BRIDION

Sugammadex is a selective relaxant binding agent indicated for reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide during surgery.

Rocuronium bromide and vecuronium bromide are neuromuscular blocking medications that cause temporary paralysis and are especially useful for general anesthesia, ventilation, or tracheal intubation that patients may require for surgery.

Sugammadex provides a new treatment option to reverse the effects of those medications and possibly help patients recover sooner post-surgery.

Sugammadex (brand name Bridion) is marketed by Merck Sharp and Dohme, and was approved by the United States FDA on December 15, 2015.

Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide in adults and pediatric patients who are undergoing surgery.

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.

This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium. 12.2 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.

BRIDION 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.

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.

The observed steady-state volume of distribution of sugammadex is approximately 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 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 and 8 days, respectively.

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.

In adult anesthetized patients with normal renal function, the elimination half-life (t 1/2 ) 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.

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 impairment.

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

In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t 1/2 was progressively prolonged with declining renal function.

Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively.

Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal impairment.

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.

The pharmacokinetics of sugammadex in pediatric patients have been evaluated in 2 clinical studies following administration of intravenous doses of 2 or 4 mg/kg sugammadex administered for reversal of moderate or deep neuromuscular blockade, respectively.

In one study, sugammadex pharmacokinetic parameters were estimated in pediatric patients to <17 years of age with patients enrolled into 3 age groups (2 to <6, 6 to <12 and to <17 years of age).

In a second study, sugammadex pharmacokinetic parameters were estimated in pediatric patients birth to <2 years of age with patients enrolled into 4 age groups (birth to 27 days, 28 days to <3 months, 3 months to <6 months and 6 months to < 2 years).

Sugammadex exposure (AUC 0-inf and C max ) increased in a dose-dependent, linear manner following administration of 2 or 4 mg/kg across patients birth to <17 years of age.

Sugammadex exposure was approximately 40% lower in patients <6 years of age following administration of 2 or 4 mg/kg sugammadex compared to older pediatric patients (6 to <17 years) and adults; however, this difference was not clinically relevant.

Both clearance and volume of distribution increase with increasing age in pediatric patients, whereas elimination half-life is generally similar across pediatric patients.

As a result, the observed steady-state volume of distribution of sugammadex is approximately to 10 liters and clearance is approximately to 95 mL/min resulting in a half-life of approximately 1-2 hours in pediatric patients to <17 years of age.

By comparison, observed steady-state volume of distribution of sugammadex is approximately to 3 liters and clearance is approximately to 95 mL/min with a half-life of approximately 1-2 hours in pediatric patients birth to <2 years of age.

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.

In one clinical study of obese patients with a body mass index ≥40 kg/m 2, sugammadex 2 mg/kg and 4 mg/kg was dosed according to ABW (n=76) or IBW (n=74).

Sugammadex exposure increased in a dose-dependent, linear manner following administration according to ABW or IBW.

No clinically relevant differences in pharmacokinetic parameters were observed between obese patients and the general population, when dosed according to ABW.

Systemic exposure of sugammadex is approximately 50% lower with IBW dosing compared to ABW.

Sugammadex is a modified gamma-cyclodextrin which forms very tight water soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium >> pancuronium).

Sugammadex creates a concentration gradient which favors movement of rocurionium from the neuromuscular junction into the plasma, which quickly reverses rocuronium-induced neuromuscular blockade.

The free rocuronium in the plasma are then bound tightly to sugammadex, assisting the diffusion of the remaining rocuronium molecules out of the neuromuscular junction and increasing bound and free rocuronium in the plasma.

Sugammadex is administered

At steady state, the volume of distribution is 11-14 L in adult patients with normal renal function.

No metabolites of sugammadex were observed during clinical studies.

Renal excretion of unchanged product. >90 of dose is excreted within 24 hours. 0.02% is excreted in feces and air.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

Patients with severe renal impairment (with creatinine clearance below 30 mL/min) should avoid use of drug as their clearance of the drug is reduced and there is inconsistent evidence about its safety in this subset of patients.

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.

Dosing is based on actual body weight Monitor for twitch responses to determine the timing and dose for BRIDION administration.

Administer as a single bolus injection.

For rocuronium and vecuronium: 4 mg/kg is recommended if spontaneous recovery of the twitch response has reached 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.

Immediate reversal in pediatric patients has not been studied. 2.1 Important Dosing and Administration Information BRIDION dosing is based on actual body weight.

BRIDION (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

BRIDION administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred.

BRIDION intravenously as a single bolus injection.

The bolus injection may be given over 10 seconds, into an existing intravenous line.

BRIDION has only been administered as a single bolus injection in clinical trials.

