`
`

`

`'
`
`in #21-038
`
`l=i1.‘2
`“21033 .
`lllllllllll lllllllllllllll
`_
`lllllllllllllllll lllllllllllllllll
`
`
`'NL‘l'IIZB‘
`‘l,1.2‘
`umuu nah/IE: Precedex (dexmedetomidine n01 Injecuon)
`
`HFD-17O
`
`APPLICANT: ABBOTT LABORATORIES
`
`m-
`
`“Ml"
`
`.
`
`CHEMICAL & THERAPEUTIC CLAS'Szls
`
`
`
`Review Cycle: 1
`Submission Date112-18-98
`. Receipt Date: 12-18-98
`Goal Date:12-18-99
`ActionzAP
`
`Review Cycle: 3
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`Action:
`
`. RevieWC Acles
`
`Review Cycle: 2
`Submission Date:
`Receipt Date:
`Goal Date:
`_
`
`Review Cycle: 4
`4 Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`
`
`MEDICALzPatricia Hartwell, M.D., M.B.A.
`
`
`CHEMISTRY:Michael Theodorakis, Ph.D.
`
` ABUSE LIABILITY: BeLinda A. Hayes, Ph.D.
`
`PHARM/TOX:Harry Geyer, Ph.D.
`
`'
`
`BlOPHARMACEUTlCS:Suresh Doddapaneni, Ph.D.
`
`BlOMETRlCSflgZJonathan Ma, Ph.D.
`
`MlCROBiGLOCIST: Patricia Hughes, Ph.D.
`
`
`
`Volume 2 of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`Phannacology/Toxicology volume #(s): 4 .
`
`

`

`OJDE II ACTION PACKAGE TABLE OF CONTENTS
`
`Application #21-038
`Drug NamedPrecedex (dexmedetomidine Hydrochloride injection), 2 mL ampule/2 mL vial, 100
`mcg/mL
`
`Applicant: Abbott Laboratories
`CSO/PM: Susmita Samanta
`
`Phone: 301-827-7410
`
`Chemeher. Type: 1 S
`HFD-17O
`
`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
`
`
`CURRENT ,USER FEE GOAL DATE: December 18, 1999DateTableofContentsCompleted:9/1 3/99
`‘
`X (completed).
`s_ec_u'g;LA.- WW '
`N/A (no: applicable).
`or Comment
`
`'
`
`Tab A—l
`‘ Tab A-2
`
`Action Letter(s)
`Phase 4 Commitments:
`
`Current ActionzAP r' -
`
`Tab A-3
`
`Tab A-4
`
`Tab A-5
`
`Tab A-6
`Tab A-7
`Tab A-8
`
`a. Copy of applicants communication committing to Phase 4 ............... L.
`
`b. Agency Correspondence requesting Phase 4 Commitments ................
`
`.FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
`
`a. Package Insert
`
`b. Immediate Container and Carton Labels .L .....................................
`
`Original Proposed Labeling ...............................................................
`
`Foreign Labeling:
`
`a. Foreign Marketing History........................................................
`
`b. Foreign Labeling and Review(s)
`
`.....................................
`
`‘
`
`Labeling and Nomenclature Committee’s.Tradename Review .....................
`Summary Memoranda (e.g., Division Director, Group Leader, Office) .........
`Copy of Patent Statement ..................................................................
`
`Exclusivity Checklist (and any requests for exclusivity) .............................
`
`DCDQEQEI“ Statements ......................................................................
`
`c. 24 hour alert memorandum .......................................................
`
`Correspondences, Faxes, & Telecons ...................................................
`Tab A-9
`Tab A- l 0 Minyteslof Meetings:
`a. End-of-Phase 11 meeting ...........................................................
`
`b. Pre-NDA meeting(s) ...............................................................
`c. Filing meeting .................................................................i......
`
`d. Other meetings ......................................................................
`
`Tab A-l 1
`
`Advisory Committee Meeting:
`
`a. Questions Considered by the committee .......................................
`b. Li_s_t of Attendees ....................................................................
`
`
`
`Tab A-12
`
`Project Management Administrative Information (optional).........................
`
`
`
`
`
`

