be shortened by approximately 15 minutes after repeated administration of rocuronium at a dose of 1.2 mg/kg within 30 minutes following sugammadex administration.

Based on pharmacokinetic modeling results, for patients with mild to moderate renal impairment, the recommended time interval before re-administration of rocuronium at a dose of 0.6 mg/kg or vecuronium at a dose of 0.1 mg/kg after standard reversal of neuromuscular blockade by sugammadex is 24 hours. If a shorter interval is required, the dose of rocuronium for new neuromuscular blockade should be 1.2 mg/kg.

Re-administration of rocuronium or vecuronium after immediate reversal (16 mg/kg sugammadex)

In very rare cases, when this is necessary, the waiting time is 24 hours.

If neuromuscular blockade is required earlier than the recommended waiting time, non-depolarizing neuromuscular blocking agents should be used. The onset of action of a depolarizing neuromuscular blocker may be slightly delayed compared to expected, as the majority of postsynaptic nicotinic receptors may still be occupied by the neuromuscular blocking agent.

Renal impairment

The use of sugammadex is not recommended in patients with severe renal impairment, including patients requiring dialysis (see section "Dosage and administration").

Light anesthesia

In clinical trials, when neuromuscular blockade was intentionally reversed in the middle of anesthesia, signs of light anesthesia (movement, coughing, grimacing, or biting the endotracheal tube) were sometimes observed. If neuromuscular blockade has been reversed while anesthesia is still effective, additional doses of anesthetic and/or opioid should be administered to the patient as clinically indicated.

Profound bradycardia

In isolated cases, profound bradycardia has been observed within several minutes after sugammadex administration for reversal of neuromuscular blockade. Occasionally, bradycardia may lead to cardiac arrest. Careful hemodynamic monitoring should be performed during and after reversal of neuromuscular blockade. If clinically significant bradycardia occurs, anticholinergic agents such as atropine should be administered.

Hepatic impairment

Sugammadex is not metabolized or eliminated by the liver; therefore, no targeted studies have been conducted in patients with hepatic impairment. Treatment of patients with severe hepatic impairment should be undertaken with great caution. In cases of hepatic impairment associated with coagulopathy, refer to the above information regarding effects on hemostasis.

Use in intensive care

The use of sugammadex in patients who have received rocuronium or vecuronium in intensive care settings has not been studied.

Use for reversal of neuromuscular blocking agents other than rocuronium or vecuronium

Sugammadex should not be used to reverse blockade caused by non-depolarizing neuromuscular blocking agents such as succinylcholine or benzylisoquinoline compounds.

Sugammadex should not be used to reverse neuromuscular blockade caused by steroidal neuromuscular blocking agents other than rocuronium and vecuronium, due to lack of information on efficacy and safety in such cases.

Sugammadex is not recommended for reversal of neuromuscular blockade caused by pancuronium, as there is insufficient information on its use in such cases.

Delayed recovery

In conditions associated with reduced blood flow, such as cardiovascular disease, advanced age (see section "Dosage and administration" regarding recovery time in elderly patients), edema (e.g., in severe hepatic impairment), recovery time may be prolonged.

Hypersensitivity reactions

The physician should be prepared for possible hypersensitivity reactions (including anaphylactic reactions) and take necessary precautionary measures (see section "Adverse reactions").

Sodium

This medicinal product contains up to 9.7 mg of sodium per milliliter, equivalent to 0.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Use during pregnancy or breastfeeding

Pregnancy. There is no clinical information available on the use of sugammadex during pregnancy.

Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Sugammadex should be used with caution in pregnant women.

Breastfeeding. It is unknown whether sugammadex passes into human breast milk.

Animal studies have shown that sugammadex is excreted into breast milk. Oral absorption of cyclodextrin is generally low; no effect on the infant is expected following a single dose of sugammadex administered to a breastfeeding woman.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility. The effect of sugammadex on human fertility has not been studied. Animal fertility studies did not reveal any adverse effects.

Ability to affect reaction speed when driving or operating machinery

There is no information available on the effect of the medicinal product Bridex on the ability to drive or operate machinery.

