CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`Office of Drug Evaluation II
`Division of Anesthesia, Analgesia, and Addiction Products
`
`
`NDA/BLA #s:
`PRODUCTS:
`APPLICANT:
`FROM:
`
`202788
`Subsys (fentanyl sublingual spray)
`Insys, Inc.
`Bob A. Rappaport, M.D., Director, Division of Anesthesia,
`Analgesia, and Addiction Products
`
`
`
`January 2, 2011
`
`
`DATE:
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`require the submission of a risk evaluation and mitigation strategy (REMS) if FDA
`determines that such a strategy is necessary to ensure that the benefits of the drug
`outweigh the risks (section 505-1(a)). Section 505-1(a)(1) provides the following factors:
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E)
`The seriousness of any known or potential adverse events that may be related to
`the drug and the background incidence of such events in the population likely to
`use the drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS that includes elements to assure safe use
`is necessary for fentanyl sublingual spray to ensure that the benefits of the drug outweigh
`the risks of misuse, abuse, addiction, overdose, and serious complications due to
`medication errors. In reaching this determination we considered the following:
`
`The estimated number of patients in the United States with breakthrough cancer
`A.
`pain is between 1 to 2 million. This estimate is based upon the number of patients with
`cancer in the US (American Cancer Society), the proportion of cancer patients with
`moderate to severe pain1, and the proportion of cancer patients with breakthrough pain2.
`
`
`1 Marieke HJ, van den Beuken-van Everdingen MHJ, deRijke JM, Kessels SG, Schouten
`HC, van Kleef M, Patijn. High prevalence of pain in patients with cancer in a large
`population-based study in The Netherlands. Pain 2007;132:312-320.
`
`
`Reference ID: 3065862
`
`

`

`
`The patients for this product are cancer patients with pain that cannot be
`B.
`adequately controlled using around-the-clock oral or transdermal opioids alone. Many of
`these patients have multiple concurrent complications of their underlying disease and
`therapy.
`
`The expected benefit of the drug to patients is that the delivery system is different
`C.
`from the existing oral transmucosal fentanyl products. This product is the first of these
`products to be formulated as a sublingual spray.
`
`D. The expected duration of treatment with the drug will be from days for the sickest
`patients who are preterminal, to months for patients with less tumor burden and longer
`prognoses for survival.
`
`The most serious of the known adverse events that are related to the use of
`E.
`fentanyl-containing products include death, respiratory depression, and CNS depression
`which occur primarily if the product is not used properly. In addition to the
`aforementioned risks, fentanyl sublingual spray, as other fentanyl-containing products,
`can have a potential to increase intracranial pressure and induce bradyarrythmias.
`
`F.
`
`In accordance with section 505-1 of FDCA and under 21 CFR 208, FDA has determined
`that a Medication Guide is required for Subsys (fentanyl sublingual spray). FDA has
`determined that Subsys (fentanyl sublingual spray) poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide
`is necessary for patients’ safe and effective use of Subsys (fentanyl sublingual spray).
`FDA has determined that Subsys (fentanyl sublingual spray) is a product for which
`patient labeling could help prevent serious adverse effects and that has serious risks
`relative to benefits of which patients should be made aware because information
`concerning the risks could affect patients’ decisions to use, or continue to use Subsys
`(fentanyl sublingual spray).
`
`The elements of the REMS will be a Medication Guide, elements to assure safe use
`including prescribers training, pharmacies certification, and dispensing Subsys (fentanyl
`sublingual spray) to patients with evidence or other documentation of safe use conditions,
`an implementation system, and a timetable for submission of assessments of the REMS.
`
`
`
`Fentanyl sublingual spray is not a new molecular entity
`
`Bob A. Rappaport, M.D.
`Director, Division of Anesthesia, Analgesia, and Addiction Products
`
`
`
`
`
`2 Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer
`pain. Pain 1999;81:129-134.
`
`Reference ID: 3065862
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARA E STRADLEY
`01/02/2012
`
`BOB A RAPPAPORT
`01/03/2012
`
`Reference ID: 3065862
`
`