`

`
`
`
`
`ODE II ACTION PACKAGE TABLE or CONTENTS (continued)
`
`Application #21-038 Drug Name: Dexrnedetomidine HCL
`
`Sectional;
`
`Tab 8-]
`
`Tab B-2
`
`Clinicalmflznmatlgn
`
`Clinical Reviews and Memoranda .......................................................
`
`Safety Update Reviews .....................................................................
`
`Tab B-3
`
`, Pediatric Page .................................................... , .........................
`
`Tab B-4
`
`Statistical (Clinical) Review and Memoranda .......................I ..................
`
`Tab B-S
`
`_ Biopharmaceutics Review and Memoranda ............................................
`
`Tab B-6
`
`Abuse Liability Review .......................................
`
`Tab B-7
`Tab 8-8
`. Tab 8-9
`
`DSI Audits ....................................................................................
`.......
`Summary of Efficacy (from the summary volume of the application)
`Summary of Safety (from the summary volume of the application) .....................
`
`MM
`
`Tab C-l
`Tab C-2
`Tab C-3
`
`Chemistn: DIEDIIEEQIEIDE and CDDIIIDIS [CHIC]
`mm
`CMC Reviews and Memoranda .........................................................
`DMF Reviews ..............................................................................
`EA Reviews/FONSI .......................................................................
`
`Tab 04
`
`Micro Review (validation of sterilization) .............................................
`
`Tab C-S
`
`Statistical Review of drug stability ..................'.‘...................................
`
`Tab C-6
`
`Inspection of facilities => Decision:
`
`Date:
`
`Tab C-7
`
`Methods Validation Information .............................‘........................ ..
`
`X (completed),
`NA (not applicable),
`or Comment
`
`
`
`X(completed).
`N/A (not applicable),
`or Comment
`
`~
`
`PENDING
`
`
`
`Sectional;
`
`y; WWW -
`
`Tab D-l
`Tab D-Z
`Tab D-3
`
`Pharmacology/'1‘oxicology Reviews and Memoranda ...............................
`Carcinogenicity Review (statistical) ....................................................
`CAC/Executive Committee Report .....................................................
`
`_
`
`X (completed),
`N/A (not applicable),
`or Comment
`
`
`ADDITIONAL NOTES:
`
`
`
`

`

`
`
`
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANES'I'I-IETICS, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`
`HFD—I 70, Room 93-45, 5600 Fishers Lane, Rockville MD 2085 7
`
`Tel:(301) 827-7410
`
`MEMORANDUM
`
`to:
`John K. Jenkins, MD
`Director,
`Ofice ofDrugEvaluation II
`
`Division File: NDA # 21-038
`
`fi'om: CynthiaG. McCormick, MD
`
`. Director, Division ofAnestheticé,’ Critical Care
`Products
`
`LS‘
`
`d Addiction Drug
`
`subject: Dexmedetomidine NDA
`
`date: November 30, 1999
`
`This memorandum summarizes for the file the basis for the approval action recommended
`by the Division of Anesthetics, Critical-Care, and Addiction Drug Products for NDA #21-
`03 8, Dexmedetomedine HCl for Injection, a sedative/hypnotic agent intended for use in
`the intensive care setting.
`‘
`'
`i
`.,
`
`Background
`
`Dexmedetomidine is the dextro-enantiomer of the racemic mixture, medetomidinel and a
`selectivea-l—adrenoreceptor agonist. It has been shown in standard animal models of
`eflicacy to have anxiolytic activity (0.3-2.0 ug/kg IV), analgesic activity (3-6 ug/kg IV),
`and sglativeproperties (10-30 pig/kg IV) in a dose-related manner in mice, rats and dogs.
`Dexmedetoriiidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivered by continuous intravenous
`infusion.
`
`It was anticipated that dexmedetomidine would provide effects similar to those of
`clonidine, also an a-2-adrenergic agonist which has been used as an anesthetic adjuvant
`producing analgesia and sedation, and purported to decrease anesthetic requirements and
`
`‘ Medetornidine is a veterinary sedative widely available in Europe and approved in the US
`in 1997.
`’
`;
`
`

