Summary Basis of Decision for Bridion
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Bridion is located below.
Recent Activity for Bridion
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Bridion
Updated:
The following table describes post-authorization activity for Bridion, a product which contains the medicinal ingredient sugammadex sodium. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02451816 – 100 mg/mL, sugammadex sodium, solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02451816) market notification | Not applicable | Date of first sale:2016-02-19 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 180385 | 2014-12-23 | Issued NOC2016-02-05 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Bridion
Date SBD issued: 2016-05-13
The following information relates to the new drug submission for Bridion.
Sugammadex sodium, 100 mg/mL, solution, intravenous
Drug Identification Number (DIN):
- 02451816
Merck Canada Inc.
New Drug Submission Control Number: 180385
On February 5, 2016, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product, Bridion.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, it is considered that the benefit-harm-uncertainty profile of Bridion is favourable for reversal of moderate to deep neuromuscular blockade induced by rocuronium or vecuronium in adults undergoing surgery.
1 What was approved?
Bridion (sugammadex sodium), a selective neuromuscular relaxant binding agent, was authorized for reversal of moderate to deep neuromuscular blockade induced by rocuronium or vecuronium in adults undergoing surgery.
Bridion is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Hypersensitivity reactions, ranging from isolated skin reactions to serious systemic reactions (that is, anaphylaxis, or anaphylactic reactions); have occurred in individuals with or without prior exposure to sugammadex (medicinal ingredient in Bridion). Bridion was approved for use under the conditions stated in the Product Monograph taking into consideration the known benefits and the potential harms and uncertainties associated with the administration of this drug product.
Bridion (100 mg/mL, sugammadex, as sugammadex sodium) is presented as a solution for injection. In addition to the medicinal ingredient, the solution contains the following non-medicinal ingredients: hydrochloric acid, sodium hydroxide, and water for injection.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Bridion Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Bridion approved?
Health Canada considers that the benefit-harm-uncertainty profile of Bridion is favourable for reversal of moderate to deep neuromuscular blockade induced by rocuronium or vecuronium in adults undergoing surgery.
Bridion should be administered by a trained healthcare professional familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents and neuromuscular block reversal agents.
Surgery under general anesthesia routinely requires neuromuscular blockade to facilitate respiratory management and surgical procedures. Rocuronium and vecuronium are two common muscle relaxants given to a patient prior to surgery. Once surgery is completed, the induced neuromuscular blockade needs to be reversed. To reverse the effects of the muscle relaxant, an acetylcholinesterase inhibitor, such as neostigmine, edrophonium, or pyridostigmine, is used to increase the amount of acetylcholine in the neuromuscular junction. However, the increased cholinesterase activity is not limited to the neuromuscular junction; it also takes place in the autonomic cholinergic synapses, resulting in unwanted side effects (such as, cardiac arrhythmias, hypotension, bronchospasm, increased bronchial secretions, salivation, bowel cramps, diarrhea, nausea, and emesis). These unwanted effects can be partially antagonized with a muscarinic cholinergic antagonist, such as atropine or glycopyrrolate.
Bridion is a modified gamma cyclodextrin and offers an alternative way of reversing the effects of neuromuscular blockade induced by rocuronium or vecuronium. Bridion acts by sequestering rocuronium or vecuronium with a high efficiency. The resulting combined drug complex gets carried to the blood stream and then eliminated through the urine. This mechanism of action results in the reversal of the neuromuscular blockade induced by the muscular relaxant drug generally faster compared with the traditional method of administering a combination of an acetylcholinesterase inhibitor plus muscarinic cholinergic antagonist.
Three Phase III pivotal studies (Study 19.4.301, Study 19.4.310, and Study 19.4.302) demonstrated the efficacy of Bridion in reversing the neuromuscular blockade induced with rocuronium or vecuronium. These three pivotal studies showed that administration of Bridion in patients recovering from anesthesia resulted in a statistically significantly shorter reversal of the neuromuscular blockade compared with traditional reversal methods, as measured with a neuromuscular stimulator with specific stimulation patterns suitable for estimating moderate to deep neuromuscular relaxation.
Bridion is associated with the risk of several potential harms, but exposure to them is expected to be limited to the operating room or post-anesthesia recovery unit where they can be managed effectively. Hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, on first or subsequent exposure pose a serious safety risk. The Bridion Product Monograph includes a Serious Warnings and Precautions Box highlighting this risk. Other significant risks associated with use of Bridion include: possible interference with blood coagulation and cardiovascular effects (marked bradycardia). Relevant safety information has been captured within the Bridion Product Monograph and also on the product label.
