43/15 PRODUCT DETAILS 

Drug Name-                BRIDION

Active Ingredient-      Sugammdex 

 Approved date         12/15/2015                                                                                       

FDA approved use-  To reverse effects  of neuromuscular blocking drugs during                                              surgery                                                                       

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use                              BRIDION safely and effectively.

See full prescribing information for BRIDION. BRIDION® (sugammadex) Injection, for intravenous use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE --

 BRIDION is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.

Adverse Reactions

. Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with BRIDION.

The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous BRIDION was 0.3% (n=1 in the BRIDION 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration.

The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups.

CONTRAINDICATIONS-

 Known hypersensitivity to sugammadex or any of its components.

WARNINGS AND PRECAUTIONS-

 • Anaphylaxis: Anaphylaxis has occurred in 0.3% of healthy volunteers. Observe patients for an appropriate period of time after administration.

• Marked Bradycardia: Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after administration. Monitor for hemodynamic changes and administer anticholinergic agents such as atropine if clinically significant bradycardia is observed.

 • Respiratory Function Monitoring: Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Should neuromuscular blockade persist after BRIDION or recur following extubation, take appropriate steps to provide adequate ventilation.

 • Waiting Times for Re-Administration of Neuromuscular Blocking Agent: If re-administration of a neuromuscular blocking agent is required after reversal with BRIDION, waiting times should be based on the dose of BRIDION, and the renal function of the patient. Consider use of a nonsteroidal neuromuscular blocking agent.

DOSAGE AND ADMINISTRATION -

 • Monitor for twitch responses to determine the timing and dose for BRIDION administration.

 • Administer as a single bolus injection. (2) For rocuronium and vecuronium:

• 4 mg/kg is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation.

 • 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second twitch in response to TOF stimulation.

For rocuronium only:

• 16 mg/kg is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium.

DOSAGE FORMS AND STRENGTHS-

 • 200 mg/2 mL (100 mg/mL) in a single-dose vial for bolus injection (3) • 500 mg/5 mL (100 mg/mL) in a single-dose vial for bolus injection

PATIENT COUNSELING INFORMATION

• Advise females of reproductive potential using hormonal contraceptives that BRIDION may reduce the contraceptive effect. Instruct females to use an additional, non-hormonal method of contraception for the next 7 days following BRIDION administration

Manufacturing Services LLC, Greenville, NC 27834 USA For patent information: www.merck.com/product/patent/home.html Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.

CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                        BRIDION is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction.

2. Pharmacodynamics BRIDION has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response trials of rocuronium-induced blockade (0.6, 0.9, 1 and 1.2 mg/kg with and without maintenance doses) and vecuronium-induced blockade (0.1 mg/kg with or without maintenance doses) at different time points/depths of block. In these trials a clear dose-response relationship was observed.

Cardiac Electrophysiology At a dose 2 times the maximum recommended dose, sugammadex does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex.

Distribution-

 The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis).

Metabolism -                                                                                                                      In clinical studies, no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.

Elimination-                                                                                                                       In adult anesthetized patients with normal renal function, the elimination half-life (t1/2) of sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min (based on compartmental pharmacokinetic analysis)

. A mass balance study demonstrated that >90% of the dose was excreted within 24 hours. Ninety-six percent (96%) of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex.

Excretion- via feces or expired air was less than 0.02% of the dose.

Administration of BRIDION to healthy volunteers resulted in increased renal elimination of rocuronium in complex.

Patients with Renal Impairment-                                                                           Sugammadex is known to be substantially excreted by the kidney. The half-life of sugammadex in patients with mild, moderate and severe renal impairment is 4, 6, and 19 hours, respectively. In one study, exposure to sugammadex was prolonged, leading to 17-fold higher overall exposure in patients with severe renal impairmen

Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal impairment.

IAge: Geriatric Population Geriatric patients may have mild or moderate renal impairment.

Population pharmacokinetic analysis indicated that, beyond the effects of a decreased creatinine clearance, increased age has limited impact on sugammadex PK parameters [

Sex No pharmacokinetic differences between male and female subjects were observed. Race In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in Black or African Americans.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -

There are no data on BRIDION use in pregnant women to inform any drug-associated risks.

.2. Lactation Risk Summary-                                                                                          No data are available regarding the presence of sugammadex in human milk, the effects of sugammadex on the breast fed infant, or the effects of sugammadex on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BRIDION and any potential adverse effects on the breastfed infant from BRIDION or from the underlying maternal condition.

3 Females and Males of Reproductive Potential Contraception -                                 Upon administration of BRIDION, the efficacy of hormonal contraceptives may be reduced for up to 7 days.

Advise female patients of reproductive potential using hormonal contraceptives to use an additional, non-hormonal contraceptive for the next 7 days following BRIDION administration 

4. Pediatric Use The safety and efficacy of BRIDION in pediatric patients have not been established.

5.Renal impairment-                                                                                                     BRIDION is not recommended for use in patients with severe renal impairment due to insufficient safety information combined with the prolonged and increased overall exposure in these patients

6. Hepatic Impairment-                                                                                         BRIDION is not metabolized nor excreted by the liver; therefore, dedicated trials in patients with hepatic impairment have not been conducted.

Exercise caution when administering BRIDION to patients with hepatic impairment accompanied by coagulopathy or severe edema

7. Cardiac Patients-                                                                                                      One trial of 76 patients who were diagnosed with or have a history of cardiac disease (e.g., patients with ischemic heart disease, chronic heart failure, or arrhythmia) of primarily NYHA (New York Heart Association) Class II investigated time to recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg following administration of 2 mg/kg or 4 mg/kg BRIDION given at the reappearance of T2.

8. Pulmonary Patients -                                                                                                  One trial of 77 patients who were diagnosed with or have a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg BRIDION given at the first signs of recovery (reappearance of T2).