206976Orig1s000 - Food and Drug Administration...As part of the approval process for Licart...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

206976Orig1s000

OTHER REVIEW(S)

****Pre-decisional Agency Information****

Memorandum Date: November 28, 2018 To: Christina L. Fang, Clinical Reviewer Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Sandy Truong, Regulatory Project Manager, (DAAAP) Lisa Basham, Associate Director for Labeling, (DAAAP) From: L. Shenee Toombs, Regulatory Review Officer

Office of Prescription Drug Promotion (OPDP) CC: Sam Skariah, Team Leader, OPDP Subject: OPDP labeling comments for LicartTM (diclofenac epolamine) topical

system

NDA/BLA: NDA 206976

In response to DAAAP’s consult request dated July 16, 2018, OPDP has reviewed the proposed product labeling (PI), Medication Guide and carton and container labeling for the original NDA/BLA submission for Licart. PI and PPI/Medication Guide/IFU: OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DAAAP on November 20, 2018, and are provided below.

Carton and Container Labeling: OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on November 5, 2018, and we do not have any comments. Thank you for your consult. If you have any questions, please contact Sheneé Toombs at (301) 796-4174 or [email protected].

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion

Reference ID: 4355885Reference ID: 4369106

33 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page

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LATOYA S TOOMBS11/28/2018

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LABEL AND LABELING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: October 31, 2018

Requesting Office or Division: Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Application Type and Number: NDA 206976

Product Name and Strength: Licart (diclofenac epolamine) topical system, 1.3%

Product Type: Single Ingredient Product

Rx or OTC: Rx

Applicant/Sponsor Name: Institut Biochimique SA (IBSA)

FDA Received Date: June 25, 2018

OSE RCM #: 2018-1368

DMEPA Safety Evaluator: Valerie S. Wilson, PharmD

DMEPA Team Leader: Otto L. Townsend, PharmD


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1 REASON FOR REVIEWAs part of the approval process for Licart (diclofenac epolamine) topical system, 1.3%, the Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) requested that we review the proposed prescribing information, patient package insert, instructions for use, container label, and carton labeling for areas that may lead to medication errors.

2 REGULATORY HISTORY

On March 4, 2015, NDA 206976 was originally submitted utilizing the 505(b)(2) regulatory pathway. The reference listed drug is Flector (NDA 21234). A refuse-to-file letter was issued on April 29, 2015 due to multiple deficiencies that would not allow for a substantive review of the application.

On May 26, 2016, Institut Biochimique SA (IBSA) resubmitted NDA 206976. At that time, we reviewed the labels and labeling for NDA 206976 in OSE RCM 2016-1331.a

On March 24, 2017, NDA 206976 received a Complete Responseb from the Agency due to multiple clinical, non-clinical, and product quality deficiencies identified during the review process.

On June 25, 2018, IBSA resubmitted NDA 206976 as a Class II Resubmission to address the deficiencies outlined in the March 24, 2017 Complete Response Letter.

3 MATERIALS REVIEWED Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B

ISMP Newsletters C

FDA Adverse Event Reporting System (FAERS)* D

Other E (N/A)

Labels and Labeling F

N/A=not applicable for this review*We do not typically search FAERS for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

a Shah, M. Label and Labeling Review for diclofenac epolamine topical system (NDA 206976). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 JAN 13. RCM No.: 2016-1331.b Fields, E. Complete Response for diclofenac epolamine topical system 1.3%. Silver Spring (MD): FDA, CDER, OND, DAAAP (US); 2017 MAR 24. NDA 206976.


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4 FINDINGS AND RECOMMENDATIONS

To inform our review of Licart, we searched the FAERS database for the reference product, Flector. We identified cases describing cutting patches and accidental exposure of Flector patches to children. We determined the characteristics of the Licart topical system and proposed labeling reasonably mitigates these risks of medication error and we have no recommendations to address these risks. See Appendix D for details.

Tables 2 and 3 below include the identified medication error issues with the submitted prescribing information, container label, and carton labeling, DMEPA’s rationale for concern, and the proposed recommendation to minimize the risk for medication error.

Table 2: Identified Issues and Recommendations for Division of Antiviral Products

Prescribing Information

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION

Full Prescribing Information1. The strength statement

under the DOSAGE FORMS AND STRENGTHS section is not consistent with the strength statement in the HOW SUPPLIED/STORAGE AND HANDLING section.

