Deaths tn Dexmedetomidlne Clinical Studies
`A: Repbrted by. October 5. 1999
`
`Number of Deaths
`
`..
`
`ecu-:19”:
`
`-5=Innruzr1rn«:1,meern-rn
`
`
`
` _Em.\awmytgcum-tufiw;
`
`
`
`”manna-2x1-=‘n-‘=’'
`
`_____
`
`g"
`DEXQS-OOZ
`oassom 2
`
`— —.-_
`
` Phase III - Orion
`3005003
`
`
`
`
`Phase m - Abbot! + Orion
`15
`
`
`.._..._.....
`
`”w...”
`
`
`
` ‘ SOUREES:
`Abbou Studies - SAGE Report 050cm " =
`
`
`Orion Shadies - synopses
`‘ ~_ =-
`
`Gemesmoz - SAGE Repon 050cm
`
`DEXdeatthads
`
`‘ _
`
`omn- - Study Nos.
`
`9/9'd
`66:, BB_
`LSBA-BESQVB) $816136 93! 5880 HUSVHI
`
`
`

`

`~
`
`acres '99 24:14PMW
`..‘ "
`
`
`
`ABBOTT
`
`Hospital Products Division
`200 Abbott Park Rd.
`_
`Abbott Park, IL 60064-3537
`
`"
`
`"
`
`P.4/4
`
`
`
`.-
`.
`.
`No. ofPages:
`
`.4.
`
`Date:
`1M5 lag
`landuding' coverpage)
`
`From-Jean Conaway
`Regulatory Affairs D389/AP30
`
`'
`
`'
`
`(847) 937-3413 (telephone)
`(847) 938-7867 (fax)
`
`.
`
`

`

`
`
`OCT 85 '99 04:13:11
`
`
`
`P.1/4
`
`aAaaaTr '
`
`Hospital Products Division
`Abbott Laboratories
`0389, Bldg. AP30
`200 Abbott Park Road
`Abbott Park. Illinois 800m
`
`-
`
`October 5, 1 999
`
`CENTER FOR DRUG EVALUATION AND RESEARCH ‘
`ANESTHETIC. CRITICAL CARE & ADDICTION DRUG PRODUCTS, HFD #170
`Attn: DOCUMENT CONTROL ROOM #98—23
`5600 Fishers Lane
`
`'
`
`Rockville Maryland 20857-1706
`
`ATTENTION: Cynthia McCormick, M.D.
`Director
`.
`
`-
`
`Fax:
`
`Dr. Susmita Samanta
`301-480-8682
`‘
`
`Re;
`
`. NDA 21-038 Dexmedetomidine Hydrochloride Injection
`
`Abbott Laboratories hereby amends the above-referenced new drug application for the
`subject drug product to provide for Case Report Forms (CRFs) and a table for the nine
`specified patients We are responding to the teleconference on October 4 1999
`between Dr. Patricia Hartwell and Dr. Susmita Samanta FDA and Dr. Thomas Willer.
`Abbott Laboratories
`
`The Agency requested the following:
`
`REQUEST:
`
`the
`specified in
`all nine deaths
`for
`Please provide CRFs
`teleconference between the Agency and Abbott Laboratories on
`September 28,1999 and reported in the amendment dated
`October 1, 1999.
`
`RzESPONSE The nine patients reportedm the amendment dated October 1 1999 are
`as follows:
`
`
`
`

`

`ocr as '99 84:13PM m p.24
`
`Cynthia McCormick, MD.
`Page Two
`October 5. 1999
`
`Study
`No.
`W97-245
`u
`v
`we7—245
`
`
`Patient Number
`
`CRF ,
`Available
`
`#01001'
`I
`
`‘
`
`Study Drug
`
`PCANo‘J Related
`or Unrelated
`9906355- Unrelated
`
`9907455- Unrelated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Placebo-died 5 days
`
`oat-stud
`i
`
`Placebo-died 12 days
`oost-stud
`.
`
`I‘ m:- 9905913- Unrelated None received
`#105
`ws7-245
`[I_ 9906688- Unrelated None received
`#6301
`W97-245
`
`' W97'245 _—I_ 9906525- Umelated
`
`' W97-246 _II_ 9907483- Unrelated
`
`W97-246
`#12406'
`9907027- Unrelated
`
`
`
`
`
`W97-246
`
`#11601
`
`9906654- Unrelated
`
`3005003
`Orion
`
`#0901
`
`Yes
`
`9904548-Probably
`not related
`
`
`Placebo— died 35 days
`ost-stud
`Dexmedetomidine—
`died 5 da 5 - -st-stud
`Placebo— died 1 month
`- oat-stud
`
`'lnclIuded in the Integrated Summary of Safety, Appendix 3, submitted as part of NDA-21-038,
`Volume 301 of 726, page 8/10-239-162. Not included in the clinical safety database.
`
`"Consent form signed. but patient was not randomized pn'orto the start of surgery. Patient died
`intraoperatively.
`
`Provided in ngBlT I are Case Report Forms for the following five patients:
`
`01001, 010401, 012406, 011601, 0901.
`
`.
`
`—
`
`The Case Report Forms for the remaining four patients will be sent to the Agency as
`soon as available.
`
`REQUEST:
`
`Please provide a table which includes the number of deaths
`according to the following:
`1. Groups: dexmedetomidine. placebo and active control groups,
`2. Sponsor: Abbott , Orion and total,
`3. Clinical Study Phase: Phase I, II and Ill.
`
`RESPONSE: The above request is acknowledged‘and will be provided as soon-as
`available.
`.
`-
`I
`.
`I
`I,
`I
`I
`'
`
`
`
`

