Brydan - instructions for use, doses, side effects, contraindications

Active substanceSugammadexSugammadex

Similar drugsTo uncover

solution in / in

Dosage form: & nbspsolution for intravenous administration

Composition:

1 ml of the solution contains:

Active substance: sugammadex 100 mg (the claimed amount of active substance corresponds to 108.8 mg of sodium salt of sugammadex or 108.0 mg of sodium salt Org 48302¹).

Excipients: hydrochloric acid q.s. before pH 7.5, sodium hydroxide q.s. before pH 7.5, water for injection up to 1 ml.

¹ ABOUTrg 48302 is a pharmacologically active impurity to sugammadex, which is present in all batches of active substance in the amount of 2-6%.

Description:

Transparent solution from colorless to light yellow color.

Pharmacotherapeutic group:Antitote of muscle relaxants selective

ATX: & nbsp

V.03.A.B Antidotes

Pharmacodynamics:

Mechanism of action

Sugammadex is a modified gamma-cyclodextrin, which is a compound that selectively binds muscle relaxants. It forms a complex with muscle relaxants rocuronium bromide and vecuronium bromide 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.

Pharmacodynamic effects

There was a clear dependence of the effect on the dose of sugammadex, which was administered at different periods of time and at different depths of the neuromuscular block. Sugammadex was administered at doses of 0.5 to 16 mg / kg as after single administration of rocuronium bromide in doses of 0.6, 0.9, 1.0 and 1.2 mg / kg or after administration of vecuronium bromide in a dose 0.1 mg / kg. and after the administration of maintenance doses of these muscle relaxants.

Clinical efficacy and safety

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

Restoration of neuromuscular conduction in the case of deep neuromuscular blockade

In a randomized clinical trial, patients were divided into 2 groups (vecuronium bromide group and rocuronium bromide group). After the last dose of rocuronium bromide and vecuronium bromide 1-2 post-tetanic responses, 4 mg / kg sugammadex, or 70 μg / kg neostigmine were randomly administered.

Time (minutes) from the administration of sugammadex or neostigmine with deep neuromuscular blockade (1-2 post-tetanic responses) after application of rocuronium bromide or vecuronium bromide until the ratio T₄/T₁ up to 0,9:

The drug for creating a neuromuscular block (muscle relaxant)	Used therapy regimens
	Sugammadex (4 mg / kg)	Neostigmine (70 μg / kg)
Rokuronium bromide
N (number of patients)	37	37
Median (min)	2,7	49,0
Varying	1,2-16,1	13,3-145,7
Vecuronium bromide
N (number of patients)	47	36
Median (min)	3.3	49,9
Varying	1,4-68,4	46,0-312,7

Restoration of neuromuscular conduction in the case of an average neuromuscular blockade

In another randomized clinical trial, the patients were divided into 2 groups (vecuronium bromide group and rocuronium bromide group). After the administration of the last dose of rocuronium bromide or vecuronium bromide, when a T₂ 2 mg / kg sugammadex or 50 mkt / kg neostigmine were randomly administered.

Time (min) from administration of sugammadex or neostigmine in explaining the response of T₂ after application of rocuronium bromide or vecuronium bromide until the ratio T₄/ T₁, up to 0,9:

The drug for creating notiromoshechnogo block (muscle relaxant)	Used therapy regimens
	Sugammadex (2 mg / kg)	Neostigmine (50 μg / kg)
Rokuronium bromide
N (number of patients)	48	48
Median (min)	1,4	17,6
Varying	0,9-5,4	3,7-106,9
Vecuronium bromide
N (number of patients)	48	45
Median (min)	2,1	18,9
Varying	1,2-64,2	2,9-76,2

The reversion of the neuromuscular block induced by rocuronium bromide with sugammadex was compared with the reversal of the neuromuscular block induced by cis-atracurium, with the help of neostigmine.For this, after the appearance of the answer T₂ applied sugammadex in a dose of 2 mg / kg or neostigmine at a dose of 50 μg / kg. Sugammadex provided a faster reversion of the neuromuscular block induced by rocuronium bromide, compared with neostigmine used to reverse the neuromuscular block induced by cis-atracurium.

