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    Approval Package for:


    Name: Fentanyl Transdermal System, 25 mcg/hour,

    50 mcg/hour, 75 mcg/hour and 100 mcg/hour

    Sponsor: TEVA Pharmaceuticals USA Approval Date: October 20, 2008




    Reviews / Information Included in this Review Approval Letter X Tentative Approval Letter Labeling X Labeling Reviews X Medical Reviews Chemistry Reviews X Bioequivalence Reviews X Statistical Reviews X Microbiology Reviews Other Reviews X Administrative & Correspondence Documents X





    Food and Drug Administration Rockville, MD 20857

    ANDA 77-449 TEVA Pharmaceuticals USA Attention: Philip Erickson, R.Ph.

    Senior Director, Regulatory Affairs 1090 Horsham Road P.O. Box 1090 North Wales, PA 19454 Dear Sir: This is in reference to your abbreviated new drug application (ANDA) dated December 17, 2004, submitted pursuant to section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act), for Fentanyl Transdermal System, 25 mcg/hour, 50 mcg/hour, 75 mcg/hour and 100 mcg/hour. Reference is also made to your amendments dated May 3, and June 5, 2006; January 16, January 31, April 3, April 26, August 30, and November 28, 2007; and March 14, June 3, June 18, August 26, and September 18, 2008. We have completed the review of this ANDA and have concluded that adequate information has been presented to demonstrate that the drug is safe and effective for use as recommended in the submitted labeling. Accordingly the ANDA is approved, effective on the date of this letter. The Division of Bioequivalence has determined your Fentanyl Transdermal System, 25 mcg/hour, 50 mcg/hour, 75 mcg/hour, and 100 mcg/hour to be bioequivalent and, therefore, therapeutically equivalent to the reference listed drug, Duragesic-25, Duragesic-50, Duragesic-75 and Duragesic-100 Transdermal System, respectively, of Ortho McNeil Janssen. Your dissolution testing should be incorporated into the stability and quality control program using the same method proposed in your application. The interim dissolution specifications are as follows:

  • In-vitro dissolution testing should be conducted in 500 mL (for the 25 and 50 mcg/hour strengths) and 900 mL (for the 75 and 100 mcg/hour strengths) of phosphate buffer, pH 6.8 at 32C0.5, using USP apparatus 6 (cylinder), at 50 rpm. The test product should meet the following interim specifications: Time (hours) Percent of Labeled Amount Dissolved

    2 6

    12 72

    These interim dissolution test(s) and tolerances should be finalized by submitting dissolution data from the first three production size batches. These data should be submitted as a Special Supplement Changes Being Effected if there are no revisions to be made to the interim specifications, or if the final specifications are tighter than the interim specifications. In all other instances, the information should be submitted in the form of a Prior Approval Supplement. Under section 506A of the Act, certain changes in the conditions described in this ANDA require an approved supplemental application before the change may be made. We note that if FDA requires a Risk Evaluation & Mitigation Strategy (REMS) for a listed drug, an ANDA citing that listed drug also will be required to have a REMS, See 505-1(i). Postmarketing reporting requirements for this ANDA are set forth in 21 CFR 314.80-81 and 314.98. The Office of Generic Drugs should be advised of any change in the marketing status of this drug. Promotional materials may be submitted to FDA for comment prior to publication or dissemination. Please note that these submissions are voluntary. If you desire comments on proposed launch promotional materials with respect to compliance with applicable regulatory requirements, we recommend you submit, in draft or mock-up form, two copies of both the promotional materials and package insert directly to:

    (b) (4)

  • Food and Drug Administration Center for Drug Evaluation and Research Division of Drug Marketing, Advertising, and Communications 5901-B Ammendale Road Beltsville, MD 20705 We call your attention to 21 CFR 314.81(b)(3) which requires that all promotional materials be submitted to the Division of Drug Marketing, Advertising, and Communications with a completed Form FDA 2253 at the time of their initial use. Within 14 days of the date of this letter, submit updated content of labeling [21 CFR 314.50(1)] in structured product labeling (SPL) format, as described at http://www.fda.gov/oc/datacouncil/spl.html, that is identical in content to the approved labeling. Upon receipt and verification, we will transmit that version to the National Library of Medicine for public dissemination. For administrative purposes, please designate this submission as Miscellaneous Correspondence SPL for Approved ANDA 77-449.

    Sincerely yours, {See appended electronic signature page} Gary Buehler Director Office of Generic Drugs Center for Drug Evaluation and Research

  • ---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Robert L. West10/20/2008 11:11:29 AMDeputy Director, for Gary Buehler





  • Full Prescribing InformationFOR USE IN OPIOID-TOLERANT PATIENTS ONLYFentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion.Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

    requires continuous, around-the-clock opioid administration for an extended period of time, and

    cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids

    Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid.Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:

    in patients who are not opioid-tolerant in the management of acute pain or in patients who require opioid analgesia

    for a short period of time in the management of post-operative pain, including use after out-patient or

    day surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn])

    (See CONTRAINDICATIONS for further information.)Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY, Drug Interactions; WARNINGS; PRECAUTIONS; and DOSAGE AND ADMINISTRATION for further information).The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, Pediatric Use).Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require mon