Active ingredients: Sugammadex
BRIDION 100 mg / ml - Injectable Solution
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
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01.0 NAME OF THE MEDICINAL PRODUCT
BRIDION 100 MG / ML SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 mL contains sugammadex sodium equivalent to 100 mg of sugammadex
Each 2 mL vial contains sugammadex sodium equivalent to 200 mg sugammadex
Each 5 mL vial contains sugammadex sodium equivalent to 500 mg sugammadex
Excipient (s) with known effect
Each mL contains up to 9.7 mg of sodium (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, colorless to light yellow solution.
The pH is between 7 and 8 and the osmolarity is between 300 and 500 mOsm / kg.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Antagonism of neuromuscular block induced by rocuronium or vecuronium in adults.
For the pediatric population: sugammadex is only recommended for the routine reversal of rocuronium-induced blockade in children and adolescents 2-17 years of age.
04.2 Posology and method of administration
Dosage
Sugammadex should only be administered by or under the supervision of an anesthetist. The use of an appropriate neuromuscular monitoring technique is recommended to monitor recovery from neuromuscular block (see section 4.4).
The recommended dose of sugammadex depends on the level of neuromuscular block to be reversed.
The recommended dose does not depend on the anesthetic regimen.
Sugammadex can be used to antagonize different levels of neuromuscular block induced by rocuronium or vecuronium.
Adults
Routine antagonism:
If recovery from rocuronium or vecuronium-induced blockade has reached a value of at least 1-2 PTC (Post Tetanus Count), the recommended dose of sugammadex is 4 mg / kg body weight. The median time to recovery of a T4 / T1 ratio of 0.9 is approximately 3 minutes (see section 5.1).
A dose of 2 mg / kg body weight of sugammadex is recommended in the presence of spontaneous recovery until the reappearance of T2 after block induced by rocuronium or vecuronium. The median time to recovery of a T4 / T1 ratio of 0.9 is approximately 2 minutes (see section 5.1).
Use of the recommended doses for routine antagonism results in a median time to recovery of the T4 / T1 ratio slightly faster than 0.9 for rocuronium when compared with vecuronium-induced neuromuscular block (see section 5.1).
Immediate antagonism of rocuronium-induced blockade:
When it is clinically necessary to achieve immediate antagonism after administration of rocuronium, a dose of 16 mg / kg body weight of sugammadex is recommended. When 16 mg / kg body weight of sugammadex is administered 3 minutes after a bolus dose of 1.2 mg / kg body weight of rocuronium bromide, a median time to restore to 0.9 of the ratio can be expected. T4 / T1 of approximately 1.5 minutes (see section 5.1).
There are no data to recommend the use of sugammadex for immediate antagonism after vecuronium-induced blockade.
Re-administration of sugammadex:
In the "exceptional occurrence of new postoperative neuromuscular block (see section 4.4), following an initial dose of 2 mg / kg or 4 mg / kg of sugammadex, it is recommended that a" further 4-dose of sugammadex be administered. mg / kg.
After a second dose of sugammadex, the patient should be monitored closely to ensure valid restoration of neuromuscular function.
Re-administration of rocuronium or vecuronium after sugammadex:
For waiting times for re-administration of rocuronium or vecuronium after antagonism with sugammadex see section 4.4.
Learn more about particular patient populations
Kidney damage:
The use of sugammadex in patients with severe renal impairment (including patients requiring dialysis (ClCr
Studies in patients with severe renal impairment did not provide sufficient information on the safety profile to support the use of sugammadex in these patients (see also section 5.1).
In the presence of mild to moderate renal impairment (creatinine clearance ≥ 30 e
Elderly patients:
After administration of sugammadex and T2 reappearance following rocuronium-induced block, the median time to recovery of the T4 / T1 ratio in adults to 0.9 (18-64 years) was 2.2 minutes. in elderly subjects (65-74 years) of 2.6 minutes and in very elderly subjects (≥ 75 years) of 3.6 minutes. Although recovery times tend to be slower in the elderly, the same dosage recommendations as in adults should be followed (see section 4.4).
Obese patients:
In obese patients the sugammadex dose should be based on actual body weight. The same dosage recommendations as for adults should be followed.
Hepatic impairment:
No studies have been conducted in patients with hepatic impairment. Caution should be exercised when considering the use of sugammadex in patients with severe hepatic impairment or when hepatic impairment is accompanied by coagulopathy (see section 4.4).