`

`OCT 05 '99 04:14PM ;.a-~—v--—————_____——-—————_———
`
`P.3/4
`
`Cynthia McCormick. MD.
`Page Three
`October 5. 1999
`
`“.7
`
`If you have any additional questions. please do not hesitate to contact rne at
`(847) 937-3413 or after October 7, 1999, Dr. Thomas Willer at (847) 937-6845.
`
`Sincerely.
`
`_
`
`” ”
`
`4
`
`ABBO'IT LABORATORIES ‘
`
`_
`
`‘ ng-Cfiwj
`
`Jean M. Conaway. R.Ph.
`Manager, Regulatory Affairs
`Hospital Products Division
`Phone:
`(847) 937-3413
`Fax:
`(847) 938-7867
`
`JMijc.
`
`GM O-QSIde.jn1c.doc1
`
`7
`
`APPEARS THIS WAY
`0” ORIGINAL
`
`~
`
`

`

`
`
`aAaaclTT
`
`Hospital Products Division
`Abbott Laboratories
`0-389. Bldg. AP30
`200 Abbott Park Road
`Abbott Park, Illinois 60064-8157
`
`'
`
`October 1. 1999
`
`-'
`
`'- ~“
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`ANESTHETlC, CRITICAL CARE 8. ADDICTION DRUG PRODUCTS. HFD #170
`Attn: DOCUMENT CONTROL ROOM #98-23
`5800 Fishers Lane
`1
`Rockville, Maryland 20857-1706
`
`'
`
`‘
`
`ATTENTION: Cynthia McCormick, M.D.
`Director
`
`'
`
`—.-_I.-'_.1_-_-r2:
`-:.—L=v.-'~."c‘-x-~
`
`..
`3'
`J
`
`l
`
`. Re: NBA 21-038 Dexmedetomidine Hydrochloride Injection
`
`Abbott Laboratories hereby amends the above-referenced new drug application for the subject
`drugproduct. The FDA and Abbott Laboratories conducted a teleconference on September
`,
`1999. Participating for the FDA were the following individuals: Dr. Fl. Rapapport, Aasist
`t
`Division Director; Dr. P. Hartwell. Medical Reviewer; and Dr. S. Samanta, Project Mamag r.
`
`Please refer to Section 11 of the Integrated Summary of Safety (Additional Serious Adverse .
`Event Reports from Abbott-Sponsored Studies) in the NDA. It reads as follows:
`
`“Abbott Laboratories‘ maintains a centralized database ofserious adverse global evegs
`
`(SAG E). This database includes all serious adverse events reported for subjects/patie s
`from the time informed consent is signed to at least 30 days after participation in ‘.n
`Abbott-sponsored study.
`
`Serious adverse events reported for subjects/patients within 24 hours (48 hours ibr
`Study DEX-95004) of participation in an Abbott-sponsored dexmedetomidine study ware
`to have been included in the clinical database for the specific study and Consequently in
`the overall safety database, in addition to their inclusion in the SAGE database. Seriotis
`adverse events reported for subjects/patients'24 hours (48 hours for Study DEX-$0059)
`after participation up to 30 days in an Abbott-sponsored dexmedetomidine study were to
`have been included in the SAGE database. but may not have been included in the clinifil
`database for the specific study or in the overall safety database.“
`,2
`
`in order to accurately-reflect the number of serious. adverse events reported during the Abb . -
`sponsored dexmedetomidine clinical program, a reconciliation of the overall safety data
`a
`and the SAGE database was performed (presented. in Section 11 of the ISS. Tables 35 and 3
`
`~
`
`‘\
`I
`
`——_——'—J
`
`

`

`a
`
`'
`
`Cynthia McCormick. M.D.
`Page Two
`October 1. 1999
`
`~
`
`.
`
`tabular form. as follows:
`
`Patient Number
`#1001'
`
`CRF
`Avallable
`Yes
`
`
`
`Y
`
`es
`
`9904548-Probably
`not related
`
`I!
`,,
`
`
`
`
`
`
`
`
`g
`'2
`
`
`
`
`
`12
`
`
`
`The nine patients specified in the teleconference of September 28. 1999 are preserved
`
`
`
`
`PCA NoJ Related ~ Study Drug
`Study
`or Unrelated
`No.
`9906355- Unrelated ~ Placebo-died 5 days '
`W977245
`
`9907455- Unrelated
`Placebo-died 12 @ys g
`W97-245
`
`-OSt-S’tud
`-
`mmm 9905913- Unrelated
`
`W97-245 mm 9906686- Unrelated None received
`W97-245 —.'_II_ 9906525- Unrelated
`
`W97-246 Elm—m- 9907483- Unrelated
`W97—246
`#12406‘
`Yes
`9907027- Unrelated ___Placebo- died 35 days;
`
`’
`'
`‘
`oost-stud
`t?
`W97-246
`#11601
`9906654- Unrelated Dexmedetomidinej-
`
`
`died 5 da
`
`
`
`
`
`
`in the integrated Summary of Safety. Appendix B, submitted as part of NDA-210$.
`'lncludéd'
`Volume 301 of 726, page 8/10-239-162. Not included in the NDA safety database.
`l
`"Consent form signed. but patient was not randomized prior to the start of surgery. Patieht d?!
`intraoperativeiy.
`
`1‘
`3
`l
`
`‘ywqu.:..
`
`-
`
`i
`'
`
`_
`
`,
`
`.
`.'
`
`:
`,
`
`a
`Please note that four patients (105. 6301. patient from W97-245 for whom no number wés
`assigned, and 704) died intraoperatively and never‘received study‘drug (either placebo
`I’
`dexmedetomidine). These patients were neVer considered part of the study because they he
`r
`entered the ICU and received study drug. Therefore, these patients were not includediin
`e
`E
`NDA safety database or in the clinical study reports.
`r
`Three patients (1001. 10401, and 12406) received placebo, but all died at least five days a
`the end of study drug infusion (5, 12 and 35 days, respectively). The study follow-up ipe ' d
`defined by the protocols was 24 hours. Because these three deaths occurred more
`24 hours after completion of the study. they were not-included in the NDA safety database.
`noted above, they were included in the SAGE database and in narratives. which appeared
`Appendix B of the lSS (Volume 301 of 726, page 8/10-239-1-62).
`.
`One Abbott patient (11601) who received dexmedetomidine died 5 days after study corn lei
`
`Since the death occurred more than 24 hours after study completion, this patient
`included in the clinical study database.
`It would appear, however.
`that
`this patieet
`
`inadvertently omitted from Appendix B of the lSS.
`One Orion patient (901) who received placebo die'd one month after study completion. T_ 3
`patient was submitted as part of NDAe21-038. Volume 541 of 726. page 8/10-237-263.
`';
`
`5
`
`l-
`
`-
`
`.-.
`
`