`

`
`
`improve hemodynamic stability. The theoretical basis for the use of the oz-2-adrenergic
`"agonists as adjunctive medications is that they are thought to act as neuromodulators,
`regulating central (medullary) cardiovascular or peripheral vasomotor responses such as
`those to anesthetics, thus producing an anesthetic-sparing efl‘ect. These efl‘ects were not
`specifically characterized for approval purposes, although some exploratory studies were
`undertaken during early development.
`- ,. .-
`
`A unique feature of dexmedetomidine as a sedative which was observed in phase I studies
`was its property of providing adequate sedation but with ease of alerting and without
`‘
`persisting central efl‘ects, once the patient is aroused.
`
`..
`Efficacy
`The Sponsor submitted two adequate and well-controlled studies of similar design in
`support of the proposed indication for sedation. The studies were randomized, double
`blind, double-dummy parallel group multicenter trials comparing the efi‘ects of
`‘
`dexmedetomidine infusion with placebo. The trials evaluated the sedative properties of
`dexmedetomidine and control by inference, that is, they compared the amount of rescue
`medication (midazolam in one trial and propofol in the second) required to achieve a
`specified level of sedation (by the standardized Ramsay‘sedation scale) between the
`placebo and treatment group from onset to extubation. There were a number of
`potentially confounding variables that were assessed as secondary outcome measures,
`particularly time to extubation and amount of morphine used for analgesia.
`
`In study W97-245, 175 patients were randomized to the placebo arm and 178 patients
`were randomized to receive dexmedetomidine by intravenous infusion at doses of 0.4
`u/kg/hr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an initial bolus
`of 6 rig/kg IV. Patients were allowed to receive midazolam as needed to maintain a
`Ramsay sedation score 012.23. In addition, morphine sulfate could be administered as an
`analgesic as needed. The primary outcome measure for this study was the total amount of
`rescue medication (midazolam) needed to maintain sedation as specified while intubated.
`There was a statistically significantly greater use of midazolam in patients randomized to
`placebo than to dexmedetomidine during treatment.
`- 1‘ ”.S‘.
`
`A second prospective primary analysis was undertaken at the request of the division to
`obtain a direct assessment of the sedative efi‘ects of dexmedetomidine, that is, a
`compafison‘of the percentage of patients who were able to achieve a Ramsay sedation
`score of 23 during intubation, without the use of additional rescue medication, between
`the dexmedetomidine and the placebo groups. It can be seen from the results reported in
`the table on the following page that a significantly greater number of patients in the
`dexmedetomidine group (61%) compared to the placebo group (25%) maintained a
`Ramsay sedation score of 23 without any additional midazolam rescue.
`
`NDA #21-03'8Dexmedetomidine HCl
`
`‘
`
`.
`
`Page 2 of 10
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`

`M M
`
`idazolam use as rescue medication during intubation (I'I'l‘)
`,
`Stud! WSW-245
`PBO
`Dexmedetomidine
`
`p-value
`
`-
`
`N=175
`
`' ~ ~N=178
`
`Mean total dose (mg) of midazolam
`
`18.6 mg
`
`4.8 mg
`
`0.0011‘
`
`Categorized midazolam use
`# pts used
`..
`~.
`,
`
`108 (61%)
`43(25%)
`0mg
`36(20%)
`34 (19%)
`0-4 mg
`34 (19%)
`98 (56%)
`>4 mg
`‘ ANOVA model with rx and ctr. "Chi-square ( afier J.Ma’s table 3.2, review, p.5)
`
`.
`<0.001"
`
`In study W97-246, 198 patients were randomized to the placebo arm and 203 patients
`were randomized to receive dexmedetornidine by intravenous infiasion at doses of 0.4
`pkg/hr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an initial bolus
`of 6 pig/kg IV. Patients were allowed to receive propofol as needed to maintain a
`Ramsay sedation score of 23. In addition, morphine sulfate could be administered as an
`analgesic as needed. The primary outcome measure for this study was the total amount of
`rescue medication (propofol) needed to maintain sedation as specified while intubated.
`There was a statistically significantly greater use of propofol in patients randomized to
`placebo than to dexmedetomidine during treatment.
`
`The same prospective primary analysis that was performed in study W97-24S was also
`performed in this study. It can be seen fi'om the results reported in the table below that a
`significantly greater number of patients in the déxmedetomidine group (66%) compared to
`the placebo group (24%) maintained a Ramsay sedation score of 23 without any
`additional propofol rescue.
`
`
`Midaznlam use as rescue medication during intubation (ITT)
`Stud W97-246
`
`Mean total dose (mg) of propofol
`
`_
`
`513 mg
`
`PBO
`
`N=198
`
`Dexmedetomidine
`
`p-value
`
`N=203
`
`72 mg
`
`.
`
`<0.0001‘
`
`Categorized propofol use
`# pts used
`
`122 (60%)
`47(24%)
`0mg
`43 (21%)
`30 (15%)
`0-50 mg
`38 (19%)
`121 (61%)
`>50 mg
`‘ ANOVA model with at and ctr. “Chi-square (afier lMa’s table 3.5, review, p.9)
`
`<0.001”
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a very conservative approach, not significantly difi‘erent between groups. For
`more detail,_'l)r. Jonathan Ma’s analysis p. 10-11 should be referenced.
`In addition the
`
`NDA #21-03fiDexmedetomidine HCl
`
`,
`
`Page 3 of 10
`
`
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`
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`

