CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`021338Orig1s005
`
`Trade Name:
`
`Ionsys
`
`Generic or Proper
`Name:
`
`Fentanyl iontophoretic transdermal system
`
`Sponsor:
`
`The Medicines Company
`
`Approval Date:
`
`April 30, 2015
`
`Indication:
`
`the short-term management of acute post-
`For
`operative pain in adult patients requiring opioid
`analgesia in the hospital.
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`021338Orig1s005
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`X
`X
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`021338Orig1s005
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 021338/S-005
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`The Medicines Company
`900 Saginaw Dr., Suite 200
`Redwood City, CA 94063
`
`Attention: Deborah Ware
`
`Senior Director, Regulatory Affairs
`
`Dear Ms. Ware:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated June 30, 2014, received
`June 30, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for IONSYS (fentanyl iontophoretic transdermal system.)
`
`We acknowledge receipt of your amendments dated July 24, September 8, October 2, and 29,
`November 12, and December 12, and 17, 2014, and January 9, 23, 28, and 30, February 5, and 27,
`March 6, and 12, and April 21, 28, and 29, 2015.
`
`This “Prior Approval” supplemental new drug application provides for conversion of the approved
`package insert to the Physicians Labeling Rule (PLR) format, a reformulation of the device into
`two separate components, and a proposed risk evaluation and mitigation strategy (REMS).
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated
`drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert), with the addition
`of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as
`annual reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled,
`SPL Standard for Content of Labeling Technical Qs and As, available at
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 2
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UC
`M072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter, with
`the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes
`approved in this supplemental application, as well as annual reportable changes and annotate each
`change. To facilitate review of your submission, provide a highlighted or marked-up copy that
`shows all changes, as well as a clean Microsoft Word version. The marked-up copy should
`provide appropriate annotations, including supplement number(s) and annual report date(s).
`
`We request that the labeling approved today be available on your website within 10 days of receipt
`of this letter.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and immediate container labels that are identical to enclosed carton and
`immediate container labels, as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry, Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and
`Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit
`12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar
`material. For administrative purposes, designate this submission “Final Printed Carton and
`Container Labels for approved NDA 021338/S-005.” Approval of this submission by FDA is
`not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active
`ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the product
`for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or
`inapplicable.
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`However, we remind you of your previous PREA postmarketing requirement (PMR), specified in
`our May 22, 2006, original NDA approval letter:
`
`
`1191-1 Deferred pediatric study under PREA for the treatment of short-term management
`of acute post-operative pain in patients requiring opioid analgesia during
`hospitalization in pediatric patients ages 6 to less than 17 years of age.
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 3
`
`
`
`As noted in the deferral extension granted letter dated December 13, 2013, you will conduct this
`study according to the following schedule:
`
`
`Final Report Submission: 03/2017
`
`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling changes
`you believe are warranted based on the data derived from these studies. When submitting the
`reports, please clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC
`ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the submission.
`
`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`
`2905-1
`
`Continue to use microscopy techniques to monitor for corrosion during the stability
`studies. If any discoloration of the circuitry is observed, an analytical technique
`such as XPS or SEM should be used to characterize the discoloration. If corrosion is
`observed, evaluate the potential impact on device performance. Monitoring of
`corrosion must continue for a minimum of 3 years from the date of commercial
`launch of the product. Submit a Field Alert if corrosion is observed. If no corrosion
`is observed, this result can be submitted in the annual report.
`
`
`The timetable you submitted on April 21, 2015, states that you will submit the results of this
`monitoring according to the following schedule:
`
`
`Final Report Submission: 12/2018
`
`Note that for PMR 2905-1, when you submit your final report, you may also submit a Prior
`Approval Supplement with supportive data to the NDA to request reduced monitoring, which
`will be reviewed by the Agency.
`
`
`2905-2 Due to the complexity of the product and the continued concern for malfunction and
`safety of the system, provide quarterly reports of any device malfunctions, any
`adverse events or medication errors associated with or suspected to be associated
`with device malfunction, and any patient or provider complaints regarding device
`malfunction. After three years of submitting quarterly reports, submit a
`comprehensive discussion of the reports of any device malfunctions, any adverse
`events or medication errors associated with or suspected to be associated with
`device malfunction, and any patient or provider complaints regarding device
`malfunction, and provide an explanation of how you addressed those adverse
`events.