`

`Cynthia McCormick, M.D.
`Page Three
`October 1. 1999
`
`‘
`
`All patients were noted as “unrelated” or “probably not related" with regard to study drug
`causality.
`.
`
`If you have any additional questions, please do not hesitate to contact me.
`
`-
`
`Sincerely,
`
`. ABBOTT LABORATORIES
`
`W 522/0254
`
`Thomas F. Willer, PhD.
`Associate Director, Regulatory Affairs
`Hospital Products Division
`Phone: (847) 937-6845
`Fax:
`(847) 938—7867
`Internet. WILLETF©hpd.abbott.com
`
`APPEARS THIS WAY \
`0N ORIGINAL
`
`TFW2tw
`
`g:10-99f.tfw/18
`
`
`
`

`

`
`
`EXHIBIT I '
`
`I
`
`(1) ONGOING CLINICAL STUDIES
`
`- DEXMEDETOMIDINE HYDROCHLORIDE
`
`(2) COMPLETED CLINICAL STUDIES
`
`SINCE SUBMISSION OF NDA (12/98)
`
`- DEXMEDETOMIDINE HYDROCHLORIDE
`
`
`
`

`

`
`
`ONGOING CLINICAL STUDIES-DEXMEDETOMIDINE
`HYDROCHLORIDE
`
`Protocol Number: W98-263
`Study Title: A Pilot Phase ll, Multi~Center. Randomized. Placebo-Controlled, Double-Blind
`Study Evaluating the Safety and Efficacy—of Dexmedetomidine in Medical ICU Patients (France,
`Canada, and UK.)
`Estimated Study Completion Q4. 2000
`Estimated Final Report: 01. 2001
`Summary:
`Pan I: 16 of 21 patients complete. Part II: 0 of 24 patients complete.
`
`The-objective of the study is to evaluate the safetyand efficacy of dexmedetomidine in medical
`patients being intubated and ventilated for a minimum of six hours and not more than 24 hoors.
`Patients admitted to the ICU for pulmonary disease requiring intensive treatment
`(i.e..
`pneumonia, asthma, chronic obstructive airway disease j“(COPD).
`smoke inhalation. or
`postoperative patients [>72 hours postoperatively] who develop pulmonary or chest infections),
`patients with pancreatitis. myasthenia gravis. or neuropathy, such as Guillain-Barre syndrome
`are eligible for the study.
`‘
`
`Patients enrolled in Part I of the study will receive open label dexmedetomidine, and patients
`enrolled in Part ll of the study will be randomizad to either dexmedetomidine or placebo. All
`patients may receive propofol and morphine if required as additional medication for sedation or
`analgesia respectively.
`
`receive a loading 'dose of 1.0 meg/kg over 10 minutes followed by a
`All patients will
`maintenance infusion at an initial rate of 0.4 mcg/kg/hr. Following the initial rate, patients will be
`maintained within the range of 0.2 —- 0.7 mog/kg/hr (France and Canada), titrated to maintain a
`Ramsay sedation score of 33 while intubated, and 32 after extubation. Four patients in the UK
`were completed under this dosing regimen, and it was decided to expand the range of
`maintenance infusion. Patients in the UK will be maintained within the range of 0.2 — 2.5
`meg/kg/hr, and may receive additional boluses of 12 mcg (3 ml) of dexmedetomidine if needed.
`
`Patients requiring sedation beyond 24 hours will be'enrolled into study W98-264.
`
`Protocol Number: W98-264
`Study Title: A Phase II, Multi-Center, Open-Label Study Evaluating the Safety and Efficacy of
`Dexmedetomidine in Medical ICU Patients (France, Canada, and U.K.)
`Estimated Study Completion Q4, 2000
`Estimated Final Report: 01,2001
`Summary:
`-
`6 patients of 32 complete
`
`Patients completing the 24 hour infusion in study W98—263 are 'eligible for study W98-264, in‘
`which all patients receive open-label dexmedetomidine for up to an additional 6 days.
`
`-q .—v-
`
`..U 9—“ ,.,.,,..,.
`
`.
`
`! rfifi .—~.
`
`(5
`
`