Time (minutes) from the administration of sugammadex or neostigmine when a T₂ after using rocuronium bromide or cis-atracurium until the ratio T₄/ T₁up to 0.9:

The drug for creating a neuromuscular block (muscle relaxant)	Used therapy regimens
	Rokuronium bromide sugammadex (2 mg / kg)	Cis-atracurium and neostigmine (50 μg / kg)
N (number of patients)	34	39
Median (min)	1,9	7,2
Varying	0,7-6,4	4,2-28,2

For immediate reversion

The time to recovery after succinylcholine-induced (1 mg / kg) neuromuscular block was comparable to that of sugammadex (16 mg / kg, 3 min after the administration of muscle relaxant) after rocuronium-induced bromide (1,2 mg / kg) of the neuromuscular block.

Time (minutes) from the administration of rocuronium bromide and sugammadex or succinylcholine until recovery until response T₁ 10%:

The drug for creating a neuromuscular block (muscle relaxant)	Used therapy regimens
	Rokuronium bromide and sugammadex (16 mg / kg)	Succinylcholine (1 mg / kg)
N (number of patients)	55	55
Median (min)	4,2	7,1
Varying	3,5-7,7	3,7-10,5

In the group analysis, the following recovery time with sugammadex (16 mg / kg) was shown after application of rocuronium bromide (1,2 mg / kg).

The time (s) from the administration of sugammadex 3 minutes after the administration of rocuronium bromide until the ratio T₄/ T₁to 0.9, 0.8 or 0.7:

	T₄/ T₁, up to 0.9	T₄/ T₁, before 0,8	T₄/ T₁, up to 0.7
N (number of patients)	65	65	65
Median (min)	1,5	1,3	1,1
Varying	0,5-14,3	0,5-6,2	0,5-3,3

Impaired renal function

Two open clinical trials compared the efficacy and safety of sugammadex in patients with or without severe renal dysfunction undergoing surgery.

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 was introduced when a second response appeared in the four-digit stimulation mode (T₂) (2 mg / kg, n = 30). Recovery of neuromuscular conduction after blockade was slightly longer in patients with severe impairmentkidney function compared to patients without impaired renal function. Cases of residual neuromuscular blockade or its renewal in patients with severe renal dysfunction were not observed in these studies.

Influence on the interval QTc

In three clinical trials (n= 287) 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 QT/QTc interval. These data are supported by the analysis of generalized ECG results and undesirable phenomena in phase studies II and III.

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 (Cl) and the volume of distribution (V), are considered the same for sugammadex. located outside the complex, and sugammadex. being in the complex with a muscle relaxant.

Distribution

The observed volume of sugammadex distribution in the stable state of yof adult patients with normal renal function is 11 l to 14 l (based on standard pharmacokinetic analysis without compartmentalization). Neither sugammadex, nor the sugammadex-rocuronium bromide complex binds to blood plasma proteins or erythrocytes. With bolus administration of sugammadex at doses of 1 to 16 mg / kg, its pharmacokinetics is linear.

Metabolism

Sugammadex is excreted by the kidneys unchanged. To date, no precital and clinical studies have shown sugammadex metabolites.

Excretion

In adults with normal renal function who underwent anesthesia, the half-life (T_1/2) sugammadex is about 2 hours, and the expected clearance from the plasma - 88 ml / min. More than 90% of the dose is excreted within 24 hours: 96% of the dose is excreted in the urine, of which 95% is unchanged sugammadex. Less than 0.02% of sugammadex is excreted through the intestine and with exhaled air. The use of sugammadex in healthy volunteers led to an increased excretion of rocuronium bromide in the kidneys in combination with sugammadex.

Special patient groups

Patients with impaired renal function and the elderly

Pharmacokinetic parameters in elderly patients with varying degrees of renal impairment, as measured by the determination of creatinine clearance, were evaluated using population pharmacokinetic analysis.

Results of a pharmacokinetic study comparing patients with severe renal dysfunction and patients with normal renal function showed that sugammadec concentrationscand in plasma were similar within the first hour after administration of the drug and subsequently decreased more rapidly in the control group. Total duration of action sugammadeccand in patients with severe renal dysfunction was increased, which was expressed in 17-fold of its lengthening. In patients with severe renal dysfunction, low concentrations of sugammadeccbut were detected in the plasma for at least 48 hours after the administration of Bradan®.