Bridion may also be associated with other safety uncertainties linked with the peri-operating anesthetic environment, such as the anesthetic requirement to ensure adequate anesthesia. Airway management in patients recovering from the surgery and anesthesia also requires active monitoring to ensure adequate recovery of the airway protection and respiratory function. While these safety issues are not directly linked to Bridion, they are nonetheless relevant to its clinical use and have been addressed in the Bridion Product Monograph.
A Risk Management Plan (RMP) for Bridion was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the post-marketing monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.
Overall, the therapeutic benefits seen in the pivotal studies are comparable to traditional reversal methods and the benefits of Bridion therapy are considered to outweigh the risks of harm and potential safety uncertainties. Bridion has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate peri-operative monitoring. Appropriate warnings and precautions are in place in the Bridion Product Monograph to address the identified safety concerns. The product use instructions will be complemented by the post-marketing pharmacovigilance monitoring.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Bridion?
A New Drug Submission (NDS) (control number [no.] 117204) for Bridion was filed on July 30, 2008. Upon review of this NDS, a Notice of Deficiency (NOD) was issued to the sponsor on October 9, 2009 as it was determined that a benefit-risk analysis could not be conducted adequately with the information available. Health Canada requested additional study data from the sponsor in order to allow for a comprehensive assessment. Given that the sponsor was unable to provide the requested data within the NOD response timeline, the sponsor decided to withdraw NDS 117204 on April 1, 2010.
The sponsor refiled an NDS (control no. 162165) for Bridion on February 1, 2013. In this refiled submission, the sponsor provided study results from Study 194.117 which evaluated the risk of hypersensitivity reactions associated with Bridion in healthy volunteers. However, Study 194.117 was found to fall short of regulatory clinical trial standards. Health Canada issued a Notice of Non-Compliance (NON) to the sponsor on January 16, 2014 primarily due to inadequacies noted in Study 194.117 and the need for additional safety data to allow for a full comprehensive assessment of these hypersensitivity reactions. Given the sponsor was unable to address all identified deficiencies within the NON response timeline, the sponsor decided to withdraw the NDS (control no. 162165) on March 7, 2014.
The sponsor then refiled an NDS (control no. 180385) for Bridion on December 23, 2014. This submission was essentially a response to the NON issued previously in the NDS control no. 162165. Upon review of the NDS control no. 180385, Health Canada considers that the safety issues identified in the NON for NDS 162165 have been addressed satisfactorily. A Notice of Compliance (NOC) was therefore issued on February 5, 2016.
Submission Milestones: Bridion
| Submission Milestone | Date |
|---|---|
| New Drug Submission (NDS) Control Number: 117204 | |
| Submission filed: | 2008-07-30 |
| Screening | |
| Screening Deficiency Notice issued: | 2008-09-19 |
| Response filed: | 2008-10-31 |
| Screening Acceptance Letter issued: | 2008-12-12 |
| Review | |
| Quality Evaluation complete: | 2009-10-09 |
| Clinical Evaluation complete: | 2009-10-09 |
| Notice of Deficiency (NOD) issued by Director General, Therapeutic Products Directorate (safety issues): | 2009-10-09 |
| Cancellation Letter received: | 2010-04-01 |
| Refile NDS Control Number: 162165 | |
| Pre-submission meeting: | 2011-01-26 |
| Submission filed: | 2013-02-01 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-03-27 |
| Review | |
| Quality Evaluation complete: | 2014-01-16 |
| Clinical Evaluation complete: | 2014-01-16 |
| Notice of Non-Compliance (NON) issued by Director General, Therapeutic Products Directorate (safety issues): | 2014-01-16 |
| Cancellation Letter received: | 2014-03-07 |
| Refile NDS Control Number: 180385 | |
| Submission filed: | 2014-12-23 |
| Screening | |
| Screening Acceptance Letter issued: | 2015-04-13 |
| Review | |
| Quality Evaluation complete: | 2016-02-04 |
| Clinical Evaluation complete: | 2016-02-04 |
| Labelling Review complete: | 2016-02-03 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2016-02-05 |
The Canadian regulatory decision on the quality, non-clinical, and clinical review of Bridion was based on a critical assessment of the Canadian data package. The European Public Assessment Report completed by the European Union's European Medicines Agency (EMA) via its centralized procedure in 2008 was consulted and referenced, as well as reviews by the Australian Therapeutic Goods Administration (TGA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The materials from two Advisory Committee meetings, dated March 11, 2008 and November 2015, conducted by the United States Food and Drug Administration (FDA) were consulted and referenced.