`

`
`
`
`
`Protocol Number: Wes-266
`Study Title: Phase l Single-Center, Open~label Study Evaluating the Pharmacokinetics and
`Pharamcodynamics of Dexmedetomidine in Pediatric Patients (Canada)
`Estimated Study Completion 03. 2000
`"
`Estimated Final Report: Q4, 2000
`Summary:
`1 of 18 patients complete
`
`this study is to evaluate the pharrnacokinetics and safety of a single
`The objective of
`intravenous dose of dexmedetomidine in pediatric patients between two and twelve years of
`age. Pediatric patients undergoing urological, abdominal, or other surgeries requiring general
`and epidural anesthesia and overnight stay in the hospital are eligible for the study.
`
`A 10 minute infusion of dexmedetomidine will be administered 2 hours before. induction of
`anesthesia. Dosing will be administered in an ascending dose-ranging fashion in three dose
`groups: 2.0 mcg/kg/hr for Group l, 4.0 mcg/kg/hr for Group ll'fl‘and 6.0 mcg/kg/hr for Group ill.
`in
`each group, four patients will receive dexmedetomidine. and two will serve as controls.
`
`M“
`
`Protocol Number: W99302
`Study Title: A Phase lllb, Multi-Center, Open-Label, Randomized Study Comparing the Safety
`and Efficacy of Dexmedetomidine to Propofol-Based Standard of Care. for ICU Sedation
`Following Coronary Artery Bypass Graft Surgery.
`Estimated Study Completion: 02, 2000
`Estimated Final Report: Q4, 2000
`Summary:
`49 of 300 patients complete
`
`Patients undergoing CABG surgery are eligible for this study in which patients are randomized
`to either dexmedetomidine or standard of care treatment with propofol. Dexmedetomidine
`infusion is initiated at time of last sternal wire, with a loading dose of 3.0 mcg/kg/hr for 20
`minutes followed by an initial maintenance infusion of 0.4 mcg/kg/hr which is titratable between
`0.2 and 0.7 mcg/kg/hr.
`Infusion will continue for at least 6 hours following extubation, for up to
`24 hours total.
`
`Protocol Number W99-294
`Study Title European Study in Post-Op Patients in the iCU; Open study w/Dex
`Estimated Study Completion 02, 2000
`.
`Estimated Final Report: Q4, 2000
`Summary:
`00 of 500 patients complete
`
`in
`Patients undergoing major surgery requiring general anesthesia are eligible for this study.
`which two loading doses of dexmedetomidine are compared. Dexmedetomidine infusion will be
`initiated at time of first suture. Patients in Group i will receive a loading dose of 6.0 mcg/kg/hr
`for 10 minutes. and patients in Group II will receive a loading dose of 3.0_mcg/kg/hr for 20
`minutes. Both groups will receive an initial maintenance infusion of 0.4 mog/kg/hr which is
`titratable between 0.2 and 0.7 mog/kg/hr.
`
`Infusion will continue through extubation and after extubation, for a recommended minimum of 6
`hours. Maximum total infusion duration is 24 hours.
`
`5
`
`

`

` Protocol Number W99-314
`Study Title CABG study in Latin America and S. Africa
`Estimated Study Completion Not started
`Summary
`
`Patients undergoing CABG surgery are eligible'for this study in which patients are randomized-
`to either dexmedetomidine. or standard of care treatr'ne‘ntwith propofol. Dexmedetomidine
`infusion is initiated at time of last sternal wire, with a loading dose of 3.0 mog/kg/hr for 20
`minutes followed by an initial maintenance infusion of 0.4 mog/kg/hr which is titratable between
`0.2 and 0.7.mcg/kg/hr.
`Infusion will continue for at least 6 hours following extubation, for up to
`24 hours total.
`
`» _
`
`l ii
`
`.
`
`.
`
`._..,_§
`
`
`l
`
`_.- - __.~.._.
`
`\
`- \
`
`
`
`4‘w—-’-n")mm~u
`
`
`
`.’/__.....a...
`
`l l l l ii
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`
`
`

`

`COMPLETED CLINICAL STUDIES SINCE SUBMISSION OF NDA (1298!»
`
`—
`
`I
`
`DEXMEDETOMIDINE HYDROCHLORIDE
`
`“
`
`V
`
`D5
`
`.
`
`Protocol Number W98—272
`Study TItle:
`A Phase I. Single-~Center. Deuble-blind, Randomized, Placebo-Contollefi
`Crossover Study Evaluating Dexmedetomidine as a Sedating Agent'In Healthy Volunteers
`"
`Summary:
`
`Eighthealthyadultvolunteersweretobeenrolled Eachsubjectwastoreceive IVinfusionif
`
`(hi
`(low dose) 0.6 mog/kg/h dexmedetomidine HCl
`0.2 mcg/hg/h dexmedetomidine HCI
`dose) and a corresponding placebo via a standard syringe pump. Following an eight hour fa
`subjects were to receive a 10—minute loading dose of 6.O mcg/kg/h. followed by a SO-IpI
`maintenance infusion of the designated study drug. Subjects randomized to placebo Mere IoL‘
`receive a loading dose of 0.9% sodium chloride solution.
`
`The primary objectives of this study were to determine the sedative properties of low doses
`dexmedetomidine in young. healthy volunteers. and to evaluate the effects of these loont
`on analgesia, sedation. and cognitive function.
`
`f
`
`Final Report Submitted to FDA on May 12. 1999.
`
`I
`Protocol Number W98-273
`Study Title: A Phase I, Placebo-controlled, Double—blinded. Dose Ranging Study to Evialuée
`the Effects of Dexmedetomidine on SedationIn Japanese Subjects.
`3’
`Summary:
`in healtliy
`This trial designed as a two--part, Phase I, placebo-controlled, double-blinded trial
`subjects of ethnic Japanese origin.
`Part
`I was to consist of a dose-ranging study in
`approximately 40 subjects, 8 subjects per dose. to receive a 1-hour infusion. Part II was 0
`consist of four long term infusion, dosing sessions in approximately 32 subjects, 8 subje
`randomly assigned to each treatment group.
`Infusion times of 12 & 24-hours were-to
`studied.
`
`e
`
`to identify the dose/response relationship for sedation for sinQIe
`The primary objectives were 1)
`intravenous doses of dexmedetomidine. 2) to select and include 3 doses for the long to
`infusion portion of Part II of this study, and 3) to investigate the effects of long term infusions (2
`& 24 hours) of dexmedetomidine on the sedative profile compared to single doses.
`I.
`Final Report Submitted to FDA on September 3, 1999.
`.
`ll
`
`1'
`'
`
`.
`
`'
`
`.
`.
`'~
`
`WP
`
`Study Title: A Phase II Study entitled, “Alphaz-Agonists as Components for Analgosedajtioniin
`Intensive Care:
`Bispectral
`Index (BIS) Guided Sedation with Dexmedetomidine.
`PA
`Randomized. Placebo-Controlled. Double-Blinded, Prospectrive Study”.
`Summary:
`I
`The objective the study was to evaluate the safety and efficacy of dexmedetomicfine in paties
`requiring ventilation, sedation and intensive care fora minimum of 6 hours following surgery.
`9.
`The primary efficacy variable for this studyIs the total dose of propofol required in adcfitlon 0‘
`study drug, to achieve adequate sedation, as deemed clinically necessary and as assessed y
`BlS, to achieve and maintain a BIS Score of 60 to 70 (indicating deep sleep) and a BIS $0ne f
`85 to 95 after extubation (equivalent to a Ramsay Score of 2-3).
`
`rotocol Number W98-274
`
`Study drug will be administered for a minimum of 6 hours prior to extubation and a minimu
`6 hours post--extubation. The Investigator may continue the infusion at his/her discretidn
`maximum of 72 hours total study drug infusion.
`Estimated Final Report: December, 1999
`
`
`.
`of
`a '
`
`
`
`
`
`