The discrepancy between the two sections may cause confusion.

To avoid confusion and for consistency, consider revising the storage statement in the DOSAGE FORMS AND STRENGTHS section to read,

2. The Special Precautions subsection of the DOSAGE AND ADMINSTRATION section does not include instruction to avoid the use of certain skin care products on the skin where the patch is to be applied.

According to the applicant, use of moisturizing soap, lotion, astringent, or other skin care products limits patch adherence to the skin.

Consider including instruction under the Special Precautions subsection of the DOSAGE AND ADMINSTRATION section, stating, for example,


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Table 3: Identified Issues and Recommendations for Institut Biochimique SA (entire table to be conveyed to Applicant)

Container Labels (re-sealable envelope) and Carton Labeling

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION1. The strength is not

included on the container label or carton labeling.

The product strength is required on the container label and carton labeling in accordance with 21 CFR 201.10(d)(1).

To comply with 21 CFR 201.10 (d)(1), include the strength of the product on the principal display panel of the container label and carton labeling. For example, revise to read:

Licart (diclofenac epolamine) topical system

1.3%1. The statement

“Date first opening” appears on the outer carton for the product.

End users could misinterpret this statement on the outer carton to mean they are to indicate the date the outer carton is first opened.

To mitigate confusion, we recommend you remove the statement, “Date first opening,” from the outer carton but retain the statement on each individual envelope.

2. An area for the lot number and expiration date is not included on the container label and carton labeling.

The lot number and expiration date are required on the immediate container label and carton labeling in accordance with 21 CFR 201.10(i)(l) and 21 CFR 201.17, respectively.

To comply with 21 CFR 201.10(i)(l) and 21 CFR 201.17, ensure the lot and expiration date are included on the container label and carton labeling. Additionally, to minimize confusion and reduce the risk for deteriorated drug medication errors, identify the format you intend to use to express the expiration date. We recommend using a format like either:

YYYY-MMM-DD (e.g., 2013-JAN-31)

General Formatting Recommendations3. For consistency, we recommend replacing the dash symbol located in the storage

statement with the word “to”. For example, revise to, “Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].”


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4. The carton of 30 units and the container (envelope) of 5 units should have different NDC package numbers. We recommend you revise the last two digits of the NDC numbers so that the container label and carton labeling package numbers are different for these two packaging configurations.

5. Decrease the prominence of the statement “Rx Only” as this information appears more prominent than the established name on the principal display panel of the container label and carton labeling.

5 CONCLUSION

Our evaluation of the proposed prescribing information, container label, carton labeling, and Instructions for Use identified areas of vulnerability that may lead to medication errors. Above, we have provided recommendations in Table 2 for the Division and Table 3 for the Applicant. We ask that the Division convey Table 3 in its entirety to the applicant so that recommendations are implemented prior to approval of this NDA.


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APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 4 presents relevant product information for Licart that Institut Biochimique SA submitted on June 25, 2018, and the listed drug (LD). Table 4. Relevant Product Information for Listed Drug and Licart

Product Name Flector Patchc Licart

Initial Approval Date January 31, 2007 N/A

Active Ingredient Diclofenac epolamine Diclofenac epolamine

Indication Topical treatment of acute pain due to minor strains, sprains, and contusions.

Topical treatment of acute pain due to minor strains, sprains, and contusions.

Route of Administration Topical Topical

Dosage Form Topical Patch Topical system

Strength 1.3% 1.3%

Dose and Frequency One (1) patch twice a day One (1) once daily

How Supplied Re-sealable envelopes each containing 5 patches, with 6 envelopes per box

Re-sealable envelopes each containing 5 , with 6 envelopes per box

Storage Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled RoomTemperature].

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Once the envelope has been opened, LICART is stable up to 6 months, if stored at room temperature in the re-sealed envelope.

Container Closure Re-sealable envelopes in secondary carton

Re-sealable envelopes in secondary carton

c Flector Patch [Prescribing Information]. Drugs@FDA. U.S. Food and Drug Administration. 2018 SEP 07. Available from: https://www.accessdata.fda.gov/drugsatfda docs/label/2018/021234s015lbl.pdf.


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APPENDIX B. PREVIOUS DMEPA REVIEWSB.1 Methods

On September 6, 2018, we searched the L:drive and AIMS using the terms, Licart and NDA 206976, to identify reviews previously performed by DMEPA.

