# Presentation: 172649

## SUGAMMADEX (SDX)Preliminary Efficacy Findings

**Robert B. Shibuya, M.D.**
**Medical Officer**
**CDER/OND/DAARP**

## Overview of Presentation

**Indications proposed by Applicant**
**Studies 301 and 302**
**Study 303**
**Conclusions**

## Indications proposed by Applicant

- _Routine Reversal_
**“...****(sugammadex sodium) is indicated for routine reversal of shallow or profound neuromuscular blockade induced by rocuronium or vecuronium.”**
- _Immediate Reversal_
**“...****(sugammadex sodium) injection is indicated for immediate reversal of neuromuscular blockade at 3 minutes after administration of rocuronium.”**

## Key Studies

**“****Routine” reversal of “shallow” neuromuscular blockade (NMB)**
**Study 301 **
**“****Routine” reversal of “profound” NMB**
**Study 302**
**“****Immediate” reversal 3 minutes following administration of rocuronium**
**Study 303**

## Studies 301 and 302

**R, safety observer blinded, single-dose, active-controlled safety and efficacy studies.**
**Enrolled patients (ASA 1-3) scheduled for surgery with general anesthesia in the supine position.**
**Treatment arms**
**Rocuronium/vecuronium followed by SDX or neostigmine **
**Reversed at return of the second twitch in a train of four (T****2****) or 1-2 post-tetanic counts (PTC)**
**Endpoint – time to T****4****/T****1**** = 0.9**

## Results - Studies 301 and 302

| Study # | N | Scenario | SDX
(mm:ss) | Neostigmine
(mm:ss) | p-value |
| --- | --- | --- | --- | --- | --- |
| 301 | 96
93
 | Routine
Shallow | 01:29 (R)
02:48 (V) | 18:30
16:48 | <0.0001 |
| 302 | 74
83 | Routine
Profound | 02:52 (R)
04:28 (V) | 50:22
66:12 | <0.0001 |

## Study 301 (“shallow”)

## Study 302 (“profound”)

## Study 303

**Randomized, safety assessor blinded, single-dose, active-controlled, safety and efficacy study**
**Enrolled adults (ASA 1-2) scheduled for surgery with general anesthesia in the supine position**
**Treatment arms**
**Rocuronium 1.2 mg/kg followed in 3 minutes with SDX 16 mg/kg**
**Succinylcholine 1.0 mg/kg**
**Endpoint – Time from NMBA administration to T****1**** = 0.1**

## Summary - Primary Endpoint

**Source: Applicant’s Clinical Study Report**

## Indications proposed by Applicant

- _Routine Reversal_
**“...****(sugammadex sodium) is indicated for routine reversal of shallow or profound neuromuscular blockade induced by rocuronium or vecuronium.”**
- _Immediate Reversal_
**“...****(sugammadex sodium) injection is indicated for immediate reversal of neuromuscular blockade at 3 minutes after administration of rocuronium.”**

## Applicant wishes to extrapolate findings from Study 303 

**“...****Org 25969 will allow for easier management of the cannot-intubate-cannot-ventilate (CICV) scenario...As a result, use of Org 25969 in a CICV situation following rocuronium administration may prevent the need for emergency non-invasive airway ventilation including rigid bronchoscopy, combitube ventilation, or transtracheal jet ventilation, and may prevent the need for emergency invasive airway access such as surgical or percutaneous tracheostomy or cricothyrotomy.” **

**“****Clinical Overview,” pages 91 and 92**

## Applicant wishes to extrapolate findings from Study 303

**“****As described above, the results from Trial 19.4.303 support the conclusion that replacement of succinylcholine with a combination of rocuronium followed by Org 25969 to reverse the neuromuscular blockade **_**would potentially markedly reduce the morbidity and mortality caused by a CICV scenario**_**.” [emphasis added]**

**“****Clinical Overview,” page 92**

## FDA observations regarding language in Clinical Overview

**Sugammadex was not tested in the CICV or emergency scenario.**
**The statements in the Clinical Overview do not address other reasons for apnea such as the drugs used for induction.**