`
`
`The timetable you submitted on April 21, 2015, states that you will conduct this reporting
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 4
`
`
`according to the following schedule:
`
`
`First quarterly report – Year 1: 10/2015
`Second quarterly report – Year 1: 1/2016
`Third quarterly report – Year 1: 4/2016
`Fourth quarterly report – Year 1: 7/2016
`First quarterly report – Year 2: 10/2016
`Second quarterly report – Year 2: 1/2017
`Third quarterly report – Year 2: 4/2017
`Fourth quarterly report – Year 2: 7/2017
`First quarterly report – Year 3: 10/2017
`Second quarterly report – Year 3: 1/2018
`Third quarterly report – Year 3: 4/2018
`Final Report Submission – Year 3: 7/2018
`
`
`Submit clinical protocols to your IND 041574 for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition,
`under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of
`each commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies/trials, number of patients entered into each study/trial. All
`submissions, including supplements, relating to these postmarketing commitments should be
`prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment
`Final Report,” or “Postmarketing Commitment Correspondence.”
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA becomes aware of new safety information and makes a
`determination that such a strategy is necessary to ensure that the benefits of an approved drug
`outweigh the risks.
`
`Since IONSYS was approved on May 22, 2006, based in part on data included in your
`supplemental NDA submission, including information regarding the nature and functioning of the
`new delivery device, we have become aware of the risk of respiratory depression resulting from
`accidental exposure to persons for whom it is not prescribed. Accidental exposure to a person for
`whom IONSYS is not prescribed may occur either in the hospital when a health care provider or
`another person interacts with a patient wearing an IONSYS device or if the device were not
`removed from the patient before he/she was discharged from the hospital. We consider this
`information to be “new safety information” as defined in section 505-1(b) of the FDCA.
`
`In accordance with section 505-1 of the FDCA, we have determined that a REMS is necessary for
`IONSYS to ensure the benefits of the drug outweigh the risk of respiratory depression resulting
`from accidental exposure to persons for whom it is not prescribed.
`
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 5
`
`
`Pursuant to 505-1(f)(1), we have determined that elements necessary to assure safe use are
`necessary to mitigate the risk of respiratory depression resulting from accidental exposure to
`persons for whom IONSYS is not prescribed.
`
`Your REMS includes the following elements to mitigate these risks:
`
` 
`
` Health care settings that dispense the drug are specially certified
` The drug is dispensed to patients only in certain health care settings
`
`
`Your proposed REMS, submitted on April 28, 2015, and appended to this letter, is approved.
`
`The REMS consists of elements to assure safe use, an implementation system, and a timetable for
`submission of assessments of the REMS.
`
`The REMS assessment plan must include, but is not limited to, the following:
`
`The following metrics should be reported for every reporting period, unless specified otherwise, to
`assess the effectiveness of the IONSYS REMS program:
`
`
`a) IONSYS REMS Program Implementation Metrics
`1. Dates of IONSYS REMS program launch, to be completed for the first six month
`assessment only, should include the following:
`a. REMS website goes live
`b. REMS Call Center is operational
`c. Hospitals are able to complete the REMS certification process
`d. First notification of hospital certification is sent
`
`b) IONSYS REMS Program Utilization Metrics (Provide data for each reporting period and
`cumulatively)
`1. Hospital enrollment and education statistics
`a. Number of Hospitals enrolled stratified by:
`State
`i.
`ii. Method of enrollment (i.e., online or fax or mail or e-mailed)
`b. Number of incomplete enrollments, and the number of these that subsequently
`became enrolled
`c. Number of sent certification notification letters and returned mailings for each
`reporting period
`d. Number of Hospital Authorized Representatives who successfully completed the
`IONSYS REMS Knowledge Assessment for each reporting period and
`cumulatively
`i. Descriptive statistics (mean, median, and range) of the number of attempts
`associated with completion of IONSYS REMS Knowledge Assessment
`ii. Correct answer rates for each question in the IONSYS REMS Knowledge
`Assessment
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 6
`
`
`
`e. Number of Hospitals de-certified for non-compliance with the IONSYS REMS
`Program requirements and reasons for decertification for each reporting period and
`cumulatively in tabular format
`2. Compliance with the IONSYS REMS-required distribution statistics
`a. Number of wholesalers/distributors enrolled
`b. The number of orders received and shipped for IONSYS
`c. Number of certified hospitals that have received at least one shipment of Ionsys
`d. Number of orders shipped to non-certified or decertified hospital locations and
`corrective actions taken for each non-compliance instance
`
`3. Compliance with the IONSYS REMS-required dispensing statistics
`a. Number of accidental exposures to IONSYS in the inpatient setting, stratified by the
`following:
`i. Healthcare providers
`Patients for whom IONSYS is not prescribed
`ii.