B.2 Results

Our search identified one previous reviewd, and we confirmed that our previous recommendations were implemented or considered.

d Shah, M. Label and Labeling Review for diclofenac epolamine topical system (NDA 206976). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 JAN 13. RCM No.: 2016-1331.


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APPENDIX C. ISMP NEWSLETTERSC.1 Methods

On August 22, 2018, we searched the Institute for Safe Medication Practices (ISMP) newsletters using the criteria below, and then individually reviewed each newsletter. We limited our analysis to newsletters that described medication errors or actions possibly associated with the label and labeling. Table 6. ISMP Newsletters Search Strategy

ISMP Newsletter(s) Acute Care, Community, and Nursing

Search Strategy and Terms Match Exact Word or Phrase: Flector

C.2 Results

Our search did not identify any articles relevant to this review.


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APPENDIX D. FDA ADVERSE EVENT REPORTING SYSTEM (FAERS)D.1 MethodsNDA 206976 was submitted under the 505(b)(2) regulatory pathway. Flector is the reference listed drug. The applicant proposes a similar label, labeling, and packaging for Licart that is currently used for Flector. On August 22, 2018, we searched FAERS using the criteria in the table below to identify any cases that describe errors possibly associated with the label, labeling, or packaging of Flector, which could be used to inform our review of Licart. Our search identified 127 cases. We used the NCC MERP Taxonomy of Medication Errors to code the type and factors contributing to the errors when sufficient information was provided by the reporter.e We excluded 105 cases because they described medication errors unrelated to Flector (n=13), product quality complaints: patch falling off (n=20), dry patch upon opening sealed envelope (n=5), fluid leaking out of patch (n=1), and foul smell (n=1); intentional use of expired patch(es) (n=19); intentional misuse of patch (n=15); patients not removing patch after 12 hours (n=9); patients using more than 1 patch at once (n=14); accidental exposure to caregiver while applying the patch (n=1); accidental self-exposure to mouth after removing patch (n=1); applying patch over open wound (n=1); labeled drug-drug interaction (n=2); missed dose (n=2); and insufficient details to determine a medication error occurred (n=1).

Table 7. Criteria Used to Search FAERS

Initial FDA Receive Dates: All reports up to August 22, 2018

Product Name: Flector

Product Active Ingredient (PAI): Diclofenac epolamine

Event: SMQ Medication errors (Narrow)

Country (Derived): USA

D.2 Results

Our search identified 22 cases relevant to this review as described below.

Users cut the patch (n=18)We received 18 reports describing patients cutting their patch (es) in half or into smaller pieces. Majority of the reports did not specify a root cause; however, the root cause for some reports described the cutting the patch under the direction of the provider. Only six reports described adverse events such as localized skin irritation (n=1), itching/edema at the site of application (n=1), increased liver enzymes (n=1), black stool (n=1), and lack of effect (n=2).

e The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Taxonomy of Medication Errors. Website http://www.nccmerp.org/pdf/taxo2001-07-31.pdf.


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Based on the limited information contained within these reports, it is unclear if the adverse events described in the reports are directly linked to users cutting the patch. Localized skin reactions at the site of treatment are known adverse events included in the Flector labeling. The labeling also includes warning and precaution to abnormal liver tests and systemic manifestations with the use of Flector. Therefore, the reported adverse events described in the 6 cases referenced above, may have occurred regardless to the users cutting the patch.

We reached out to our Office of Pharmaceutical Quality (OPQ) colleagues to help us determine if cutting the Licart topical system would present risk of serious harm. Our OPQ colleagues informed us that Licart is a matrix-based topical system, as opposed to a reservoir-based type system. Due to this characteristic, cutting the Licart matrix-based topical system is not likely to result in serious adverse events. Based on the collective information, we have little concern that cutting Licart would result in serious adverse events; therefore, we have no recommendations at this time.

Accidental Exposure in Children (n=4)

Three reports (FAERS Case # 7183022, 7098034, and 7556651) describe accidental exposure in children ranging from age 6 months to 2 years between 2009 and 2010. Two cases (FAERS Case# 7183022 and 7556651) describe a child chewing on the Flector patch for an unknown amount of time. FAERS Case# 7098034, describes a child removing a patch from her mother’s back and placing it on her own leg for an unknown amount of time.

One report from 2012 (FAERS Case # 8425150) did not indicate the age of the child involved. It was reported that the child placed Flector patch in his mouth and that immediately afterwards, the caregiver took the patch out of the child’s mouth.