`

`Date:
`
`To:
`
`
`Through:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`December 29, 2011
`
`
`
`
`
`
`
`
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia and Analgesia Products (DAAP)
`
`Claudia Karwoski, Pharm.D., Director
`Division of Risk Management (DRISK)
`
` Scientific Lead,
`
`Doris Auth, Pharm.D., Risk Management Analyst
`
` DRISK Review Team
`
`Megan Moncur, M.S., Team Leader
`
`Gita A. Toyserkani, Pharm.D., MBA, Senior Risk
`
`Management Analyst
`
`
`
`
`Final Risk Evaluation and Mitigation Strategy (REMS)
`review for Subsys (Fentanyl) sublingual spray
`
`Subsys, fentanyl citrate sublingual spray
`
`
`From:
`
`
`
`
`
`
`
`
`Subject:
`
`
`
`Drug Name (Established
`Name):
`
`Dosage and Route:
`
`Sublingual spray 100mcg, 200mcg, 400mcg, 600mcg, and
`800mcg
`
`
`
`
`
`
`
`Opioid
`
`Insys Therapeutics, Inc
`
`
`Therapeutic Class:
`
`Application Type/Number: NDA 202-788
`
`Applicant:
`
`
`
`Effective Date: 12/29/20111
`
`Reference ID: 3065316
`
`

`

`1. INTRODUCTION
`The purpose of this review is to evaluate the proposed Risk Evaluation and Mitigation
`Strategy (REMS) for Subsys (Fentanyl) sublingual spray.
`1.1 Product Overview
`Subsys is a formulation of fentanyl, a potent opioid analgesic, for administration as a
`spray via the sublingual route, and a member of a group of Schedule II controlled
`substances that the Agency has collectively termed transmucosal immediate release
`fentanyl (TIRF) products. Actiq, Fentora, Onsolis, Abstral, and Lazanda are approved
`TIRF medicines indicated for the management of breakthrough pain in patients with
`cancer, 18 years of age and older, who are already receiving and who are tolerant to
`opioid therapy for their underlying persistent cancer pain. These formulations deliver
`fentanyl rapidly via the oral mucosa in a variety of dosage forms. Drug delivery in this
`manner eliminates first pass metabolism that occurs with oral formulations and results in
`increased bioavailability. Subsys is the first of the transmucosal products to be delivered
`as a spray for sublingual administration.
`The time to maximum concentration for Subsys varies with dosage, ranging from 0.67
`hours for the 600mcg dose to 1.25 hours for the 100 and 200mcg doses. The proposed
`indication for Subsys the same as for the approved TIRF medicines.
`The rate and maximum plasma concentrations vary considerably between the available
`TIRF medicines, as well as Subsys, therefore, they are not interchangeable. Life-
`threatening respiratory depression may occur at any dose in the following situations: in
`patients who are not opioid tolerant, if accidentally consumed by a child or for anyone for
`whom they were not prescribed, or if used for the treatment of acute or postoperative
`pain. It is because of these risks that a REMS is required for the transmucosal immediate-
`release fentanyl products.
`1.2
`Regulatory and Review History for Subsys and the TIRF REMS
`Subsys has been part of ongoing and interrelated discussions within the Agency that
`included the review teams for other TIRF products, and often involved Senior
`Management. Following receipt of the Subsys NDA, Insys Therapeutics, Inc became a
`member of the TIRF REMS Industry Working Group (TRIG) and began collaborating
`with the group to align the Single-Shared System (SSS).
`Following are highlights of key regulatory actions and communications regarding the
`REMS for Subsys as well as the TIRF REMS Single Shared System:
`17 August 2010: Pre-NDA meeting, fentanyl sublingual spray (FSS), (IND 72-411,
`meeting minutes memo dated 10/18/10, Author: Compton, K) Insys was instructed to
`submit a REMS for FSS with their original NDA submission which must include a
`Medication Guide, Elements to Assure Safe Use, an Implementation System, and a
`Timetable for Assessments. The development of a Single Shared REMS for all
`manufacturers of TIRF products was discussed and Insys was encouraged to work with
`other manufacturers towards this goal.
`28 October 2010: Meeting with all TIRF medicine sponsors (innovator and generic), to
`inform them that, in order to minimize the burden on healthcare providers and patients, a
`
`Effective Date: 12/29/20112
`
`Reference ID: 3065316
`
`