The results of a second study comparing patients with moderate or severe renal dysfunction to patients with normal renal function showed that the sugammadec clearancecbut gradually decreases and T_1/2 gradually increases with a decrease in kidney function. Pthe 2 times and 5 times higher in patients with moderate and severe renal dysfunction, respectively. Sugammadex It was not detected after 7 days after the dose was given to patients with severe renal dysfunction.

The summarized data of pharmacokinetic parameters of sugammadex with regard to age and renal function are presented below:

Patient parameters				The average value of the projected pharmacokinetic parameters (KB%)
Demographic group	Renal function (creatinine clearance, ml / min)			Clearance ml / min	The volume of distribution (L)	Time half-life (h)
Adults 40 years. 75 kg	Normal		100	88 (22%)	12	2 (21%)
	Disrupted	Lightweight	50	51 (22%)	13	4 (22%)
		Average (moderate)	30	31 (23%)	14	6 (23%)
		Heavy	10	9 (22%)	14	19 (24%)
Elderly 75 years old, 75 kg	Normal		80	75 (23%)	12	2 (21%)
	Disrupted	Lightweight	50	51 (24%)	13	3 (22%)
		Average (moderate)	30	31 (23%)	14	6 (23%)
		Heavy	10	9 (22%)	14	19(23%)
Padolescents 15 years, 56 kg	Normal		05	77 (23%)	9	2 (22%)
	Disrupted	Lightweight	48	44 (23%)	10	3 (22%)
		Average (moderate)	29	27 (22%)	10	5 (23%)
		Heavy	10	8 (21%)	11	17 (23%)
Children 7 years, 23 kg	Normal		51	37 (22%)	4	2 (20%)
	Disrupted	Lightweight	26	19 (22%)	4	3 (22%)
		Average (moderate)	15	11 (22%)	4	5 (22%)
		Heavy	5	3 (22%)	5	20 (25%)

KB-coefficient of variation.

Indications:

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

- elimination of neuromuscular blockade caused by rocuronium bromide, in children and adolescents aged 2 to 17 years.

Contraindications:

- Hypersensitivity to the active substance or to any of the excipients (see section "Composition");

- children up to 2 years;

- severe impairment of kidney function (creatinine clearance <30 ml / min) and / or liver.

Pregnancy and lactation:

Pregnancy

Clinical studies on the use of Bradan ® with the participation of pregnant women have not been conducted.

Studies in animals showed no direct or indirect damaging effect on the course of pregnancy, embryo / fetal development, childbirth and postnatal development.

Apply the drug Brydan® in pregnant women, be careful.

Lactation

There was no study of the allocation of suhammadex to milk in breast-feeding women. Studies in animals have shown that sugammadex penetrates into breast milk.

Absorption of cyclodextrins when taken internally low and has no effect on the infant breastfed after the bolus dose of sugammadex has been administered to the lactating mother.

Apply the drug Brydean^® women in the period of breastfeeding should be cautious.

Fertility

The study of the effect of Brydan® on fertility in humans has not been conducted. Studies in animals have not shown a negative effect.

Dosing and Administration:

Sugammadex should be administered only by an anesthesiologist or under his supervision. To monitor the extent of neuromuscular blockade and the restoration of neuromuscular conductivity, it is recommended that an appropriate monitoring method be used. The recommended dose of sugammadex depends on the degree of neuromuscular blockade, which must be eliminated.

The recommended dose does not depend on the type of anesthesia.

Sugammadex is used to eliminate the blockade of neuromuscular conduction of varying depths caused by rocuronium bromide or vecuronium bromide.

Adults

Elimination of neuromuscular blockade caused by rocuronium bromide or vecuronium bromide in standard clinical situations

Sugammadex at a dose of 4.0 mg / kg is recommended to be administered when the recovery of neuromuscular conduction has reached the level 1-2 post-tetanic contractions (post-tetanic account (PTS)) after blockade caused by rocuronium bromide or vecuronium bromide.

The mean time to complete recovery of neuromuscular conduction (restoration of the ratio of the amplitudes of the fourth and the first responses in the four-digit stimulation mode (T₄/ T₁) to 0.9) is approximately 3 minutes (see the section "Pharmacodynamics").