## Study 303 – Time from SDX administration to T1 = 0.1

| Elapsed time | N (%) |
| --- | --- |
| < 60 sec | 26 (48) |
| 60-119 sec | 23 (43) |
| 120-179 sec | 4 (7) |
| >179 sec | 1 (2) |

## Study 303 – Time from SDX administration to T4 /T1 = 0.9

| Elapsed time | N (%) |
| --- | --- |
| < 60 sec | 7 (13) |
| 60-119 sec | 26 (48) |
| 120-179 sec | 14 (26) |
| >179 sec | 7 (13) [range - 3:30 – 14:18] |

## Study 303 – Time from SDX administration to T1 = 0.9

| Elapsed time | N (%) |
| --- | --- |
| < 60 sec | 0 (0) |
| 60-119 s | 11 (21) |
| 120-179 s | 25 (47) |
| 180-239 s | 11 (21) |
| 240-299 s | 1 (2) |
| 300-359 s | 2 (4) |
| 360-419 s | 1 (2) |
| > 7 min | 2 (4) |

## Conclusions

**Our preliminary findings are:**
**Study 301 showed that Sugammadex is effective in the “routine,” “shallow” scenario.**
**Study 302 showed that Sugammadex is effective in the “routine,” “profound” scenario. **
**The extrapolation of the results of Study 303 to an emergency or CICV situation is not supported.**

## Clinical Assessment of the Safety of Sugammadex

**Anesthetic and Life Support Drugs **
**Advisory Committee **
**March 11, 2008**
**Arthur Simone, M.D., Ph.D.**
**Medical Officer **
**Division of Anesthesia, Analgesia and**
**Rheumatology Products**

**Center for Drug Evaluation and Research**** **

## Introductory Remarks

**The safety review is ongoing.**
**The results presented are preliminary.**

## Sugammadex Safety Database

**28 clinical trials were conducted for the NDA.**
**1,973 adults were exposed to sugammadex.**
**1,845 adults were exposed to sugammadex ****	****and a neuromuscular blocking agent ****	****(NMBA).**
**88% of the subjects were ASA 1 and 2.**
**51 pediatric subjects were exposed to ****	****sugammadex.**
**6 infants (0-2y)**
**20 children (2-11y)**
**25 adolescents (12-17y)**
**The results of a hypersensitivity study conducted were recently submitted.**

## Exposures and Serious Adverse Events

|  | Incidents of Serious Adverse Events  |  |  |  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Tx | 
Plb.
 | Sugammadex
(mg/kg) |  |  |  |  |  |  |  |  |  | Neostig-mine
(mcg/kg) |  |
| Dose | N/A | 0.5 | 1 | 2 | 3 | 4 | 6 | 8 | 12 | 16 | 32 | 50 | 70 |
| N | 336 | 124 | 178 | 613 | 9 | 729 | 28 | 154 | 39 | 127 | 164 | 135 | 74 |
| Exps. | 418 | 124 | 178 | 613 | 9 | 813 | 28 | 154 | 39 | 131 | 578 | 136 | 74 |
| SAEs | 10 | 13 | 7 | 73 | 1 | 41 | 2 | 4 | 3 | 6 | 1 | 6 | 6 |
| % | 3 | 10 | 4 | 12 | 11 | 6 | 7 | 3 | 8 | 5 | 1 | 4 | 8 |

## Preliminary Safety Findings 

**Most findings have not been inconsistent **
**with those of the Applicant.**
**Two areas of concern have been**
** ****identified to date:**
**ECG abnormalities**
**Anaphylactic/anaphylactoid reactions**

## ECG Findings

## Deaths

**Three deaths**
**two following sugammadex**
**one following placebo**

## Sugammadex Deaths

**65 y.o. female presented for resection of colon ca.  **
**PMH: HTN, PUD and RA **
**Subject had received 0.5 mg/kg of sugammadex.**
**23 hours after uncomplicated surgery, she developed atrial fibrillation and respiratory failure.**
**No medications were listed in the CRF for tx of either AE.  She was described as having recovered with sequelae.**
**Died POD 42 from MI, cardiogenic shock, and pulmonary edema.**

