anesthetics and life support drugs advisory committee march 11, 2008 sugammadex (sdx) preliminary...

Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee March 11, 2008March 11, 2008

SUGAMMADEX (SDX)SUGAMMADEX (SDX)Preliminary Efficacy FindingsPreliminary Efficacy Findings

SUGAMMADEX (SDX)SUGAMMADEX (SDX)Preliminary Efficacy FindingsPreliminary Efficacy Findings

Robert B. Shibuya, M.D.Medical Officer

CDER/OND/DAARP

Robert B. Shibuya, M.D.Medical Officer

CDER/OND/DAARP

2Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee March 11, 2008March 11, 2008

Overview of PresentationOverview of PresentationOverview of PresentationOverview of Presentation

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

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


Indications proposed by ApplicantIndications proposed by ApplicantIndications proposed by ApplicantIndications 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.”

Routine Reversal


Immediate Reversal



Key StudiesKey StudiesKey StudiesKey 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

• “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 302Studies 301 and 302Studies 301 and 302Studies 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 (T2) or 1-2 post-tetanic counts (PTC)

• Endpoint – time to T4/T1 = 0.9

• 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 (T2) or 1-2 post-tetanic counts (PTC)

• Endpoint – time to T4/T1 = 0.9


Results - Studies 301 and 302Results - Studies 301 and 302Results - Studies 301 and 302Results - Studies 301 and 302

Study # N Scenario SDX(mm:ss)

Neostigmine(mm:ss)

p-value

301 9693

RoutineShallow

01:29 (R)02:48 (V)

18:3016:48

<0.0001

302 7483

RoutineProfound

02:52 (R)04:28 (V)

50:2266:12

<0.0001


Study 301 (“shallow”)Study 301 (“shallow”)Study 301 (“shallow”)Study 301 (“shallow”)Study 301 - "Kaplan-Meier" analysis - Time to T4/T1 = 0.9

- Sugammadex-treated patients only

0

0.2

0.4

0.6

0.8

1

0 1000 2000 3000 4000

Time from injection of Sugammadex to T4/T1 = 0.9 (sec)

Pro

po

rtio

n o

f p

atie

nts

mee

tin

g T

4/T

1 =

0.9


Study 302 (“profound”)Study 302 (“profound”)Study 302 (“profound”)Study 302 (“profound”)Study 302 - "Kaplan-Meier" Time of sugammadex

injection to T4/T1 = 0.9

0

0.2

0.4

0.6

0.8

1

0 1000 2000 3000 4000

Time from sugammadex injection to T4/T1 = 0.9 (sec)

Pro

po

rtio

n o

f p

atie

nts

mee

tin

g T

4/T

1 =

0.9


Study 303Study 303Study 303Study 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 T1 = 0.1

• 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 T1 = 0.1


Summary - Primary EndpointSummary - Primary EndpointSummary - Primary EndpointSummary - Primary Endpoint

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


Indications proposed by ApplicantIndications proposed by ApplicantIndications proposed by ApplicantIndications proposed by Applicant

Routine Reversal


Immediate Reversal


Routine Reversal


Immediate Reversal



Applicant wishes to extrapolate Applicant wishes to extrapolate findings from Study 303 findings from Study 303

Applicant wishes to extrapolate Applicant wishes to extrapolate findings from Study 303 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.”

• “…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“Clinical Overview,” pages 91 and 92


Applicant wishes to extrapolate Applicant wishes to extrapolate findings from Study 303findings from Study 303

Applicant wishes to extrapolate Applicant wishes to extrapolate findings from Study 303findings 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]

• “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“Clinical Overview,” page 92


FDA observations regarding FDA observations regarding language in Clinical Overviewlanguage in Clinical OverviewFDA observations regarding FDA observations regarding

language in Clinical Overviewlanguage in Clinical Overview

1. Sugammadex was not tested in the CICV or emergency scenario.

2. The statements in the Clinical Overview do not address other reasons for apnea such as the drugs used for induction.

1. Sugammadex was not tested in the CICV or emergency scenario.

2. 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 Study 303 – Time from SDX administration to Tadministration to T11 = 0.1 = 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 - "K-M" for time to T1 = 0.1

0

0.2

0.4

0.6

0.8

1

0:00:00 0:00:43 0:01:26 0:02:10 0:02:53 0:03:36

Time from suggamedex injection to T1 = 0.1 (mm:ss)

Pro

po

rtio

n e

nd

po

inti

ng

Study 303 - "K-M" for time to T1 = 0.1

0

0.2

0.4

0.6

0.8

1

0:00:00 0:00:43 0:01:26 0:02:10 0:02:53 0:03:36

Time from suggamedex injection to T1 = 0.1 (mm:ss)