`

`Protocol Number DEX-96-O‘l7
`Study Title: Beta Blocker Interaction: A Phase II, Single-Center, Double-Blind. Randomized,
`Placebo-Controlled Study Evaluating the Effect of Esmolol on the Pharmacodynamics of
`Dexmedetomidine in Patients Undergoing Elective Cardiac Surgery.
`Summary:
`this study was to evaluate the impact of dexmedetomidine 0n
`The primary objective of
`hemodynamix following administration of a beta-blocker (esmolol) to patients undergoing
`elective cardiac surgery.
`
`At least 40 adult, ASA Class II - IV patients (tour in the esrnolol dose-verification portion ofthe
`study and 12 per treatment group in the double-blind, placebo-controlled portion) scheduled for
`cardiac surgery were to be enrolled.
`'
`
`‘ 0.3 or 0.6 ng/ml of dexmedetomidine was to be administered ,from approximately 1 hour prior to
`the induction of anesthesia until 6 hours after the end of surgery.
`Estimated Final Report: October, 1999
`
`‘
`
`'
`
`'
`
`-
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`
`
`

`

`
`
`
`
`
`
`ABBOTT
`I
`_‘ Hospital Products Division
`
`—»
`
`To:W.
`
`Company:
`
`
`
`F ‘D/Jr
`
`FAX #
`
`3a /— $60“ -— R6092
`
`
`
`9/43 “ 7c) GK?
`
`‘
`
`£
`
`' NO. Of Pages:
`
`(including cover page)
`
`.
`
`From: Dr. Tom Willer
`
`‘
`
`Regulatory Affairs
`
`(847) 937-6845(telephone)
`(84V) 938-7867 (fax)
`
`.
`
`i
`
`
`
`

`

`aAsaoTT
`
`Hospital Products Division
`Abbott Laboratories
`bees. Bldg. APSO
`zoo Abbott Park Road
`Abbott Park. Illinois 50064—6157
`
`‘
`
`September16,1999
`
`‘
`
`'
`
`.
`
`.,
`
`I
`
`_
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`ANESTHETIC, CRITICAL CARE & ADDICTION DRUG PRODUCTS, HFD #170
`Attn:- DOCUMENT CONTROL ROOM #98-23
`5600 Fishers Lane ‘
`'
`Rockviile, Maryland 20857-1706
`
`ATTENTION: Cynthia McCormick, M.D.
`'
`Director
`
`" '
`
`Re: NDA 21-038 Dexmedetomidine Hydrochloride Injection
`
`Abbott Laboratories hereby amends the above-referenced new drug application for the subject
`drug. We are responding to two telephone requests from the FDA- to Abbott Laboratories.
`
`(1) FDA-Abbott Laboratories Teleconference, September 14, 1999
`
`r—
`
`
`
`
`
`
`
`
`
`. I . - _. _ ..-' . ._
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FDA request (b) was for information pertaining to the collection oi PK data in ongoing and future
`clinical studies. Pharrnacokinetic data will be obtained from the following ongoing studies: W98-
`268 (Pediatric). W98-263 (Mediwl ICU Patients) and W98-264 (Medical ICU Patients). Final
`reports may be available in mid-2000. Abbott Laboratories is not in a position to project, at this
`time, what future studies will be conducted and which ones will or will not incorporate the
`collection of pharmacOkinetic data.
`_
`‘
`
`
`
`