In the presence of mild to moderate hepatic impairment: As sugammadex is mainly excreted via the kidney, no dose adjustments are required.
Pediatric population
Data on the pediatric population are limited (only one study for the antagonism of rocuronium-induced blockade upon reappearance of T2).
Children and adolescents:
For the routine antagonism of rocuronium-induced blockade to reappearance of T2 in children and adolescents (2-17 years), the administration of 2 mg / kg of sugammadex is recommended.
Bridion 100 mg / mL can be diluted to 10 mg / mL to increase dose accuracy in the pediatric population (see section 6.6).
Other situations of routine antagonism have not been investigated and are therefore not recommended until further data become available.
The immediate reversal of blockade in children and adolescents has not been studied and is therefore not recommended until further data become available.
Term newborns and infants:
The experience on the use of sugammadex in young children (30 days to 2 years of age) is limited and in full-term infants (less than 30 days old) the use of the drug has not been studied. sugammadex in term infants and young children is therefore not recommended until further data become available.
Method of administration
Sugammadex should be administered intravenously as a single bolus injection. Bolus injection should be administered rapidly, over 10 seconds, into an existing intravenous line (see section 6.6). In clinical studies sugammadex was administered as a single bolus injection only.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
As in normal post-anesthesia practice, after neuromuscular block, it is recommended to monitor the patient in the immediate postoperative period to rule out undesirable events, including the reappearance of neuromuscular block.
Respiratory function monitoring during recovery:
After the antagonism of neuromuscular block, patients should undergo respiratory support until adequate spontaneous breathing is restored. Even if the antagonism of neuromuscular blockade is complete, other medicines used in the peri- and postoperative period may reduce respiratory function and therefore respiratory support may continue to be required.
Adequate ventilation should be provided in the event that neuromuscular block recurs after extubation.
Return of neuromuscular block:
In clinical trials with subjects treated with rocuronium or vecuronium, in which sugammadex was administered using a dose indicated for deep neuromuscular block, a "0.20% incidence of reoccurrence of neuromuscular block was observed based on neuromuscular monitoring or "clinical evidence. Use of lower than recommended doses may lead to an increased risk of neuromuscular block returning after initial antagonism and is not recommended (see section 4.2 and section 4.8).
Effect on hemostasis:
In a study in volunteers doses of 4 mg / kg and 16 mg / kg of sugammadex resulted in prolongations of the mean maximal activated partial thromboplastin time (aPTT) of 17 and 22%, respectively, and of the international normalized ratio of prothrombin time. [PT (INR)] of 11 and 22%, respectively. These mean limited prolongations of aPTT and PT (INR) were of short duration (≤ 30 minutes). Based on clinical databases (N = 3,519) and of a specific study in 1,184 patients undergoing hip fracture surgery / major joint replacement surgery there was no clinically relevant effect of sugammadex given 4 mg / kg alone or in combination with anticoagulants on the incidence of peri- or post-operative.
In studies in vitro A "pharmacodynamic interaction (prolongation of aPTT and PT) with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran was noted. In patients undergoing routine postoperative anti-coagulation prophylaxis, this pharmacodynamic interaction is not clinically relevant. Caution should be exercised when considering the use of sugammadex in patients receiving anti-coagulation therapy for a pre-existing or co-morbid condition.
An increased risk of bleeding cannot be excluded in patients:
• with hereditary deficiencies of vitamin K dependent clotting factors;
• with pre-existing coagulopathies;
• on coumarin derivatives and with an INR greater than 3.5;
• who use anticoagulants and take a dose of 16 mg / kg of sugammadex.
If there is a medical need to administer sugammadex to these patients, the anesthesiologist should decide whether the benefits outweigh the possible risks of bleeding complications, taking into account the patients' history of bleeding and the type of surgery planned. If sugammadex is administered to these patients, monitoring of haemostasis and coagulation parameters is recommended.
Waiting times for re-administration of neuromuscular blocking agents after antagonism with sugammadex:
Re-administration of rocuronium or vecuronium after routine antagonism (up to 4 mg / kg sugammadex):
The onset of neuromuscular block may be prolonged to approximately 4 minutes, and the duration of neuromuscular block may be reduced to approximately 15 minutes after re-administration of 1.2 mg / kg rocuronium within 30 minutes after administration of sugammadex.
