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`AEEroval Letter
`Tenative Aggroval Letter
`A rovable Letter
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`Medical Review(s)
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`Chemistry Reviews!
`EA/FONSI
`Pharmacoloa Reviews;
`Statistical Reviewgs!
`Microbiology Review(s)
`Clinical Pharmacology
`Biogharmaceutits Review(s)
`Bioeguivalence Review(s)
`Administrative Document(s)
`Corresgondence
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`‘(C DEPARTMENT or HEALTH 9. HUMAN SERVICES
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`NDA 21-038
`
`Food and Drug Administration
`Rockville MD 20857
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`Abbott Laboratories
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`.
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`Hospital Products Division
`200 Abbott Park Road
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`Abbott Park, Illinois 60064-3537
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`'Attention: Thomas F. winei, PhD.
`Assistant Director, Regulatory Affairs
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`0
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`.
`EC 1 7 1999'
`
`Dear Dr. Willer: -
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`-
`
`Please refer to your new drug application (NDA) dated December 18, 1998, received December 18,
`1998, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for PRECEDEX
`(dexmedetomidine hydrochloride injection) 2 mL ampule/2 mL vial, 100 mcg/mL.
`
`We acknowledge receipt of your submissions dated February 4, March 10,15,30 and 31, April 30,
`Ma_v4, 10, 12, 21, and 24, June 17 and 18, July 2, August 12, 17, 20, and 27, September2, 3, 10, 16,
`and 20 October], 5, 8, 19, and 27, November], 4, 17, and19, December2, 3, 5, 6, 7, 9, 14, 16, and
`17.1999
`
`This 1'18“ drug application provides for the use of dexmedetomidine hydrochloride 2 mL ampule/2
`mL \ial 100 mcg/mL, for sedation of initially intubated and mechanically ventilatedpatients in an
`intensive care unit (ICU) setting.
`
`We have completed the review of this application, as amended, 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 agreed upon enclosed labeling text. Accordingly, the application is approved
`effective on the date of this letter.
`
`The final printed labe‘ling (FPL) must be identical to the enclosed labeling (text for the package
`insert) and to the carton_and container labels submitted on December 17,1999. Marketing the
`product \\ith FPL‘that isznot identical to the approved labeling may render the product misbranded
`and an unapproved new drug
`_
`
`Please submit 20 copies of the FPL as soon as it is available, in no case more than 30 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 "FPL for approved NDA 21-038."
`Approval of this submission by FDA is not required before the labeling is used.
`
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`NDA 21-038
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`Page 2
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`We remind you of your Phase 4 commitments specified in your submission dated December 16,
`1999. These commitments, including completion dates agreed upon, are listed below.
`
`1. Conduct a 2-week study in dogs, followed by a 2-week recovery phase, to evaluate general
`toxicology and effects on the HPA axis.
`
`Protocol submission: Completed
`Study Start: Completed
`Final Report Submission: Within 6 months following the date of this letter
`
`Conduct a 2-week study in dogs to evaluate changes in drug metabolism following 2 weeks of
`drug infusion.
`
`Protocol Submission: Completed
`Study Start: Completed
`Final Report Submission: Within 6 months following the date of this letter
`
`Conduct a study to evaluate the effects of the three major human metabolites that are absent in
`the‘ra’t and the dog in a human-relevant animal species or, altematively, by direct
`administration of these metabolites in an appropriate animal species.
`
`Protocol Submission: Within 4 months following the date of this letter
`Study Start: Within 6 months following the date of thisJetter
`Final Report Submission: Within 12 months following the date of this letter
`
`Conduct an in vitro human lymphocyte chromosomal aberration assay using the human liver S-9
`fraction as the metabolic activation system.
`
`Protocol Submission: Within 4 months following the date of this letter
`Study Stan: Witgnfi months following the date of this letter
`Final Report Submission: Within 12 months following the date of this letter
`
`. Conduct a stuayF‘to assess the effect of temperature on the in-vivo micronucleus assay in mice.
`
`Protocol Submission: Within 4 months following the date of this letter
`Study Start: Within 6 months following the date of this letter
`Final Report Submission: Within 12 months following the date of this letter
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`NDA 21-038
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`Page 3
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`6. Conduct a long-term continuous infusion study in patients to evaluate the pharmacokinetics,
`safety, and extended effectiveness of Precedex in the ICU setting.