## Deaths

**Atrial fibrillation following sugammadex administration cannot be ruled out as a possibly sugammadex-related event.**
**The two other reported deaths were likely not related to the study drug.**

## Serious Adverse Events - Cardiac

| Preferred Term | Number of Serious Adverse Events |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Plb. | Sugammadex 
(mg/kg) |  |  |  |  |  |  | Neostig. 
(μg/kg) |  |
|  |  | 0.5 | 2 | 4 | 8 | 12 | 16 | 32 | 50 | 70 |
|      Total | 3
(1) | 3
(2) | 18
(3) | 8
(1) | 1
(1) | 3
(8) | 4
(3) | 1
(1) | 1
(1) | 2
(3) |
|      Atrial fibrillation |  | 1 | 4 |  |  |  |  |  |  |  |
|      Cardiac arrest |  |  |  | 1 |  |  |  |  |  |  |
|      Cardiogenic shock |  | 1 |  |  |  |  |  |  |  |  |
|      EMD |  |  |  | 1 |  |  |  |  |  |  |
|      Myocardial infarction |  | 1 |  |  |  |  |  |  |  |  |
|      Vent.  tachycardia |  |  | 1 |  |  |  |  |  |  |  |
|      QTc prolonged | 2 |  | 12 | 6 | 1 | 3 | 4 | 1 |  |  |

## Adverse Events - Cardiac

## Thorough QT Studies

**Two were conducted to assess:**
**Effects of sugammadex alone**
**Effects of sugammadex when administered following an NMBA**
**Neither study indicated a QTc**
**prolongation effect with sugammadex.**

## ECG Morphology 

**Applicant analyzed morphological features of ECG across studies.**
**No differences from placebo were noted for HR, PR, QRS, T, U.**

## Anaphylactic/Anaphylactoid Reactions

## Hypersensitivity

**“****Hypersensitivity” or “Drug Hypersensitivity**
**  ****was reported as an AE for 8 subjects**
**3 events in the 2 mg/kg group**
**2 events in the 4 mg/kg group**
**3 events in the 32 mg/kg group**

## Hypersensitivity

**105.101.028 – 3 min. after sugammadex 32 mg/kg**
**105.101.030 – 2 min. after sugammadex 32 mg/kg**
**109.101.073 – 2 min. after sugammadex 32 mg/kg**
**209.101.016 – occurred earlier (after propofol)**
**301.102.005 – occurred earlier (after VCB)**
**301.104.026 – time uncertain (periorbital itching **
**	****                        ****and swelling were attributed to**
** ****	****                        ****bepanthen)**
**305.106.309 – occurred earlier (after Cipro)**
**311.107.016 – occurred earlier (after Cipro)**

## Hypersensitivity

**105.101.028 – increased HR, palpitations, ****	****	****   ****	****extrasystoles, erythema, tachypnea**
**105.101.030 – tachycardia, flushing, dyspnea, ****	****paresthesias, drowsiness**
**109.101.073 – rash, agitation, nausea, abdominal ****	****cramps, ****	****“possible allergic reaction”**
**The infusion was terminated prematurely in 101.101.073.  This subject was noted to have an increase in QTcB > 60 msec at 1 min. after the infusion was stopped.**
**No other treatments were noted in the AE database.**
**No NMBAs were involved**
**The dermal, cardiac and gastrointestinal AEs are all consistent with anaphylactic/anaphylactoid reactions.**

## Adverse Event Database Search

**The AE database was searched for subjects who had multiple AEs suggestive of anaphylactic/anphylactoid reactions.**
**967 subjects experienced 1,628 AEs.**

## Adverse Event Database Search

**Number of AEs****	****     Number of Subjects**
**	****3****	****	****	****	****109**
**	****4****	****	****	****	****  29**
**	****5****	****	****	****	****   9**
**	****6****	****	****	****	****   8**
**	****7****	****	****	****	****   2**
**       ****12****	****	****	****	****   1**
**6 subjects had a combination suggestive of an anaphylactic or anaphylactoid reaction.**