Based on PK (pharmacokinetic) modeling in patients with mild or moderate renal impairment the recommended waiting time for reuse of 0.6 mg / kg rocuronium or 0.1 mg / kg vecuronium after routine antagonism with sugammadex it must be 24 hours. If a shorter waiting time is required, the dose of rocuronium for new neuromuscular block should be 1.2 mg / kg.
Re-administration of rocuronium or vecuronium after immediate antagonism (16 mg / kg of sugammadex): for the very rare cases where this may be necessary, a waiting time of 24 hours is recommended.
If neuromuscular blocking is required before the recommended waiting time has elapsed, a non-steroidal neuromuscular blocking agent should be used.
The onset of the effect of a depolarizing neuromuscular blocking agent may be slower than expected, since a substantial fraction of postjunctional nicotinic receptors may still be occupied by the neuromuscular blocking agent.
Kidney damage:
The use of sugammadex is not recommended in patients with severe renal impairment, including those patients requiring dialysis (see section 5.1).
Light anesthesia:
In clinical studies, signs of light anesthesia (movements, coughing, grimacing and sucking of the endotracheal tube) have occasionally been observed in the intentional antagonism of neuromuscular block during anesthesia.
If neuromuscular block is reversed while anesthesia remains, further doses of anesthetic and / or opioid should be administered, as clinically indicated.
Marked bradycardia:
In rare cases, marked bradycardia has been observed within minutes after administration of sugammadex for antagonism of neuromuscular block. Bradycardia can occasionally lead to cardiac arrest (see section 4.8). Patients should be carefully monitored for haemodynamic changes during and after the antagonism of the neuromuscular block. If clinically significant bradycardia is observed, treatment with anticholinergic agents such as atropine should be given.
Hepatic impairment:
As sugammadex is neither metabolised nor excreted via the liver, no studies have been conducted in patients with hepatic impairment. Patients with severe hepatic impairment should be treated with great caution. In case hepatic impairment is accompanied by coagulopathy, see information on effect on haemostasis.
Use in intensive care unit:
Sugammadex has not been studied in patients who received rocuronium or vecuronium in an intensive care unit.
Use for the antagonism of the block induced by muscle relaxants other than rocuronium and vecuronium:
Sugammadex should not be used to reverse blockade induced by non-steroidal neuromuscular blocking agents, such as succinylcholine or benzylisoquinoline compounds.
Sugammadex should not be used to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium and vecuronium, since no data on efficacy and safety are available in these circumstances. Limited data are available on the antagonism of block-induced blockade. pancuronium, but sugammadex should not be used in this circumstance.
Delayed recovery:
Conditions resulting in prolonged circulation time, such as cardiovascular disease, old age (for time to recovery in the elderly see section 4.2) or edematous state (eg severe hepatic impairment), may be associated with longer recovery times.
Drug hypersensitivity reactions:
Physicians should be prepared for the eventuality of drug hypersensitivity reactions (including anaphylactic reactions) and take necessary precautions (see section 4.8).
Patients who must follow a low sodium diet:
Each mL of solution contains up to 9.7 mg of sodium. Products containing 23 mg of sodium are considered to be essentially "sodium free". If more than 2.4 mL of solution is to be administered, this should be considered for patients on a low sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
The information reported in this section is based on the binding affinity between sugammadex and other medicinal products, on non-clinical studies, clinical studies and on simulations performed using a model that took into account the pharmacodynamic effect of neuromuscular blocking agents and the interaction pharmacokinetics between neuromuscular blocking agents and sugammadex Based on these data, no clinically significant pharmacodynamic interactions with other medicinal products are expected, except for the following:
Displacement interactions could not be excluded for toremifene and fusidic acid (clinically relevant seizure interactions are not expected).
For hormonal contraceptives it was not possible to exclude a clinically relevant "seizure interaction (no displacement interactions expected).
Interactions that could compromise the efficacy of sugammadex (displacement interactions):
The administration of some drugs after sugammadex could theoretically displace rocuronium or vecuronium from sugammadex. This could lead to a reappearance of neuromuscular block. In this case the patient must be ventilated. In the event of an infusion, the administration of the drug causing the displacement should be stopped. In conditions where potential displacement interactions can be expected, if another medicinal product is administered parenterally within 7.5 hours following the administration of sugammadex, patients should be monitored closely for signs of reoccurrence of neuromuscular block (for a maximum period of about 15 minutes).