For additional information about the drug submission process, refer to Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database(DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documentsfor the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Part III: Patient Medication Information, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Bridion is a selective relaxant binding agent with a modified gamma cyclodextrin structure. It acts by sequestering the steroidal neuromuscular blocking agents, such as rocuronium and vecuronium, by forming a complex with these agents. The drug complex is then eliminated through the urine. This mechanism of action of Bridion differs from the current methods used to reverse the effects of neuromuscular blockade by rocuronium or vecuronium.
The clinical pharmacology studies provided an adequate characterization of sugammadex (medicinal ingredient of Bridion), to support the use of Bridion for reversal of moderate to deep neuromuscular blockade induced by rocuronium or vecuronium. Note however, dedicated studies in patients with hepatic impairment have not been conducted, given Bridion is neither metabolized nor excreted by the liver in humans.
Sugammadex has also been found to increase the activated partial thromboplastin time (aPTT) and prothrombin time (PT) in human plasma in vitro and in vivo. In clinical studies of patients undergoing hip fracture surgery and joint replacement surgery, where routine thrombo-prophylaxis is necessary, small and transient increases were observed in aPTT and PT international normalized ratio (INR). However, these observations did not translate into an increased bleeding risk with Bridion when compared with traditional reversal methods.
Sugammadex in higher doses may also alter the outcomes of laboratory tests (for example [e.g.], estrogen, progesterone, etc.)
Sugammadex showed clinically meaningful drug-drug interactions with hormonal contraceptives and glucocorticoids. For interactions with hormonal contraceptives, the end effect is estimated to be equivalent to missing one daily dose. For interaction with steroidal hormones (mainly the glucocorticoids) the clinical impact is estimated to be manageable, even in those where supplemental use is needed.
For further details, please refer to the Bridion Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Bridion in reversing a moderate neuromuscular blockade induced by rocuronium or vecuronium was demonstrated in two active-controlled studies (Study 19.4.301 and Study 19.4.310). The efficacy of Bridion in reversing a deep neuromuscular blockade was demonstrated in a third active-controlled Study 19.4.302.
Based on the convention set by the American Society of Anesthesiologists (ASA), all surgical patients enrolled in these studies were classified according to their general physical condition, to facilitate anesthetic and risk management. The groups included those in general good health except for the disease condition for the pending surgery (ASA I), those with mild system disease (ASA II), those with severe compensated system disease (ASA III), and those with severe decompensated system disease (ASA IV).
Neuromuscular functioning was monitored using standardized electromyography. Two patterns of stimulation were used to evaluate the level of neuromuscular blockade. Train-of-Four (TOF) stimulation consists of four consecutive stimuli (T1 through T4) which are delivered on the skin surface along the path of the ulnar nerve that results in contractions of the thumb. The pattern of the contractions is used to evaluation the neuromuscular blockade. When neuromuscular conduction is low, Post-Tetanic Count (PTC) stimulation is used. Tetanic stimulation consists of very rapid delivery of stimuli over a five second period, followed by slower stimuli. The resulting number of contractions is used to evaluate the level of neuromuscular blockade.
Pivotal Trials
Study 19.4.301 (Reversal of Moderate Neuromuscular Blockade)
Study 19.4.301 was a multicentre, randomized, parallel group, comparative, active controlled, safety-assessor-blinded, Phase III, pivotal trial, conducted in adult patients which compared Bridion 2.0 mg/kg with 50 μg/kg neostigmine as a reversal agent of a neuromuscular blockade induced by rocuronium or vecuronium. A total of 198 patients enrolled and underwent elective laparoscopic or open surgical procedures which required general anesthesia. The surgical procedures were mainly endocrine, ocular, ear(s) nose throat (ENT), abdominal (gynecological, colorectal, urological), orthopedic, vascular, or dermatological in nature.
The study design included four groups: two groups received rocuronium for neuromuscular blockade, followed by reversal with Bridion 2.0 mg/kg or neostigmine 50 μg/kg; two other groups received vecuronium for neuromuscular blockade followed by reversal with Bridion 2.0 mg/kg or neostigmine 50 μg/kg. The study planned to include patients of ASA I-IV.