Pro

po

rtio

n e

nd

po

inti

ng


Study 303 – Time from SDX Study 303 – Time from SDX administration to Tadministration to T44 /T /T11 = 0.9 = 0.9Study 303 – Time from SDX Study 303 – Time from SDX administration to Tadministration to T44 /T /T11 = 0.9 = 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 - "K-M" for time to T4/T1 = 0.9

0

0.2

0.4

0.6

0.8

1

1.2

0:00:00 0:02:53 0:05:46 0:08:38 0:11:31 0:14:24 0:17:17

Time from injection of sugammadex to T4/T1 = 0.9 (mm:ss)

Pro

po

rtio

n t

o e

nd

po

int

Study 303 - "K-M" for time to T4/T1 = 0.9

0

0.2

0.4

0.6

0.8

1

1.2

0:00:00 0:02:53 0:05:46 0:08:38 0:11:31 0:14:24 0:17:17

Time from injection of sugammadex to T4/T1 = 0.9 (mm:ss)

Pro

po

rtio

n t

o e

nd

po

int




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)

Study 303 - "K-M" time to T1 = 0.9

0

0.2

0.4

0.6

0.8

1

0:00:00 0:02:53 0:05:46 0:08:38 0:11:31

Time from sugammadex injection to T1 = 0.9 (mm:ss)

Pro

port

ion

of p

atie

nts

endp

oint

ing

Study 303 - "K-M" time to T1 = 0.9

0

0.2

0.4

0.6

0.8

1

0:00:00 0:02:53 0:05:46 0:08:38 0:11:31

Time from sugammadex injection to T1 = 0.9 (mm:ss)

Pro

port

ion

of p

atie

nts

endp

oint

ing


ConclusionsConclusionsConclusionsConclusions

• 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.

• 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 Clinical Assessment of the Safety of SugammadexSafety of Sugammadex

Clinical Assessment of the Clinical Assessment of the Safety of SugammadexSafety of Sugammadex

Anesthetic and Life Support Drugs Anesthetic and Life Support Drugs Advisory Committee Advisory Committee

March 11, 2008March 11, 2008

Arthur Simone, M.D., Ph.D.Arthur Simone, M.D., Ph.D.Medical Officer Medical Officer Division of Anesthesia, Analgesia andDivision of Anesthesia, Analgesia andRheumatology ProductsRheumatology Products

Anesthetic and Life Support Drugs Anesthetic and Life Support Drugs Advisory Committee Advisory Committee

March 11, 2008March 11, 2008

Arthur Simone, M.D., Ph.D.Arthur Simone, M.D., Ph.D.Medical Officer Medical Officer Division of Anesthesia, Analgesia andDivision of Anesthesia, Analgesia andRheumatology ProductsRheumatology Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research


Introductory RemarksIntroductory RemarksIntroductory RemarksIntroductory Remarks

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


Sugammadex Safety DatabaseSugammadex Safety DatabaseSugammadex Safety DatabaseSugammadex 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.

• 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 Exposures and Serious Adverse EventsSerious Adverse Events

Exposures and Exposures and Serious Adverse EventsSerious 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 Preliminary Safety Findings Preliminary Safety Findings 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

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 FindingsECG FindingsECG FindingsECG Findings


DeathsDeathsDeathsDeaths

• Three deaths– two following sugammadex– one following placebo

• Three deaths– two following sugammadex– one following placebo


Sugammadex DeathsSugammadex DeathsSugammadex DeathsSugammadex 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.

• 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.


DeathsDeathsDeathsDeaths

• 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.

• 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 - CardiacSerious Adverse Events - CardiacSerious Adverse Events - CardiacSerious 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

Total3

(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 - CardiacAdverse Events - CardiacAdverse Events - CardiacAdverse Events - Cardiac

Number of Adverse Events Sugammadex

(mg/kg) Neostig.

µg/kg Preferred Term

Plb. 0.5 1 2 4 6 8 12 16 32 50 70

Angina pectoris 1 3 Arrhythmia 1 2 Atrial fib. 2 1 8 1 Bradycardia 2 4 3 8 5 2 6 2 3 Sinus tach. 1 1 2 1 Tachycardia 1 2 4 7 9 1 1 3 V. tachycardia 2 1 WPW syndrome 2 Total 6 4 8 33 16 3 7 2 3 2 3 3 % 2 3 4 5 2 10 5 5 2 1 2 4


Thorough QT StudiesThorough QT StudiesThorough QT StudiesThorough QT Studies

Two were conducted to assess:– Effects of sugammadex alone– Effects of sugammadex when

administered following an NMBA

Neither study indicated a QTcprolongation effect with sugammadex.