## Adverse Event Database Search

**105.101.030 – rash, flushing, tachycardia,**
**	****	****abdominal cramps, diarrhea**
**106.101.008 – rash, flushing, tachycardia,**
**	****	****palpitations, nausea, visual **
**	****	****disturbances, paresthesias, (BP not**
**	****	****recorded for 30 minutes)**
**302.103.105 – pruritus, hypotension, **
**	****	****nausea, vomiting**
**302.106.101 – rash, hypotension, nausea**
**308.109.003 – pruritus, nausea, abdominal**
**	****	****pain**
**311.107.013 – pruritus, hypotension, nausea,**
**	****	****vomiting**

## Adverse Event Database Search

**105.101.030 – 4 mg/kg; no NMBA**
**106.101.008 – 32 mg/kg; no NMBA**
**302.103.105 – 4 mg/kg; 0.1 mg/kg VCB**
**302.106.101 – 4 mg/kg; 0.1 mg/kg VCB**
**308.109.003 – 2 mg/kg; 0.6 mg/kg RCB**
**311.107.013 – 4 mg/kg; 0.6 mg/kg RCB**
**Infusion was prematurely stopped on 106.101.008.**
**No other treatments were noted in the database.**

## Subject 106.101.008

**At 1,3 and 6 h post-dose, tryptase levels were drawn.  **
**Levels were 19, 29 and 9 ****μg/L****, respectively (nl < 15 ****μg/L)**
**Subject was given an SPT 7 months later and an IDT 9 months later; both produced a positive result.**
**IgE was never assessed.**
**These results were the driving force behind study 19.4.110.**

## Products Containing β Cyclodextrans

## Summary

**The safety review is ongoing.**
**Preliminary findings are not inconsistent with Applicant’s.**
**Issues to be resolved:**
**electrocardiographic abnormalities noted, particularly QTc prolongations**
**anaphylactic/anaphylactoid drug reactions**

## Sugammadex Deaths

**61 y.o. male with prostate ca. presented for radical prostatectomy.**
**PMH: none reported**
**Subject received 2 mg/kg of sugammadex.**
**Surgery was complicated by perforation of the colon.  D/C’d on POD 6 with surgical drain *****in situ*****.**
**Hospitalized on POD 15 for PE, noted to have pelvic thrombosis.**
**Tx’d with heparin; died 2 days later.**

## Placebo Death

**73 y.o. male presented for resection of cerebral meningioma.**
**PMH: MI, S/P CABG, HTN and deficits related to the meningioma**
**Post operatively he developed cerebral edema, intraventricular and subarachnoid bleeding, with midline shifts.**
**He died on POD 11 with subfalx and transtentorial herniation; autopsy revealed a surgical lesion of the L middle cerebral artery.**

## Serious Adverse Events

**No SAE appeared to be dose dependent.**
**No respiratory, neuromuscular, renal or hepatic SAEs appeared to be related to sugammadex.**
**No hypersensitivity reactions rose to the level of SAE.**
**Cardiac events related to use of sugammadex did not appear to be dose related; however, they cannot be ruled out as possibly related to sugammadex exposure, particulary, QTc interval prolongation.**

## SugammadexNonclinical Findings in Bone and Teeth

**Anesthetics and Life Support Drugs **
**Advisory Committee Meeting**
**March 11, 2008**
**Adam M. Wasserman, Ph.D. **
**Supervisory Pharmacologist**
**Division of Anesthesia, Analgesia and Rheumatology Products**

## Nonclinical Response from FDA

**Review of submitted studies is currently ongoing**
**Several issues would benefit from further detail or clarification:**
**Safety margins descriptions (based on bone concentrations)**
**Use of data for predicting safety margins in pediatric patients**
**Study endpoints/parameters in adult and juvenile animal studies**
**Bone and teeth observations at doses at or above the NOAEL (No Observed Adverse Effect Level)**
**Absence of positive controls in bone evaluations (anabolic or catabolic states) to demonstrate assay sensitivity **

