021303Orig1s009

CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: 021303Orig1s009 Trade Name: ADDERALL XR Generic or Proper Dextroamphetamine Saccharate , Amphetamine Name: Aspartate Monohydrate Dextroamphetamine Sulfate Amphetamine Sulfate Sponsor: Shire Approval Date: 07/21/2005 Indication: ADDERALL XR™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). CENTER FOR DRUG EVALUATION AND RESEARCH 021303Orig1s009 CONTENTS Reviews / Information Included in this NDA Review. Approval Letter X Other Action Letters X Labeling X REMS Summary Review X Officer/Employee List Office Director Memo Cross Discipline Team Leader Review Medical Review(s) X Chemistry Review(s) X Environmental Assessment Pharmacology Review(s) Statistical Review(s) X Microbiology / Virology Review(s) Clinical Pharmacology/Biopharmaceutics Review(s) X Other Reviews X Risk Assessment and Risk Mitigation Review(s) Proprietary Name Review(s) Administrative/Correspondence Document(s) X CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021303Orig1s009 APPROVAL LETTER NDA 21-303/S-009 Page 2 Promotional Materials In addition, submit three copies of the introductory promotional materials that you propose to use for this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to this division/ the Division of Psychiatry Products and two copies of both the promotional materials and the package insert directly to: Division of Drug Marketing, Advertising, and Communications, HFD-42 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 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: MEDWATCH, HFD-410 FDA 5600 Fishers Lane Rockville, MD 20857 We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, call Richardae C. Taylor, Pharm.D., Regulatory Project Manager, at (301) 594-5793. Sincerely, {See appended electronic signature page} Thomas Laughren, M.D. Acting Director Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research Enclosure --------------------------------------------------------------------------------------------------------------------- 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 7/21/05 03:17:47 PM CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021303Orig1s009 OTHER ACTION LETTERS NDA 21-303/S-009 Page 2 a set of criteria for potentially clinically significant laboratory values and provide an analysis of the number of patients who start in the normal range and then have excursions into PCS ranges during treatment. 5. Please present, by dose, the proportion of patients who had a 5, 10, or 15 mm Hg increase in systolic blood pressure, and the proportion of patients, by dose, who had a 2, 4, 6, or 8 mm Hg increase in diastolic blood pressure in the controlled trial. 6. We believe you should document, in a Phase 4 clinical study, the responsiveness of Adderall-induced hypertension to various classes of anti-hypertensive agents. We would be happy to discuss the design of such a study with you. Clinical Pharmacology & Biopharmaceutics The metabolic pathways of amphetamine are not described in the labeling of Adderall. Although there appears to be a role for CYP2D6, amphetamine metabolism has not been well characterized in the literature. We recommend that in vitro studies be performed to characterize the metabolic pathways and specific enzymes involved in the metabolism of Adderall. This type of information will determine the importance of specific pathways and the potential for drug interactions mediated by these pathways and will help determine the necessity for in vivo evaluation. Similarly, it would be useful to characterize the effect of Adderall on drug metabolizing enzymes. For guidance, you can refer to the Draft Preliminary Concept Paper “Drug Interaction Studies – Study design, data Analysis, and Implications for Dosing and Labeling” (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004- 4079B1_04_Topic2-TabA.pdf). In addition, before this application may be approved, you must submit draft labeling for this drug. The attachment to this letter provides a draft of the labeling that the Agency asks you to adopt for Adderall XR upon approval of this supplemental application. The base document used for our draft labeling is your last approved labeling. Although sections of this proposal are taken verbatim from the labeling proposed by you in the sNDA, other sections have been revised. Please also note that we have embedded in brackets throughout the text of the attached draft labeling several comments and further revisions of the labeling. We also ask that when you submit draft labeling for Adderall XR, you include in the labeling all previous revisions, as reflected in the most recently approved package insert. To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes and identify which version of labeling was used as the base document. If additional information relating to the safety or effectiveness of this drug becomes available, revision of the labeling may be required. Safety Update 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. 1. Describe in detail any significant changes or findings in the safety profile. 2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows: NDA 21-303/S-009 Page 3 • 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. 3. 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. 4. 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. 5. 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. 6. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries. 7. Provide English translations of current approved foreign labeling not previously submitted. Promotional Materials In addition, submit three copies of the introductory promotional materials that you propose to use for this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to this division/ the Division of Neuropharmacological Drug Products and two copies of both the promotional materials and the package insert directly to: Division of Drug Marketing, Advertising, and Communications, HFD-42 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Within 10 days after the date of this letter, you are required to amend the 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. Under 21 CFR 314.102(d), you may request a meeting or telephone conference with this division to discuss what further steps need to be taken before the application may be approved. This product may be considered to be misbranded under the Federal Food, Drug, and Cosmetic Act if it is marketed with these changes before approval of this supplemental application. NDA 21-303/S-009 Page 4 If you have any questions, call Richardae C. Taylor, Pharm.D., Regulatory Project Manager, at (301) 594-5793. Sincerely, {See appended electronic signature page} Russell Katz, M.D. Director Division of Neuropharmacological Drug Products Office of Drug Evaluation I Center for Drug Evaluation and Research 12 Page(s) of Draft Labeling has been Withheld in Full as b4 (CCI/TS) immediately following this page --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed

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