`

`
`
`amount of morphine used for analgesia in both studies was found to be significantly
`greater in the control group. These are both important findings combined with the
`primary analysis, since they establish that the treatment group did not succeed based on
`the sedation afi‘orded by morphine sulfate or because of a longer time and therefore
`greater access to more medication.
`
`Dexmedetomidine is said to have been studied as adjunctive therapy insofar as rescue with
`a second agent was required in many cases to achieve the specified sedation, rather than
`increasing the infusion (and thus the dose) of dexmedetomidine as needed. Clearly it was
`the primary agent. The sponsor compared between the two randomized groups in both
`studies, the percentage'of patients who received only dexmedetomidine and who required
`no rescue medication, confirming its eficacy as monotherapy in two trials;
`
`The primary review team and Dr.Rappaport have carefully reviewed these trials. There is
`nothing to add to the Medical and Statistical analyses and I concur with their conclusions
`that these studies, while somewhat unique in their design, clearly establish that
`dexrnedetomidine is an efi'ective sedative when administered by intravenous infusion at
`doses of 0.4 u/kg/hr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an
`initial bolus of 6 ug/kg IV.
`
`Safety
`Nonclinical
`
`No significant animal toxicity was described in acute studies in rats or dogs. However,
`chronic dosing of up to 28 days in dogs and rats was associated with hepatic toxicity,
`specifically enlarged livers, eosinophilic inclusions in hepatocytes, and elevated LFTs.
`These changes were not observed in the acute studies. The genesis of the hepatotoxicity
`has not been characterized as to whether it is correlated with parent compound or any
`specific metabolite. While there appears to be an adequate safety margin in dosing, the
`contribution of a difi‘erent human metabolic profile may theoretically alter the toxicity of
`this compound with chronic dosing in humans. This bears further evaluation.
`
`Dexrnedetomidine had no efi‘ect on ACTH-stimulated cortisol release in dogs given just a
`single dosesof 80 ug/kg/dose S.C., but after one week of treatment with 3. pg/kg/hr, the
`ACTH-stimulated release of cortisol was reduced by 40%. This has implications on the
`hypothalamic-pituitary-adrenal axis with prolonged ICU treatment with this agent, and
`should be fifrther elaborated concurrently with human trials evaluating the safety of long-
`terrn infusion.
`-
`_
`
`The nonclinical pharmacokinetics of dexmedetomidine are similar to humans with the
`exception of metabolism, which difi‘ers by two major metabolites. The two major
`metabolites found in human (the 2 glucuronides of imidazole nitrogen) and absent in the
`rat and dog, were never studied in animals. Because it is projected that this product will be
`used in ICU for longer than 24 hrs of infusion, the potential toxicity of these human
`metabolites should be evaluated. This should be done as a Phase 4 study of long-term
`
`NDA #21-03‘8 Dennedctomidine HCl
`
`'
`
`Page 4 of 10
`
`
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`