## Nonclinical Response from FDA

**Safety margins described in the presentation estimate human bone concentration of Sugammadex at the 4 mg/kg dose (4.5 μg/g bone).  However, the Applicant is requesting approval of up to 16 mg/kg Sugammadex (18.5 μg/g bone estimated). Therefore, margins should be reduced approximately 4-fold for the highest dose.**
***Bone Studies (young adult rat)***
**NOEL (single-dose) = 70X ****→ 17X**
**Detailed bone-specific observations including μCT**
**Above the NOEL, apparent slight resorptive effect on trabecular bone parameters and a slight reduction in bone strength in one of several assessments (femur indentation stiffness), not observed at 6-weeks post-dose.**
**NOEL (4-week) = 1000X → 270X**
**Fewer bone-specific observations (expanded histopath and BMD), no μCT for micro-architecture or bone strength assessments.**

## Nonclinical Response from FDA

***Bone Studies (Juvenile rat)***
**NO**_**A**_**EL (juvenile rat; 4-week study) = >1000X ****→ 270X**
**Effects on femur micro-architecture (↑trabecular BMD, thickness and number) noted at end of treatment, reversible by 8-weeks of recovery.  Femur size not different at end of treatment but smaller at end of  recovery period, coincident with ↓body weight gain.  **
**Relationship of femur size to decreased body weight gain possible but micro-architecture findings not temporally correlated, preceding ↓body weight gain.**
**Bone strength testing not conducted**
**Bone concentration estimated in humans is derived from mass-balance studies (retention of drug) in adults, where bone formation is more limited; in pediatric population, deposition of Sugammadex in bone is likely to be higher.**
**	****(adult rat ~3% of dose retained; juvenile rat ~13% retained)**

## Nonclinical Response from FDA

***Evaluation of teeth (juvenile rat)***
**NOEL (single-dose) = 48X ****→ 12X**
**One observation of disrupted enamel in incisors; probable background**
**NOEL (4-week) = 480X → 120X**
**Above this level:**
**Incisor discoloration, malocclusion**
**Disrupted amelogenesis (enamelization)**
**Deposition of “amorphous” material in incisors (less in molars)**
**Agree that rat molars may be more appropriate for risk assessment of adult  and pediatric patients in which enamelization is complete, however incisors may be more appropriate for very young children.  Nevertheless, a safety margin exists.**

## Nonclinical Response from FDA

**Preliminary Conclusions:**
**We are in agreement with the Applicant’s assertion that there are significant safety margins for single-dose use in adult patients for observed effects on bone and teeth based on data from studies from young adult and juvenile rat.  **
**Additionally, the probability that a limited deposition of Sugammadex will occur in the mature skeleton is reassuring.**

## Nonclinical Response from FDA

**Preliminary Conclusions (continued):**
**Although the Sponsor has used conservative assumptions when estimating bone/teeth-deposition in adults (maximum possible retention in adults based on mass-balance studies; absence of rocuronium), the estimated safety margins for use in the pediatric population – which is not the subject of the current application – may be more narrow.**
**Rapid bone growth is likely to produce greater deposition in the pediatric patient compared with adult (as observed in rat distribution studies). Therefore, safety margins may be reduced to an unknown extent.   At this time there are no pediatric mass-balance data in pediatric subjects to inform deposition estimates.  **
**All safety margins assume single-exposure in pediatric patients.  Nonclinical data indicates prolonged retention in bones (mean ~ 170 days in rats).  The duration of Sugammadex retention in the bones of a human is unknown but may be assumed to be similarly prolonged.  Therefore, repeated exposure may result in accumulation and reduced safety margins.**

## Nonclinical Response from FDA

**Preliminary Conclusions (continued):**
**Though juvenile animal studies did not demonstrate marked effects, these studies did not incorporate bone strength testing at the end of treatment when mild changes to bone micro-architecture were observed.**
**Although effects on juvenile bone micro-architecture reversed when evaluated 57-days after maximal deposition, effects of retention of Sugammadex over longer periods, such as Sugammadex half-life in bone or at the time of skeletal maturity, has not been evaluated. **
**The Applicant’s argument that fracture healing should not be affected by Sugammadex is plausible but is unsupported by data in nonclinical models of fracture.**