From the time of

BRIDION 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

BRIDION does not depend on the anesthetic regimen.

Preparation of dilution for pediatric use

BRIDION 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 vial of BRIDION 2-mL single-dose vials 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.

BRIDION injection is a single-dose sterile solution without preservatives.

Discard any unused portion from the vial. 2.2 Recommended Dosing BRIDION can be used to reverse different levels of rocuronium.

• or vecuronium-induced neuromuscular blockade.

For rocuronium and vecuronium

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

A dose of 2 mg/kg BRIDION is recommended if spontaneous recovery has reached the reappearance of the second twitch (T 2 ) in response to TOF stimulation following rocuronium.

For rocuronium only

A dose of 16 mg/kg BRIDION 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 BRIDION following administration of vecuronium has not been studied.

Immediate reversal in pediatric patients has not been studied. 2.3 Drug Compatibility May inject BRIDION 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 BRIDION and other drugs.

Do not mix

BRIDION with other products except those listed above.

BRIDION 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.

(sugammadex) injection is a clear, colorless to slightly yellow-brown, non-pyrogenic aqueous solution intended for intravenous infusion.

BRIDION is available in the following presentations: BRIDION 2-mL single-dose vial containing 200 mg sugammadex (100 mg/mL) NDC 84549-423-12 The packaging of this product is not made with natural rubber latex.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Protect from light.

When not protected from light, the vial should be used within 5 days.

Discard unused portion.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Protect from light.

When not protected from light, the vial should be used within 5 days.

Discard unused portion.

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

The available data from the pharmacovigilance safety database and published literature on BRIDION use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, there was no evidence of malformations following daily intravenous administration of sugammadex to rats and rabbits during organogenesis at exposures of up to and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed.

In a pre.

• and postnatal development study, sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher.

The background risk of major birth defects and miscarriage for the indicated population are unknown.

However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

In an embryofetal development study in rats, pregnant animals received daily intravenous administration of sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-17).

No treatment-related maternal and embryofetal changes were observed.

In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18).

Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of sugammadex on bone, it is possible that these findings may be attributable to drug.

There was no evidence of malformations at any dose.

In a prenatal and postnatal development study, pregnant rats were administered sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning).

Postnatal loss during

PND 1-4 was noted across control litters and treated litters from dams receiving sugammadex as a result of pup cannibalization by dams.

Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known.

An effect of sugammadex on steroidal hormones and/or pheromones cannot be ruled out.

In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development.

The safety and effectiveness of

BRIDION for reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide have been established in pediatric patients from birth and older.

Use of

BRIDION in these age groups is supported by evidence from adequate and well-controlled studies of BRIDION.

In pediatric patients, the safety profile is generally consistent with that observed in adults.

In a bone deposition study, sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% vs. 3% of the administered dose, respectively) following a single intravenous (IV) dose at 30 mg/kg (0.3 times the MRHD based on adult AUC comparison).

In a juvenile animal bone toxicity study, 7-day old rats were dosed intravenously once daily for 28 days with 0, 30, 120, and 500 mg/kg sugammadex (approximately 0.1, 0.6, and 3 times the MRHD, respectively, by adult AUC comparison).

Sugammadex at and 500 mg/kg decreased ulna and femur bone lengths by approximately 3%, which did not recover after an 8-week treatment-free period.

Reversible whitish discoloration and disturbance of enamel formation were also observed in the incisors at these dose levels.

In molars, this effect was only observed at 500 mg/kg. The no-observed-effect-level (NOEL) was 30 mg/kg. In a second juvenile animal bone toxicity study, 7-day old rats were dosed once weekly for 8 weeks with 0, 7.5, 30, and 120 mg/kg (up to 1.2 times the MRHD of 16 mg/kg based on adult AUC comparison).

No adverse effects on bone or teeth were noted.

BRIDION has been administered in a dedicated clinical study to a total 102 geriatric patients that compared the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg BRIDION given at the reappearance of T in 65-74 year-olds (N=62) and ≥75 year-olds (N=40) compared with 18-64 year-olds (N=48).

The median time to recovery of the TOF (T 4 /T 1 ) ratio to 0.9 in 18-64 year-olds was 2.2 minutes; in 65-74 year-olds it was 2.5 minutes, and in ≥75 year-olds it was 3.6 minutes.

For time to recovery from neuromuscular blockade induced by rocuronium following administration of 4 mg/kg BRIDION given at 1-2 PTCs, results across clinical trials revealed a median recovery of 2.5 minutes for geriatric patients (≥65 years, N=63) versus 2.0 minutes, for adults aged 18-64 years (N=359).

Hence no dose adjustment is necessary in geriatric patients with normal organ function.

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.