Sugammadex in a dose 2,0 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 stimulationF). The average time to restore the T ratio₄/ T₁, up to 0.9 is about 2 min (see the section "Pharmacodynamics").

PWhen the recommended doses of sugammadex are used to restore neuromuscular conduction in standard clinical situations, a faster recovery of the T ratio₄/ T₁up to 0.9 occurs when the neuromuscular blockade is caused by rocuronium bromide compared to vecuronium bromide (see the section "Pharmacodynamics").

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 16.0 mg / kg.

When 16.0 mg / kg of sugammadex was administered 3 minutes after the bolus dose of 1.2 mg / kg of rocuronium bromide was administered, the mean recovery time of the T ratio₄/ T₁up to 0.9 is about 1.5 min.

Data on the application of suhammadex in the emergency recovery of neuromuscular conduction in the blockade caused by vecuronium bromide are absent.

Repeated administration of sugammadex

In exceptional situations with rekurarizatsii in the postoperative period (see section "Special instructions"), after administration of sugammadex in 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 neuromuscular conduction until the complete restoration of the neuromuscular function.

Repeated administration of rocuronium bromide or vecuronium bromide after administration of sugammadex

The time intervals through which the muscle relaxants can be re-introduced are listed in the section "Special instructions".

Additional information on the use of the drug in specific patient groups

Impaired renal function

In patients with mild to moderate renal impairment (creatinine clearance ≥ 30and <80 ml / min), doses recommended for adult patients should be used without compromising kidney function.

The use of sugammadex in patients with severe renal dysfunction, including patients who are on program hemodialysis (creatinine clearance <30 mL / min) is contraindicated (see section "Contraindications"). The results of studies of the use of the drug in patients with severe renal dysfunction did not provide sufficient safety data, which would recommend the use of sugammadex in this group of patients (see the section "Pharmacodynamics").

Elderly patients

After the administration of sugammadex in the presence of 2 responses in the TOF stimulation against the blockade caused by rocuronium bromide, the total recovery time of neuromuscular conduction (T ratio₄/ T₁up to 0.9) in adult patients (18-64 years) averages 2.2 minutes, in elderly patients (65-74 years) 2.6 minutes and in very elderly patients (75 years and more) 3, 6 min. Although the recovery time of neuromuscular conduction in elderly patients is slightly higher, doses of sugammadex are recommended to be the same as for adult patients in the usual age group (see section "Special instructions").

Patients with obesity

In patients with obesity, the dose of sugammadex should be calculated based on the actual body weight. It is necessary to follow the recommended doses proposed for adult patients.

Patients with impaired hepatic function

In patients with mild and moderate impairment of liver function, the recommended dose of the drug remains the same as in adult patients, since sugammadex is excreted mostly by the kidneys. Due to the lack of data on the use of sugammadex in patients with severe impairment of liver function and in cases where a violation of liver function is accompanied by coagulopathy, sugammadex is recommended with extreme caution (see section "Special instructions").

Use of the drug in children

Data on the use of suhammadex in children are limited. There are data on the administration of the drug to eliminate neuromuscular blockade caused by rocuronium bromide, with the appearance of 2 responses in the mode TOF stimulation.

Children from 2 years and teenagers

To eliminate neuromuscular blockade caused by rocuronium bromide, in standard clinical practice in children and adolescents (2-17 years) it is recommended to administer sugammadex in a dose of 2 mg / kg (if there are 2 responses in the mode TOF stimulation).

Other situations of recovery of neuromuscular conduction, found in standard practice, have not been studied, so in these cases, sugammadex is not recommended until further data are received.

Emergency recovery of neuromuscular conduction in the administration of sugammadex in children from 2 years and adolescents was not studied, and therefore in these situations, the use of the drug is not recommended until further data are available.

To increase the accuracy of dosing in children, the drug Bradan® at a dosage of 100 mg / ml, should be diluted to 10 mg / ml (see section "Method of administration").

Children under 2 years

There is limited experience with sugammadex in children aged 30 days to 2 years and no experience with newborns (up to 30 days). In this regard, the use of sugammadex in this group of patients is contraindicated.