`iii.
`Pediatric non-patients
`iv. Other non-patients
`b. A root cause analysis for accidental exposures
`
`c) Periodic Surveys of healthcare providers
`A random sample of healthcare providers who prescribe, dispense, or administer IONSYS
`will be selected to assess their understanding regarding the key risk messages, appropriate
`use of IONSYS, and IONSYS REMS program requirements through periodic knowledge,
`attitude, and behavior (KAB) surveys. Survey results will be reported annually after the
`initial IONSYS REMS approval.
`
`d) Non-compliance and other issues
`1. Frequently asked questions and problems identified by the IONSYS REMS Call
`Center.
`2. Description of any incidents of prescribing/dispensing from non-IONSYS REMS
`certified hospitals and any incidents of dispensing of IONSYS for outpatient use.
`3. The number of inpatient prescriptions of IONSYS dispensed on the same day as
`discharge
`4. Corrective actions for non-compliance with REMS requirements, if identified, as well
`as the outcomes of the corrective actions will be specified for the reporting period.
`e) Adverse Events
`1. Number and descriptions of post-marketing reports of the following adverse events
`received by the Sponsor during the reporting period, and cumulatively
`a. Reports of abuse, overdose, accidental exposure, respiratory depression, or other
`serious complications associated with IONSYS
`b. Any serious adverse events associated with a dispensed and unused IONSYS
`c. Any adverse events reported from a non-IONSYS REMS certified hospital
`d. Any medication errors associated with IONSYS
`
`f) Audit Results for each reporting period and cumulatively, including but not limited to:
`1. Number of audited hospitals.
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 7
`
`
`
`3.
`
`2. Summarize all instances of non-compliance and resulting improvement plans. Group
`these observations into critical, major, or minor. Provide a definition for each
`category (critical, major, minor)
`Identify the REMS Improvement Plans (RIPs) from the current reporting period and
`from previous reporting periods that were implemented during the current reporting
`period
`4. For any Continuous Improvement Plans (CIPs) not completely implemented, explain
`why they are not complete and provide an expected completion date
`
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include with
`respect to each goal included in the strategy, an assessment of the extent to which the approved
`strategy, including each element of the strategy, is meeting the goal or whether one or more such
`goals or such elements should be modified.
`
`We remind you that in addition to the REMS assessments submitted according to the timetable in
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`modification for the addition, modification, or removal of any of goal or element of the REMS, as
`described in section 505-1(g)(4) of the FDCA.
`
`We also remind you that you must submit a REMS assessment when you submit a supplemental
`application for a new indication for use, as described in section 505-1(g)(2)(A). This assessment
`should include:
`
`
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`indication;
`b) A determination of the implications of a change in the benefit-risk profile for the current
`REMS;
`c) If the new, proposed indication for use introduces unexpected risks: A description of those
`risks and an evaluation of whether those risks can be appropriately managed with the
`currently approved REMS.
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether the
`REMS was meeting its goals at the time of that the last assessment and if any
`modifications of the REMS have been proposed since that assessment.
`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: Provision of as many of the
`currently listed assessment plan items as is feasible.
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS modification
`is necessary, the potential effect on the serious risk(s) for which the REMS was required,
`on patient access to the drug, and/or on the burden on the health care delivery system; and
`other appropriate evidence or data to support the proposed change. Additionally, include
`any changes to the assessment plan necessary to assess the proposed modified REMS. If
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 8
`
`
`
`you are not proposing a REMS modification, provide a rationale for why the REMS does
`not need to be modified.
`
`
`If the assessment instruments and methodology for your REMS assessments are not included in the
`REMS supporting document, or if you propose changes to the submitted assessment instruments or
`methodology, you should update the REMS supporting document to include specific assessment
`instrument and methodology information at least 90 days before the assessments will be
`conducted. Updates to the REMS supporting document may be included in a new document that
`references previous REMS supporting document submission(s) for unchanged portions.
