CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`Application Number :
`
`018654/8018 and 8029 and SO30
`
`Trade Name : VERSED
`
`Generic Name: Midazolam Hydrochloride
`
`Sponsor : Hoffman-La Roche Inc.
`
`Approval Date: S018 and SOZ9-December 31, 1996
`
`S030-March 18, 1997
`
`

`

`Fublic Health Service
`
`WN-qa
`
`“-\
`
`Food and Drug Administration
`Rockville MD 20857
`
`OEc 3 I 1996
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`NDA 18-654/S-018& S-029
`
`—
`
`.
`
`~offmann-La Roche Inc.
`340 Kingsland St.
`Nutley, New Jersey 07110-1199
`
`Attention:
`
`Margaret J. Jack
`Program Director
`Drug Regulatory Affairs
`
`Dear Ms. Jack:
`
`Please refer to your supplemental new drug applications (NDA) dated April 16, 1989 and
`September 13, 1995, respectively, submitted under section 505 (b) of the Federal Food,
`Drug, and Cosmetic Act for Versed (midazolam HC1) 5mg/ml and 1 mghnl vials.
`
`We acknowledge receipt of your amendments for supplemental application S-018 dated
`September 16, 1994; August 26 and October 22, 1996. We also acknowledge receipt of
`your amendments for supplemental application ‘S-029 dated June 6 and 27; August 26;
`September 13; and October 22, 1996.
`
`Supplemental application S-018 provides for label revisions of the Pharmacokinetic Data
`
`found under the CLINICAL PHARMACOLOGY SECTION.Supplementalapplication S-029 provides for continuous infusion for sedation of intubated
`mechanically ventilated patients.
`
`We have completed the review of these supplemental applications,
`draft labeling, and have concluded that adequate information has been presented to
`demonstrate that the drug product
`is safe and effective for use as recommended in the
`enclosed revised draft labeling, submitted on October 22, 1996. Accordingly,
`applications are approved effective on the date of this letter.
`
`The fiml printed labeling(FPL)must be identical to the enclosed revised draft labeling.
`
`Marketing the product with FPL Chatis not identical to this draft labeling may render the
`product misbranded and an unapproved new drug.
`
`Please submit sixteen copies of the FPL as soon as it is available,
`days after it is printed. Please individually mount ten of the copies on heavy weight paper or
`similar material. For administrative purposes this submission should be designated “FINAL
`
`

`

`NDA 18-654/S-018& S-029
`
`~
`
`Page 2
`
`,
`
`PRINTED LABELING” for approved NDA 18-654. Approval of this submission by FDA
`is not required before the labeling is used.
`
`information relating to the safety or effectiveness of thk drug becomes
`Should additional
`avaiiable, revision of that labeling may be required.
`
`Please submit one market package of the drug when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`Should you have any questions, please contact:
`
`David Morgan
`Consumer Safety Offker
`Telephorux (301) 443-3741
`
`Sincerely yours,
`
`Curtis Wright, M. D., M.P.H.
`Acting Director
`Division of Anesthetic, Critical Care, and
`Addiction Drug Products, HFD-170
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`..
`
`..
`
`,,
`
`

`

`NDA 18-654/S-018& S-029
`
`Page 3
`
`cc:
`Original NDA 18-654
`HF-2/MedWatch (with draft labeling)
`HFD-2/MLumpkin
`HFD-92 (with draft labeling)
`HFD-103/PBotstein (with draft labeling)
`HFD-170/Div. File
`HFD-170/CSO/DMorgan j (I.Q n n *
`I-IFD-170/Landow/Cemy /hckwood/Ross/Moody
`HFD-101/LCarter
`HFD40/DDMAC (with draft labeling)
`HFD-613 (with draft
`labeling)
`HFD-735 (with draft labeling
`DISTRICT OFFICE
`HFD-820/New Drug Chemistry Director
`drafted: DM/December 24/18654.29a
`r/d initials: CMoody/12-30-96
`Final: SLiu/12-30-96
`
`APPROVAL
`
`(A.P)
`
`_
`
`.—
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockvil[e MD 20857
`
`fdAR I 8 W?
`...
`
`/-
`
`NDA 18-654/S-030
`
`Roche Inc.
`“Hofiann-h
`340 Kingsland Street
`Nutley, New Jersey
`
`07110
`
`Attention:
`
`Margaret J. Jack
`Program Director
`
`Dear Ms. Jack:
`
`.
`Please refer to your supplemental new drug application dated September 28, 1995,
`received October 2, 1995, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act for Versed (midazolarn HCI) 5mg/rnl and lmghnl vials.
`
`We acknowledge receipt of your submissions dated November 18; December 23, 1996;
`and February 13, 1997.
`
`The supplemental application provides for intramuscular,
`intravenous infusion for sedation in pediatric patients.
`
`intraven~s,
`
`or continuous
`
`We have completed the review of this supplemental application including the submitted
`draft labeling and have concluded that adequate information has been presented to
`demonstrate that the drug product
`is safe and effective for use as recommended in the
`enclosed marked-up draft. Accordingly,
`the supplemental application is approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed marked-up draft
`labeling. Marketing the product with FPL that is not identical to this draft labeling may
`render the product misbranded and an umpproved new drug.
`
`in no case more than 30 days
`Please submit 20 copies of the FPL as soon as it is available,
`after it is printed. Please individually mount ten of the copies on heavy-weight paper or
`similar material. For administrative purposes,
`this submission should be designated
`“FINAL PRINTED LABELING” for approved supplemental NDA 18-654/S-030.
`Approval of this submission by FDA is not required before the labeling is used.
`
`Should additional information relating to the safety and effectiveness of the drug become
`*-
`available, revision of that labeling may be required.
`
`.-
`
`

