Sugammadex - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

N-holinomimetiki

Included in the formulation

Brydan®

solution in / in

Organon, N.V. Netherlands

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

V.03.A.B Antidotes

Pharmacodynamics:

Selective antidote for muscle relaxants rocuronium bromide and vecuronium bromide. Sugammadex is a modified gamma-cyclodextrin, which is a selective binding compound rocuronium bromide and vecuronium bromide. He forms a complex with them in the blood plasma, which leads to a decrease in the concentration of muscle relaxant binding to nicotinic receptors in the neuromuscular synapse. This leads to the elimination of neuromuscular blockade caused by rocuronium bromide or vecuronium bromide.

Sugammadex can be used at various times after the administration of rocuronium bromide or vecuronium bromide.

Renal failure. Two open clinical trials compared the efficacy and safety of sugammadex in patients with or without severe renal insufficiency undergoing surgical intervention. In one of the studies sugammadex was introduced to eliminate the blockade caused by rocuronium bromide in the presence of 1-2 post-tetanic responses (4 mg / kg, n = 68); in another study sugammadex were introduced at the appearance of the second response in the four-digit stimulation (T2) mode (2 mg / kg, n = 30).Recovery of neuromuscular conduction after blockade was slightly longer in patients with severe renal insufficiency compared with patients without renal failure. Cases of residual neuromuscular blockade or its resumption in patients with severe renal insufficiency in these studies were not observed.

Effect on the QTc interval. In three clinical studies of sugammadex used in monotherapy or in combination with rocuronium bromide or vecuronium bromide, or in combination with propofol or sevoflurane, there was no clinically significant increase in the QT / QTc interval.

Pharmacokinetics:

The pharmacokinetic parameters of sugammadex are calculated by summing the concentrations of free sugammadex and sugammadex in the sugammadex-muscle relaxant complex. Pharmacokinetic parameters, such as clearance and Vd, are considered the same for sugammadex outside the complex, and sugammadex, which is part of the complex with the muscle relaxant.

After IV introduction to adult patients sugammadex exhibits the following pharmacokinetic properties: a rapid phase distribution with a half-distribution period of 2.9 min; a slow phase of distribution with a half-distribution period of 27 minutes; the elimination half-life is 1.8 h, Vss - 11-14 l. The clearance of the drug is 88 ml / min.

Sugammadex is excreted by the kidneys unchanged. In adult patients with normal renal function who underwent anesthesia, the half-lifesugammadex is about 2.5 hours, and the expected clearance from the plasma is 75 ml / min (based on a pharmacokinetic analysis using a three-compartment model). More than 90% of the dose is excreted within 24 hours. 96% of the dose is excreted in urine, of which 95% is unchanged sugammadex. Less than 0.02% of sugammadex is excreted with feces and with exhaled air.

Pharmacokinetics in special clinical cases

Pharmacokinetic parameters in elderly patients with varying degrees of renal dysfunction, as measured by QC, were evaluated using population pharmacokinetic analysis.

The results of two pharmacokinetic studies comparing patients with severe renal insufficiency and patients with normal renal function,that the plasma sugammadex concentrations were similar for at least the first 20 min after administration of the drug and subsequently decreased in the control group. The total duration of action of sugammadex in patients with impaired renal function was increased, which was expressed in almost 15-fold of its lengthening. In some patients with severe renal failure, the minimum concentrations of sugammadex were determined in the plasma even 1 month after the administration of the drug.

Indications:

- elimination of neuromuscular blockade caused by rocuronium bromide or vecuronium bromide;

- elimination of neuromuscular blockade caused by rocuronium bromide in children aged 2 years and adolescents in standard clinical situations.

ICD-10

XIX.T36-T50.T48 Poisoning with drugs that are effective for smooth and skeletal musculature and respiratory organs

Contraindications:

- renal failure of severe degree (CK <30 ml / min);

severe hepatic impairment;

- Pregnancy;

- the period of breastfeeding;

- Children under 2 years;

- Hypersensitivity to the components of the drug.

Carefully:

Application during lactation

Pregnancy and lactation:

Application in pregnancy and during breastfeeding is not recommended, due to the lack of sufficient clinical observations. Use sugammadex women in the period of breastfeeding should be cautious.

The category of FDA recommendations is not defined.

