Sugammadex

1 INDICATIONS AND USAGE Sugammadex injection is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients aged 2 years and older undergoing surgery. Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s BRIDION ® (sugammadex) injection. However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information. Sugammadex injection is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients aged 2 years and older undergoing surgery. (1)

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sugammadex injection 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. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium. 12.2 Pharmacodynamics Sugammadex injection 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. Sugammadex injection may contain up to 7% of the mono OH-derivative of sugammadex. In preclinical pharmacology studies, the mono OH-derivative was demonstrated to have ~50% of the affinity as sugammadex for rocuronium and vecuronium and that product with up to 7% of the mono OH-derivative has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade. Although sugammadex has greatest affinity for aminosteroid neuromuscular blocking agents such as rocuronium and vecuronium, plasma levels of endogenous or exogenous compounds with a similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of sugammadex [see Drug Interactions (7.3)] . Cardiac Electrophysiology At a dose 2 times the maximum recommended dose, sugammadex does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anesthetized patients. 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). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose. In nonclinical drug distribution studies, sugammadex is retained in sites of active mineralization, such as bone and teeth, with a mean half-life of 172 and 8 days, respectively [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.2)] . 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. Eli

2 DOSAGE AND ADMINISTRATION • Dosing is based on actual body weight (2.1) • Monitor for twitch responses to determine the timing and dose for sugammadex injection administration. (2.1) • Administer as a single bolus injection. (2.1) 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. (2.2) • 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second twitch in response to TOF stimulation. (2.2) 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. Immediate reversal in pediatric patients has not been studied. (2.2) 2.1 Important Dosing and Administration Information Sugammadex injection dosing is based on actual body weight. Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of sugammadex injection administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer sugammadex injection intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex injection has only been administered as a single bolus injection in clinical trials. From the time of sugammadex injection administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of sugammadex injection does not depend on the anesthetic regimen. Preparation of dilution for pediatric use : Sugammadex injection 100 mg/mL may be diluted to a concentration of 10 mg/mL, using 0.9% sodium chloride injection, USP, to increase the accuracy of dosing in the pediatric population. • To prepare the required dose, aseptically transfer all the contents of the 2 mL Pre-filled syringe of sugammadex injection 2-mL single-dose pre-filled syringe containing 200 mg sugammadex (100 mg/mL) to a bottle (or intravenous bag) containing 18 mL of 0.9% sodium chloride injection, to achieve a final concentration of 10 mg/mL sugammadex. The diluted solution should be used immediately. • Sugammadex injection is a single-dose sterile solution without preservatives. Discard any unused portion from the pre-filled Syringe. 2.2 Recommended Dosing Sugammadex injection can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. For rocuronium and vecuronium : • A dose of 4 mg/kg sugammadex injection 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 following rocuronium- or vecuronium- induced neuromuscular blockade [see Warnings and Precautions (5.8)] . • A dose of 2 mg/kg sugammadex injection is recommended if spontaneous recovery has reached the reappearance of the second twitch (T 2 ) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade [see Warnings and Precautions (5.8)] . For rocuronium only : • A dose of 16 mg/kg sugammadex injection 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. The efficacy of the 16 mg/kg dose of sugammadex injection following administration of vecuronium has not been studied. Immed