`

`NDA 18-654/S430
`Page 2
`
`that you
`In addition, please submit three copies of the introductory promotioml material
`propose tousefor
`this product. Allproposed materials should resubmitted
`indraftor
`mock-up form, not final print. P1ease submit one copy to this Division and ~o copies of
`both the promotioml material and the package insert directly to:
`
`.
`
`Food and Drug Administration
`Division of Drug Marketing, Advertising
`and Communications, HFD40
`5600 Fishers Lane
`Rockville, Maryland
`
`20857
`
`information about this drug product (i.e., a
`Should a letter communicating important
`“Dear Doctor” letter) be issued to physicians and others responsible for patient care, we
`request that you submit a copy of the letter to this NDA and a copy to the following
`.
`@
`address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20852-9787
`
`,
`
`.?:‘
`
`Please submit one market package of the drug product when it is ~~ailable.
`
`We remind you that you must comply with the requirements for an approved NDA set
`forth under 21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact David Morgan, Consumer Safety Offker, at
`(301) 443-3741.
`
`mwy-
`
`Cu@s Wright, M. D., M.P.H.
`Acting Director
`Division of Anesthetic, Critical Care and
`Addiction Drug Products, HFD-170
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`*-
`
`,,
`
`.,
`
`-..
`
`. .
`
`

`

`NDA 18-654/S-030
`Page 3
`
`—
`
`“,
`
`/–
`
`cc:
`Original NDA 18-654
`HFD-170/Div.
`tiles
`‘ HF-2/MedWatch (with dra~=labeling)
`xHFD-002/ORM ( with draft labeling)
`‘ HFD-92/DDM-DIAB (with draft labeling)
`x HFD-103/Office Director (with draft labeling)
`-HFD-101/L.Cafier
`HFD-170/CSO/D. Morgan
`HFD-170/I.Cerny/L. Landow/J.Ross/A. DStiC. Moody
`- HFD40/DDMAC (with labeling)
`‘HFD-613/OGD (with draft labeling)
`~ HFD-735/Df$E (with draft labeling)
`‘HFD-021/ACS (with draft labeling)
`DISTRICT OFFICE
`HFD-820 /ONDC Division Director
`V HFI-20/Press OffIce (with draft labeling)
`
`Drafted by: DM/Febma~ 25, 1997/versed.30
`Initialed by: CPMoOdy/CW/3/13/97
`fml:
`trh/3/13/97
`
`APPROVAL (AP)
`
`.“
`
`.“
`
`

`

`Public Health Service
`
`Food and Drug Administration
`Rockville MD 20857
`
`SEP I 8 1996
`
`$ / DEPARTMENT OF HEALTH & HIJMAN SERVICES
`
`-.
`
`c
`
`‘i~DA 18-654/S029 & S-030
`
`J30iTrnann-La Roche Inc.
`340 Kingsland St.
`Nut.ley, New Jersey 07110-1199
`
`..-
`
`Attention:
`
`Margaret J. Jack
`Program Director
`Drug Regulatory Affairs
`
`Dear Ms. Jack:
`
`*4”
`
`.*z
`
`:.
`
`*%
`
`++‘+
`7*41a
`
`Please refer to your September 13, and 28, 1995 supplemental new drug applications
`(NDAs) submitted under section 505 (b) of the Federal Food, Drug, and Cosmetic Act for
`Versed (midazoQm HCI) Injection 5mg/ml and 1 mg/ml vials respectively.
`
`We acknowledge receipt of your amendments dated June 6, 27, and August 26, 1996.
`
`Supplemental application S-029 provides for continuous intravenous infusion of Versed for
`sedation of intubated mechanically ventilated patients.
`
`intravenous, or continuous
`Supplemental application S-030 provides for intramuscular,
`intravenous infusion of Versed in pediatric patients for sedation.
`
`We have completed the review of these supplemental applications as submitted with draft
`labeling, and they are approvable.
`
`The bulk of the labeling for the two supplements is acceptable as written in your
`submission dated August 26, 1996. However,
`there are specific areas of concerns
`regarding the safe use of the drug in adults and childres as proposed in the labeling.
`Confkrnation of the safe use in these populations and revisions in the labeling are needed.
`Before these supplements may be approved,
`it will be necessary for you to provide the
`following:
`
`_.
`
`1.
`
`The proposed labeling is very complex, providing dosing information that
`varies substantially according to body composition (ideal body weight),
`indication, setting ,“patient age, concurrent medication and medical
`conditions. Provide,
`through some reasonable means, some evidence that
`the proposed labeling is comprehensible to prescribers of the drug, who
`would be able to follow the label to select a proper dose and use the drug
`safely.
`
`.
`
`