Dosing and Administration:

Sugammadex at a dose of 4 mg / kg is recommended to be administered when the recovery of neuromuscular conduction reached the level of 1-2 post-tetanic contractions (in the post-tetanic count (PTS) mode) after a blockade caused by rocuronium bromide or vecuronium bromide. The mean time to complete recovery of neuromuscular conduction (recovery of the ratio of the amplitudes of the fourth and the first responses in the four-digit stimulation (T4 / T1) to 0.9) is approximately 3 minutes. Sugammadex at a dose of 2 mg / kg is recommended to be administered when spontaneous recovery of neuromuscular conduction after blockade caused by rocuronium bromide or vecuronium bromide reached at least 2 responses in the four-digit stimulation (TOF) mode. The average time to restore the ratio of T4 / T1 to 0.9 is about 2 minutes.

When sugammadex is administered at recommended doses to restore neuromuscular conduction in standard clinical situations, a faster recovery of the T4 / T1 ratio to 0.9 occurs when the neuromuscular blockade is caused by rocuronium bromide compared to vecuronium bromide.

Emergency elimination of neuromuscular blockade caused by rocuronium bromide

If there is a need for immediate restoration of neuromuscular conduction in the blockade caused by rocuronium bromide, the recommended dose of sugammadex is 16 mg / kg.

When sugammadex was administered at a dose of 16 mg / kg 3 minutes after the bolus dose of 1.2 mg / kg of rocuronium bromide was administered, the average recovery time of the T4 / T1 ratio to 0.9 was about 1.5 minutes.

Repeated administration of sugammadex

In exceptional situations, with rekurarizatsiya in the postoperative period, after the administration of sugammadex at a dose of 2 mg / kg or 4 mg / kg, the recommended repeated dose of sugammadex is 4 mg / kg. After the introduction of a repeated dose of sugammadex, it is necessary to monitor the neuromuscular conduction until the complete restoration of the neuromuscular function.

Side effects:

Complications of anesthesia

The appearance of motor activity, coughing during anesthesia or during the most operative intervention, which reflects the restoration of neuromuscular function.

Unintentional preservation of consciousness during anesthesia

In patients who received sugammadex, in some cases there was an unintentional restoration of consciousness during anesthesia. However, the connection with the administration of sugammadex was regarded as unlikely.

Renewal of neuromuscular blockade

The incidence of blockade recurrence, which was assessed by monitoring neuromuscular conduction, was 2% after the administration of sugammadex. However, this frequency was noted in cases of sub-optimal dose of sugammadex (less than 2 mg / kg).

Hypersensitivity reactions

Hypersensitivity reactions after application of sugammadex, incl. and anaphylactic, were observed in several people, incl. from volunteers. In clinical trials in patients undergoing surgical treatment, these reactions were rare, and data on the incidence of such reactions after drug delivery is not available.

Clinical manifestations of hypersensitivity reactions ranged from isolated cutaneous to severe systemic reactions (ie anaphylaxis, anaphylactic shock) and were noted in patients who had not previously received sugammadex.

Symptoms that accompany these reactions may include redness, urticaria, erythematous rash, a sharp decrease in blood pressure, tachycardia, edema of the tongue and larynx. Severe hypersensitivity reactions can be fatal.

Patients with lung diseases.

When managing patients with complications from the lungs in an anamnesis, the doctor should always remember the possibility of developing bronchospasm.

Overdose:

So far, one report has been received about a random overdose of the drug at a dose of 40 mg / kg. There were no significant side effects. Sugammadex is well tolerated in doses up to 96 mg / kg with no side effects associated with or unrelated to the dose.

Treatment: it is possible to remove sugammadex from the bloodstream by hemodialysis using a filter with high hydraulic permeability, but not a filter with low hydraulic permeability.Based on clinical studies after a 3-6-hour hemodialysis session with a filter with high hydraulic permeability, the concentration of sugammadex in plasma decreases by approximately 70%.

Interaction:

Interaction by the type of binding (hormonal contraceptives)

Due to the administration of sugammadex, the effectiveness of certain drugs may decrease due to a decrease in their (free) plasma concentration. In such a situation, it is necessary either to reintroduce this medication, or to prescribe a therapeutically equivalent drug (preferably another chemical class).

Interaction due to the displacement of the muscle relaxant from the complex with sugammadex.

