CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022063Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 22-063
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`
`Shire Development
`Attention: Zohra Lomri
`Associate Director, Regulatory Affairs
`725 Chesterbrook Blvd.
`Wayne, PA 19087-5637
`
`Dear Mrs. Lomri:
`
`Please refer to your new drug application (NDA) dated and received July 21, 2006, submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for
` (mixed salts of a single entity
`amphetamine) 12.5 mg, and 25 mg Extended Release Capsules.
`
`We acknowledge receipt of your submissions dated August 29, 2006, September 7, 18, 29, 2006,
`October 9, 2006, November 9, 14, 17, 29, 2006, January 22, 31, 2007, March 7, 2007 and April 10 and
`27, 2007.
`
` (mixed salts of a single entity amphetamine)
`This new drug application provides for the use of
`12.5 mg, and 25 mg Extended Release Capsules for the treatment of attention deficit hyperactive
`disorder (ADHD).
`
`We have completed our review of this application, as submitted, and it is approvable. Before the
`application may be approved, however, it will be necessary for you to address the following
`deficiencies and respond to our requests listed below:
`
`Office of Clinical Pharmacology:
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`• We find your proposed dissolution methodology acceptable. However, we request that the
`specifications be changed to allow a % range.
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`• Please perform dissolution studies for all
` strengths using the current dissolution
`conditions with the addition of 0%, 5%, 20% and 40% of ethanol to the dissolution media.
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`
`
`• These studies must be completed and submitted to this NDA with your complete response to
`this action letter.
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`Dissolution Method and Specification
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`We ask that you agree to the following final dissolution method and specification for all strengths:
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`NDA 22-063
`Page 2
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`Apparatus:
`Paddle Speed:
`Media:
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`Temperature:
`Dissolution Volume:
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`Specification:
`Time
`2
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`3
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`10
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`USP Apparatus II (paddles)
`50 RPM
`Media 1: pH 1.1 ± 0.1, Dilute HCl
`Media 2: pH 6.0 ± 0.1, Phosphate Buffer
`Media 3: pH 7.5 ± 0.1, Phosphate Buffer
`37.0oC ± 0.5oC
`750mL Dilute HCl for the first 2 hours
`950mL pH 6.0 Phosphate Buffer for the 3rd hour
`1000mL pH 7.5 Phosphate Buffer for the remainder
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`Percent Dissolved
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`Expiry
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`Based upon your submitted stability data, we are granting a 24 month expiry for all strengths of
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`Labeling
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`Please submit revised draft labeling for the drug. The labeling should be identical in content to the
`enclosed labeling (text for the package insert).
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`Additionally, please note that we have not incorporated your proposed 37.5 mg and 50 mg strengths
`since there was no additional efficacy at these higher doses, and there were additional adverse events
`associated with these higher doses.
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`If additional information relating to the safety or effectiveness of this drug becomes available, revision
`of the labeling may be required.
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`Proprietary Name and Container Label
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`The Division of Medication Errors and Technical Support (DMETS) finds the proprietary name
`, acceptable. However, our approval of the proprietary name is tentative based upon the final
`date of NDA approval. If final approval of this application extends beyond July 2007, the name will
`be reevaluated by DMETS.
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`Additionally, we note that you have already addressed some of DMETS safety concerns regarding the
`labels and labeling. However, we continue to have the following areas in which we believe
`improvement is needed in order to minimize error.
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`GENERAL COMMENT
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`1.
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`A.
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` named
`Currently, there is an approved extended release formulation of
`Adderall XR, which is also marketed by you. This product is marketed as 5 mg, 10 mg,
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-063
`Page 3
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`2.
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`1.
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`15 mg, 20 mg, 25 mg, and 30 mg capsules to adults and pediatric patients. Your
`proposed product,
` contains
`mixed amphetamine salts
`found in Adderall XR, and is equivalent to an Adderall XR plus a follow-up dose of
`Adderall.
` duration of action is 16 hours and the pharmacokinetic profile is
`equivalent to dosing with Adderall XR followed 8 hours later by the immediate-release
`formulation, Adderall.
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`The introduction of this proposed formulation in the marketplace is potentially
`problematic and may lead to errors because it will be difficult for practitioners to readily
`discern these different formulations. Additionally,
` will not have a modifier to
`identify it as an extended release product. Therefore, practitioners will look to its
`established name for differences between this and Adderall XR. However, Adderall
`and
` will have the same established name. Moreover, they have an overlapping
`dose at 25 mg. DMETS is concerned that both patients and health care practitioners
`will not be aware of the formulation differences because the products contain the same
`active ingredients and have an overlapping strength and frequency of administration.