`Alternatively, updates may be made by modifying the complete previous REMS supporting
`document, with all changes marked and highlighted. Prominently identify the submission
`containing the assessment instruments and methodology with the following wording in bold capital
`letters at the top of the first page of the submission:
`
`
`NDA 021338 REMS CORRESPONDENCE
`(insert concise description of content in bold capital letters, e.g.,
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`METHODOLOGY)
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA, contact
`us to discuss what will be required in the authorized generic drug REMS submission.
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval of
`an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could result
`in enforcement action.
`
`Prominently identify any submission containing the REMS assessments or proposed modifications
`of the REMS with the following wording in bold capital letters at the top of the first page of the
`submission as appropriate:
`
`
`NDA 021338 REMS ASSESSMENT
`NEW SUPPLEMENT FOR NDA 021338
`CHANGES BEING EFFECTED IN 30 DAYS
`< other supplement identification >
`PROPOSED MINOR REMS MODIFICATION
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 021338
`PRIOR APPROVAL SUPPLEMENT
`< other supplement identification >
`PROPOSED MAJOR REMS MODIFICATION
`
`or
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 9
`
`
`
`
`NEW SUPPLEMENT FOR NDA 021338
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`SUBMITTED IN SUPPLEMENT XXX
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 021338 REMS ASSESSMENT
`
`< other supplement identification >
`PROPOSED REMS MODIFICATION (if included)
`
`REMS REVISIONS FOR NDA 021338
`
`
`If you choose to submit a REMS revision, prominently identify the submission containing the
`REMS revisions with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`
`To facilitate review of your submission, we request that you submit your proposed modified
`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such as
`enrollment forms, are only in PDF format, they may be submitted as such, but the preference is to
`include as many as possible in Word format.
`
`ADDITIONAL COMMENTS
`
`You revised your labeling to include the MR UNSAFE symbol in the Prescribing Information and
`you wish to retain the previously approved labeling on the product including the text “WARNING:
`REMOVE BEFORE MRI.” We remind you that for future production of the product, you have
`agreed to add the MR Unsafe icon symbol to the product together with the current text
`“WARNING: REMOVE BEFORE MRI.”
`
`Section 7.2.1 of IEC 60601-1 (3rd Edition) requires certain symbols and explanations to be
`permanently labeled on the housing. We remind you that for future production of the product, you
`have agreed to add the Applied Parts symbol to the product together with the explanatory text.
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and (3)
`the package insert(s) to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Reference ID: 3744414
`
`

`

`NDA 021338/S-005
`Page 10
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form FDA
`2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA
`2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any new
`safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials should
`include prominent disclosure of the important new safety information that appears in the revised
`package labeling. Within 7 days of receipt of this letter, submit your statement of intent to comply
`with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`REPORTING REQUIREMENTS
`
`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 Kimberly Compton, Sr. Regulatory Project Manager, at (301) 796-
`1191.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`
`
`
`Sharon Hertz, MD
`Director
`Division of Anesthesia, Analgesia, and
`Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`REMS
`REMS Materials
`
`
`Reference ID: 3744414
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KIMBERLY A COMPTON
`04/30/2015
`
`SHARON H HERTZ
`04/30/2015
`
`Reference ID: 3744414
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`021338Orig1s005
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use IONSYS
`safely and effectively. See full prescribing information for IONSYS.
`IONSYS® (fentanyl iontophoretic transdermal system), CII
`Initial U.S. Approval: 1968
`
`WARNING: HOSPITAL USE ONLY; LIFE-THREATENING
`RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE,
`AND MISUSE; and CYTOCHROME P450 3A4 INTERACTION
`See full prescribing information for complete boxed warning.
`
` Use of IONSYS may result in potentially life-threatening respiratory
`depression and death. Only the patient should activate dosing. (2.1, 5.1)
` Accidental exposure to an intact IONSYS or to the hydrogel component,
`especially by children, through contact with skin or mucous
`membranes, can result in a fatal overdose of fentanyl. (5.1)
` IONSYS is for use only in patients in the hospital. Discontinue IONSYS
`before patients leave the hospital. (5.1)
` Because of potentially life-threatening respiratory depression resulting
`from accidental exposure, IONSYS is only available through a
`restricted program called the IONSYS REMS Program. (5.2)
` IONSYS exposes users to risks of addiction, abuse, and misuse, which
`can lead to overdose and death. Assess patient’s risk before prescribing,
`and monitor regularly for these behaviors or conditions. (5.3)
` Initiation of CYP 3A4 inhibitors or discontinuation of CYP 3A4
`inducers can result in a fatal overdose of fentanyl from IONSYS. (5.15,
`7.3, 12.3)
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Boxed Warning
`
`
`04/2015
`Indications and Usage (1)
`
`04/2015
`Dosage and Administration (2)
`
`04/2015
`Contraindications (4)
`
`04/2015
`Warnings and Precautions (5)
`
`04/2015
`-----------------------------INDICATIONS AND USAGE--------------------------
`IONSYS contains fentanyl, an opioid agonist. IONSYS is indicated for the
`short-term management of acute postoperative pain in adult patients requiring
`opioid analgesia in the hospital. (1)
`
`Limitations of Use:
` Only for use in patients who are alert enough and have adequate cognitive
`ability to understand the directions for use. (1)
` Not for home use. IONSYS is for use only in patients in the hospital.