`

`NDA 18-654/029& S-030
`
`Page 2
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`there have been a number of practice
`Since Versed was fust approved,
`guidelines proposed for the safe sedation of children. In addition, in
`comection with a new medication now approved for this use, there has
`been extensive consideration by experts in this field, of labeling language,
`to arrive at clear and appropriate wording to provide for safe use. Your
`labeling needs to be consistent
`in its use of language with the current
`standards of practice for prescribers beyond the anesthetic community.
`
`The range of doses recommended is internally inconsistent, and might lead
`to excessively high doses being administered to larger, older children. The
`dosing guidelines need to be revised to provide patient safety.
`
`The proposed labeling and indications need to be more specific as to which
`indications are and are not being sought for pediatric usage.
`
`The Clinical Pharmacology section should be revised to include some
`information on the pharmacodynamics of midazolam.
`
`The proposed labeling is silent on the use of midazolam infusion in
`unintubated, unventilated patients as part of monitored anesthesia care, ICU
`practice of conscious sedation.
`It should either make a-direct
`recommendation for or against such usage.
`
`We are considering discussion of the labeling at a forthcoming meeting of the Anesthetic
`& Life Support Drugs Advisory Committee.
`
`If additional information relating to the safety or effectiveness of this drug becomes
`available, revision of the labeling may be required.
`
`In addition, please submit three copies of the introductory promotioml material that you
`.
`propose to use for this product. All proposed materials should be submitted in draft or
`mock-up form, not fiml print. Please submit one copy to this Division and two copies of
`both the promotioml material and the package insen-directly to:
`
`.,
`
`Food and Drug Administration
`‘“Division of. Drug Marketing, Advertising and
`HFD40
`‘
`5600 Fishers Lane
`Rockville, Maryland
`
`20857
`
`Communications,
`
`.
`
`

`

`.
`
`.
`
`NDA 18-654/029& S-030
`
`Page 3
`
`Within 10 days after the date of this letter,” you are required to amend the supplemental
`applications, noti~ us of your intent to file an amendment, or follow one of your other
`options under 21 CFR 314.110.
`In the absence of such action FDA may take a~tion to
`---
`withdraw the applications.
`
`These changes may not be implemented until you have been notified in writing that these
`supplemental applications are approved.
`
`Should you have any questions, please contact:
`
`David Morgan
`Consumer Safety Officer
`Telephone:
`(301) 443-3741
`
`Sincerely yours, .
`
`Paula Botstein, M.D
`Acting Director
`OffIce of Drug Evaluation HI
`Center for Drug Evaluation and Research
`
`..-
`
`.,
`
`