`

`Cynthia McCormick. MD.
`Page Two
`September 16. 1999
`
`(2) FDA-Abbott Laboratories Teleconterence, September 16. 1999
`
`_
`
`A teleconference was held on September 16. 1999 among the following individuals: Dr. P.
`Hartwell. FDA Medical Reviewer; Dr. 5. Samanta. FDA Project Manager; and from Abbott
`Laboratories: Dr. T. Willer Associate Director. Hospital Products Regulatory; Ms. 9‘. Seaman.
`Associate Director.
`international Regulatory; Ms. R. Tiehen. Senior Regulatory Affairs
`Associate,
`International Regulatory;
`.and Ms.
`J. Sayre. Senior Operations Manager,
`Dexmedetomidine Venture. The FDA requested that the paragraph pertaining to~“Perioperative
`Studies” on page 5 of the annotated package insert be revisedto remove all references to study
`Dex-96-012. The references deleted or modified‘include the following items:
`- Evaluated in‘7” studies; Total of "1 199’"patients; With "761” receiving tM
`Target concentrations of "0.15"; Infusions of 15 minutes( 002:004, Oil-2..."); “1-hour (012)"
`
`Dr. Hartwell further requested that a caveat be added to the last sentence of the paragraph
`mentioning that although the drug is ‘Well tolerated." an increase in hypotension may be seen
`with dexmedetomidine, as stated in other sections of the package insert. Per FDA request, the
`paragraph entitled “Perioperative Studies” has been revised and now reads as follows:
`
`i“; . has been evaluated in 6 clinical trials involving a total of 1165 patients. with 752
`receiving 'T“\_.A loading dose followed by a maintenance infusion was administered
`to achieve target concentrations of 0.3 or 0.6 ng/mL using continuous infusions of
`15 minutes (002. 004, 014, 015, 016. and 021) prior to induction of anesthesia and
`continued until determination of MAC response (016), the end of surgery (002). 2 hours (014
`
`and 021), 6 hours (004). or 12 hours (015) postoperativety.
`X was well tolerated
`during pre-, intra-. and postoperative administration." However. reports of hypotension have
`been associated with \—-—~( infusion.
`
`-.
`
`We recognize that the Agency has not accepted a brand name for this product and we will
`update the package insert once that occurs.
`If you have any additional questions. please do not
`hesitate to telephone me.
`
`Sincerely,
`
`ABBOTT LABORATORIES
`
`Thomas F. Willer, Ph.D.
`Associate Director. Regulatory Affairs
`Hospital Products Division
`Phone: (847) 937-6845
`Fax:
`(847) 938-7867
`lnternet: WlLLETF©hpd.abbott.com
`
`TFW:tw
`
`g:9-991.ttw/59
`
`——_—i
`
`

`

`CA We?”
`j/ m“ {Mala 9/” ~i
`ABBOTT
`51.“ {M
`,
`.p.
`, Hospital Products Division
`Tor“-
`- E)? S Sflflxfiw—f—
`‘
`Company;
`F979 '
`.
`FAX#:
`59/ ~4/¢/3~ 7oé£~
`
`‘
`
`,
`
`-
`
`
`
`
`
` E i“ We A
`(847) 938-7867 (fax)
`
`I. NO. Of, Pages:
`
`3 ‘
`
`Date: ' ?/é /& '
`.(inoilioing coverpage)
`_
`
`
`
`From: Dr. Tom Wilier
`Regulatory Affairs
`
`(847) 937-6845 (telephone)
`
`VQQ v_c~:~cz Ihf:\ cg?“ ‘V _"_, 5—3; paa- .. .LA .-.—.
`
`F) H-
`
`.
`
`i
`
`.a-
`
`;
`.;
`
`.
`
`i
`E
`5
`
`i
`g
`
`

`

`“
`
`ABBOTT
`
`_ Hospital Prodiicis Division ' {05/ M .
`TO:-
`.9
`5Mflfl/774_
`Company:
`. Ffiflk
`
`FAX#:
`
`3a/—- 7%— J’éfa.
`
`Datezl 9 /a/92
`
`‘
`
`NO. Of. Pages:
`
`’2 é
`
`(inciyding cover page)
`
`_
`
`From: D'r.Tom Willer
`
`Regulatory Affairs
`
`(847) 937-6845 (telephone)
`(847) 938-7867 (fax)
`
`
`
`-- '~- .-
`
`mouccérwm amt-UN a?! 6880 ”89968 66. at £5
`
`

`

`'aAaBoTT
`
`Hos ital Products Division
`Abbott Laboratories
`D689, Bldg. Apao
`209 Abbott Park Road
`Abbott Park, lllinoh scoot-0157
`
`-
`
`~~
`
`‘
`
`"
`
`.
`
`September 10, 1999
`
`5
`
`-
`
`_
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`ANESTHETIC. CRITICAL CARE & ADDICTION DRUG PRODUCTS, HFD #170
`Ann: DOCUMENT CONTROL ROOM #93-23
`5600 Fishers Lane
`
`Rockville, Maryland 20857-1706
`
`ATTENTION: Cynthia McCormick, M.o.
`Director
`
`.
`
`7".
`
`Re:
`
`NDA 21-038 Dexmedetomldine Hydrochloride Injection
`
`mar;:1-":
`
`a.
`
`'..~.'.:-rr_§:a‘.cv;.--
`
`“rm“
`
`.r.u,9'.v"..f.“‘._-':=l.
`
`Abbott Laboratories hereby amends the above-referenced new drug application for the subjgt
`drug product. We are responding to a teleconference on September 9,1999 between FDA
`Patricia. Hartwell and Dr. Susmita Samanta and Abbott Laboratories. Ms. Patricia Seaman, NE.
`Rita TIehen and Dr Thomas. WiIIer The FDA requested a translated copy of a Case Rep
`Form— Adverse Event lnforrnation for Patient No. 9, dated August 9.1995. We were able
`telephone Japan late yesterday and the requested translation was faxed to Abbott tod
`Please see Exhibit I.
`
`'I
`
`_
`
`We trust that this submission is complete“ If additional information or clarification is needefl.
`please telephone me at your earliest request.
`
`Sincerely.
`
`ABBOTT LABORATORIES
`
`2%.... am '
`
`Thomas F. Willer, PhD.
`Associate Director. Regulatory Affairs
`Hospital Products Division
`Phone: (847) 937-6845
`Fax:
`(847) 938-7867
`Internet: WILLETFthdabbothom
`
`Z
`
`‘
`
`.
`
`.
`
`TFW:tw
`
`g:9-991.ti\\I/36
`Attachment
`
`;
`
`.
`
`—
`
`_i
`
`.3
`1
`
`._
`
`i
`
`E
`i
`a}
`’2
`A
`'IJ
`‘
`
`
`
`MHI'E'lmhm".Prue-w::3
`
`66: BI CBS'
`’°°’-°°C'19°‘ gfiTt‘iid 933 SBEG UU93168
`'
`‘_ _.
`————_———_
`
`