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Anaphylaxis and Hypersensitivity [see Contraindications (4), Warnings and Precautions (5.1)] • Marked Bradycardia [see Warnings and Precautions (5.2)] Most common adverse reactions (reported in ≥10% of adult patients at a 2, 4, or 16 mg/kg sugammadex injection dose and higher than the placebo rate): vomiting, pain, nausea, hypotension, and headache. (6.1) Most common adverse reactions (reported in ≥10% of pediatric patients 2 to <17 years of age at sugammadex injection doses of 2 or 4 mg/kg) were pain, vomiting, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Steriscience at 1-888-278-1784 or www.steri-science.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients The data described below reflect 2914 subjects exposed to 2, 4, or 16 mg/kg sugammadex injection and 544 to placebo in pooled Phase 1-3 studies. The population was 18 to 92 years old, 47% male and 53% female, 34% ASA (American Society of Anesthesiologists) Class 1, 51% ASA Class 2, and 14% ASA Class 3, and 82% Caucasian. Most subjects received a single dose of sugammadex injection 2 mg/kg or 4 mg/kg. Adverse reactions reported in ≥ 10% of patients at a 2, 4, or 16 mg/kg sugammadex injection dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache. All adverse reactions occurring in ≥ 2% of subjects treated with sugammadex injection and more often than placebo for adult subjects who received anesthesia and/or neuromuscular blocking agent in pooled Phase 1 to 3 studies are presented in Table 2. Table 2: Percent of Subject Exposures in Pooled Phase 1 to 3 Studies with Adverse Reactions Incidence ≥2% Sugammadex Placebo Body System Preferred Term 2 mg/kg (N=895) n (%) 4 mg/kg (N=1921) n (%) 16 mg/kg (N=98) n (%) (N=544) n (%) Injury, poisoning and procedural complications Incision site pain 58(6) 106(6) 4(4) 6(1) Procedural complication 13(1) 27(1) 8(8) 3(1) Airway complication of anesthesia 11(1) 13(1) 9(9) 0 Anesthetic complication 8(1) 14(1) 9(9) 1(<1) Wound hemorrhage 5(1) 38(2) 0 8(1) Recurrence of neuromuscular blockade 0 1(<1) 2(2) 0 Gastrointestinal disorders Nausea* 208(23) 503(26) 23(23) 127(23) Vomiting* 98(11) 236(12) 15(15) 57(10) Abdominal pain* 48(5) 68(4) 6(6) 17(3) Flatulence 17(2) 51(3) 1(1) 10(2) Dry mouth 9(1) 5(<1) 2(2) 0 General disorders and administration site conditions Pain* 434(48) 993(52) 35(36) 207(38) Pyrexia 77(9) 109(6) 5(5) 17(3) Chills 30(3) 61(3) 7(7) 27(5) Nervous system disorders Headache 61(7) 99(5) 10(10) 42(8) Dizziness 44(5) 67(3) 6(6) 13(2) Hypoesthesia 12(1) 24(1) 3(3) 9(2) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 42(5) 66(3) 5(5) 27(5) Cough 13(1) 49(3) 8(8) 11(2) Musculoskeletal and connective tissue disorders Pain in extremity 13(1) 35(2) 6(6) 15(3) Musculoskeletal pain 16(2) 33(2) 1(1) 6(1) Myalgia 5(1) 17(1) 2(2) 3(1) Psychiatric disorders Insomnia 20(2) 103(5) 5(5) 22(4) Anxiety 14(2) 19(1) 3(3) 1(<1) Restlessness 3(<1) 17(1) 2(2) 2(<1) Depression 2(<1) 5(<1) 2(2) 0 Investigations Red blood cell count decreased* 13(1) 34(2) 1(1) 2(<1) Electrocardiogram QT interval abnormal* 13(1) 7(<1) 6(6) 4(1) Blood creatine phosphokinase increased 9(1) 14(1) 2(2) 1(<1) Vascular disorders Hypertension* 48(5) 96(5) 9(9) 38(7) Hypotension* 33(4) 102(5) 13(13) 20(4) Skin and subcutaneous tissue disorders Pruritus 17(2) 50(3) 2(2) 9(2) Erythema 5(1) 31(2) 0 6(1) Metabolism and nutrition disorders Hypocalcemia 15(2) 12(1) 0 4(1) Cardiac disorders Tachycardia* 17(2) 29(2) 5(5) 4(1) Bradycardia* 9(1) 21(1) 5(5) 6(1) Surgical and medical procedures Hysterec

5 WARNINGS AND PRECAUTIONS Anaphylaxis : Be prepared for hypersensitivity reactions (including anaphylactic reactions) and take necessary precautions. (5.1) 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. (5.2) Respiratory Function Monitoring: Ventilatory support is mandatory until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Provide adequate ventilation if neuromuscular blockade persists after sugammadex injection or recurs following extubation. (5.3, 5.4) Waiting Times for Re-Administration of Neuromuscular Blocking Agents: If re-administration of a neuromuscular blocking agent is required after reversal with sugammadex injection, waiting times should be based on the dose of sugammadex injection and the renal function of the patient. Consider use of a nonsteroidal neuromuscular blocking agent. (5.5) 5.1 Anaphylaxis and Hypersensitivity Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions [see Contraindications (4), Adverse Reactions (6.1)] . Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with sugammadex injection. The nature and frequency of anaphylaxis and hypersensitivity associated with sugammadex injection administration were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study in which 375 subjects were randomized to receive 3 doses of sugammadex injection IV with a 5-week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous sugammadex injection was 0.3% (n=1 in the sugammadex injection 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. Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 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 important 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. 5.2 Marked Bradycardia Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of sugammadex injection [see Adverse Reactions (6.2)] . Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed. 5.3 Respiratory Function Monitoring During Recovery Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade persist aft

4 CONTRAINDICATIONS Sugammadex injection is contraindicated in patients with known hypersensitivity to sugammadex or any of its components. Hypersensitivity reactions that occurred varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to sugammadex [see Warnings and Precautions (5.1), Adverse Reactions (6)] . Known hypersensitivity to sugammadex or any of its components. (4)

10 OVERDOSAGE In premarketing clinical trials, one case of accidental overdose with 40 mg/kg sugammadex injection was reported without significant effects. Sugammadex injection can be removed using hemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, sugammadex injection concentrations in plasma are reduced with a high-flux filter by about 70% after a 3- to 6-hour dialysis session.