`

`ORUGSTUJIES ~ PEI.)MIRIG PATIENTS
`(To be co@eted
`for
`all MllZ’s mmmendeci
`t’orapproval)
`
`Check any of
`page:
`
`the following
`
`that
`
`apply and explain,
`
`as necessary,
`
`on the next
`
`-
`
`----
`
`towara a specific
`is oirecteu
`labeling
`1. A proposeu claim in the draft
`pediatric
`illness.
`T* application
`contains
`adequate
`and well-
`Controlled
`studies
`in pediatric
`patients
`to support
`that
`claim.
`
`2.
`
`is not
`information
`dosing
`pediatric
`includes
`laoefing
`The draft
`The
`in cnildren.
`stuuies
`and welA+ontraLleu
`basea on aaequate
`application
`contains
`a m~st
`under ZL (ER Z1.O.580r 314.M6(c)
`waiver
`the requirement
`at 21 ffR 201.57(t)
`for A&W studies
`of
`children.
`
`for
`
`in
`
`that
`
`a.
`
`b.
`
`i
`
`aIIU
`
`UIC
`
`contains
`
`cl
`
`I CGIA
`
`The application
`u4acaac
`and chilaren
`in adults
`to children.
`from adults
`grantea
`ano a statement
`action
`letter.
`
`the
`of
`the%ourse
`showing that
`aata
`ui
`LIE uLuy dL”c auJ I LLLtxl LAy sM1uLdA”
`to permit
`extrapolation
`of
`the data
`The waiver
`request
`should be
`to traat ef’feet
`is
`included
`in the
`
`aoes not
`application
`in the
`induaea
`The information
`adequately
`s@port
`the waiver
`request.
`should
`Tne request
`inciuded
`and a statement
`to that
`etlkct
`is
`be granted
`not
`the action
`letter.
`(CO@ete
`#3 or #4 oelow as appropriate.
`
`in
`
`)
`
`3.
`
`Peaiatric
`pnarmacoicinetic,
`dose-finding,
`{e.g.,
`studies
`aoverse
`snoulci
`adequate
`and well-controlled
`for Safety and efficacy)
`reaction,
`be done after
`approval.
`for use
`The drug proauct
`has s& potential
`ea12y Widespread
`in children,
`but
`there
`1S no mason
`to expect
`exaqle,
`alternative
`drugs are available
`pediatric
`use (because,
`for
`or
`the
`condition
`is uncamon m cnilaren).
`
`a.
`
`The applicant
`required.
`
`has Comittea
`
`to dOlng such studies
`
`as will De
`
`(l)
`(Z)
`(>J
`
`(f4J
`
`are ongoing.
`been submitted
`hWe
`have been submitted
`
`Studies
`Protocols
`Protocols
`review.
`on tne next
`nas oeen suomittea,
`no prottiol
`lf
`pa$e exphin tne StatUS of discussions.
`
`ana approvea.
`ana are unaer
`
`t).
`
`.We sponsor is not willing to uo pematric stuuies,
`If
`attach copies of FbA’s written
`oe
`request that such studies
`acme anu of the sponsor’s written response t~ mat request.
`
`4.
`
`Pediatric studies do not need to be encourage because tne arug
`proauct nas llttle pocentlal
`for use in ctlilcmen.
`
`

`

`Page
`
`i!
`
`--
`
`Urug Studies
`
`in tWiatric Patients
`
`.
`
`3.
`
`if none or
`
`tne aoove ap@y,
`
`exp~ain.
`
`-.
`
`fffj?-
`
`Signatui+
`
`of Preparer
`
`Urig NIJA
`cc:
`HFW17C/L)iv
`File
`ti.
`.. —.Action Package
`
`/
`
`,
`
`-.
`
`/
`/?/it//l
`
`-/
`
`r
`
`Date
`
`.
`
`.
`
`.
`
`*
`
`

`

`- 02/27/97
`
`14:54
`
`~201
`
`812
`
`3554
`
`1).K.A.
`
`.-
`
`-.
`
`..
`
`DEBARMENT CERTIFICATION
`
`/
`
`- b Roche Inc. hereby certifiesthat it did not and will not use in any
`Hofhmann
`capacity the services of any person debarred under 21 U.S.C. 335a (a) and (b), in
`connection with these applications.
`
`,,
`
`.
`
`

`

`1.
`
`Active Ingredient(s):
`
`strength(s):
`
`Trade Name:
`
`PATENT INFORMATION
`
`~Midazolam
`
`5 mg/ml
`
`VERSED@
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Dosage Form and Route of
`Administration:
`
`Continuous infhsion
`
`&@kam (l%@ Name:
`
`Hoffinann-La Roche Inc.
`
`NDA Number:
`
`NDA 18-654
`
`First Approval Date:
`
`l
`
`Exclusivity: Date f~st
`ANDA could be submitted
`or approved and length
`of exclusivity period:
`
`Patent Information:
`Patent number(s)
`and expiration date(s):
`Type of Patent
`Patent Owner:
`
`Original NDA approved December 20, 1985
`pending S 029, submitted
`September 13, 1995
`For Continuous infhsion for sedation of
`intubated, mechanically ventilated adult patients
`
`Three years from date of
`approval of pending supplement
`
`4,280,957, expires December 20, 1999
`Drug
`Hoffmann-La Roche Inc.
`
`While this submission was prepared in good faith, no wamanty or guarantee is made
`regarding the accuracy or completeness of the information contained therein.
`
`CONFIDENTIAL
`
`INFORMATION
`
`to&e New Drug Application has not yet been approved, this
`Since the Supplement
`submission is considered as constituting trade secrets or commercial or financial
`information
`which is privileged or confidential within the meaning of the Freedom of Morrnation Act (5
`U.S,C. 552). It is requested that this submission not be published until the Supplement to the
`.
`New Drug Application has been approved.
`
`