Mode of application

Sugammadex is administered intravenously as a single bolus injection, which is administered within 10 seconds to the intravenous system (see section "Special instructions").

The drug Brydan® can be introduced into onesystem for intravenous administration along with the following infusion solutions: 0.9% (9 mg / ml) with sodium chloride solution; 5% (50 mg / ml) with glucose solution; 0.45% (4.5 mg / ml) with sodium chloride solution with 2.5% (25 mg / ml) glucose solution; Ringer's solution with lactic acid; Ringer's solution; 5% (50 mg / ml) solution of glucose in 0.9% (9 mg / ml) solution of sodium chloride.

The infusion system should be thoroughly washed (eg with 0.9% sodium chloride solution) between the use of Bradan ® and other preparations.

For use in children, Bradan® should be diluted 0.9% (9 mg / ml) with a solution of sodium chloride to a concentration of 10 mg / ml.

Side effects:

The safety of sugammadex was evaluated and studies involving 3519 patients by combining the safety data base obtained from clinical phase studies I-III.

In a group of pooled placebo-controlled trials in which patients received anesthesia and / or neuromuscular blockers (1078 participants in the sugammadex study compared with 544 participants in the placebo group), the following adverse reactions were observed in ≥2% of patients who received sugammadex, which is at least twice as high as in the placebo group:

System-Organ Class	Side effect (preferred term)	Sugammadex	Platsebo
System-Organ Class	Side effect (preferred term)	N = 1078	N = 544
		%	%
Injuries, poisonings and procedural complications	Complication in the airways after anesthesia	4	0
	Complications of anesthesia	3	<1
	Arterial hypotension due to procedure	3	2
	Pprocedural complications	2	1
Disturbances from the respiratory system, chest and mediastinal organs	Cough	5	2

In clinical trials, the complications observed during anesthesia or surgical procedure and described by the researcher using the appropriate terms were grouped according to the following categories of adverse events, and included:

Complications of respiratory anesthesia

Complications of respiratory organs associated with anesthesia included resistance to the endotracheal tube, cough, a slight motor reaction to the introduction of the endotracheal tube, a CNS activation reaction during a surgical procedure, a cough during the administration of anesthesia or performing a surgical procedure, or spontaneous breathing of the patient associated with anesthesia .

Complications of anesthesia

The appearance of motor activity, coughing, grimace, retraction of the endotracheal tube during anesthesia or during the most operative intervention, which reflects the restoration of neuromuscular function (see section "Special instructions").

Complications caused by procedures

Complications caused by procedures include coughing, tachycardia, bradycardia, movement and increased heart rate.

Description of some unwanted reactions

Renewal of neuromuscular blockade

In clinical trials involving patients who received rocuronium bromide or vecuronium bromide, with the use of sugammadex at the dose shown for the corresponding depth of the neuromuscular blockade (N = 2022), the neuromuscular block resumption rate, estimated by monitoring neuromuscular conduction or clinical data, was 0.20% (see "Specific guidance" ).

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactic, were observed in several people, including volunteers (see subsection "Information on healthy volunteers") after applying sugammadex.In clinical trials in patients undergoing surgical treatment, these reactions were rare, and data on the frequency of development of such reactions after the release of the drug on the market are absent.

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, swelling of the tongue and pharynx, bronchospasm, and seizures associated with obstructive pulmonary disease. Severe hypersensitivity reactions can be fatal.

Information about healthy volunteers

A randomized, double-blind study on the incidence of hypersensitivity reactions was conducted with the participation of healthy volunteers who received up to 3 repeated doses of placebo (N = 76), sugammadex in a dose of 4 mg / kg (N = 151) or sugammadex in a dose of 16 mg / kg (N = 148). Reports on suspected hypersensitivity were considered by the Commission using a blind method.The incidence of recognized hypersensitivity was 1.3%, 6.6% and 9.5% in placebo, sugammadex 4 mg / kg and sugammadex 16 mg / kg, respectively. Reports of anaphylaxis cases after placebo or sugammadex 4 mg / kg were not available. One case of recognized anaphylaxis was observed after the first dose of sugammadex was administered at 16 mg / kg (incidence 0.7%). Any evidence of an increase in the frequency or severity of hypersensitivity after the application of a repeated dose of sugammadex was not detected.