`Furthermore, indicators will not be available to clue practitioners to the fact that the
`products are different and they cannot be substituted for one another. This will become
`even more problematic when the product becomes available as a generic equivalent.
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`Therefore, we ask that you create and implement a plan for the education of healthcare
`professionals and consumers about the difference between
` and the available
`Adderall formulations. Advice from practicing healthcare providers should be sought
`on how to label and educate to adequately address the fact that the products are different
`despite having the same active ingredients, established name, dose, and dosing
`intervals. This plan should be executed for the life-cycle of the product.
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`Ensure that the product labels and labeling are not similar to and do not overlap with the
`existing color scheme of Adderall XR product labels and labeling.
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`B. CONTAINER LABEL
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`It appears, from the all capital presentation and bolded font of the proprietary name, that
`it is more than twice the size of the established name. Although the size of the
`established name may meet the regulatory requirements, the prominent presentation of
`the proprietary name makes the established name appear smaller than ½ of the size of
`the proprietary name. We recommend increasing the prominence of the established
`name.
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`Postmarketing experience has shown that medication errors have occurred due to
`confusion of the net quantity for the product strength if they are in close proximity to
`each other. Thus, we request relocation of the net quantity statement so that it is not in
`close proximity to product strength.
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`We note that the font color used for the text of the net quantity statement is the same
`color used for the strength. Post-marketing error reports describe confusion of the
`strength and net quantity when they appear with a similar color to one another. DMETS
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`2.
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`3.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`recommends that the color of the net quantity be revised so that it is not presented in the
`same color as the strength.
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`NDA 22-063
`Page 4
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`1.
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`C. INSERT LABELING
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`We recommend that you delete the use of trailing zeros corresponding to the strength of
`each active ingredient in the ‘Description’ section of the package insert labeling. FDA
`launched a campaign on June 14, 2006, warning health care providers and consumers
`not to use error-prone abbreviations, acronyms, or symbols. Trailing zeros are listed as
`one of these dangerous abbreviations. Thus, we request that the Divisions not approve
`or use trailing zeros in their labels and labeling because the labeling habits carry over to
`prescribing habits. If the strength is prescribed with trailing zeros as seen in the
`labeling, this provides an opportunity for error. The decimal point may not be readily
`apparent and lead to a ten-fold dosing error.
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`Additionally, the use of terminal zeroes in the expression of strength or volume is not in
`accordance with the USP General Notices (page 10) of 2004, which states, "... to help
`minimize the possibility of error in the dispensing and administration of the drugs...the
`quantity of active ingredient when expressed in whole numbers shall be shown without
`a decimal point that is followed by a terminal zero." We further note that the use of
`trailing zeros are specifically listed as dangerous abbreviations, acronyms, or symbols
`in the 2006 National Patient Safety Goals of The Joint Commission for Accreditation of
`Hospitals (JCAHO). Lastly, safety groups, such as the Institute for Safe Medication
`Practices (ISMP), also list trailing zeros on their dangerous abbreviations and dose
`designations list.
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`Since patients may need counseling on alternative administration of this product (i.e.,
`sprinkle the entire contents on applesauce), DMETS recommends that you include
`section 17 (Patient Counseling Information) so that it can be provided to patients.
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`2.
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`Risk Management Plan (RMP)
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`We request that you summarize in a section of the Periodic report or Periodic Safety Update Report
`(PSUR) all cases of abuse, misuse, and diversion regardless of whether an adverse event occurred.
`Sources of such cases include, but are not limited to, the toll-free line, the Internet Monitoring
`Program, News/Media monitoring, and the general information phone lines and direct emails. In
`addition, you should provide a summary in the Periodic report or PSUR of all other surveillance
`monitoring data (e.g., from Federal Surveys, School/Community Monitoring, DAWN Live! etc.). We
`also request that you send a desk copy of the report, via the usual method of sending desk copies,
`clearly identified for “OSE Risk Management Program Coordinator.”