`

`
`
`
`
`EXHIBIT I-
`
`CASE REPORT FORM
`
`ADVERSE EVENT INFORMATION FOR PATIENT NO. 9
`
`DATED AUGUST 9, 1995
`
`APPEARSTHISWAY
`
`OH ORIGINAL
`
`NOTE
`
`WE PROVIDE THE ORIGINAL JAPANESE AE FORM.
`
`THE ENGLISH TRANSLATION HAS BEEN TYPED IN BELOW TH
`
`JAPANESE WORDING.
`
`FOR THE CONVENIENCE OF THE AGENCY. SINCE THE TYPE I
`RATHER SMALL, WE PROVIDE A TYPED COPY FOLLOWING
`EACH ORIGINAL PAGE.
`
`I I
`
`I
`
`T!
`
`...J.&!‘~-4w.1.._.
`
`i
`
`I
`I
`
`'
`
`I
`
`; I
`
`;
`
`;-
`
`.gf
`
`-
`
`.
`3
`I'
`I
`
`- I
`
`I-
`Ii?
`‘
`M
`’°°’-°F")VR‘ °¥THEEH 93! 6850 “895368 66' BI dES
`
`
`3
`
`

`

`V
`
`:E:§’3‘25772
`
`’--
`
`I
`
`IIII'l'o-ml
`.-..----
`-
`.v—e-v-wzw
`CFC Clinic
`555.23% GP: 95 05
`Study No.
`smelt??- : In t
`Subject No.
`.
`Subjeu Initlnl:
`
`geek (1)
`Adverse Event
`
`max -;-— ;‘j ;
`Slucly Period
`
`‘
`
`
`
`areas-zoom
`Any Advene Event Observed ?
`
`.
`
`5E! a
`Yes
`
`I '3 015%? it li'FOlFElIZEA'TZ:
`If Yes Complete One Column Per Event.
`
`
`
`Subject Admission
`~ Follow-u §l
`I
`
`‘E'E/ ‘5
`l
`*—
`a
`.
`3:
`‘
`3'
`:
`A E
`‘?
`
`-
`
`
`
`
`
`': no?
`.-
` I
`fis’filsmvs?‘32w
`tiff‘i‘eotw‘fsgsrr
`,
`
`'ch)-1/léba.,le,ar°¢~»m.
`mug-:93-..EEZ’flIfi,‘
`-
`
`
`REE 3 it.r~
`" ‘figfifgidf?
`«.31 ~4HLLEE<QJK~J~M ’
`
`
`
`‘ * .I-JWMI9:- tel/21~~H;)?:=j‘—_3
`omtsim “1] eaten-d curing the period from I minuIes (O!0!) am: the gun or may dnt;
`. “’0“#1172.th E125
`dosing Iill.‘ hours and 29 minutes 03:30) one! coupleuon el'tlu 1&6) on»; infusion.
`‘nIe subjeet
`éF;e‘-.‘—Z<’aa<et§./g23/xnrées
`
`
`\\as able to open his.
`Inat easilv whentunnel“ to verballs but hogan felling asleep agotr. an the
`mob”: IInun-“7»; .
`3
`
`hunt: at suchInnmetions.
`
`ll:00)
`_ ll! - Baum:(immedmely.‘ttnrenewing theone to monitor \ltal Jinn) 2 hours 50
`£1 ( r)
`.Jfl 8 ll?
`
`V -
`' Onset Date
`if” oompleucn “f "“' ““3"“- Th’ "51‘!” 993399 was flanged Eton sent- ’5‘:b m
`
`In ‘
`when the was lmb- "In" allowed 'co hang vertically “501 the lower extension -'~' -; M
`‘
`'l
`. present: at um a'me was 5707mm”; Ana Lv. administration at 0Sn; meh ol'- -" thou
`I
`
`9mm Enema: and the setter: emanated. 3(3th (ml-Imam I: on) I:
`am} - -_
`-
`--
`- “hen the blood prewar: decreased. hone-vet use eubnel‘s pulse rate M ,- “-1.19
`
`Egg
`Rectum] the atropine sulfate. Blood pressure and puke rate In} almost res-end b “I.“
`
`-..£1;‘2.:.'_..
`.._. .....
`.mgm
`lVlUUClnu.
`Slight
`.aeveu. .
`I
`
`
`.
`
`fig"
`Grade
`
`-
`
`$5
`.— l-I— -
`
`~
`
`The whee: complained of we: at
`
`the completion or blood temple collation
`
`d,
`
`.
`
`n'gn
`
`am
`Omcome
`'
`
`figé‘flfi-fi
`fi-Eilfixifif-EEE
`Event Conunuing
`Event Continuing
`l. [jaw 2.
`[274595
`1. [Jam 2. [jams
`..
`1
`(Yes)
`(No)
`(Yes)
`'
`(No)
`D tezztrrnetIztxo-osmmse D t-emz'rmmumsaa .2 all
`
`Event Resolved at End of Study
`Event Resolved at End ofS‘t
`-y j
`
`.
`
`~
`
`7.:ng
`Event Contse
`
`
`
`fii‘fét-l:
`Continuous
`.
`l. D Yes
`2. [a No
`No when: E‘J— WNW t
`. If No. Number of Episodes
`ETD
`-
`
`#355195
`Continuous
`t. D Yes
`2". [3 No
`No 0mm: 2' y- Foam
`If No. Number of Episodes
`{EU}
`
`
`
`.
`
`rszzI-agecm: {m 4. gm;
`
`Physician'in Charge
`
`
`*_—_——-~——.
`
`Date
`
`talc/ls]
`
`1!! (yr)
`
`[F
`
`,5] (mtlt)
`
`El (db l
`
`1..--.".‘“""‘
`3|] 3
`
`
`
`-48-
`- 2~ . Ic°;_:~c~cr mo» cyYuJJu on): com woq:gg 55, at £81;
`
`
`
`