The primary endpoint of the study was to compare the time to recovery from a neuromuscular blockade induced by rocuronium or vecuronium following reversal with Bridion 2.0 mg/kg compared with reversal with 50 µg/kg neostigmine, both given at the reappearance of T2.
A total of 189 patients were included in the efficacy analysis. Study results showed that the geometric mean reversal time for rocuronium was 1.5 minutes with Bridion 2.0 mg/kg (Number of patients [n] = 48, range 0.9 to 5.4 minutes) compared with 18.5 minutes with neostigmine 50 μg/kg (n = 48, range 3.7 to 106.9 minutes) (p<0.0001). The geometric mean reversal time for vecuronium was 2.8 minutes with Bridion 2 mg/kg (n = 48, range 1.20 to 64.2 minutes) compared with 16.8 minutes with neostigmine 50 μg/kg (n = 45, range 2.92 to 76.2 minutes) (p<0.0001).
Study 19.4.310 (Reversal of Moderate Neuromuscular Blockade)
Study 19.4.310 was a multicentre, randomized, safety-assessor-blinded, parallel group, active controlled comparative trial, conducted in adult patients that compared Bridion 2.0 mg/kg with neostigmine 50 μg/kg as a reversal agent of a neuromuscular blockade induced by rocuronium or vecuronium. A total of 84 patients enrolled and underwent either elective laparoscopic or open surgical procedures which required general anesthesia. The surgical procedures were mainly abdominal, ENT, orthopedic, or reconstructive in nature.
The study design consisted of patients being assigned randomly to two treatment groups: the first group received rocuronium as a neuromuscular blockade followed by reversal with Bridion 2.0 mg/kg; second group received cis-atracurium as a neuromuscular blockade followed by reversal with neostigmine 50 µg/kg. The study planned to include patients of ASA I-III.
The primary endpoint of the study was to compare the time to recovery from neuromuscular blockade induced by rocuronium followed by reversal with Bridion 2.0 mg/kg with that induced by cis-atracurium followed by reversal with 50 µg/kg neostigmine, both given at the reappearance of T2.
A total of 73 patients were included in the efficacy analysis. Study results showed that the geometric mean reversal time for rocuronium was 2.0 minutes with Bridion 2.0 mg/kg (n = 34, range 0.7 to 6.4 minutes) compared with 8.8 minutes for cis-atracurium with neostigmine 50 μg/kg (n = 39, range 4.2 to 28.2 minutes) (p<0.0001).
Study 19.4.302 (Reversal of Deep Neuromuscular Blockade)
Study 19.4.302 was a multicentre, randomized, parallel group, comparative, active-controlled, safety-assessor-blinded, Phase III, pivotal trial conducted in adult patients that compared Bridion 4.0 mg/kg with neostigmine 70 µg/kg as reversal agent for neuromuscular blockade induced by rocuronium or vecuronium. A total of 182 patients were enrolled and underwent elective laparoscopic or open surgical procedures which required general anesthesia. The surgical procedures were mainly abdominal (gynecological, colorectal, urological), orthopedic, reconstructive, or neurological in nature.
The primary endpoint of the study was to compare the time to recovery from neuromuscular blockade induced by rocuronium or vecuronium following reversal with Bridion 4.0 mg/kg or neostigmine 70 µg/kg, both given at the reappearance of PTC 1-2.
The study design consisted of two groups of patients receiving rocuronium for neuromuscular blockade followed by reversal with Bridion 4.0 mg/kg or neostigmine 70 µg/kg; two other groups received vecuronium followed by reversal with Bridion 4.0 mg/kg or neostigmine 70 µg/kg.
A total of 157 patients were included in the final study analysis. Study results showed that the geometric mean reversal time for rocuronium was 2.9 minutes with Bridion
4.0 mg/kg (n = 37, range 1.2 to 16.1 minutes) compared with 50.4 minutes with neostigmine 70 µg/kg (n = 37, range 13.3 to 145.7 minutes) (p<0.0001). The geometric mean reversal time for vecuronium was 4.5 minutes with Bridion 4.0 mg/kg (n = 47, range 1.4 to 68.4 minutes) compared with 66.2 minutes with neostigmine 70 µg/kg (n = 36, range 46.0 to 312.7 minutes) (p<0.0001).