One case (FAERS Case # 7183022) reported adverse events described as two episodes of diarrhea and one episode of vomiting, after which, symptoms were reported as resolved. No adverse events were reported in the other 3 cases.

Except for FAERS Case# 7098034, it was not reported how the child obtained the Flector patch, that is, it was not reported whether they removed the patch from the carton, resealable envelope, or if they gained access to a patch that had already been removed from the packaging. We note Flector Patch envelopes and carton labeling include the warning statements, “Envelope not child resistant. Keep used and unused patches out of the reach of children and pets.” Additionally, instructions are included stating to “throw away used patches where children and pets cannot get them.”

Licart will be supplied in a similar manner to Flector patch, that is 5 patches in resealable envelopes, in cartons containing 6 envelopes. Additionally, Licart envelopes and cartons will include the same warning statements and instructions as those described above. Given the limited information describing how the children in the above cases obtained the Flector Patch,


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we find the warning statements and instructions for Licart should be sufficient for mitigating accidental exposure to children. We have no additional recommendations at this time.

D.3 List of FAERS Case Numbers

Below is a list of the FAERS case number and manufacturer control numbers for the cases relevant for this review.

FAERS Case Number Manufacturer Control Number

12868883 US-PFIZER INC-2016484030

12623160 US-PFIZER INC-2016356407

14798326 US-PFIZER INC-2018167345

14446275 US-PFIZER INC-2018032528

13688094 US-PFIZER INC-2017270784

13471710 US-PFIZER INC-2017174326

8518959 US-PFIZER INC-2012094109

9049867 US-PFIZER INC-2013040996

12195882 US-PFIZER INC-2016155214

9632121 US-PFIZER INC-2013296500

14648468 US-PFIZER INC-2018104832

9732455 US-PFIZER INC-2013345643

8490802 US-PFIZER INC-2012080676

8234973 US-PFIZER INC-2011263734

741408214533969 US-PFIZER INC-2018058694

14141704 US-GLAXOSMITHKLINE-US2017GSK165326

14120670 US-PFIZER INC-2017449664

7183022 US-KINGPHARMUSA00001-K200901125



8425150 US-PFIZER INC-K201100913


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D.4 Description of FAERS

The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's postmarket safety surveillance program for drug and therapeutic biologic products. The informatic structure of the FAERS database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation. FDA’s Office of Surveillance and Epidemiology codes adverse events and medication errors to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Product names are coded using the FAERS Product Dictionary. More information about FAERS can be found at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm.


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APPENDIX F. LABELS AND LABELING F.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,f along with postmarket medication error data, we reviewed the following Licart labels and labeling submitted by Institut Biochimique SA on June 25, 2018.

Text embossed on Patch Carton labeling Container label Instructions for Use (on container label and carton labeling) Medication Guide (image not shown) Prescribing Information (Image not shown)

F.2 Label and Labeling Images

f Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.



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VALERIE S WILSON10/31/2018

OTTO L TOWNSEND10/31/2018

Signature Page 1 of 1


****Pre-decisional Agency Information****

Memorandum Date: January 22, 2018 To: Spiros Nicols, Regulatory Project Manager Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) From: L. Shenee Toombs, Regulatory Review Officer (OPDP) CC: Olga Salis, Senior Regulatory Health Project Manager (OPDP) Michael Wade, Regulatory Health Project Manager (OPDP) Subject: NDA 206976

OPDP labeling comments for Diclofenac Epolamine topical system 1.3% Labeling Review

OPDP acknowledges receipt of your June 9, 2016, consult request for the proposed Package Insert for Diclofenac Epolamine topical system 1.3%. Reference is made to the March 24, 2017, Compete Response (CR) letter. As a result, OPDP will provide comments regarding labeling for this application during a subsequent review cycle. OPDP requests that DAAAP submit a new consult request during the subsequent review cycle. Thank you for the opportunity to comment on these proposed materials. If you have any questions, please contact Shenee’ Toombs at (301) 796-4174 or [email protected].