`
`Protocol Submission: Within 10 months following the date of this letter
`Study Start; Within 12 months following the date of thisletter
`Final Report Submission: Within 36 months following the date of this letter
`
`7. Conduct a second long-term, continuous infusion study in patients with renal failure. ~ This study
`should include an adequate number of patients with mild, moderate, and severe renal failure to
`fully assess that patient population. Metabolite levels should be 'quantified to assess their
`accumulation with long-term use of Precedex in patients with renal failure.
`
`Protocol Submission: Within 4 months following the date of this letter
`Study Start: Within 6 months following the date of this letter .
`Final Report Submission: Within 36 months following the date of this letter
`
`Submit protocols, data, and final reports for clinical studies to your IND for this product and send a
`copy ofthe cover letter to this NDA. For other types of Phase 4 commitments, please submit
`protocols, data and final reports to this NDA as correspondence. In addition, under 21 CFR
`314.82(b)(2)(vii), we request that you include a status summary of each commitment in your annual
`report to this NDA. The status summary should include the number of patients entered in each
`clinical study, expected completion and submission dates, and any changes in plans since the last
`annual report. For administrative purposes, all submissions: including labeling supplements, relating
`to these Phase 4 commitments should be clearly designated "Phase 4 Commitments."
`
`Validation of the regulatory methods has not been completed. At the present time,-it is the policy of
`the Center not to withhold approval because the methods are being validated: Nevertheless, we
`expect your continued cooperaticm to resolve any problems that may be identified.
`
`Be advised that, as 0.6.15:le l, 1999, all applications for new active ingredients, new dosage
`forms, new indications, new routes of administration, and new dosing regimens are required to
`contain an assessment ofihe safety and effectiveness of the product in pediatric patients unless this
`requirement is waived or deferred (63 FR 66632). We note that you have not fulfilled_the
`requirements of 21 CFR 314.55. We are deferring submission of your pediatric studies until
`December 2. 2000. However, in the interim, please submit your pediatric drug development plans
`within 120 days from the date of this letter unless you believe a waiver is appropriate.
`
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`NDA 21-038
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`Page 4
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`If you believe that this drug qualifies for a waiver of the pediatric study requirement, you should
`submit a request for a waiver with supporting information and documentation in accordance with the
`provisions of21 CFR 314.55 within 60 days from the date ofthis letter. We will notify you within
`120 days of receipt of your response whether a waiver is granted. If a waiver is not granted, we will
`ask you to submit your pediatric drug development plans within 120 days from the date of denial of
`the waiver.
`
`Pediatric studies conducted’under the terms ofsection 505A of the Federal Food, Drug, and
`Cosmetic Act may result in additional marketing exclusivity for certain products (pediatric
`exclusivity). You should refer to the Guidancefor Industry on Qm‘zlrfi/ingfor Pediatric Exclusiviry
`(available on our web site at www. (do. gander/pediatric) for details. If you wish to qualify for
`pediatric exclusivity, you should submit a "Proposed Pediatric Study Request" (PPSR) in addition to
`your plans for pediatric drug development described above. We recommend that you submit a
`Proposed Pediatric Study Request within 120 days from the date of this letter. If you are unable to --
`meet this time frame but are interested in pediatric exclusivity, please notify the Division of
`Anesthetic, Critical Care, and Addiction Drug Products in writing. FDA generally will not accept
`studies submitted to an NDA before issuance of a Written Request as responsive to a Written
`Request. Sponsors should obtain a Written Request before submitting pediatric studies to an NDA.
`If you do. not submit a PPSR or indicate that you are interested in pediatric exclusivity, we will
`proceed with the pediatric drug deveIOpment‘pl'an that you submit, and notify you of the pediatric
`studies that are required under section 21 CFR 314.55. Please note that satisfactionof the
`requirements in 21 CFR 314.55 alone may not qualify you for pediatric exclusivity. FDA does not
`necessarily ask a sponsor to complete the same scope of studies to qualify for pediatric exclusivity as
`it does to fulfill the requirements of the pediatric rule.
`5
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`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock-up form, not final
`print. Please send one copy to the Division of Anesthetic, Critical Care, and Addiction Drug
`Products and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug‘Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lam
`Rockville, Maryland 20857
`
`Please submit one market package of the drug product 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.
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`NDA 21-038
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`Page 5
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`If you have any questions, call'Susmita Samanta, Regulatory Project Manager, at 301-827-7410.
`
` fflce of Drug Evaluation II
`
`Enclosure
`
`Center for Drug Evaluation and Research
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`. APPEARS THIS WAY
`0N ORIGINAL
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