`

`FOR DRUG EVALUATION
`
`CRmcAL
`
`CARE,
`
`AND ADDICTIVE
`
`DIVISION OF mESTHmICs
`DRUGS
`HFD 170, Room 9645
`5600 Fishers Lane
`Rockville MD 20857
`
`INTEGRATED EFFICACY & SAFETY REVIEW
`
`NDA # 18-854 S#30
`Sponsoc Hoffman-La Roche Inc
`Type of Submission:
`INDA
`Date of Submission: 13 September 1995
`Date Reoeived:
`Date of Review: 1-30 August 1996
`Peer Reviewer Curtis Wright MD
`Date Cleared Peec
`Reviewer Laurence Landow MD
`
`RESUME
`This is an lnt&ctive NDA for continuous intravenous infusion of Versed (midazolam) to
`intubated, adult ICU patients who require sedation during mechanical ventilation. Midazolam has gained
`widespread acceptance as a safe and effective sedative for patients about to undergo surgery and for
`conscious sedation during short diagnostic or therapeutic procedures outside the operating room. Off-
`Iabel use has included sedation of ICU patients who require mechanical ventilation for acute respiratory
`failure.
`
`Questions that remain unanswered center on safety issues such as appropriate dosage, drug
`interactions, and potential side-effects of administering this drug continuously,
`for days or weeks at a time.
`In an attempt to answer these questiins,
`the sponsor supported three prospective,
`randomized, double-
`blind, dose-finding studies in the cardiac and aortic aneurysm repair surgery populations. Based on these
`and related studies in the Iitemture,
`the following recommendations can be made for administration of
`midazolam in the ICU:
`i) Loading Dose: in the immediate postoperative period following cardiac and major
`vascular surgery, an appropriate loading dose is approximately 0.01 mg/kg (administered over Z2 rein) for
`patients receiving a moderate-dose (25-75 ug/kg loading dose) fentanyl anesthetic, and 0.02 mg/kg; for
`patients receiving a Iowdose (5-20 ug$kg loading dose) fentanyl, or sufentanil or alfentanil anesthetic.
`Clinical experience and several welldesigned studies from the literature suggest that in intubated patients
`with acute respiratory failure who require sedation for mechanical ventilation, a bolus (administered in
`divided doses over 22 rein) as low as 7 ug/kg in frail, elderty patients, and as high as 200 ug/kg in young,
`agitated adults, is appropriate.
`ii) Infusion Dose: an appropriate infusion rate in the immediate postoperative period
`following cardiac and major vascular surgery is approximately 15 ug/kg-h. Clinical experience and several
`welldesigned studies from the literature indicate that infusion rates for patients in acute respirato~ failure
`depend on a number of clinical factors. Generally speaking, the initial rate in frail, elderty patients is -‘
`approximately 30 ug/kg-h (0.5 ug/kg-min) whereas in agitated, young adults, rates as high as 200 ug/kg-h
`(3.3 uglkg-min) occasionally maybe indicated. Infusion rates overtime for a given patient are often a
`function of disease severity; the dose should be assessed periodically and titrated to the lowest effective
`,,
`rate.
`
`is sim’ilar to those_ i
`side-effects - primarily hypotension -
`The incidence of non-respidtory
`described in the current labeling for induction of anesthesia. The likelihood of withdrawal symptoms
`following termination of long-term midazolam administration is minimized by weaning the infusion over
`several days. There is the potential for several drugs given routinely to ICU patients to interfere with
`midazolam’s metabolism, although the clinical significance of this is as yet unclear.
`
`.
`
`