Method of Administration and Dosage

Bridex should be administered intravenously as a single bolus injection. The bolus injection should be given rapidly, within 10 seconds, via an existing intravenous infusion system.

During clinical trials, sugammadex administration was performed only as a single bolus injection.

Bridex may be administered through the same intravenous infusion system together with the following solutions: 0.9% sodium chloride solution (9 mg/mL); 5% glucose solution (50 mg/mL); 0.45% sodium chloride solution (4.5 mg/mL) and 2.5% glucose solution (25 mg/mL); Ringer's lactate solution; Ringer's solution; 5% glucose solution (50 mg/mL) in 0.9% sodium chloride solution (9 mg/mL).

The infusion system should be thoroughly flushed (e.g., with 0.9% sodium chloride solution) after administration of Bridex prior to administering other drugs.

Use in Children

For use in pediatric patients, Bridex may be diluted with 0.9% sodium chloride solution to a concentration of 10 mg/mL.

Any unused solution should be disposed of according to local requirements.

The medicinal product should be administered only by an anesthesiologist or under their supervision.

Appropriate neuromuscular monitoring techniques are recommended to observe recovery from neuromuscular blockade.

The recommended dose of sugammadex depends on the degree of neuromuscular blockade to be reversed and is independent of the anesthetic regimen.

Sugammadex may be used to reverse various levels of neuromuscular blockade induced by rocuronium or vecuronium.

Adults

Standard reversal of neuromuscular blockade

The recommended dose of sugammadex for recovery reaching at least 1–2 post-tetanic counts during blockade induced by rocuronium or vecuronium is 4.0 mg/kg. The median time to recovery of the T4/T1 ratio to 0.9 is approximately 3 minutes (see section "Pharmacological Properties. Pharmacodynamics").

The recommended dose of the drug for spontaneous reappearance of T2 during blockade induced by rocuronium or vecuronium is 2 mg/kg. The median time to recovery of the T4/T1 ratio to 0.9 is approximately 2 minutes (see section "Pharmacological Properties. Pharmacodynamics").

When recommended doses are used for standard reversal, recovery of the T4/T1 ratio to 0.9 occurs in a slightly shorter median time if neuromuscular blockade was induced by rocuronium compared to vecuronium (see section "Pharmacological Properties. Pharmacodynamics").

Immediate reversal of rocuronium-induced neuromuscular blockade

In cases where immediate reversal of rocuronium-induced neuromuscular blockade is required, the recommended dose of sugammadex is 16 mg/kg. When 16 mg/kg of sugammadex is administered 3 minutes after a bolus dose of 1.2 mg/kg rocuronium bromide, the median time to recovery of the T4/T1 ratio to 0.9 is approximately 1.5 minutes (see section "Pharmacological Properties. Pharmacodynamics").

There are no data on the use of sugammadex for immediate reversal of blockade induced by vecuronium.

Repeat administration of sugammadex

Repeat administration of sugammadex at a dose of 4 mg/kg is recommended only in exceptional cases of recurrence of neuromuscular blockade in the postoperative period (see section "Special Warnings and Precautions for Use") following an initial dose of sugammadex of 2 mg/kg or 4 mg/kg. After administration of a second dose of sugammadex, patients should be carefully monitored to ensure complete recovery of neuromuscular function.

Repeat administration of rocuronium or vecuronium after sugammadex

For information on the interval between repeat administration of rocuronium or vecuronium after sugammadex, see section "Special Warnings and Precautions for Use".

Renal impairment

Use of sugammadex in patients with severe renal impairment, including those requiring dialysis (creatinine clearance < 30 mL/min), is not recommended (see section "Special Warnings and Precautions for Use").

Clinical studies in patients with severe renal impairment have not provided sufficient safety data for sugammadex use in this population (see section "Pharmacological Properties. Pharmacodynamics").

In patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min and < 80 mL/min), the recommended doses are the same as for adults with normal renal function.

