Sugammadex Sodium Drug 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. 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.

• 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. Immediate reversal in pediatric patients has not been studied [see Clinical Studies (14.1)] . 2.3 Drug Compatibility May inject sugammadex injection into the intravenous line of a running infusion with the following intravenous solutions:
• 0.9% sodium chloride
• 5% dextrose
• 0.45% sodium chloride and 2.5% dextrose
• 5% dextrose in 0.9% sodium chloride
• isolyte P with 5% dextrose
• Ringer's lactate solution
• Ringer’s solution Ensure the infusion line is adequately flushed (e.g., with 0.9% sodium chloride) between administration of sugammadex injection and other drugs. Do not mix sugammadex injection with other products except those listed above. Sugammadex injection is physically incompatible with verapamil, ondansetron, and ranitidine. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. 2.4 Instructions for the Use of Pre-filled Syringe CAUTION: Assure that the needle or Needleless Luer Access Device (NLAD) is securely attached before beginning the injection. Visually inspect the syringe-needle or syringe-NLAD connection before and during drug administration. Administration Technique 1. Remove glass syringe barrel from blister pack and check that it is not damaged. 2. Inspect visually for particulate matter and discoloration prior to administration. Do not use the solution if it is colored or cloudy, or if it contains particulate matter. Figure 1 3. Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and carefully TWIST THE SYRINGE TIP CAP COUNTER-CLOCKWISE until the cap disconnects for removal (see Figure 2). Figure 2 4. Pull the cap (A) off in a straight upward direction. DO NOT TOUCH THE STERILE SYRINGE TIP (Luer-Lok) (B) (see Figure 3). Figure 3 5. Connect the syringe to an appropriate injection connection depending on the route of administration. 6. Depress plunger rod to deliver the required dose of medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 7. Discard unused portion. NOTES:
• All steps must be performed sequentially.
• This product is for single dose only; discard unused portion.
• Store the pre-filled syringe at room temperature and keep it away from light and heat. image description image description image description

• 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 Hysterectomy 0 0 2(2) 0 * Combinations of preferred terms are as follows: Nausea includes preferred terms nausea and procedural nausea Vomiting includes preferred terms vomiting and procedural vomiting Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, and epigastric discomfort Pain includes preferred terms pain and procedural pain Red blood cell count decreased includes preferred terms red blood cell count decreased, hemoglobin decreased, and hematocrit decreased Electrocardiogram QT interval abnormal includes preferred terms electrocardiogram QT interval abnormal and electrocardiogram QT interval prolonged Hypertension includes preferred terms hypertension, procedural hypertension, and blood pressure increased Hypotension includes preferred terms hypotension, procedural hypotension, and blood pressure decreased Tachycardia includes preferred terms tachycardia and heart rate increased Bradycardia includes preferred terms bradycardia and heart rate decreased Pediatric Patients The safety of sugammadex injection has been assessed in a randomized, active-controlled study of pediatric patients 2 to <17 years of age, with 242 receiving treatment with sugammadex injection. Adverse events occurring in ≥5% of pediatric patients are presented in Table 3. The safety profile was generally consistent with that observed in adults. Table 3: Pediatric Patients with (2 to < 17 years of age) Adverse Events Incidence ≥5% in One or More Treatment Groups Up to 7 Days Post-Treatment Sugammadex 2 mg/kg Sugammadex 4 mg/kg n (%) n (%) Subjects in population 51 191 with one or more specific adverse events 40 (78) 143 (75) with no specific adverse events 11 (22) 48 (25) Cardiac disorders 5 (10) 16 (8) Bradycardia* 5 (10) 13 (7) Eye disorders 3 (6) 1 (1) Gastrointestinal disorders 8 (16) 35 (18) Nausea 1 (2) 12 (6) Vomiting 4 (8) 20 (10) Injury, poisoning and procedural complications 34 (67) 121 (63) Incision site pain 3 (6) 6 (3) Procedural nausea 4 (8) 9 (5) Procedural pain 30 (59) 111 (58) Procedural vomiting 3 (6) 5 (3) * Combines preferred terms of bradycardia and sinus bradycardia Every subject is counted a single time for each applicable row and column. A system organ class or specific adverse event appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding. Anaphylaxis and Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing clinical trials and in post-marketing spontaneous reports. In a dedicated hypersensitivity study in healthy volunteers, the frequency of anaphylaxis was 0.3% [see Warnings and Precautions (5.1)] . These reactions 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. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal. A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given 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 adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1%, 7% and 9% in the placebo, sugammadex 4 mg/kg and sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of sugammadex 16 mg/kg. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous sugammadex was 0.3%. There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing. In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after sugammadex 16 mg/kg (incidence 1% in the 298 healthy volunteers treated with sugammadex). Recurrence of Neuromuscular Blockade In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex injection was administered using a dose labeled for the depth of neuromuscular blockade (N=2022), an incidence of <1% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence [see Warnings and Precautions (5.8)] . Bronchospasm In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications [see Use in Specific Populations (8.9)] , bronchospasm was reported as a possibly related adverse event. 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. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of sugammadex injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders : Cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex [see Warnings and Precautions (5.2)] . Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, electrocardiographic (ECG) ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia. Anaphylaxis associated with ECG ST segment changes (elevation or depression) consistent with myocardial ischemia or coronary spasm has also been reported. General Disorders and Administration Site Conditions : Cases of sugammadex injection not having the intended effect. Immune System Disorders : Hypersensitivity events including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, and Type 1 hypersensitivity have been reported [see Warnings and Precautions (5.1)] . Respiratory, Thoracic, and Mediastinal Disorders : Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported.

Summary

The information reported in sections 7.2 – 7.4 is based on binding affinity between sugammadex injection and other drugs, preclinical experiments, clinical studies and simulations of a pharmacokinetic-pharmacodynamic (PK-PD) model. Based on these considerations, no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene and hormonal contraceptives.

Interactions Potentially Affecting the Efficacy of Sugammadex Injection Toremifene For toremifene, which

has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with sugammadex injection could occur. The recovery to TOF ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery.

Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives

In vitro binding studies indicate that sugammadex injection may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of sugammadex injection is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that sugammadex injection is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days.

In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days.

Interference with Laboratory Tests Sugammadex injection may interfere with the serum progesterone

assay. Interference with this test was observed at sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose.

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 . Known hypersensitivity to sugammadex or any of its components.

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.