In a previous similar study, three cases of anaphylaxis occurred after administration of sugammadex 16 mg / kg (incidence rate 2.0%).

The most common adverse reaction in the group of healthy volunteers was dysgeusia (10%).

Pronounced bradycardia

In post-registration studies, individual cases of severe bradycardia with cardiac arrest within a few minutes after sugammadex administration were eliminated when neuromuscular blockade was eliminated (see section "Special instructions"). Careful observation of patients with changes in hemodynamic parameters during and after the removal of neuromuscular blockade is necessary.In case of severe bradycardia, treatment with cholinergic blockers (for example, atropine) should be performed.

Additional information about some patient groups

Patients with bronchopulmonary diseases

In post-registration clinical study with patients with bronchopulmonary disease in history, bronchospasm was observed in patients. Possible cause and effect relationship of this phenomenon with the use of the drug Brydan®. The physician should be aware of the possible development of bronchospasm in patients with bronchopulmonary diseases in the anamnesis.

Children

Limited data show that the safety profile of sugammadex (up to 4 mg / kg inclusive) in children was the same as in adults.

Overdose:

So far, according to clinical studies, one report of a random overdose of the drug at a dose of 40 mg / kg. There were no significant side effects. Sugammadex was used in doses up to 96 mg / kg with no side effects associated with or unrelated to the dose. Concerning hemodialysis, see the section "Special instructions".

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:

The information presented in this section on the ability to bind sugammadex to other drugs was obtained on the basis of preclinical and clinical studies, as well as modeling, taking into account the pharmacodynamic effects of neuromuscular blockers and the pharmacokinetic interaction between neuromuscular blockers and sugammadex.

It is not expected clinically significant pharmacodynamic interaction of sugammadex with other drugs, except for clinically significant pharmacodynamic interaction with drugs:

- toremifene and fusidic acid interactions are not excluded by the type of displacement (clinically significant interaction by binding type is not expected) 4

- for hormonal contraceptives, the possibility of interaction in the type of binding is not excluded (clinically important interaction but type of embryo is not expected).

Interactions, potentially affecting the effectiveness of sugammadex (see also section "Dosing and Administration")

Toremifene

Toremifene, which has a relatively high affinity with sugammadex and for which a relatively high plasma concentration may occur, is able to displace to some extent vecuronium bromide or rocuronium bromide from the complex with sugammadex. Therefore, the restoration of the ratio T₄/ T₁ up to 0.9 may be delayed in patients who received toremifene in the day of the operation.

Fusidic acid with intravenous administration

The introduction of fusidic acid in the preoperative period may lead to some delay in recovery 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 (see also section "Dosing and Administration")

Hormonal contraceptives

The interaction between sugammadex (4 mg / kg) and progesterone may lead to a decrease in progesterone exposure (34% AUC), which is similar to the decrease observed when taking a daily dose of oral contraceptive 12 hours later than usual, which, in turn, can lead to a decrease in the 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 one missed daily dose of oral hormonal contraceptives (combined or containing only progesterone).

If oral contraceptive was taken on the day of application of sugammadex, refer to the section on oral contraceptive use, describing 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. A possible exception is a test for the quantitative determination of progesterone in the blood serum (at a concentration of suhammadex in blood plasma 100 μg / ml).

Children

Special studies in children to study the interaction of the drug Brydan^® with other medicines has not been carried out. When using the drug in children, it is necessary to take into account the data obtained from adults, as well as the information presented in the section "Special instructions".

Possible types of interaction

Interactions by binding type

Due to the administration of sugammadex, the effectiveness of certain drugs may decrease due to a decrease in their (free) plasma concentration (see section "Interaction with other drugs", subsection "Hormonal contraceptives"). In this situation, it is necessary either to reintroduce this medication, or to prescribe a therapeutically equivalent drug (preferably of another chemical class) and / or the corresponding non-pharmacological effect.

Interactions 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. PAppropriate types of interaction are observed only with certain drugs (eg, toremifene, fusidic acid (see section "Interaction with other drugs")). As a result of the use of these drugs, neuromuscular blockade can be resumed. In such cases it is necessary to resume the use of artificial ventilation. Infusion introduction of the preparation, 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 the parenteral administration of another drug (which was done within 7.5 hours after application of suhammadex), it is necessary to carry out a constant control (approximately 15 minutes) after the level of neuromuscular conduction to identify signs of renewal blockade.