Toremifene:
With respect to toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations may be present, some displacement of vecuronium or rocuronium from sugammadex may occur. Physicians should be aware that restoration a value of 0.9 of the T4 / T1 ratio could therefore be delayed in patients who received toremifene on the same day of surgery.
Intravenous administration of fusidic acid:
The use of fusidic acid in the pre-operative phase can cause some delay in restoring a value of 0.9 of the T4 / T1 ratio. In the post-operative phase the reappearance of neuromuscular block is not expected, since the infusion rate fusidic acid has a duration of several hours and blood levels are cumulative beyond 2-3 days For re-administration of sugammadex see section 4.2.
Interactions that could compromise the efficacy of other medicines (seizure interactions):
Administration of sugammadex may cause a reduction in the efficacy of some medicinal products due to reduced (free) plasma concentrations. If this is observed, the physician should consider re-administering the medicinal product, administering an equivalent medicinal product. from the therapeutic point of view (preferably from a different chemical class) and / or to intervene in a non-pharmacological way, depending on what is more appropriate.
Hormonal contraceptives:
It has been estimated that the interaction between 4 mg / kg of sugammadex and a progestogen results in a reduction in progestogen exposure (34% of the AUC) similar to the reduction observed by taking the daily dose of an oral contraceptive with a delay of 12 hours, an "event that can lead to a reduction in efficacy. As for estrogen, it is assumed that the effect is less marked. Therefore, the administration of a bolus dose of sugammadex is considered equivalent to a daily dose not taken of steroid oral contraceptives (combined or progestogen-only). If sugammadex is administered on the same day as an oral contraceptive, the instructions in the package leaflet of the oral contraceptive should be referred to regarding the missed doses. In the case of non-oral hormonal contraceptives, the patient must use an additional non-hormonal method of contraception for the next 7 days and refer to the instructions in the package leaflet of the medicinal product.
Interactions due to the prolonged effect of rocuronium or vecuronium:
When using drugs that potentiate neuromuscular block in the postoperative period, particular attention should be paid to the possible reappearance of neuromuscular block. Refer to the package leaflet of rocuronium or vecuronium for the list of specific medicinal products that potentiate neuromuscular block. If a reappearance of neuromuscular block is observed, the patient may require mechanical ventilation and re-administration of sugammadex (see section 4.2).
Interference with laboratory analyzes:
In general sugammadex does not interfere with the results of laboratory analyzes; possible exceptions are the dose of progesterone in serum. Interference with this assay was observed at sugammadex plasma concentrations of 100 mcg / mL (plasma peak following 8 mg / kg bolus).
In a study in volunteers doses of 4 mg / kg and 16 mg / kg of sugammadex resulted in prolongations of the mean maximum aPTT of 17 and 22%, respectively, and of PT (INR) of 11 and 22%, respectively. limited mean prolongations of aPTT and PT (INR) were of short duration (≤ 30 minutes).
In studies in vitro A pharmacodynamic interaction (prolongation of aPTT and PT) with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran was noted (see section 4.4).
Pediatric population
No formal interaction studies have been performed. For the pediatric population, the interactions mentioned above for adults and the warnings given in section 4.4 should be considered.
04.6 Pregnancy and breastfeeding
Pregnancy
For sugammadex, no clinical data on exposed pregnancies are available.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised in administering the medicine to pregnant women.
Feeding time
It is not known whether sugammadex is excreted in human milk. Animal studies have shown excretion of sugammadex in breast milk. Oral absorption of cyclodextrins in general is low and no effects on the infant are expected following single dose administration to a breastfeeding woman.
Sugammadex can be used while breastfeeding.
Fertility
The effects of sugammadex on human fertility have not been tested. Animal studies to evaluate fertility have not revealed harmful effects.
04.7 Effects on ability to drive and use machines
Bridion has no known influence on the ability to drive and use machines.
