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`Public Health Service
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` Food and Drug Administration
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`Rockville, MD 20857
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`NDAs 21-436/S-026, 21-713/S-019, 21-729/S-012, 21-866/S-013
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`Otsuka Pharmaceutical Development & Commercialization, Inc.
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`Attn: Dr. Kusuma Mallikaarjun, Senior Director – Regulatory Affairs
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`2440 Research Blvd.
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`Rockville, MD 20850
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`Dear Dr. Mallikaarjun:
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`Please refer to your supplemental new drug application dated and received July 16, 2008,
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`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Abilify
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`(aripiprazole) tablets, Abilify Discmelt (aripiprazole) orally disintegrating tablets, Abilify
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`(aripiprazole) oral solution, and Abilify (aripiprazole) injection.
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`Reference is also made to an FDA letter dated June 16, 2008 notifying you, under Section
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`505(o)(4) of the FDCA, of new safety information that we believe should be included in the
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`labeling for antipsychotic drugs. This information pertained to the warning regarding use of
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`antipsychotics and increased mortality in elderly patients with dementia-related psychosis.
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`Your supplemental application provides for revisions to the labeling for Abilify (aripiprazole)
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`tablets, Abilify Discmelt (aripiprazole) orally disintegrating tablets, Abilify (aripiprazole) oral
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`solution, and Abilify (aripiprazole) injection, consistent with our June 16, 2008 letter.
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`This supplemental new drug application provides for the following changes to product labeling:
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`Under the BOXED WARNING section, the addition of a warning regarding increased mortality
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`in elderly patients with dementia-related psychosis. [This new section will be added to the
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`beginning of the label with bolded font and enclosed in a black box.]
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`WARNING
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`Increased Mortality in Elderly Patients with Dementia-Related Psychosis —
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`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10
`weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-
`treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the
`course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about
`4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were
`varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)
`or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical
`antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
`The extent to which the findings of increased mortality in observational studies may be attributed
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`Page 2
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`to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
`Abilify is not approved for the treatment of patients with dementia-related psychosis (see
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`WARNINGS).
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`Under WARNINGS the language below will be implemented in bolded font in the
`WARNINGS section as the first paragraph in this section.
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`WARNINGS
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`Increased Mortality in Elderly Patients with Dementia-Related Psychosis —
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`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at
`an increased risk of death. Abilify is not approved for the treatment of patients with
`dementia-related psychosis (see BOXED WARNING).
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`We have completed our review of this supplemental application. This application is approved,
`effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling
`text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert, text for the patient package insert). Upon receipt, we will transmit that
`version to the National Library of Medicine for public dissemination. For administrative
`purposes, please designate this submission, “SPL for approved supplement NDAs
`21-436/SLR-026, 21-713/SLR-019, 21-729/SLR-012, 21-866/SLR-013.”
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`In addition, within 21 days of the date of this letter, amend any pending applications for this
`NDA with content of labeling in structured product labeling (SPL) format to include the changes
`approved in these applications.
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`Marketing the product with FPL that is not identical to the approved labeling text and in the
`required format may render the product misbranded and an unapproved new drug.
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`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter and that the revised labeling be reflected in the next printing of the
`labeling. While you may use labeling already printed, we request that revised labeling
`accompany any newly shipped product within 60 days from the date of this letter.
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`Failure to make these changes promptly could make your product misbranded under Sections
`201(n) and 502(a) of FDCA.
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`PROMOTIONAL MATERIALS
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`Page 3
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`You must promptly revise all promotional labeling and advertising for this product to make it
`consistent with the labeling changes described above. These revisions should include prominent
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` disclosure of the important new information described in the BOXED WARNING section that
`appear in the revised package labeling.
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`In addition, submit three copies of the introductory promotional materials that you propose to use
`for these products. Submit all proposed materials in draft or mock-up form, not final print. Send
`one copy to the Division of Psychiatry Products and two copies of both the promotional
`materials and the package insert(s) directly to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you issue a letter communicating important information about this drug product (i.e., a “Dear
`Health Care Professional” letter), we request that you submit a copy of the letter to this NDA and
`a copy to the following address:
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`MEDWATCH
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`Food and Drug Administration
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`5515 Security Lane
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`HFD-001, Suite 5100
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`Rockville, MD 20852
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call LCDR Sonny Saini, Pharm. D., Safety Project Manager, at
`(301) 796-0532.
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`Enclosure
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`Sincerely,
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`{See appended electronic signature page}
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`
`Thomas Laughren, M.D.
`Director
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`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
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`---------------------
`Thomas Laughren
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`8/14/2008 08:29:30 PM
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