`

`infusion in an appropriate animal species, either indirectly by administration to an animal
`species that does not produce these metabolites or in an animal species which produces
`the same metabolites.
`
`Dexmedetomidine was not shown to be teratogenic in rats 'or rabbits. However fetal
`toxicity was observed in rats, evidenced by increased postirnplantation losses and reduced
`number of live pups per litter. Prenatal and postnatal efi‘ects included reduced pup body
`weights during and afier nursing and delayed motor development. Placental transfer of
`dexmedetomidine was observed in rats.
`
`Dexmedetomidine was not mutagenic in the‘Ames test or the mouse lymphoma assay. It
`was shown to be clastogenic in both the in vitro human lymphocytes chromosomal
`aberration assay in the presence of metabolic activation and in in vivo mouse micronucleus
`assay. -‘
`'
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`
`M T
`
`
`.
`he safety data for this NDA Was combined from two sources, ‘---
`,
`Japanese original development program, and subsequent Abbott Laboratories data from
`' the more recent development. The safety databaSe of dexmedetomidine exposure includes
`3038 subjects, of whom 1473 were ICU patients who received the drug by continuous
`infusion. The bulk of exposure was in the range of 4-6 mg/kg and less than 16 hours. The
`dose and duration of exposure provide suflicient experience to be able to assess the safety
`of this product for the proposed duration of up to 24 hours infusion.
`
`There was also limited exposure (78 patients) who received infusion longer than 24 hours
`with the longest infiision lasting between 30-40 hours in 2 patients.
`
`The deaths and serious adverse events reported Were not unexpected for the ICU
`population under study in this NDA either in quality or in quantity.
`
`In the placElio-controlled infiision studies in Phase 2-3, the only commonly reported
`adverse events observed in more than 1% of patients treated with dexmedetomidine and
`occurring with a frequency more than 2-fold that of the placebo were predictably
`hypotension (22%) , hypertension (12%) , and bradycardia (5%).
`
`NDA #21-038—Dexmedetomidine HCl
`
`_
`
`Page 5 of 10
`
`

`

`Summary of Treatment-Emergent Adverse Events Occurringin >1% of Dexmedetomidine patients in
`Phase II/III Continuous Infusion ICU Sedation Studies2
`
`Adverse Event
`
`5
`
`-
`
`Placebo
`Randomized dexmedetomidine
`N=379
`(N=387)
`16 (4%)
`84 (22%)"
`Hypotension
`24 (6%)
`47 (12%)‘
`Hypertension
`6(2%)
`20 (5%)‘
`Bradycardia
`4 (1%)
`13 (3%)
`Mouth Dry
`20 (5%)
`16 (4%)
`Nausea
`‘Statistically significant difi’erence between randomized dexmedetornidine and placebo patients ps0.05
`Data source 2.2.5. 5
`
`Abnormal laboratory findings, which might have been anticipated fiom the preclinical
`studies, such as elevated LFTs and glycosuria, were not borne out in laboratory testing
`
`There are no safety data in pediatric patients. The sponsor will be required to study this
`product in children from birth to 16 years of age as a Phase 4 commitment.
`
`Approximately 500 patients over 65 years of age have been studied in this NDA An
`additional analysis of patients over 75 years has been requested of the sponsor with
`comparison of adverse events by age, separating the elderly by >65 to 75 and >75 years of
`age This will be undertaken in an efl‘ort to assess whether dosage adjustment may be
`neededin the very elderly patients based on anticipated PD difi‘erences associated with
`sedative agents.
`
`Abuse Potential
`
`~
`
`Dexmedetornidine might be expected, based on its clinical pharmacological efi‘ects and its
`similarity to clonidine’,to have some abuse liability. Indeed animal studies indicate that
`there are some reinforcing properties. Reinforcing behaviorin primates was elicited by
`dexmedetomidine 1.0 ug/kg/dose >saline and equivalent to saline at 0.0625 ug/kg/dose.
`At a dose of 0.25 ug/kg/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CIV); Dexmedetornidine also has been shown to attenuate morphine
`withdraWalfsuggestive but not conclusive evidence for dependence liability. A mild
`withdrawal syndrome has been described in rodents after 7 days of treatment.
`
`Extensive receptor binding studies using stande radioligands were presented in the
`NDA, demonstrating very high afiinity for the a-adrenergic receptors andmoderate
`affinity for the serotonergic receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`‘
`
`‘
`
`2 After Sponsor’s Table 21 188 8/10-239-65
`3 Clonidine is not currently controlledin the CSA There have been reports of abuse with
`clonidine, mostly of reports of opiate addicts using clonidine to suppress withdrawal
`symptoms rather than forits psychotropic efi‘ects.
`
`NDA #21-03&Dexmedetomidine HCl
`
`‘
`
`Page 6 of 10
`
`
`
`