04.8 Undesirable effects
Summary of the safety profile
Bridion is administered concomitantly with neuromuscular blocking agents and anesthetics in surgical patients. The causality of adverse events is therefore difficult to assess. The most commonly reported adverse reactions in surgical patients were cough, respiratory complication of anesthesia, complications of anesthesia, procedural hypotension and procedural complication (Common (≥ 1/100,
Table of adverse reactions
The safety of sugammadex was evaluated in 3,519 unique subjects using a pooled Phase I-III safety database. In placebo-controlled studies in which subjects received anesthesia and / or neuromuscular blocking agents (1,078 subjects exposed to sugammadex versus 544 exposed to placebo) the following adverse reactions were reported:
[Very common (≥ 1/10), common (≥ 1/100,
Description of selected adverse reactions
Drug hypersensitivity reactions:
Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (for information on volunteers, see Information on Healthy Volunteers below). In clinical trials of surgical patients these reactions were reported as uncommon and in post-marketing reports the frequency is unknown.
These reactions ranged from isolated skin reactions to severe systemic reactions (such as anaphylaxis, anaphylactic shock) and occurred in patients who had no previous exposure to sugammadex.
Symptoms associated with these reactions may include: flushing, hives, rash erythematous, (severe) hypotension, tachycardia, swollen tongue, swollen pharynx, bronchospasm and obstructive pulmonary events. Severe hypersensitivity reactions can be fatal.
Respiratory complication of anesthesia:
Airway complications of anesthesia included resistance against the endotracheal tube, cough, mild resistance, wake-up reaction during surgery, cough during the anesthetic procedure or during surgery, or spontaneous breathing of the patient related to the anesthetic procedure. .
Complication of anesthesia:
Complications of anesthesia that indicate restoration of neuromuscular function include movement of a limb or body, or coughing during anesthetic or surgical procedure, grimacing or sucking of the endotracheal tube. See section 4.4 "light anesthesia".
Procedural complication:
Procedural complications included cough, tachycardia, bradycardia, movement, and increased heart rate.
Marked bradycardia:
In post-marketing experience, isolated cases of marked bradycardia and cardiac arrest bradycardia have been observed within minutes after administration of sugammadex (see section 4.4).
Return of neuromuscular block:
In clinical studies with subjects treated with rocuronium or vecuronium, in which sugammadex was administered using a dose indicated for deep neuromuscular block (N = 2,022), a "0.20% incidence of reoccurrence of neuromuscular block was observed based on neuromuscular monitoring or clinical evidence (see section 4.4).
Information on healthy volunteers:
A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers treated with up to 3 doses of placebo (N = 76), sugammadex 4 mg / kg (N = 151) or sugammadex 16 mg / kg. (N = 148). Reports of suspected hypersensitivity were ascertained by a blinded commission. The incidence of ascertained hypersensitivity was 1.3%, 6.6% and 9.5% in the placebo, sugammadex groups, respectively 4 mg / kg and sugammadex 16 mg / kg. There have been no reports of anaphylaxis after placebo or sugammadex 4 mg / kg. There was a single case of anaphylaxis established after the first dose of sugammadex 16 mg / kg (incidence of 0.7%). There was no evidence of an increase in the frequency or severity of hypersensitivity with repeated doses. by sugammadex.
In a previous study of similar design, there were three established cases of anaphylaxis, all after sugammadex 16 mg / kg (incidence 2.0%).
In the pooled database of phase 1 studies, adverse events considered common (≥ 1/100, 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%).
Learn more about particular patient populations
Patients with a history of pulmonary complications:
Bronchospasm was reported in post-marketing data and in a dedicated clinical study in patients with a history of pulmonary complications. As with all patients with a history of pulmonary complications, the physician should be aware of the possible occurrence of bronchospasm.
Pediatric population
A limited database indicates that the safety profile of sugammadex (up to 4 mg / kg body weight) in pediatric patients is similar to that in adults.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In clinical studies, 1 case of accidental overdose with a dose of 40 mg / kg body weight was reported but had no significant adverse reactions. In a human tolerability study, sugammadex was administered in doses up to 96 mg / kg body weight. No dose-related adverse events or serious adverse events were reported.
Sugammadex can be removed using hemodialysis with a high-flow filter, but not with a low-flow filter. Based on clinical studies, sugammadex plasma concentrations are reduced by up to 70% after a 3 to 6 hour dialysis session.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: all other therapeutic products, antidotes, ATC code: V03AB35
Mechanism of action:
Sugammadex, a gamma-modified cyclodextrin, is a selectively binding agent for muscle relaxants.It complexes with the neuromuscular blocking agents rocuronium or vecuronium in the plasma and consequently reduces the amount of neuromuscular blocking agent able to bind to the nicotinic receptors present on the neuromuscular junction. This results in an antagonism of the neuromuscular block induced by rocuronium or vecuronium.