`

`single-shared REMS should be implemented for the TIRF medicines (Meeting Minutes:
`memo dated 01/03/2011; Author: Adeolu, Abolade A).
`12 November 2010: REMS Notification letters were issued to all of the sponsors of the
`pending and approved TIRF products. The letters described the elements of the TIRF
`single-shared REMS that could be standardized and implemented for each TIRF product
`individualy, and ultimately across all TIRF medicines collectively, as a single-shared
`REMS.
`04 March 2011: Subsys (NDA 202788; Seq No. 000) submitted. The original
`submission included a proposed REMS similar to the approved individual REMS for
`Abstral.
`09 December 2011: Submission of the TIRF REMS SSS to the NDAs for Actiq, Fentora,
`Onsolis, Abstral, Lazanda, and to the ANDA for Fentanyl Citrate Oral Transmucosal
`Lozenge.
`28 December 2011: Approval of the TIRF REMS Single Shared System for the above
`TIRF medicines.
` 28 December 2011: Submission of SUBSYS REMS (NDA 202-788, Sequence
`028).
`
`2. MATERIALS REVIEWED
`2.1 Data and Information Sources reviewed
`Subsys Proposed REMS, submitted on December 28, 2011
`Subsys Prescribing Information, original submitted on 3/4/11, revision December
`28, 2011
`
`2.2 Data and Information Sources referenced
` DRISK Final REMS Review for the TIRF Products, Reviewer Toyserkani GA,
`dated December 27, 2011.
`3. RESULTS OF REVIEW OF PROPOSED SUBSYS RISK EVALUATION AND
`MITIGATION STRATEGY
`Insys submitted the proposed REMS for Subsys which is identical to the approved TIRF
`REMS SSS with the following exceptions:
` The Subys product name was added to the following documents:
`o All Letters (Dear Healthcare Provider, Inpatient and Outpatient Pharmacy,
`and Distributor)
`o Patient Prescriber Agreement
`o REMS Supporting Document
` Attachment 1 of the REMS (approved TIRF products) was also updated to include
`Subsys and is appended to the following documents:
`o All Overviews (Prescriber, Outpatient and Inpatient Pharmacy, Patient and
`Caregiver, Wholesaler)
`
`Effective Date: 12/29/20113
`
`Reference ID: 3065316
`
`

`

`o All Enrollment forms (Prescriber, Outpatient, Chain, and Inpatient
`Pharmacy, and Wholesaler/Distributor)
` Product specific information on Subsys was added to the Educational Program.
`Please refer to the December 27, 2011 Final REMS Review which describes the REMS
`document and REMS appended materials and provides DRISK’s concurrence with the
`single-shared REMS for the TIRF medicines.1
`4. DISCUSSION AND RECOMMENDATIONS
`The DRISK Review Team finds the proposed REMS for SUBSYS, as submitted
`December 28, 2011 (and appended to this review) to be acceptable, and recommends
`approval. Following approval of Subsys, each sponsor of an approved TIRF product in
`the SSS, will submit a proposed REMS modification which will be updated to include
`Subsys.
`
`
`
`
`
`1 Toyserkani G. Final REMS Review for Transmucosal Immediate-Release Fentanyl (TIRF) Products
`(NDAs 22-510, 20-747, 21-947, 22-569, 21-947, and 22-266), dated December 27, 2011.
`
`Effective Date: 12/29/20114
`
`Reference ID: 3065316
`
`109 Page(s) has been Withheld in Full as B4 (CCI/TS)
`immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DORIS A AUTH
`12/29/2011
`
`CLAUDIA B KARWOSKI
`12/30/2011
`concur
`
`Reference ID: 3065316
`
`