Overall, three Phase III pivotal studies (Study 19.4.301, Study 19.4.310, and Study 19.4.302) demonstrated that reversal of neuromuscular blockade induced by vecuronium or rocuronium was statistically significantly faster with Bridion than with traditional reversal methods. Uncertainties however remain with regard to the extent to which faster reversal of the neuromuscular blockade translates into a meaningful clinical advantage for patient recovery. In addition, questions also remain as to why some patients show a far slower response to the effect of sugammadex compared with other patients; and, how to improve the use of Bridion in patients with special health conditions. It is believed that these uncertainties may be resolved in clinical practice and future clinical studies. When used under the recommended conditions of use, provided in the approved Bridion Product Monograph, the benefit-harm-uncertainty profile for Bridion is considered acceptable at this time.
In this New Drug Submission (NDS) the sponsor sought approval for the following indication: Bridion (sugammadex sodium) is indicated for reversal of moderate or deep neuromuscular blockade induced by rocuronium or vecuronium.
Health Canada’s approved indication is as follows: Bridion (sugammadex sodium) is indicated for reversal of moderate to deep neuromuscular blockade induced by rocuronium or vecuronium in adults undergoing surgery.
Pediatrics (<18 years of age):
The safety and efficacy of Bridion in pediatric patients have not been established.
For further details, please refer to the Bridion Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Bridion was evaluated based on the data provided from the active-controlled pivotal studies previously described the Clinical Efficacy section in addition to pooled safety data collected in Phase I-II clinical trials.
In the active-controlled dataset, the overall Adverse Events (AEs) were 79.8% on rocuronium plus Bridion compared with 84.2% on rocuronium plus neostigmine and 93.8% on vecuronium plus Bridion compared with 94.0% on vecuronium plus neostigmine. The AE that occurred in at least 2.0% of Bridion patients and at least twice as frequently as in neostigmine patients was hypertension (3.8% Bridion, 1.5% neostigmine). In the placebo-controlled dataset, which included 1,078 patients exposed to Bridion and 544 patients exposed to placebo, the overall frequencies of all adverse events (AEs) were 70.7% on rocuronium plus Bridion compared to 82.5% on rocuronium plus placebo and 88.7% on vecuronium plus Bridion compared to 95.2% on vecuronium plus placebo. The AEs that occurred in at least 2.0% of Bridion patients and at least twice as frequently as in placebo patients included cough (4.7% Bridion, 2.0% placebo), airway complication of anesthesia (3.9% Bridion, 0% placebo), anesthetic complication (3.4% Bridion, 0.2% placebo), procedural hypotension (3.3% Bridion, 1.7% placebo), and procedural complication (2.0% Bridion, 0.6% placebo).
The Bridion clinical development program identified several safety issues. Those of significant interest were as follows: serious hypersensitive reactions, interference with the blood coagulation, and cardiovascular effects (marked bradycardia).
Hypersensitivity Reactions
Bridion has been associated with serious hypersensitivity reactions (including anaphylactic reactions) upon first exposure and subsequent exposure. The mechanism of these hypersensitivity reactions is currently not well understood. Cases of serious hypersensitivity reactions were identified in Phase I and II studies as part of the Bridion clinical program. A designated clinical trial (Study P101) in 375 healthy volunteers given up to three doses of placebo or Bridion showed that Bridion may cause hypersensitivity reactions with observed rates of 1.3% (1/76) on placebo, 6.6% (10/151) on Bridion 4 mg/kg, and 9.5% (14/148) on Bridion 16 mg/kg. One case of anaphylaxis was seen in the group on Bridion 16 mg/kg (0.7%, 1/148). Anaphylaxis and anaphylactoid reactions have also been reported in the post-marketing setting, including at doses in the range of 2 to 4 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption), and clinically significant hypotension often requiring the use of vasopressors for circulatory support. In addition, prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports.
In addition, clinicians may face airway management challenges when a patient develops an anaphylactic reaction to sugammadex. The Bridion Product Monograph includes in the Warnings and Precautions section a Box warning which cautions clinicians regarding the risk of hypersensitivity reactions (including anaphylaxis or anaphylactoid reactions).
Hematologic
In clinical studies, Bridion doses up to 16 mg/kg were associated with limited (≤25%) and transient (≤1 hour) increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time (PT) international normalized ratio (PT[INR]) in healthy volunteers. In surgical patients concomitantly treated with anticoagulant, small and transient increases were observed in aPTT and PT(INR) associated with Bridion 4 mg/kg, which did not translate into an increased bleeding risk with Bridion compared with usual treatment.
