CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: 021303Orig1s005 Trade Name: ADDERALL XR Generic or Proper Dextroamphetamine Saccharate , Amphetamine Name: Aspartate Monohydrate Dextroamphetamine Sulfate Amphetamine Sulfate Sponsor: Shire Approval Date: 08/11/2004 Indication: ADDERALL XR™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). CENTER FOR DRUG EVALUATION AND RESEARCH 021303Orig1s005 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: 021303Orig1s005 APPROVAL LETTER NDA 21-303/S-005 Page 2 69009) and was effective June 8, 2004. For additional information, consult the following guidance for industry: Regulatory Submissions in Electronic Format – Content of Labeling (February 2004). Pediatric Research Equity Act (PREA) 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. We are waiving the pediatric study requirement for ages less than 6 years and deferring pediatric studies for ages 13 to 17 years for this application. Your deferred pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA) are considered required postmarketing study commitments. The status of these postmarketing studies shall be reported annually according to 21 CFR 314.81. These commitments are listed below. LIST POSTMARKETING COMMITMENTS: 1. Deferred pediatric study under PREA for the treatment of ADHD in pediatric patients ages 13 to 17. Final Report Submission: May 2008 Submit final study reports to this NDA. For administrative purposes, all submissions related to this/these pediatric postmarketing study commitments must be clearly designated “Required Pediatric Study Commitments”. 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 Medwatch 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). NDA 21-303/S-005 Page 3 If you have any questions, call Richardae 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 Enclosure --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 8/11/04 10:58:28 AM CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021303Orig1s005 OTHER ACTION LETTERS (b) (4) 2. We were unable to find any analyses of ECG abnormalities and changes from baseline to endpoint by dose group in Study 303. Please provide this along with a summary of your findings. In addition, we note that you have detected a slight increase in the mean QTc interval in patients treated with Adderall XR compared to placebo in Study 303. However, we have not been able to determine the method of correction you used to calculate the QTc interval. Please present the method you performed and the rationale for this particular choice. 3. We were not able to clearly establish the extent of exposure of Adderall XR in the studies in the adult population. Your Table 4, Extent of Exposure in Multiple Dose Studies, implies that only 60 patients received Adderall XR for 6-months or greater at any dose and that only 19 patients received 60-mg for a period of 6-months or greater. Please confirm whether or not this is correct. Based on discussions with you, we had anticipated that you would present data on a much larger group of adults (about 200 patients treated for at least 6 months). If we are correct in our calculations of the number of patients who received treatment for 6 months or longer, you will need to accrue considerably more long-term, prospective, well-monitored safety experience prior to approval. 4. As part of the review of the NDA supplement, the FDA's Adverse Event Reporting System was searched for adverse events reported in association with Adderall products. Among these adverse events were a number of serious events including myocardial infarctions, cerebrovascular accidents, sudden deaths, and non-fatal cardiac arrhythmias. Of particular concern to us is the fact that a number of these events occurred in relatively young adults who appeared to have no other explanation for their event. While it is not possible to assign drug causality in individual cases, one way to assess potential safety signals is to calculate reporting rates for each of the adverse events of interest and compare them to the pertinent background rates. We request that you calculate reporting rates (number of cases/person-time exposure) for the following adverse events and compare these rates to the pertinent background rates. o Sudden death o Myocardial infarction o Cerebrovascular accidents/transient ischemic attacks o Non-fatal ventricular arrhythmia o Cardiomyopathy o Seizure o Ischemic organ damage 5. Because many of the events are occurring in a relatively young population (20's-40's), it is crucial that the reporting rates be stratified into the pertinent age strata. The reporting rates should then be compared to background rates that are stratified by age. Background rates for these events may be available in the medical literature. Alternatively, there may be some events for which a background rate may be estimated from a data source such as the National Hospital Discharge Survey. 2 Under 21 CFR 314.102(d) of the new drug regulations, you may request an informal 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 prior to approval of this supplemental application. If you should have any questions, please call Ms. Richardae Taylor, Pharm D, Regulatory Management Officer, 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 Attachment 11 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page. 5 --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 10/17/03 01:39:30 PM CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021303Orig1s005 LABELING ADDERALL XR CAPSULES CII Rx Only AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION ADDERALL XR™ is a once daily extended-release, single-entity amphetamine product. ADDERALL XR™ combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate. The ADDERALL XR™ capsule contains two types of drug-containing beads designed to give a double-pulsed delivery of amphetamines, which prolongs the release of amphetamine from ADDERALL XR™ compared to the conventional ADDERALL® (immediate- release) tablet formulation. EACH CAPSULE CONTAINS: 5 mg 10 mg 15 mg 20 mg