Clinically significant pharmacodynamic interaction with other drugs can be expected:

- for toremifene and fusidic acid, interactions by the type of displacement are not excluded (a clinically significant interaction but the type of binding 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).

More detailed information on the temporal increases in coagulation parameters observed in clinical trials, as well as on in vino interaction with anticoagulants, see the section "Special instructions".

Pharmaceutical incompatibility

The drug Brydan^® should not be mixed with other drugs and solutions, except those specified in the section "Method of administration and dose".

If Bradan® is injected through a single infusion line with other medications, it must be washed (for example, 0.9% solution of sodium chloride) after the administration of Brydean^®.

Physical incompatibility sugammadex was observed with verapamil, ondansetron and ranitidine.

Special instructions:

In normal anesthetic practice, when using anesthesia accompanied by neuromuscular blockade, it is recommended that patients be monitored during the postoperative period for the development of adverse events, including repeated neuromuscular blockade.

Monitoring respiratory function during recovery of neuromuscular conduction

To carry out artificial ventilation of the lungs is necessary until 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 artificial ventilation may be required.

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

Influence on hemostasis

In studies on volunteers, doses of sugammadex 4 mg / kg and 16 mg / kg caused prolongation of mean maximum values of activated partial thromboplastin time by 17% and 22%, respectively, and prothrombin time (INR - normalized normal ratio) by 11% and 22%, respectively.This limited prolongation of activated partial thromboplastin time and prothrombin time (INR) was of short duration (≤ 30 min).

Analysis of the clinical database (N = 3519) showed that there was no clinically significant effect of sugammadex, used as monotherapy or in combination with anticoagulants, on the frequency of peri- or postoperative bleeding.

In a study involving 1184 patients who underwent surgery and who received concomitant anticoagulant therapy, there was a slight and transient increase in activated partial thromboplastin time and prothrombin time (INR) associated with the use of sugammadex at a dosage of 4 mg / kg, which increased the risk of bleeding by compared with conventional treatment.

In experiments in vitro an additional increase in activated partial thromboplastin time and prothrombin time was observed with sugammadex with vitamin K antagonists, unfractionated heparin, low molecular weight heparins, rivaroxaban and dabigatran.Given the short-term nature of the limited increase in activated partial thromboplastin time and 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 the risk of bleeding has not been systemically studied with the administration of higher than 4 mg / kg doses of sugammadex, coagulation rates should be carefully monitored in accordance with standard clinical practice in patients with diagnosed coagulopathies and in patients taking anticoagulants and sugammadex in a dose of 16 mg / kg.

In patients who received standard postoperative prophylactic therapy with anticoagulants, pharmacodynamic interaction was not clinically important. Caution should be exercised when using sugammadex in patients who are receiving anticoagulant therapy or who received it earlier. An increased risk of bleeding can occur in the following patients:

- with a hereditary deficiency of vitamin K-dependent clotting factors;

- with a history of coagulopathy;

- with coumarin derivatives and INR above 3.5;

- taking anticoagulants and sugammadex in a dose of 16 mg / kg.

If the use of sugammadex is still necessary, the anesthesiologist should evaluate the benefits of using sugammadex and the risk of bleeding, taking into account various factors (bleeding history, type of surgical intervention). Also, patients who are at risk of bleeding, it is necessary to monitor the parameters of hemostasis and clotting of blood.

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 (2-25) ° 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 delayed, the observance of the time and storage conditions prior to its use is the responsibility of the physician. If the dilution was performed in uncontrolled and unallocated aseptic conditions, the storage time of the diluted solution should not exceed 24 h at a temperature of (2-8) ° C.

When storing in the dark place, the contents of the vial should be used for 5 days.

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.

Renewal of neuromuscular blockade

In clinical trials involving patients who received rocuronium bromide or vecuronium bromide, when sugammadex was used at the dose shown for the corresponding depth of the neuromuscular blockade (N = 2022), the neuromuscular block renewal rate, estimated by monitoring neuromuscular conduction or clinical data, was 0.20%. The use of doses lower than those recommended may lead to an increased risk of resumption of neuromuscular blockade after the initial resumption of neuromuscular conduction, and is therefore not recommended (see the "Dosage and Administration" section and the "Side effect" section).