A safety warning regarding increases in coagulation parameters is included in the Bridion Product Monograph along with the need to monitor coagulation parameters in patients with known coagulopathies and in patients using anticoagulants who receive a dose of Bridion higher than 4 mg/kg.
Cardiovascular
Marked bradycardia has been observed within minutes after the administration of Bridion for reversal of neuromuscular blockade. Isolated cases of bradycardia with cardiac arrest have been reported. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. In certain instances, treatment with anti-cholinergic agents such as atropine may be required.
Peri-Operative Considerations
Bridion may be associated with other risks linked with the peri-operating anesthetic environment, such as the anesthetic requirement to ensure adequate depth of the anesthesia appropriate for surgical and anesthetic intervention and airway management in patients recovering from the surgery and anesthesia. These safety issues are not directly linked to Bridion, but because it is used, it may give false confidence in the use of rocuronium or vecuronium, and other anesthetic practice. This information is included in the Warning and Precautions section of the Bridion Product Monograph, for management of the associated uncertainties.
Safety Conclusion
The Bridion safety development program identified and addressed several safety issues. The most significant risk associated with sugammadex is hypersensitivity reactions, including anaphylactic reactions, on first exposure and subsequent exposure. The mechanism of these reactions is not clear at this time. Most of the hypersensitivity reactions seem to require little or no medical intervention. Severe cases, including anaphylactic reactions, seem to respond to standard of care in the post-surgical anesthetic care environment. The Bridion Product Monograph includes a boxed warning and clear language to caution clinicians about this risk.
The benefit that has been demonstrated for Bridion in clinical trials is faster reversal of the neuromuscular blockade, induced with either vecuronium or rocuronium, than traditional reversal methods in surgical patients receiving general anesthesia. The identified potential harms associated with Bridion have been adequately evaluated in non-clinical and clinical studies. It is believed that these potential harms, along with the identified safety uncertainties, can be adequately managed through warnings and instructions of use provided in the Bridion Product Monograph.
Uncertainties however remain regarding the extent to which faster reversal of the neuromuscular blockade translates into a meaningful clinical advantage for patient recovery. In addition, there remain unanswered questions as to why some patients have far slower response to the effect of Bridion; and, how to improve use of Bridion in patients with special health conditions. These uncertainties may be resolved in clinical practice and future clinical studies.
For more information, refer to the Bridion Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In laboratory animals, sugammadex (medicinal ingredient in Bridion) is widely distributed in the body once injected, including in the placenta and the fetus. It is also excreted in the milk of lactating females. Circulating sugammadex is eliminated quickly, mainly through the urine in rats or through feces in dogs.
In laboratory studies, sugammadex was found to increase the activated partial thromboplastin time (aPTT) and prothrombin time (PT), which reflect, respectively, the function of the internal and external blood coagulation cascades. Sugammadex was shown to slow down the activation of Factor Xa which is the integration point of both internal and external coagulation pathways.
In animal studies, sugammadex was noted to deposit in bone and teeth, by binding to hydroxyapatite. The extent of this deposit is considerable only in repeated dosing in animal studies, but the deposit did not seem to change the structure or strength of the bone and tooth. Animal studies also found that sugammadex had little potential to interfere with fracture repair. Given the intended human use, sugammadex will likely be limited to a single or a few repeated doses, the negative impact of sugammadex on bone deposit is not expected to pose a significant risk to humans.
Repeated dosing of sugammadex for a period of 7 to 14 days had a No Observed Adverse Effect Level (NOAEL) of approximately 30 mg/kg daily. The NOAEL for fertility and maternal toxicity is approximately 20 mg/kg daily. The NOAEL for embryofetal toxicity is at least at 65 mg/kg daily.
Carcinogenicity studies were waived as sugammadex is intended mainly for single use and repeated use is uncommon.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Bridion Product Monograph. In view of the intended use of Bridion, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Bridion Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Bridion has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted for Bridion, the proposed shelf life of 36 months when stored at 15°C to 30°C is acceptable when protected from light.
Proposed limits of drug-related impurities are considered adequately qualified (that is [i.e.] within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BRIDION | 02451816 | MERCK CANADA INC | SUGAMMADEX (SUGAMMADEX SODIUM) 100 MG / ML |