`

`NDA # 18-654 S830
`
`INTRODUCTION
`
`Versed (midazolam HCI) is a water-soluble, short-acting benzodiazepine that depresses the
`central nervous system.
`It is 95% plasma-protein bound and subject to approximately 55% first pass
`metabolism. Midazolam is currently approved for three indications: preoperative sedation; intravenous
`induction of anesthesia; and conscious sedation during therapeutic procedures. A supplemental
`application (No. 029) to the manufacturer’s previous NDA was submitted on 13 September 1995 providing
`data for a new indicatbn - COntrnWs intravenous infusion for sedation of intubated, mechanically
`ventilated patients.
`in order to
`Since the late 1980s, intensivists in the US have been using midazolam off-label
`sedate critically ill patients receiving mechanical ventilation. Independent audits of hospital practices
`suggest
`that 25°A of the current use of midazolam in the US is for sedation of ICU patients. Midazolam is
`used as a sedative for over 2,000,000 ICU patientdays yearly. Continuous infusions account for
`approximately 45 percent of thk use. In 30 percent of cases, the duration of administration is for three
`days or longer.
`
`The Review Task
`
`respect
`
`There is no doubt that midazolam is safe and effective. Questions that need to be answered with
`to continuou%infusions include the following:
`
`0
`
`*
`
`0
`
`9
`
`What is the minimum Wective dose required to sedate post-surgical patients and ICU patients?
`
`What are the sideeffects of prolonged midazolam infusions?
`
`Is there tolerance to, or withdrawal from, midazolam infusions?
`
`What drug interactions (eg, proionged elimination) are observed when midazolam is administered
`to ICU patients?
`
`the sponsor provided data from a variety of supported
`To answer dosing and safety mncems,
`studies i) three pivotal dos4nding
`studies [Martineau et al, Ralley et al, and Teasdale et al]; ii) two
`repeat-bolus studies [Lesfii et al, Ramsey et al]; iii) one mntinuous infusion study (safety data only)~ite
`et al]; and iv) eight open-label, uncontrolled investigations. In addition, the sponsor generated a detailed
`literature review of the aduft ICU population that included 26 prospective, randomized, controlled,
`continuous infusion studies (22 of which included a compantor, usually propofol ); 23 uncontrolled studies;
`and more than almost 200 miscellaneous papers (abstracts, case reports) from the world literature. One
`study, still ongoing,
`is a pharrnacokinetic study using a computer-assisted controlled infusion (CACI).
`
`CHEMISTRY
`
`data for midazolam with 5% dextrose and 0.9% sodium chloride in PVC bags was
`Compatibifii
`submitted as a supplement m the application, S-020, dated 4 February 1991 and approved 19 September
`1991. The compatibility data show that midazolam Injection, 5 mg/mL, when diluted to a midazolam
`concentration of 0.5 mg/mL with 5°A dextrose or 0.9%sodium chloride is chemically and physically stable
`for -z24 h.
`For this ND~ the sponsor has prepared midazolam infusion solutions with PVC tubing to
`compare its compatibility with !he tubing. Midazolam infusion solutions were made up at midazolam
`concentrations of 0.3 rng/mL and 0.5’mg/mL, diluted with 5% dextrose and 0.9% sodium chloride. The
`concentration of midazolam was assayed over a 24 h period using HPLC. The data recorded is within the
`specification limits of
`9’0.
`From a chemistry viewpoint
`
`the supplement can be approved.
`
`.
`
`

`

`NDA # 18-654 S#30
`
`3
`
`CLINICAL PHARMACOLOGY
`
`Three dose-ranging studies supported by the sponsor investigated midazolam infusions in ICU
`patients (for a more complete description of these studies see “Summary of Clinical Studies”, below). Two
`of these (Ralley et al and Teasdale et al) were really safety studies rather than true dose-response
`studies, because if patients were not at a predetermined level of sedation, the infusion was increased or
`decreased accordingly. Steady-state plasma concentrations measured in the third study (Matiineau et al),
`in which the dose of midazolam was essentially unchanged throughout
`the study (whereas the dose of
`narmtic analgesia was varied), ranged horn a mean of 76 ng/mL (range 31-140 ng/mL), 130 ng/mL (40-
`270), and 205 ng/mL (100470)
`for the low, medium, and high treatment groups, respectively. Interim
`analysis of data collected from a partially completed CACI study indicates that midazolam has a
`therapeutic window between 50-100 ng/mL for sedation foJlowing corona~ artery bypass surgery. Similar
`values were obtained for the low, moderate, and high dose groups with respect to clearance rate, volume
`of distribution, and elimination half-life and agreed with other studies in the literature.
`In their literature review, the sponsor found studies in volunteers that lasted as long as 26 h with
`infusion rates up to 40 ug/kg-h. Mean plasma clearance in this group ranged from 6.1 to 9.6 mL/min-kg.
`Mean volume of distribution ranged fmm 1.0 to 2.7 Ukg. Studies in patiefits undergoing cardiac,
`abdominal aortic, and maxillofacial surgery demonstrated a mean plasma clearance and volume of
`distribution that were similar to those in volunteers,
`ie, 3.4-10.5 mUmin/-kg and 1.0-3.1 tfkg, respectively.
`For ICU patients, corresponding values were 0.4-10.3 mUmin/-kg and 0.7-4.6 L/kg, findings that are not
`unexpected in patients with hepato-renal dysfunction who are typically edematous and hypoalbuminemic.
`Because of the high variabilii
`in Vd and Cl in critically ill patients, cautious dosing should be emphasized.
`This is reflected in the observation that 14% of patients in the sponsor-supported studies experienced
`hypotension, most of these cases occurring immediately following the midazolam loading dose.
`Midazolam undergoes hepatic metabolism to 1-hydroxy midazolam which is then mnjugated and
`excreted by the kidneys.
`In the literature rev”~w, the sponsor presented several studies that measured
`levels of the unconjugated rnetabotiie, which were considerably lower than those of the parent compound.
`This finding, together with the tower receptor affinity and lower relative brain uptake of l-hydroxy
`“
`midazolam relative to the parent compound, make it likely that the net pharmacological effect of
`midazolam administration is attributable to the parent compound. Since the glucuronide is excreted by the
`kidney, its plasma levels will rise in patients with renal insufficiency. This is not of clinical importance,
`however, since the glucuronide conjugate is pharmacologically inactive.
`
`l#lDow
`
`.
`
`