The time intervals through which the muscle relaxants can be re-introduced after the restoration of neuromuscular conduction with sugammadex.

Repeated administration of rocuronium bromide or vecuronium bromide after application of sugammadex (up to 4 mg / kg) is possible at the following intervals:

The minimum time interval	Miorelaxant and dose for administration
5 minutes	1,2 mg / kg rocuronium bromide
4 hours	0,6 mg / kg rocuronium bromide or 0,1 mg / kg of vecuronium bromide

When administered rocuronium bromide at a dose of 1.2 mg / kg for 30 min after the recovery of neuromuscular conduction under the action of the drug Braydan® recurrence of neuromuscular blockade may occur with a delay of about 4 minutes, and duration of neuromuscular blockade may be shortened to about 15 minutes.

Based on the pharmacokinetic model, the time interval through which can be repeatedly administered 0.6 mg / kg rocuronium bromide or 0.1 mg / kg vecuronium bromide sugammadex after application to patients with mild or moderate renal impairment, must be 24 hours. In the case where It takes a shorter time to resume neuromuscular blockade, the dose of rocuronium bromide should should be 1.2 mg / kg.

Repeated administration 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 impairment of renal function, including in patients who need dialysis (see the section "Pharmacodynamics").

Interactions caused by prolonged action of rocuronium bromide or vecuronium bromide

In case of use in the post-operation period of drugs potentially affecting neuromuscular blockade, special attention should be paid to the possible resumption of neuromuscular blockade. Also note 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 is observed, artificial ventilation of the lungs and repeated administration of sugammadex may be required. Information on other possible types of interaction (by type of binding or displacement) is presented in the section "Interaction with other drugs".

Surface anesthesia

When the recovery of neuromuscular conduction was intentionally performed during anesthesia (during clinical trials), signs of superficial anesthesia (movement, cough, grimaces, retraction of the endotracheal tube) were occasionally noted.

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

Pronounced bradycardia

In rare cases, pronounced bradycardia was observed within a few minutes after the administration of sugammadex to eliminate neuromuscular blockade.

Single cases of bradycardia with cardiac arrest are described (see section "Side effect"). Patients should carefully monitor the state of hemodynamics during and after removal of the neuromuscular blockade.Treatment with anticholinergic drugs, such as atropine, should be prescribed if clinically significant bradycardia is observed.

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. In the event that the violation of liver function is accompanied by coagulopathy, see subsection "Influence on hemostasis".

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.

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

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

Sugammadex should not be used to eliminate neuromuscular blockade,caused by other steroid muscle relaxants other than rocuronium bromide or vecuronium bromide, since 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, elderly age (see the section "Dosing and Administration" for elderly patients), an edematous condition (for example, due to severe impairment of liver function)), the recovery time of neuromuscular conduction increase.

Hypersensitivity reactions

The physician should be prepared for the appearance of possible hypersensitivity reactions and must observe the necessary precautions (see the "Side effect" section).

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.

Effect on the ability to drive transp. cf. and fur:

Avoidance of potentially hazardous activities requiring high rates of psychomotor reactions, such as driving vehicle or control mechanisms.

There is no data on the effect of Brydan® on the ability to drive vehicle or control mechanisms.

Form release / dosage:

Solution for intravenous administration, 100 mg / ml.

Packaging:

2 ml or 5 ml in bottles of hydrolytic glass type 1 (EF), sealed with rubber stoppers and crimping aluminum and caps.

Pabout 10 Vials in a cardboard pack together with instructions for use.

Storage conditions:

Store at temperatures between 2 ° C and 30 ° C, in a place protected from light. Not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:For hospitals

Registration number:LSR-003970/10

Date of registration:06.05.2010

Expiration Date:18.10.2016

The owner of the registration certificate:Organon, N.V.Organon, N.V. Netherlands

Manufacturer: & nbsp

ORGANON, N.V. Netherlands

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp17.04.2017

Illustrated instructions

Instructions

Brydan® (Braydan®)