Elderly patients

After sugammadex administration at the reappearance of T2 during rocuronium-induced blockade, the median time to recovery of the T4/T1 ratio to 0.9 was 2.2 minutes in adults (18–64 years), 2.6 minutes in elderly patients (65–74 years), and 3.6 minutes in very elderly patients (≥75 years). Although recovery time is prolonged in elderly patients, the recommended dose of sugammadex is the same as for adult patients (see section "Special Warnings and Precautions for Use").

Obese patients

For obese patients, including those with morbid obesity (body mass index ≥ 40 kg/m²), the dose of sugammadex should be based on actual body weight. Recommended dosing guidelines for adult patients should be followed.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. Sugammadex should be used with caution in patients with severe hepatic impairment and in patients with hepatic impairment associated with coagulopathy (see section "Special Warnings and Precautions for Use").

Dose adjustment is not necessary in patients with mild to moderate hepatic impairment, as sugammadex is primarily excreted via the kidneys.

Children

Children and adolescents (from 2 to 17 years of age)

The medicinal product Bridex at a concentration of 100 mg/mL may be diluted to a concentration of 10 mg/mL to optimize dosing accuracy in children (see section "Method of Administration and Dosage").

Standard reversal

The recommended dose of sugammadex for reversal of rocuronium-induced blockade reaching at least 1–2 post-tetanic counts is 4 mg/kg. The recommended dose of sugammadex for reversal of rocuronium-induced blockade at the reappearance of T2 is 2 mg/kg (see section "Pharmacological Properties. Pharmacodynamics").

Immediate reversal

Immediate reversal has not been studied in children and adolescents.

Term newborns and children under 2 years of age

Experience with sugammadex in children (from 30 days to 2 years of age) is limited, and its use in term newborns (under 30 days of age) has not been studied. Therefore, the use of sugammadex in term newborns and children under 2 years of age is not recommended until additional data become available.

Overdose

One case of accidental overdose of sugammadex (40 mg/kg) was reported during clinical trials, with no significant adverse reactions observed. In human tolerance studies, sugammadex was administered at doses up to 96 mg/kg, with no dose-dependent adverse reactions or serious adverse events reported.

Sugammadex can be removed from the body by hemodialysis using a high-flux filter, but not with a low-flux filter. Clinical study data show that plasma concentrations of sugammadex decreased by up to 70% after 3–6 hours of dialysis.

Side effects

Bridex is administered concurrently with neuromuscular blocking agents and anesthetics during surgical procedures in patients. Therefore, it is difficult to assess the causal relationship of adverse events.

During surgical procedures in patients, the most commonly reported adverse reactions were cough, respiratory complications during anesthesia, anesthetic complications, hypotension occurring during the procedure, and procedure-related complications (common — from ≥1/100 to <1/10).

List of adverse reactions

The safety of sugammadex administration was studied in 3519 subjects based on pooled data from phase I–III clinical trials.

In placebo-controlled studies, where subjects received anesthesia and/or neuromuscular blockade (1078 subjects received sugammadex compared to 544 who received placebo), the adverse reactions listed below were reported.

Frequency is defined as follows: very common — ≥1/10, common — from ≥1/100 to <1/10, uncommon — from ≥1/1000 to <1/100, rare — from ≥1/10,000 to <1/1000, very rare — <1/10,000, frequency not known — cannot be estimated from available data.

Description of individual adverse reactions

Hypersensitivity reactions to the drug

Hypersensitivity reactions (including anaphylaxis) have been observed in some patients and healthy volunteers (see section "Data from studies in healthy volunteers" below). During clinical trials involving patients requiring surgery, reports of these reactions were infrequent, while in post-marketing reports the frequency is unknown.

These reactions varied in presentation: from isolated skin reactions to severe systemic reactions (i.e., anaphylaxis, anaphylactic shock) and occurred in patients without prior exposure to sugammadex.

Symptoms associated with these reactions may include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, tongue swelling, throat swelling, bronchospasm, and pulmonary obstructive complications. Severe hypersensitivity reactions may be fatal.

Post-marketing reports have documented hypersensitivity reactions following administration of sugammadex and the sugammadex–rocuronium complex.

Respiratory complications during anesthesia

Respiratory complications during anesthesia include resistance to endotracheal intubation, coughing, moderate resistance, emergence agitation during surgery, coughing during anesthesia procedure or during surgery, or spontaneous breathing by the patient related to the anesthesia procedure.

