`
`Abbott Laboratories
`Hospital Products Division
`200 Abbott Park Road
`Abbott Park, Illinois 60064-3537
`
`Attention: Thomas F. Willer, Ph.D.
` Assistant Director, Regulatory Affairs
`
`Dear Dr. Willer:
`
`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, May
`4, 10, 12, 21, and 24, June 17 and 18, July 2, August 12, 17, 20, and 27, September 2, 3, 10, 16, and 20,
`October 1, 5, 8, 19, and 27, November 1, 4, 17, and 19, December 2, 3, 5, 6, 7, 9, 14, 16, and 17,
`1999.
`
`This new drug application provides for the use of dexmedetomidine hydrochloride 2 mL ampule/2 mL vial,
`100 mcg/mL, for sedation of initially intubated and mechanically ventilated patients 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 labeling (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 with FPL that is
`not 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.
`
`
`
`NDA 21-038
`Page 2
`
`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
`
`2. 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
`
`3. Conduct a study to evaluate the effects of the three major human metabolites that are absent in the rat
`and the dog in a human-relevant animal species or, alternatively, 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 this letter
`Final Report Submission: Within 12 months following the date of this letter
`
`4. 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 Start: Within 6 months following the date of this letter
`Final Report Submission: Within 12 months following the date of this letter
`
`5. Conduct a study 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
`
`
`
`NDA 21-038
`Page 3
`
`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 this letter
`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 of
`the 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 cooperation to resolve any problems that may be identified.
`
`Be advised that, as of April 1, 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 of the 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.
`
`
`
`NDA 21-038
`Page 4
`
`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 of 21
`CFR 314.55 within 60 days from the date of this 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 of section 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 Guidance for Industry on Qualifying for Pediatric Exclusivity (available on our web site at
`www.fda.gov.cder/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 development plan that you submit, and notify you of the pediatric
`studies that are required under section 21 CFR 314.55. Please note that satisfaction of 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.
`
`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 Lane
`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.
`
`
`
`NDA 21-038
`Page 5
`
`If you have any questions, call Susmita Samanta, Regulatory Project Manager, at 301-827-7410.
`
`Sincerely,
`
`John K. Jenkins, M.D.
`Director
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure
`
`