`Discontinue treatment with IONSYS before patients leave the hospital. (1)
` IONSYS is for use after patients have been titrated to an acceptable level of
`analgesia using alternate opioid analgesics. (1)
`-------------------------DOSAGE AND ADMINISTRATION---------------------
` Do not use more than one IONSYS at a time. (2.1)
` Patients should be titrated to comfort before initiating IONSYS. (2.2)
` For transdermal use only. Apply one IONSYS to intact, non-irritated, and
`non-irradiated skin on the chest or upper outer arm. (2.2, 2.3)
` Each IONSYS operates up to 24 hours or 80 doses, whichever comes first.
`IONSYS may be used for a maximum of 72 hours of therapy for acute
`postoperative pain, with each subsequent IONSYS applied to a different
`skin site. (2.2, 2.3)
` See full prescribing information for detailed instructions concerning
`administration, disposal and discontinuation of IONSYS. (2.3, 2.4, 2 5, 2.6)
` See IONSYS Important Device Instructions for additional details including
`troubleshooting device malfunction.
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Iontophoretic transdermal system provides up to 80 doses (40 mcg each) of
`fentanyl per activation on-demand. (3)
`
`--------------------------------CONTRAINDICATIONS-----------------------------
` Significant respiratory depression. (4)
` Acute or severe bronchial asthma. (4)
` Known or suspected paralytic ileus and GI obstruction. (4)
` Hypersensitivity to fentanyl, cetylpyridinium chloride (e.g., Cepacol®), or
`any components of IONSYS. (4)
`---------------------WARNINGS AND PRECAUTIONS-------------------------
` Interactions with CNS depressants: Concomitant use may cause
`hypotension, profound sedation, respiratory depression, and death.
`Monitor patients closely if co-administration is required. (5.1, 5.4, 7.1)
` Risk of injury during MRI: IONSYS contains metal parts and must be
`removed before an MRI. (5.5)
` Risk of use during other procedures (cardioversion, defibrillation, X-ray,
`CT, diathermy): Remove IONSYS before these procedures. (5.6)
` Topical skin reactions: If reaction is severe, discontinue IONSYS. (5.7)
` Elderly, cachectic, and debilitated patients, and those with chronic
`pulmonary disease: Monitor closely because of increased risk of life-
`threatening respiratory depression. (5.8, 5.9)
` Hypotension: Monitor during dose initiation. Avoid use of IONSYS in
`patients with circulatory shock. (5.10)
` Patients with head injury or increased intracranial pressure: Monitor for
`sedation and respiratory depression. Avoid use of IONSYS in patients with
`impaired consciousness or coma. Opioids may obscure clinical course in
`patients with head injury. (5.11)
` Patients with biliary tract disease, including acute pancreatitis: Monitor for
`worsening symptoms. (5.12)
` Increased risk of seizures in patients with seizure disorders: Monitor for
`worsened seizure control during IONSYS therapy. (5.13)
` Bradycardia: Closely monitor patients with bradyarrhythmias. (5.14)
`----------------------------ADVERSE REACTIONS--------------------------------
`Most common (frequency ≥ 2%) adverse reactions were headache,
`hypotension, nausea, vomiting, anemia, dizziness, application site reaction-
`erythema, pruritus, and urinary retention. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact The
`Medicines Company at 1-877-488-6835 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`------------------------------------DRUG INTERACTIONS-------------------------
` Muscle relaxants: Monitor patients receiving muscle relaxants and
`IONSYS for signs of respiratory depression that may be greater than
`otherwise expected. (7.2)
` Monoamine oxidase inhibitors (MAOIs): Avoid use of IONSYS in patients
`taking MAOIs or within 14 days of stopping such treatment. (7.