Pharmacodynamic effects:
Sugammadex was administered in the "dose range of 0.5-16 mg / kg body weight" in dose-response studies on rocuronium-induced block (0.6 - 0.9 - 1.0 and 1.2 mg / kg body weight of rocuronium bromide with and without maintenance doses) and on vecuronium-induced blockade (0.1 mg / kg body weight of vecuronium bromide with or without maintenance doses) at different times of block and in blocks of different intensities. A clear dose-response relationship emerged in these studies.
Clinical efficacy and safety:
Sugammadex can be administered at various times after administration of rocuronium bromide or vecuronium:
Routine antagonism - deep neuromuscular block:
In a pivotal study, patients were randomly assigned to receive rocuronium or vecuronium. After the last dose of rocuronium or vecuronium, at a PTC of 1-2, 4 mg / kg body weight of sugammadex or 70 mcg / kg body weight of neostigmine were administered in random order. Administration of sugammadex or neostigmine when the T4 / T1 ratio was restored to 0.9 was as follows:
Time (minutes) between administration of sugammadex or neostigmine in course of deep neuromuscular block (PTC: 1-2) induced by rocuronium or vecuronium and the recovery of a value of 0.9 of the T4 / T1 ratio
Routine antagonism - moderate neuromuscular block:
In another pivotal study, patients were randomized to receive rocuronium or vecuronium. After the last dose of rocuronium or vecuronium, when T2 reappeared, 2.0 mg / kg body weight of sugammadex or 50 micrograms / kg body weight of neostigmine were administered in random order. The time from the start of administration. sugammadex or neostigmine when the T4 / T1 ratio was restored to 0.9 was the following:
Time (minutes) from administration of sugammadex or neostigmine to reappearance of T2 after administration of rocuronium or vecuronium until recovery of a value of 0.9 of the T4 / T1 ratio
The antagonism of rocuronium-induced neuromuscular block with sugammadex was compared to the antagonism of cis-atracurium-induced neuromuscular block with neostigmine. Upon reappearance of T2, a 2 mg / kg bw dose of sugammadex or a 50 mcg / kg bw dose of neostigmine was administered. The antagonism of rocuronium-induced neuromuscular block with sugammadex was more rapid than the antagonism of cis-atracurium-induced neuromuscular blockade with neostigmine:
Time (minutes) from administration of sugammadex or neostigmine to reappearance of T2 following administration of rocuronium or cis-atracurium until recovery of a T4 / T1 ratio of 0.9.
Immediate antagonism:
Recovery time from succinylcholine-induced neuromuscular block (1 mg / kg body weight) was compared with sugammadex-induced recovery time from rocuronium-induced neuromuscular block (1.2 mg / kg body weight).
Time (minutes) from administration of rocuronium and sugammadex or succinylcholine to recovery of 10% of T1
The following recovery times associated with the administration of 16 mg / kg body weight of sugammadex after 1.2 mg / kg body weight of rocuronium bromide emerged in a pooled analysis:
Time (minutes) from administration of sugammadex 3 minutes after rocuronium to recovery of a T4 / T1 ratio value of 0.9 - 0.8 or 0.7.
Kidney damage:
Two open-label clinical trials compared the efficacy and safety of sugammadex in surgical patients with and without severe renal impairment. In one study, sugammadex was administered after rocuronium-induced block at 1-2 PTC (4 mg / kg; N = 68); in the other study, sugammadex was administered upon reappearance of T2 (2 mg / kg; N = 30). Recovery from blockade was modestly longer for patients with severe renal impairment than for patients without renal impairment. In these studies, no residual neuromuscular block or recurrence of neuromuscular block was reported for patients with severe renal impairment.
05.2 Pharmacokinetic properties
The pharmacokinetic parameters of sugammadex were calculated from the sum total of the complex bound and unbound sugammadex concentrations. Pharmacokinetic parameters such as clearance and volume of distribution are assumed to be the same for complex bound and unbound sugammadex in anesthetized patients.