`

`On balance, the available studies suggest an abuse potential lower than some products
`controlled in schedule IV or as low'as "some not controlled at all. I do not agree with the
`controlled substances evaluation team that this product should not be scheduled due to
`lack of information, but rather that the available information suggests a rather low
`potential for abuse. Furthermore the clinical setting in which it will be used, limited to
`hospital intensive care units, reduces that potential.~ Continued vigilance is indicated,
`nevertheless, for any actual diversion and abuse that might occur in the post approval
`setting, so that appropriate measures can be taken to control this substance if needed. .
`There have been to date no reports of diversion or abuse of medetomidine approved in
`1997.
`’-
`
`. ,
`Biopharmaceutics
`The ADME of dexmedetomidine has been fairly well studied, but some unanswered
`questions remain that may be very relevant to long term infusion. For example, it is has
`been demonstrated that there is almost no accumulation of parent drug, following IV bolus
`administration, and that there is nearly complete biotransofonnation. The fate ofthe
`metabolites, however, has not been well characterized. Biotransoformation includes direct
`N-glucuronidation (two major metabolites, total of 34%) and CYP 2A6-mediated
`metabolism (three additional metabolites, 14%), and N-methylation (three metabolites,
`18%). There are additional urinary metabolites that have not been identified yet.
`Dexmedetomidine is about 94% prOteinébound.
`'
`
`Evaluation of dexmedetomidine in patients with renal failure demonstrated no change in
`dexmedetomidine PK with severe renal failure following a single dose, but there is no
`information about the possible accumulation of metabolites when dexmedetomidine is
`infiised continuously, particularly for—long periods of time. The bulk of elimination of
`metabolites is thought to be renal. Therefore, this information should be obtained in Phase
`4 in anticipation of more prolonged infusion in patients with renal insuficiency.
`
`Hepatic impairment afl‘ected the PK of dexmedetomidine as expected, and the appropriate
`adjustments for patients with mild, moderate and severe hepatic impairment will be
`included inthe package insert.
`
`There was no efi‘ect of age on the pharmacolcinetics of dexmedetomidine, although only
`20 elderly volunteers, ranging from 66 to 83 years (mean, 72) were evaluated. The
`possibility ofpharmacodynamic difl‘erences increasing with increasing age were not
`examined, but should be looked at more closely in Phase 4, as sedative/hypnotics have a
`tendency to result in more significant safety problems (hypotension, confusion, respiratory
`depression) in the elderly. Dexmedetomidine has not been evaluated in the pediatric
`population.
`
`NDA #21-osa:pmmmidrne HCl
`
`«
`
`Page 7 of 10
`
`
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`