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`NDA 22-063
`Page 5
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`Postmarketing Commitments
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`1. Exploration of Dose Response for Effectiveness
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` as a treatment for ADHD have not fully explored the dose response of
`Your studies with
`the drug for effectiveness, in particular, at the lower end. In these studies, there was no difference
`in effectiveness over the dose range studied, 25 mg to 75 mg/day. We, therefore, ask that you
`conduct additional studies to explore lower doses than those studied, i.e., 12.5 mg. This is
`particularly important given the finding of dose-relatedness for a number of adverse events.
`Accordingly, we ask for your commitment to conduct such a study as a postmarketing
`commitment.
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`2. Exploration for Cardiovascular Risk with the Use of Amphetamine Products
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`The approval of this new formulation of amphetamine would be expected to increase the use of
`amphetamine in adults. Despite the strong warning language regarding cardiovascular risk that is
`now standard in labeling for amphetamine products, we are concerned that such expanded use will
`increase cardiovascular morbidity particularly among adult users. It is not feasible to explore this
`risk question within the context of a controlled trial due to practical limitations on the size of such
`trials. However, an observational study, e.g., a retrospective cohort study, may help in better
`understanding this risk. Therefore, we ask that you commit to conducting such a study post-
`approval. Such a study would, of course, rely on reports for amphetamine products other than
` (e.g., Adderall and Adderall XR). However, we would expect that the risks associated
`with such products could be extrapolated to
` We would be happy to meet with you to
`discuss the design of such a study.
`
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`Foreign Regulatory Update
`
` (mixed salts of a single entity amphetamine) actions
`We require a review of the status of all
`taken or pending before foreign regulatory authorities. Approval actions can be noted, but we ask that
`you describe in detail any and all actions taken that have been negative, supplying a full explanation of
`the views of all parties and the resolution of the matter. If
` (mixed salts of a single entity
`amphetamine) has been approved by any non-US regulatory bodies, we ask that you provide us any
`approved labeling for
` (mixed salts of a single entity amphetamine) along with English
`translations when needed.
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`Request for Safety and World Literature Update
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` (mixed salts of a single entity amphetamine) is based on our
`Our assessment of the safety of
`review of all safety information provided in your original and subsequent submissions, including your
`safety update dated November 17, 2006. When you respond to the above deficiencies, include a safety
`update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all non-
`clinical and clinical studies of the drug under consideration regardless of indication, dosage form, or
`dose level.
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`1.
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`Describe in detail any significant changes or findings in the safety profile.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-063
`Page 6
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`2.
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`When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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`•
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`•
`•
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`•
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`Present new safety data from the studies for the proposed indication using the same
`format as the original NDA submission.
`Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
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`Present a retabulation of the reasons for premature study discontinuation by incorporating the
`drop-outs from the newly completed studies. Describe any new trends or patterns identified.
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`Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide
`narrative summaries for serious adverse events.
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`Describe any information that suggests a substantial change in the incidence of common, but
`less serious, adverse events between the new data and the original NDA data.
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`Provide English translations of current approved foreign labeling not previously submitted.
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`3.
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`4.
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`5.
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`6.
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`7.
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` (mixed salts of a single entity amphetamine), we require an
`Prior to the approval of
`updated report on the world archival literature pertaining to the safety of
` (mixed salts
`of a single entity amphetamine). We need your warrant that you have reviewed this literature
`systematically, and in detail, and that you have discovered no finding that would adversely
`affect conclusions about the safety of
` (mixed salts of a single entity amphetamine).
`The report should also detail how the literature search was conducted, by whom (their
`credentials) and whether it relied on abstracts or full texts (including translations) of articles.
`The report should emphasize clinical data, but new findings in preclinical reports of potential
`significance should also be described. Should any report or finding be judged important, a copy
`(translated as required) should be submitted for our review.
`
`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
`
`
`Promotional Material
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this/these product(s). Submit all proposed materials in draft or mock-up form, not final print. Send
`one copy to this division and two copies of both the promotional materials and the package insert(s)
`directly to:
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-063
`Page 7
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`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110. If you do not
`follow one of these options, we will consider your lack of response a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
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`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved and scheduling is complete.
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`If you have any questions, call LT Felecia Curtis, R.N., Regulatory Project Manager, at (301) 796-
`0877.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Thomas Laughren, M.D.
`Director
`Division of Psychiatry Products
`Center for Drug Evaluation and Research
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`
`Attachment (Labeling)
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`30 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
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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/
`---------------------
`Thomas Laughren
`5/18/2007 11:28:37 AM
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