Distribution:
The observed steady-state volume of the distribution of sugammadex is approximately 11-14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). As evidenced in vitro Using human male plasma and whole blood, neither sugammadex nor the sugammadex-rocuronium complex binds to plasma proteins or erythrocytes. Sugammadex exhibits linear kinetics over the dose range of 1-16 mg / kg body weight when administered as an intravenous bolus.
Metabolism:
No metabolites of sugammadex were detected in preclinical and clinical studies and the only route of elimination of the unchanged product observed was via the kidney.
Elimination:
In anesthetized adult patients with normal renal function, the elimination half-life (t1 / 2) of sugammadex is approximately 2 hours and the estimated plasma clearance is approximately 88 mL / min. A mass balance study showed that more 90% of the dose was excreted over 24 hours. 96% of the dose was excreted in the urine, and 95% of this fraction was unaltered sugammadex. Excretion via faeces or exhaled air was less than 0.02% of the dose Administration of sugammadex to healthy volunteers resulted in increased renal elimination of bound rocuronium.
Special populations:
Kidney damage and age:
In a pharmacokinetic study comparing patients with severe renal impairment to patients with normal renal function, sugammadex plasma levels were similar during the first hour after dosing and thereafter levels decreased faster in the control group. In patients with severe renal impairment the total exposure to sugammadex was prolonged resulting in exposure levels 17 times higher. Low concentrations of sugammadex are detectable for at least 48 hours after dosing in patients with severe renal impairment.
In a second study comparing subjects with moderate or severe renal impairment and subjects with normal renal function, clearance of sugammadex progressively decreased and t1 / 2 progressively prolonged with decreased renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. In subjects with severe renal impairment, sugammadex concentrations were no longer detectable beyond 7 days after dosing.
Below is a summary of sugammadex pharmacokinetic parameters stratified by age and renal function:
CV = coefficient of variation
Sex:
No gender differences were observed.
Race:
No clinically relevant differences in pharmacokinetic parameters were observed in a study in healthy Japanese and Caucasian subjects. The limited data available do not indicate differences in the pharmacokinetic parameters of black or African American subjects.
Body weight:
Population pharmacokinetic analysis of adult and elderly patients did not reveal any clinically relevant relationship of clearance and volume of distribution with body weight.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxic potential and reproductive toxicity, local tolerability or compatibility with blood.
In preclinical species sugammadex is eliminated rapidly, although residues of sugammadex have been observed in the bone and teeth of juvenile rats. Preclinical studies conducted in young and mature adult rats show that sugammadex does not adversely affect tooth color or bone quality, structure or metabolism. Sugammadex has no effect on fracture repair and bone remodeling.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
3.7% hydrochloric acid (to adjust the pH) and / or sodium hydroxide (to correct the pH).
Water for injections.
06.2 Incompatibility
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
Physical incompatibility has been reported with verapamil, ondansetron and ranitidine.
06.3 Period of validity
3 years
After first opening and dilution, chemical and physical in-use stability has been demonstrated for 48 hours at 2-25 ° C. From a microbiological point of view, the diluted product should be used immediately. If the product is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user; normally they should not exceed 24 hours at 2 to 8 ° C, unless dilution has been done under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Store below 30 ° C. Do not freeze. Keep the vial in the carton in order to protect it from light.
For information on storage of the reconstituted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
2 mL or 5 mL of solution in type I glass vial with chlorobutyl rubber stopper and aluminum flip-off cap and flip-off seal.
Pack sizes: 10 vials of 2 mL or 10 vials of 5 mL.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Bridion can be injected into the cannula of an infusion drip with the following intravenous solutions: sodium chloride 9 mg / mL (0.9%), glucose 50 mg / mL (5%), sodium chloride 4.5 mg / mL (0.45%) and glucose 25 mg / mL (2.5%), lactated Ringer's solution, Ringer's solution, glucose 50 mg / mL (5%) in sodium chloride 9 mg / mL (0.9% ).
The infusion line should be adequately flushed (e.g. with 0.9% sodium chloride) between administration of Bridion and other medicinal products.
Use in the pediatric population
For pediatric patients, Bridion can be diluted with sodium chloride 9 mg / mL (0.9%) up to a concentration of 10 mg / mL (see section 6.3).
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/466/001
EU / 1/08/466/002
038801015
038801027
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 25 July 2008
Date of most recent renewal: 21 June 2013
10.0 DATE OF REVISION OF THE TEXT
31 August 2016