Two were conducted to assess:– Effects of sugammadex alone– Effects of sugammadex when

administered following an NMBA

Neither study indicated a QTcprolongation effect with sugammadex.


ECG Morphology ECG Morphology ECG Morphology ECG Morphology

• Applicant analyzed morphological features of ECG across studies.

• No differences from placebo were noted for HR, PR, QRS, T, U.

• Applicant analyzed morphological features of ECG across studies.

• No differences from placebo were noted for HR, PR, QRS, T, U.


Anaphylactic/Anaphylactoid Anaphylactic/Anaphylactoid ReactionsReactions

Anaphylactic/Anaphylactoid Anaphylactic/Anaphylactoid ReactionsReactions


HypersensitivityHypersensitivityHypersensitivityHypersensitivity

“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” 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


HypersensitivityHypersensitivityHypersensitivityHypersensitivity

• 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)

• 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)


HypersensitivityHypersensitivityHypersensitivityHypersensitivity•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.

•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 SearchAdverse Event Database SearchAdverse Event Database SearchAdverse 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.

• The AE database was searched for subjects who had multiple AEs suggestive of anaphylactic/anphylactoid reactions.

• 967 subjects experienced 1,628 AEs.



Number of AEs Number of Subjects3 1094 295 96 87 2

12 1

6 subjects had a combination suggestive of an anaphylactic or anaphylactoid reaction.

Number of AEs Number of Subjects3 1094 295 96 87 2

12 1

6 subjects had a combination suggestive of an anaphylactic or anaphylactoid reaction.



• 105.101.030 – rash, flushing, tachycardia,abdominal cramps, diarrhea

• 106.101.008 – rash, flushing, tachycardia,palpitations, nausea, visual disturbances, paresthesias, (BP notrecorded 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

• 105.101.030 – rash, flushing, tachycardia,abdominal cramps, diarrhea

• 106.101.008 – rash, flushing, tachycardia,palpitations, nausea, visual disturbances, paresthesias, (BP notrecorded 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



• 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.

• 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 106.101.008Subject 106.101.008Subject 106.101.008Subject 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.

• 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 Products Containing ββ Cyclodextrans CyclodextransProducts Containing Products Containing ββ Cyclodextrans Cyclodextrans

Product Description Caverject (alprostadil) Injectable prostaglandin for erectile dysfunction

Daptacel (DPT vaccine) Diptheria/pertussis/tenanus vaccine Geodon (ziprasidone) Injectable antipsychotic

Sporanox IV (itraconazole) Injectable antifungal Sporanox oral solution (itraconazole) Oral antifungal

VFEND IV (voriconazole) Injectable antifungal


SummarySummarySummarySummary

• 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

• 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 DeathsSugammadex DeathsSugammadex DeathsSugammadex 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.

• 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 DeathPlacebo DeathPlacebo DeathPlacebo 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.

• 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 EventsSerious Adverse EventsSerious Adverse EventsSerious 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.

• 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.


SugammadexSugammadexNonclinical Findings in Bone and TeethNonclinical Findings in Bone and TeethSugammadexSugammadexNonclinical Findings in Bone and TeethNonclinical Findings in Bone and Teeth

Anesthetics and Life Support Drugs Anesthetics and Life Support Drugs Advisory Committee MeetingAdvisory Committee MeetingMarch 11, 2008March 11, 2008

Adam M. Wasserman, Ph.D. Adam M. Wasserman, Ph.D. Supervisory PharmacologistSupervisory PharmacologistDivision of Anesthesia, Analgesia and Rheumatology Division of Anesthesia, Analgesia and Rheumatology ProductsProducts

Anesthetics and Life Support Drugs Anesthetics and Life Support Drugs Advisory Committee MeetingAdvisory Committee MeetingMarch 11, 2008March 11, 2008

Adam M. Wasserman, Ph.D. Adam M. Wasserman, Ph.D. Supervisory PharmacologistSupervisory PharmacologistDivision of Anesthesia, Analgesia and Rheumatology Division of Anesthesia, Analgesia and Rheumatology ProductsProducts


Nonclinical Response from FDANonclinical Response from FDANonclinical Response from FDANonclinical 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

• 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 FDANonclinical Response from FDANonclinical Response from FDANonclinical 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.

• 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.



Bone Studies (Juvenile rat)

– NOAEL (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)

Bone Studies (Juvenile rat)

– NOAEL (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)



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.

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.



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.

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.



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.

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.



• 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.

• 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.

anesthetics and life support drugs advisory committee march 11, 2008 sugammadex (sdx) preliminary...

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