`

`NDA # 18-65-$ S#30
`
`4
`
`SUMMARY OF CLINICAL STUDIES*
`
`Protocol, Enrollment, Randomization, and Evaluability
`Data for three dose-finding, controlled clinical trials were submitted under the sponsor’s IND.
`Two of these were in post-CABG patients (one of which also included 4 patients who had valve
`replacement), whereas the third was in patients undergoing abdominal aortic aneurysm (AAA) surgery.
`Exceptfor the first 7 (pilot) patients in Teasdale’s CABG study in whom the loading doses were clearly too
`high, the only patients dropped from any study after being enrolled were in Ralley’s group: one Iowdose
`patient had to return to the OR for bleeding C3 h after the infusion was started; two highdose patients
`were dropped, one who received the incorrect dose, the other who required a muscle relaxant for
`excessive shivering.
`
`Fimt ISetting
`
`Author
`
`Martineau
`
`AM
`Surgery
`
`Ralley
`
`CABG +
`Valvular
`
`SurgerymTeasdale
`
`CABG
`Surgery
`
`OpioidTechnique
`(u@kg)
`
`Load:
`Fentanyl: 2-10 or AKentanil: 10-50 or
`Sufentanil: 1.
`Maintenance Total:
`Fentanyl s 15 Alfentanil: <125;
`Sufentanil: s3.
`
`Load:
`Fentanyl: 2-10 or AKentanil 10-50 or
`Sufentanil 1.
`Maintenance Total:
`Fentanyl: s 15; Atfentanil: <125;
`Sufentanil: <3.
`
`Maintenance Dose
`(uglkg-rnin)
`
`LOWK0.03
`Moderate: 0.00
`High: 0.10
`
`Continuous Infusion:
`Initial: 0.5; Optimal: 0.66
`Initial: 1.0; Optimal: 0.83
`Initial: 1.5; Optimal: 1.33
`
`45 (15 in each
`of 3 treatment
`groups)
`
`Low 0.03
`Moderate: 0.06
`High: 0.09
`
`Continuous Infusion:
`Initial: 0.5 Optimal: 0.25
`Initial: 1.0 Optimal: 0.45
`Initial 1.5 Optimal: 0.40
`
`Load:
`Fentanyl 30.
`Maintenance Total:
`Fentanyl s75.
`
`30 (10 in each
`of 3 treatment
`groups)
`
`Low 0.015-
`Moderate 0.03
`Hgh: 0.050
`
`Continuous Infusion:
`Initial: 0.5; Optimal: 0.25
`Initial: 1.0 Optimal: 0.28
`Initiak 1.5 Optimal: 0.23
`
`“*First 7 patients dropped and excluded from the analysis: Low 0.03; Moderate: 0.06; Hgh: 0.09 @kg.
`
`.
`
`Corona~ Artery Bypass Graft Surgery
`Methodology for the two studies conducted in patients undergoing CABG surgery, ie, Ralley et al
`and Teasdale et al, were similar in many respects. Patients were randomized into low, moderate, and
`high dose midazolam loading and maintenance infusion groups. The patients were comparable in terms of
`age, body surface area, duration of surgery, and ASA status. Subjects were premeditated with morphine
`and underwent a “moderate-dose” narcotic regimen with low dose inhalation agent as “background”
`anesthetic.
`They were different, however, in two key respects: i) Teasdale’s patients were induced with
`moderatedose fentanyl (30 ug/kg), whereas Ralley’s patients received either Iowdose fentanyl (2-1O
`ug/kg), or moderatedose sufentatnil or alfentanil; ii) the two studies used inverse sedation scales. A four-
`step scale was used for Ralley’s study (1=unresponsive; 2=asleep, responds to pain; 3= asleep, responds
`to verbal command; 4=awake), whereas a six step scale was usedfor Teasdale’s study (1=awake;
`2=asleep, eyes open to noise; 3=asleep, eyes open to name; 4=asleep, eyes open to touch; 5=asleep,
`moves to touch; 6=unresponsive). The goal was to achieve the same level of sedation, ie, 2-3 in Ralley’s
`study and 3-5 in Teasdale’s. For the purposes of this review, Ralley’s sedation scores have been
`transformed to comply with the results of the other two studies.
`-
`~hroughout
`this review, conversion to u~g
`assumes patient weight=70 kg.
`
`-
`
`LANoow
`
`.
`
`