`

`Interaction studies with a spectrum of anesthetics in vivo such as alfentail, rnidazolam,
`__ propofol and isoflurane did not indicate interactions when added to dexmedetomidine or
`to alfentail, rnidazolam, propofol or rocuronium when dexmedetomidine was added.
`
`Chemistry and Manufacturing
`Dexmedetomidine is the dextro-enantiomer of medetomidine (4-[1-(2,3~
`dimethylphenyl)ethyl]-lH-imidazole hydrochloride) and it is manufactured by separation
`of the isomers from the racemic mixture. Preparation and characterization of the drug
`substance, levels of impurities including optical purity (levo-enantiomer limited to s 1%)
`have all been judged acceptable. Stability data on the bulk drug substance and regulatory
`specifications were also deemed acceptable:
`
`
`
`
`
`The drug product is a sterile aqueous solution of dexmedetomidine for intravenous
`infirsion upon further dilution. The formulation consists of dexmedetomidine HCl (the
`active ingredient) and sodium chloride and water for injection. The drug product is
`prepared using standard methods, has undergone stability testing (undiluted) under ICH
`storage conditions generating data to support a 2-year shelf life, and has been shown to be
`stable in light. Sterility ofthe drug product is achieved through aseptic fill and terminal
`sterilization by autoclave. The process and data have been reviewed by microbiology and
`found to be acceptable.
`
`The drug product is prepared for use by diluting it with sterile 0.9% sodium chloride
`solution for injection after which it is stable for’24 hours.
`‘
`
`Compatibility data are provided with comrhonly used IV solutions, drugs (vasoactive
`agents, muscle relaxants, sedatives, narcotics and plasma substitute), tubing, and syringes
`commonly used for administration of IV drugs. It was observed that dexmedetomidine
`has the potential for adsorption onto certain types of natural rubber. This will be noted in
`the package insert, advising use with synthetic components or coated natural rubber .
`componéitsi
`
`A suitable trade name has not yet been selected for the drug product to which the Agency
`agrees.
`
`Data Integrity
`All questions related to data integrity were resolved during the course of review and
`inspection, including questions about some unreported deaths, randomization errors and
`protocol violations that were not reported. DSI inspections were conducted, and aside
`from some reports of careless errors in recordkeeping there was no evidence to suggest
`
`
`
`NDA #21-038_Dexmedetomidine HCl
`
`‘
`
`Page 8 of 10
`
`
`
`

`

`that the data on which the conclusions and recommendations for this NDA will be based
`have significant problems.
`'
`
`-
`Comments:
`There is adequate evidence to support the eficacy and safety of dexmedetomidine to
`approve it for ICU sedation by continuous infusion for 24 hours. It is anticipated that
`there will be increasing demand for more prolonged use of this product once it is
`approved. In addition to collecting additional safety data on prolonged use, there should
`be a better characterization of the activity, toxicity and fate of the metabolites. _
`
`Additional datats'hould be obtained for safe use at the extremes of age—pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric pharmacodynamic/safety data
`in the veryElderly >75 years should also be generated-tor existing data analyzed.
`
`Once the metabolic profile is better established with multiple dosing, its safety should be
`evaluated in patients with renal failure.
`~
`
`Surveillance for possible diversion and abuse can be done through the existing mechanisms
`such as Medwatch, SAMHSA’s DAWN database, and DEA reports.
`'
`
`Phase 4 Commitmerm
`
`The focus of the dexmedetomidine development plan was short-term ICU sedation in
`adults. It is quite clear that this product will not have use limited to this population, and
`therefore the following phase 4 commitments will be requested of the sponsor in an efi‘ort
`to obtain safety data in more extended ICU infusion, in pediatric patients and in the
`elderly.
`
`Nonclim'cal studies
`
`1. A two-week study in dogs with a'2-week recovery phase should evaluate general
`toxicology of prolonged infusion of demedetomidine and the efi‘ect of chronic
`infusion on HPA axis.
`
`2. A second study should evaluate changes in drug metabolism following two
`weeks of infusion.
`
`3:""A‘third study should evaluate the potential toxicity of human major metabolites
`which are absent in rats and dogs.
`'
`
`,
`CIinical studies
`1. Pediatrics: Studies to obtain an indication for sedation in pediatric patients from
`birth to 16 years of age in the ICU setting. The development plan should include
`pharmacokinetics and safety in pediatric patients fi’om birth to 416 years, and
`eficacy data designed at determining appropriate dosage regimens.
`2. Geriatrics: Further studies are needed to evaluate the safety v. differential
`toxicity of dexmedetomidine in very elderly patients, as has been described with
`other sedative/hypnotic drug products.
`3. Longer-term infusion studies should include safety and pharmacolcinetics.
`
`NDA #21-038Dexmedetomidin: HCl
`
`'
`
`‘
`
`Page 9 of 10
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`

`
`
`
`4. Renal Impairment: Additional data are needed to examine the potential
`accumulation of dexmedetomidine metabolites upon continuous infusion in
`patients with renal impairment.
`'
`
`It is expected that a reasonable timeline for submission ofthe protocols might be
`approximatelyfi months from approval; and completion ofthese studies, approximately 2
`years.
`'
`'
`'
`
`RecommendedAction: Approval of dexmedetomidine HCl as an adjunctivernedication
`for ICU sedation.
`
`_‘
`
`~
`
`'
`
`APPEARSTHISWAY
`on ORIGINAL
`
`*
`
`
`
`
`
`NDA #21-osépemedetomidine HCl
`
`Page 10 of 10
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`