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion


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LATOYA S TOOMBS01/22/2018


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Department of Health and Human Services Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy Initiatives Division of Medical Policy Programs

REVIEW DEFERRAL MEMORANDUM

Date: March 28, 2017 To:

Sharon Hertz, MD Director Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Through:

LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP)

From:

Morgan Walker, PharmD, MBA, CPH Patient Labeling Reviewer Division of Medical Policy Programs (DMPP)

Subject:

Review Deferred: Medication Guide (MG)

Drug Name (established name):

LICART (diclofenac epolamine) topical system 1.3%

Dosage Form and Route: Transdermal

Application Type/Number:

NDA 206976

Applicant:

Institut Biochimique SA (IBSA)


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1 INTRODUCTION On May 27, 2016, Institut Biochimique SA (IBSA) submitted for the Agency’s review a resubmission of New Drug Application (NDA) 206976 for LICART (diclofenac epolamine) topical system 1.3%. On April 29, 2015, the Applicant received a refuse-to-file (RTF) letter from the Agency identifying deficiencies that needed to be corrected before the application could be accepted. On June 9, 2016, the Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) requested that the Division of Medical Policy Programs (DMPP) review the Applicant’s proposed Medication Guide (MG) for LICART (diclofenac) topical system 1.3%.

This memorandum documents the DMPP review deferral of the Applicant’s proposed MG for LICART (diclofenac epolamine) topical system 1.3%.

2 CONCLUSIONS

Due to outstanding clinical, non-clinical, and product quality deficiencies, DAAAP has issued a Complete Response (CR) letter on March 24, 2017. Therefore, DMPP defers comment on the Applicant’s patient labeling at this time. A final review will be performed after the Applicant submits a complete response to the Complete Response (CR) letter. Please send us a new consult request at such time.

Please notify us if you have any questions.



MORGAN A WALKER03/28/2017

BARBARA A FULLER03/28/2017

LASHAWN M GRIFFITHS03/28/2017


Clinical Inspection Summary (CIS) NDA 206976 (Licart®)

Clinical Inspection Summary

Date March 9, 2017

From John Lee, M.D., Medical OfficerJanice Pohlman, M.D., M.P.H., Team LeaderKassa Ayalew, M.D., M.P.H., Branch ChiefGood Clinical Practice Assessment Branch (GCPAB)Division of Clinical Compliance Evaluation (DCCE)Office of Scientific Investigations (OSI)

To Spiros Nicols, Pharm.D., M.B.A., Regulatory Project ManagerChristina Fang, M.D., Medical OfficerEllen Fields, M.D., M.P.H., Deputy Division DirectorDivision of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Application NDA 206976

Applicant Institut Biochimique SA

Drug Diclofenac/ 1.3% (Licart®)

New Molecular Entity No

Review Priority Standard

Proposed Indication Acute pain due to minor strains, sprains, and contusions

Consultation Date September 26, 2016

CIS Goal Date March 9, 2017

Action Goal Date March 24, 2017

PDUFA Due Date March 26, 2017

I. OVERALL ASSESSMENT OF FINDINGSTwo (pivotal) studies for this NDA were audited on-site at good clinical practice (GCP) inspections of two foreign clinical investigator (CI) study sites: (1) Site 19 in Study 05DCz/FHp11, Jirí Neumann, M.D. (Dritec, Czech Republic); and (2) Site 01 in Study 06EU/FHp03, Jacek Kwarecki, M.D., Ph.D. (Warsaw, Poland).At both CI sites, a Form FDA 483 was issued for minor GCP regulatory deficiencies unlikely to be significant to impact data reliability or the rights, safety, or welfare of subjects. The data from both inspected CI sites appear reliable as reported in the NDA.


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CIS Page 2 NDA 206976 (Licart®)

II. BACKGROUNDInstitut Biochimique SA (IBSA) seeks United States (US) marketing approval of diclofenac patch with ( ), a new formulation of the currently approved diclofenac patch (Flector® Patch) modified for increased diclofenac bioavailability. Based on foreign studies (not conducted under IND), IBSA claims that this new formulation is substantially more effective than the original with the same safety profile. The sponsor proposes that is indicated for the “topical treatment of acute pain due to minor strains, sprains, and contusions.” Each study was audited at a GCP inspection of a CI site selected for large subject enrollment with few major protocol violations (two sites total).Study 05DCz/FHp11: A multicentre, prospective, double-blind, in parallel groups randomised, versus placebo and versus reference product controlled, confirmatory clinical trial of the efficacy and tolerance of Flector Tissugel Héparine in the treatment of mild-to-moderate contusionsThis double-blinded randomized controlled trial (DB-RCT) was conducted over 24 months (2006-2007) at 18 CI sites in Europe (nine each, Germany and Czech Republic) in 355 subjects with limb contusion. The primary study objective was to show that diclofenac hydroxyethylpyrrolidine (DHEP) with heparin (DHEP-Heparin) is more effective than DHEP plaster in reducing limb contusion pain.