`

`— Page48-
`
`Adverse Event (1)
`
`Study No.:CP095-05
`
`-—’
`Subject Initials:
`Subject#09
`
`
`Any AdVerse Event Observed? Yes
`
`Onset Date: 08:08, 24 August, 1995
`
`’ Observed Events.
`Drowsiness was observed during the period from 8 minutes (08:08) after the start of
`mMWMmmwaaMeuompleflm of the study drug
`infusion" The subject was able to open his eyes easily when instructed to verbally but
`began falling asleep again in the absence of such instructions
`
`Grade: 1. Slight, Outcome: Event Continuing
`
`2. No
`
`Event Course: Continuous
`
`2. No
`
`ll No. Number of Episodes
`
`1
`
`Onset Date: 11:05, 24 August. 1995
`
`Event Observed:
`
`The subject complained of nausea at the completion of blood sample collection and
`vital sign monitoring (immediately after removing the used to monitor vital signs), 2
`hours 50 minutes (11:00) after completion of the Infusion. The subject’s posture was
`changed from semi-supine to one where the upper limbs were allowed to hang
`vertically with the lower extremities raised.
`Blood pressure at
`this time was
`67/27mmHg. After l.v. administration of 0.5mg atropine sulfate, blood pressure.
`increased and the nausea disappeared. Bradycardie (minimum 23 bpm) was also
`observed when the blood pressure decreased, however the subject’s pulse rate
`gradually increased after receiving the atropine sulfate. Blood pressure and pulse rate
`had almost reverted to baseline values at 11:22.
`
`.
`
`Grade: 3. Severe, Outcome: Event Continuing
`
`2. No
`
`Event Course: Continuous
`
`2. No
`
`It No. Numberot Episodes
`
`1
`
`'
`
`"C
`b
`
`I
`
`
`
`AQBA-BESQVB) 5816.136 538 6880 ”645268 66. 8T :85
`42’9'5
`
`
`

`

`a.
`
`.
`
`IU'lU-J‘
`
`.717'mvrww
`
`f
`
`_
`
`-
`
`:5‘6-5425778
`
`fiaafi (2)
`wr='—-‘g—7U=77
`~ Adverse Event
`, CFC Cliflic
`-
`763(21 i-‘J I
`7gsxfig. : CFC 95 _ 05
`Study Period
`Swdy No-
`m5£¥$%:- \ :9» p
`
`Subjcm Admissicn
`~ Follow-up Stud
`
`.FS/ 13
`':
`:'~‘;
`3' f.
`i if
`;
`;,.
`
`E5253 5 n7; . :Dnnwxigéu dun-1am; wad: nu may drum.
`25%;;
`x. _.
`Event Observed
`
`‘_
`
`i
`
`'
`
`|
`
`I
`
`.
`
`-
`
`'
`
`'
`
`~
`
`_
`
`:
`
`‘
`
`’
`
`:
`
`fi§$§flfifififianfi
`End Due andfl'ime
`
`4i (yr)
`
`5 (mm)
`
`B (dz-y)
`
`fF- (yr)
`
`F! (mih)
`
`E (day)
`
`I
`
`f”
`
`(Hm-tho
`
`63-min)
`
`”#(zanr)
`
`19(min)
`
`L [31mm L(Notrclaxed)
`
`I
`
`1. DEWE’Z Lmotrelatcd)
`
`;
`
`;.
`
`mkmcnafimfi z [jamawaswiaw
`Relation to
`(Pmbably not related)
`Inyestigalional Drug
`3. Dfifi. 50535 b
`(Probably rclaled)
`4..%9t1t2567’="35 9(Relared)
`,
`
`_
`
`\
`
`2.Ejmfl&wt$wi&w f
`(Probably net related)
`'
`3. Dana. [figfi '9
`I
`(Probably rclarcd)’
`-
`IZIQBfif‘ZHil-Ié UCReIared)
`
`4.
`
`I
`I
`
`
`
`
`
`gamma: Lt».
`
`Prcscnt Eden: Dosing
`
`“
`32§0§E
`Acxion Taken on
`Snudy Drug Dosage
`
`.
`
`éfiofim
`
`Corrective Thampy
`
`.
`figofifi
`Dcse Changed
`
`.. L2}
`fisowfi
`None
`
`.
`agmfifi
`Dos: Changed
`
`3. D
`£%n¢m
`
`Drug Wilhdrawn
`
`'
`'
`
`T
`:
`,‘r
`:
`3
`é.
`,
`. 3'
`
`3*
`
`:
`
`;
`
`3%
`
`l g
`2.
`
`‘.
`
`e
`_ A
`- 3‘
`“ .‘
`;
`7
`
`.
`
`“ramgairzm:
`“xm 31" 3
`1 9-“
`
`
`Physician in Charge ‘-
`
`.,
`
`‘
`
`Dale
`
`5F (yr)
`
`)3 (mm)
`
`E1 (day)
`
`-
`~4v-
`ABBA—Besuve) SHIUJJU 332! 6880 ”65:68 66. at 5135;,
`2/935
`
`
`

`

`Mumw
`
`'l'a_
`
`‘J.‘..=.I.11m(tb.'.“'‘
`
`._.—vsuntan:-
`
`
`.r-un:=.‘h.::1...;z
`
`Hurt...»
`
`snag-x1:_v-~-:
`
`
`:-I—-.:x.-."Juan-I'm;
`1C1A'.-_t-A:8-=rsu:
`
`i1J
`
`i
`
`- Page49-
`
`Onset Date: 13:30, 24 August,