`

`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION or ANESTHETIC, CRITICAL CARE, AND ADDICIION DRUG PRODUCTS
`HFD-l70, Room 98-452 5600 Fishers Lane, Rockville MD 2Q8$1
`Tel:(301)443-374l
`
`
`
`
`M E M O R A N D U M
`
`
`
`DATE:
`
`' _,
`
`November 5, 3999
`
`TO:
`
`FROM:
`
`File, NDA 21-038
`
`Bob A. Rappaport, MD.
`Deputy Director, DACCADP
`Team Leader, Anesthetic Drug Group
`
`RE:
`
`Supervisory Review of NDA 21-03 8, Dexmedetomidine HCI
`
`W B
`
`ACKGROUND:
`
`NDA 21-038, Dexmedetomidine .HCl, was submitted _by Abbott Laboratories Inc. on
`December
`18,
`1998.
`Dexmedetomidine is a potent and highly selective a-Z-
`adrenoreceptor agonist.
`The sponsor claims that
`their product produces titratable,
`predictable sedation in an ICU setting, from which patients are easily arousable and
`cooperative. The sponsor also claims that their product provides improved analgesia in
`the postoperative ICU setting.
`The a-2-adrenoreceptor agonist detomidine was
`developed for‘u'se as a sedative/analgesic in horses and cattle and was registered for
`marketing in Finlandin I983. Medetomidine, launched in 1987 in Scandinavia, was a
`more selective a342-adrenoreceptor agonist used as a sedative/analgesic in cats and dogs.
`It was approved for veterinary use in the US in 1997. The sedative and analgesic activity
`of medtomidine are believed to
`reside predominantly in its dextroenantiomer
`dexmedetomidine. The enantiomer was first synthesized by Farmos Group in Finland in
`1986. Numerous perioperative indications have been evaluated since that time. Farmos
`merged with Orion Corp.
`in 1990, and Orion licensed the injectable dosage form of
`dexmedetomidine for clinical use to Abbott Laboratories in 1994.
`
`Orion conducted 56 clinical
`trials of dexmedetomidine with various modes of
`administration including rapid intravenous infusion, continuous intravenous infusion,
`
`
`
`

`

`
`
`intramuscular injection, as well as transderrnal and oral administration. Abbott initiated
`its own clinical development program and completed 21 studies (13 Phase I and 8 Phase
`II/III) in the US, Canada and Europe. They also completed 2 studies in Japan: a Phase I
`safety and pharmacokinetic study of rapid infusion in 9 healthy males, and a Phase II
`safety and dose response study of rapid infusion in 109 patients. The sponsor reported
`that the case report forms for these 2 studies were unavailable and they did not include
`the data in the ISS database.
`_ .
`
`The clinical studies of the effectiveness and safety of this new formulation have been
`reviewed [submitted August 29, 1999] by Charles Cortinovis, MD. Dr. Patricia Hartwell
`contributed two addenda [submitted September 13, 1999 and October 27, 1999]
`reviewing safety data in the original application, a supplementary safety package, and the
`lZO-Day Safety Update. The application has also been reviewed by Jonathan Ma, Ph.D.
`(biostatistics), Suresh Doddapaneni, Ph.D. (clinical pharmacology and biopharmaceutics),
`Harry Geyer‘, Ph.D. (pharmacology/toxicology), Michael Theodorakis, Ph.D. (chemistry),
`and lBeLinda A. Hayes, Ph.D. (abuse liability).
`In this memo, I will briefly review the
`effectiveness and safety data summarized in the primary clinical review, as well as any
`relevant information found in the primary reviews from the other disciplines, and make
`appropriate recommendations for action on the NDA.
`
`'
`
`EFFECTIVENESS:
`
`Evidence of efficacy has been submitted in two clinical studies W97-245 and W97-246.
`
`Study W97-245:
`
`This was a randomized, double blind, placebo-controlled, parallel group study co