Anesthesia-related complications

Anesthesia-related complications indicating recovery of neuromuscular function include limb or body movements, coughing during anesthesia or during surgery, facial grimacing, or biting of the endotracheal tube (see section "Special instructions. Light anesthesia").

Procedural complications

Procedural complications include coughing, tachycardia, bradycardia, body movement, and increased heart rate.

Profound bradycardia

During the post-marketing period, isolated cases of profound bradycardia and bradycardia with cardiac arrest were observed within several minutes after sugammadex administration (see section "Special instructions").

Return of neuromuscular blockade

In clinical trials involving patients who received rocuronium or vecuronium, where sugammadex was administered at the standard recommended dose to reverse neuromuscular blockade (N = 2022), the recurrence rate of neuromuscular blockade was 0.20%, based on neuromuscular monitoring or clinical evidence (see section "Special instructions").

Data from studies in healthy volunteers

In a randomized, double-blind study, the incidence of hypersensitivity reactions was evaluated in healthy volunteers who received up to 3 repeated doses of placebo (N = 76), sugammadex 4 mg/kg (N = 151), or sugammadex 16 mg/kg (N = 148). Suspected hypersensitivity reactions were identified by a committee reviewing blinded data. The incidence of suspected hypersensitivity reactions was 1.3%, 6.6%, and 9.5% in the placebo, sugammadex 4 mg/kg, and sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis with placebo or sugammadex 4 mg/kg. One case of suspected anaphylaxis was reported after the first dose of sugammadex 16 mg/kg (incidence 0.7%). There was no evidence of increased frequency or severity of hypersensitivity reactions with repeated dosing of sugammadex.

In a previous study with a similar design, three cases of suspected anaphylaxis were reported, all after administration of sugammadex 16 mg/kg (incidence 2.0%).

In the pooled Phase 1 database, common (≥ 1/100 to < 1/10) or very common (≥ 1/10) adverse reactions occurring more frequently in patients receiving sugammadex than in the placebo group included: dysgeusia (10.1%), headache (6.7%), nausea (5.6%), urticaria (1.7%), pruritus (1.7%), dizziness (1.6%), vomiting (1.2%), and abdominal pain (1.0%).

Additional information on specific populations

Patients with lung disease

During the post-marketing period and in one targeted clinical study involving patients with a history of pulmonary complications, bronchospasm was reported as an adverse reaction possibly related to the drug.

Physicians should be aware of the potential for bronchospasm when prescribing the drug to patients with a history of pulmonary complications.

Children

In studies involving children aged 2 to 17 years, the safety profile of sugammadex (up to 4 mg/kg) was generally similar to that observed in adults.

Patients with pathological obesity

Based on data from a specialized clinical study involving patients with pathological obesity, the safety profile was generally similar to that observed in adult patients in Phase 1–3 studies.

Patients with severe systemic disease

In a study involving patients classified as ASA class 3 or 4 (patients with severe systemic disease or severe systemic disease that is a constant threat to life), the adverse reaction profile was generally similar to that observed in adult patients in Phase 1–3 studies (see section "Pharmacological properties. Pharmacodynamics").

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store in the original packaging to protect from light at a temperature not exceeding 25 °C. Do not freeze.

After first opening, the chemical and physical stability of the solution has been demonstrated for 48 hours at temperatures from 2 °C to 8 °C and at 25 °C. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user — typically, storage should not exceed 24 hours at 2 °C to 8 °C, unless reconstitution is performed under controlled and verified aseptic conditions.

Incompatibilities

Physical incompatibility has been reported with verapamil, ondansetron, and ranitidine.

Bridex must not be mixed with any medicinal products or solutions except those specified in the section "Method and route of administration."

Packaging. 2 ml in a vial, 5 vials in a blister pack, 2 packs in a cardboard box.

Prescription status. Prescription only. For use only under hospital conditions.

Manufacturer. K.T. ROMPHARM COMPANY S.R.L.

Manufacturer's address and location of operations.

Str. Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.