`

`NDA # 18-65-$ S#30
`
`5
`
`The following tables show that all three dosing groups had a marked change in sedation scores and that
`even before they received a revised (downward) m,idazolam bolus, Teasdale’s patients were within the
`targeted range for sedation of 3-5 (in bold):
`
`“““;::-:SEIJ~l’fON~,~qRW:F0R~A8~"
`.:.:..............
`....................
`...,~.:..............,,.:,..:.:.,,,
`
`PA71ENTS:~~~~;~
`.,............. ,,.,,.,......., ..
`..
`
`, .,..............:.,.;:.,,....,:.:..:...
`~,EA~D&~~+~ti::?-:};'"
`
`: :.......::.::.,’.’..:.:’:.:.:..’.’:..,.‘.:..::
`
`,
`
`HOUR
`
`o
`
`0.25
`
`0.5
`
`1
`
`2
`
`4
`
`6
`
`Low Dose
`
`2.3/3.4
`
`4.715.3
`
`4.715.5
`
`3.615.4
`
`3.114.4
`
`2.6/3.1
`
`2.6/3.0
`
`Moderate
`Dose
`
`2.213.6
`
`5.3m.o 5.4/6.0 4,7{6.0 3.6/4.5
`
`2.6/3.9
`
`2.6/3.4
`
`Hgh Dose
`
`2.3/3.5
`
`5.615.8
`
`5.6/5.8
`
`5.116.0
`
`3.6/5.7
`
`3.614.2
`
`28/3.6
`
`I
`I
`1
`I
`I
`- Numbers in bold=sedation within the target range for the study.
`
`1
`
`t-
`
`1
`
`I
`
`~~;“~JD@Oi
`
`HOUR
`
`Low Dose
`
`o.5m.5
`
`0.52/0.33
`
`o.3m.3
`
`0.26/0.28o.21m.21
`
`0.22/0.21
`
`0.1 6/0.24
`
`Moderate
`Dose
`
`110.9
`
`0.97/0.4
`
`0.5710.4
`
`o.35m.37
`
`0,23t.O.25
`
`0.30$.21
`
`0.32/0.28
`
`High Dose
`
`1.5/1.5
`
`1.4510.74
`
`0.7510.74
`
`0.42/0.62
`
`0.30/0.35
`
`0.32/0.34
`
`0.320.25
`
`Rather than reducetheloading dose further in subsequent patients, Teasdale et al elected to reduce the
`maintenance dose by half. Regrettably, their subjects remained heavily over-sedated (ie, sedation score
`>5) for almost 2 houm, untii the infision rate was reduced to 12-18 ug/kg-h (0.2-0.3 ug/kg-min). Even
`though the degree of over-sedation in Ralley’s patients was much less, the desired level of sedation was
`not attained until the dose was decreased to the same rate as in Teasdale’s patients, ie, 12-18 ug/kg-h
`(0.2-0.3 ug/kg-min).
`It is likely that pharmacodynamic differences among the synthetic opioids accounted for this
`observation.+entanyl,
`especially in doses as high as 30 ug/kg, has a sedating effect, as opposed to
`sufentanil or atfentanil. Moreover, the duration of fentanyl’s sedative effects is longer than its congeners.
`
`.-
`
`.
`
`IANoow
`
`.
`
`

`

`,
`
`NDA # 18-654 S#30
`
`*
`
`Abdominal AoW~cAneurysm Surgey
`The study by Martineau et al was the only dose-finding study conducted in this population, In
`many respects, the methodology closely resembled that of Ralley et al. For example, the demographics of
`the patient populations were similar in terms of age, body surface area, duration of surgeV, and ASA
`status. Choice of opioid consisted of lowdose fentanyl or mediumdose sufentanil, or alfenta-nil.An
`inhalation agent was used to provide “background” anesthesia. The midazolam dosing schedule was
`virtually identical, with subjects randomized to receive a midazolam loading dose of 0.03, 0.06, or 0.10
`rates of 0.5 ucjkg-min (low dose), 1.0 ugik~-min
`mg/kg, followed by corresponding midazolam infusion
`(moderate dose), or 1.5uglkg-min (high dose). There was one noti&able difference - the se&.ati&
`scoring system was the same one as Teasdaie