Due to the introduction of some drugs after the application of sugammadex theoretically rocuronium bromide and vecuronium bromide can be displaced from the complex with sugammadex, resulting in a renewal of neuromuscular blockade. In such cases, the use of mechanical ventilation should be resumed. Infusion introduction of the drug, which led to the displacement of rocuronium bromide or vecuronium bromide from the complex with sugammadex, should be discontinued.In the case of the development of interaction by the type of displacement after parenteral administration of another drug (which was done within 6 hours after sugammadex administration), it is necessary to carry out constant monitoring of the level of neuromuscular conduction in order to identify signs of resumption of the blockade. Interactions by the type of displacement are possible after the administration of the following drugs: toremifene, flucloxacillin and fusidic acid.

Clinically significant pharmacodynamic interaction with other drugs can be expected:

- for toremifene, flucloxacillin and fusidic acid, interactions by the type of displacement are not excluded (clinically important interaction by binding type is not expected);

- for hormonal contraceptives, the possibility of interaction by the type of binding is not excluded (clinically significant interaction by the type of displacement is not expected).

Interaction, potentially affecting the effectiveness of sugammadex

Toremifene, which has a relatively high binding constant and relatively high plasma concentrations, is able to displace to some extent vecuronium bromide or rocuronium bromide from the complex with sugammadex.Therefore, the restoration of the ratio of T4 / T1 to 0.9 may be delayed in patients who received toremifene on the day of surgery.

The introduction of fusidic acid in the preoperative period may lead to some delay in the restoration of the TOF (T4 / T1) ratio to 0.9. However, in the postoperative period, the development of the recurrence is not expected, since the infusion rate of fusidic acid is more than several hours, and its cumulation in the blood is more than 2-3 days.

Interactions that potentially affect the effectiveness of other drugs

Hormonal contraceptives. The interaction between sugammadex (4 mg / kg) and progesterone may lead to a decrease in the exposure of the progestogen (34% AUC), which is similar to the decrease seen with a daily oral dose of 12 hours later, which in turn can lead to a decrease effectiveness of contraception. For estrogens, one can also expect a decrease in the effect. Therefore, the administration of a bolus dose of sugammadex is considered equivalent to a single missed daily dose of oral hormonal contraceptives (combined or containing only progestogen).If the oral contraceptive was approved on the day of application of sugammadskas, you should refer to the section on oral contraceptive application that describes the steps for skipping the dose.

In the case of hormonal contraceptives having a non-oral route of administration, the patient should use an additional non-hormonal contraceptive method for the next 7 days and seek information on the instructions for using this contraceptive.

Impact on laboratory performance

Generally sugammadex does not affect laboratory tests with the possible exception of the test for the quantitative determination of progesterone in the blood serum.

Pharmaceutical incompatibility.

The drug should not be mixed with other drugs and solutions except recommended. If the drug is injected through a single infusion line with other drugs, it must be rinsed (eg with 0.9% sodium chloride solution) between sugammadex and other drugs.

The physical incompatibility of sugammadex was observed with verapamil, ondansetron and ranitidine.

Special instructions:

Monitoring respiratory function during recovery of neuromuscular conduction. It is necessary to carry out mechanical ventilation before the complete restoration of adequate independent breathing after the removal of the neuromuscular blockade. Even if there was a complete recovery of neuromuscular conduction, other drugs that were used during the peri- and postoperative periods may depress respiratory function, and therefore prolonged ventilation may be required.

If after extubation the neuromuscular blockade re-develops, adequate ventilation should be provided in time

Renewal of neuromuscular blockade.

Re-development of neuromuscular blockade was observed mainly in cases when suboptimal (insufficient) doses of the drug were administered. To prevent the resumption of neuromuscular blockade, doses below recommended levels should not be used.

Based on the pharmacokinetic model, the time interval through which 0.6 mg / kg of rocuronium bromide or 0.1 mg / kg of vecuronium bromide can be re-introduced after sugammadex is administered to patients with mild to moderate renal failure should be 24 hours.In the event that a shorter time period is required to resume neuromuscular blockade, the dose of rocuronium bromide should be 1.2 mg / kg.

Repeated administration of rocuronium bromide or vecuronium bromide after immediate removal of neuromuscular blockade (16 mg / kg sugammadex).

In rare cases, when immediate removal of the neuromuscular block is necessary, the recommended time interval for repeated administration of muscle relaxants is 24 hours.

If there is a need for a neuromuscular blockade before the expiration of this time, non-steroid muscle relaxants should be used.

The onset of the depolarizing muscle relaxant may be slower than anticipated, due to the fact that a significant portion of the postsynaptic nicotinic receptors may still be occupied by the muscle relaxant.

Impaired renal function

Sugammadex is not recommended for use in patients with severe renal function impairment, including in patients who need dialysis.

Interactions caused by prolonged action of rocuronium bromide or vecuronium bromide.

It should be noted in the instructions for the use of rocuronium bromide or vecuronium bromide on the list of drugs that potentiate neuromuscular blockade. If resumption of neuromuscular blockade occurs, ventilation and re-administration of sugammadex may be required.

Complications of anesthesia

When the recovery of neuromuscular conduction was done intentionally during anesthesia, there were occasional signs of superficial anesthesia (movements, cough, grimaces).

If removal of the neuromuscular blockade occurs during anesthesia, additional doses of anesthetics and / or opioids may be required.

Impaired liver function

Sugammadex is not metabolized in the liver, so studies on patients with impaired liver function were not performed. When using the drug in patients with severe impairment of liver function, special care should be taken. If liver failure is accompanied by coagulopathy, see special instructions for influencing homeostasis.

Application of sugammadex in intensive care.

The use of sugammadex in patients who received rocuronium bromide or vecuronium bromide in the intensive care unit, has not been studied.

Application of sugammadex to eliminate neuromuscular blockade caused by other muscle relaxants (not rocuronium bromide or vecuronium bromide).

Sugammadex should not be used to eliminate the blockade of neuromuscular conduction caused by such muscle relaxants as suxamethonium or benzylisoquinoline compounds.

Sugammadex should not be used to remove neuromuscular blockade caused by other steroid muscle relaxants, as there is no evidence of efficacy and safety for such use. There are only limited data on the elimination of the blockade of neuromuscular conduction caused by pancuronium bromide, but their insufficient number does not allow us to recommend sugammadex to restore neuromuscular conduction in the case of using this muscle relaxant.

Slow recovery

In conditions associated with lengthening the circulation time (cardiovascular diseases, advanced age, renal and hepatic insufficiency), the recovery time of neuromuscular conduction may increase.

Hypersensitivity reactions

The physician should be prepared for possible hypersensitivity reactions and must take the necessary precautions.

Patients on a diet with controlled sodium intake.

In each ml of the solution contains 9.7 mg of sodium. The dose of sodium, equal to 23 mg, can be considered as not containing sodium. If you need to enter more than 2.4 ml of the solution, this should be taken into account in patients on a diet with limited sodium intake.

Influence on hemostasis

In experiments in vitro, an additional increase in APTT and prothrombin time was observed with sugammadex with indirect anticoagulants, unfractionated heparin, low molecular weight heparins, rivaroxaban and dabigatran. In studies in volunteers, doses of sugammadex 4 and 16 mg / kg caused prolongation of mean maximum values of APTT by 17% and 22%, respectively, and prothrombin time (MHO) values by 11-22%, respectively. This limited prolongation of APTT and prothrombin time (MHO) was of short duration (≤30 min).

To date, the clinically significant effect of sugammadex (in the form of monotherapy or in combination with these anticoagulants) on the frequency of peri-or postoperative bleeding has not been revealed.

Given the short-term nature of the limited increase in APTT and the prothrombin time induced by sugammadex (in the form of monotherapy or in combination with the above anticoagulants), it is unlikely that sugammadex increased the risk of bleeding. Since there is currently no information on the use of sugammadex in patients with coagulopathies, they should carefully monitor coagulation parameters in accordance with standard clinical practice.

After the dilution of sugammadex by infusion solutions, the physical and chemical stability of the drug is maintained for 48 hours at a temperature of 2 ° to 25 ° C. When opening a vial containing sugammadex, you must strictly follow the rules of asepsis. The preparation should be started without delay. If sugammadex is applied in a delayed manner, the observance of the time and storage conditions prior to its use is the responsibility of the physician. If the dilution was carried out in uncontrolled and unallocated aseptic conditions, the storage time of the diluted solution should not exceed 24 hours at a temperature of 2 ° to 8 ° C.

Any remains of the contents of vials of infusion lines after application of sugammadex should be destroyed in accordance with the requirements of the region.

Impact on the ability to drive vehicles and manage mechanisms.

It is necessary to avoid the performance of potentially dangerous activities requiring high speed of psychomotor reactions, such as driving a car or controlling machinery.

Instructions

Sugammadex (Sugammadexum)