Subjects were randomized in equal ratio to three arms (test/active/placebo) after screening and selection for: (1) outpatient adults of age 18-65 years, (2) unilateral mild-to-moderate muscle contusion of upper or lower limbs, (3) injury within 72 hours, (4) pain on standardized movement ≥ 50 mm on 100 mm Visual Analog Scale (VAS), (5) superficial hematoma ≤ 10 x 14 cm limited to the injury site, and (6) not requiring orthopedic/surgical intervention or physical therapy.

The study medication (medicated plaster) was applied to the injury site daily for 14 days, with three clinic visits at screening (Visit 1) and at 7 and 14 days (Visits 2 and 3).

The primary endpoint was defined as pain reduction at Day 3 in performing a specific movement (pre-defined and standardized as most painful) as self-scored by the subject, twice daily using VAS.

The major secondary endpoints included: (1) days to superficial hematoma disappearance, (2) rescue medication use, and (3) overall treatment efficacy as judged by the subject and the CI (five-point verbal scale).

Study 06EU/FHp03: A multicentre, prospective, double-blind, in parallel groups randomised, versus placebo and versus reference product controlled, confirmatory clinical trial of the efficacy and tolerance of Flector Tissugel Héparine in the treatment of ankle sprainsThis DB-RCT was conducted over 12 months (2007) at 13 CI sites in Europe (three Italy, four Poland, six Ukraine) in 430 subjects with an acute ankle sprain. The primary study objective was to show that DHEP-Heparin is more effective than DHEP in reducing pain on moving the sprained ankle.


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Subjects were randomized in equal ratio to three arms (test/active/placebo) after screening and selection for: (1) outpatient adults of age 18-65 years, (2) acute ankle inversion injury (external lateral ligaments) within 48 hours, (3) malleolar edema and pain on movement (≥ 50 mm VAS, Grade I/II O’Donoghue classification), (4) no prior treatment (other than ice application) and skin lesions over the injured area, and (5) not requiring physical therapy or surgical (including orthopedic) surgical intervention.

The study medication (medicated plaster) was applied to the injury site daily for 7 days, with 3 clinic visits at: screening (Visit 1) and at 3 and 7 days (Visits 2 and 3).

The primary endpoint was pain reduction at Day 3 in performing normal daily activities as self-scored by the subject (twice daily) using VAS.

The major secondary endpoints included: (1) pain at rest and on leaning on the injured ankle, (2) edema extension, (3) rescue medication use, and (4) overall treatment efficacy as judged by the subject and the CI (five-point verbal scale).

III. INSPECTION OUTCOMES

Clinical Investigator Site Study / SiteEnrollment

InspectionOutcome*

1

Jirí Neumann, M.D.

Sportklinik sroGolf & Spa Kunětická horaDříteč 155 533 05 Czech Republic

05DCz/FHp11Site 19

65 subjects

Jan 9 - 12,2017

VAI

2

Jacek Kwarecki, M.D., Ph.D.

Wojewódzki Szpital Chirurgii Urazowej śwAnny-Oddział Chirurgii Urazowo-Ortopedycznej ulBarska 16 20 02-315 Warszawa, Poland

06EU/FHp03Site 01

90 subjects

Jan 16 - 19,2017

VAI

Key to Compliance ClassificationNAI = no deviation from regulationsVAI = deviation(s) from regulationsOAI = significant deviations from regulations, data unreliable

*The Establishment Inspection Reports (EIRs) have not been received from the field office. The inspection outcomes shown are based on preliminary communications with the field investigators. An addendum to this Clinical Inspection Summary (CIS) may be forwarded to the review division if new significant findings are discovered at receipt and review of the final EIRs; otherwise, OSI’s written post-inspection correspondence to the CI (to be copied to review division) indicates EIR review completion with confirmation of the inspectional findings as reported in this CIS.



1. Jirí Neumann, M.D.Study 05DCz/FHp11, Site 19: 65 subjects were screened and enrolled, and all 65 completed the study. Case records were reviewed in detail for all subjects. A Form FDA 483 was issued for inadequate: (1) maintenance of subject case history files, (2) adherence to the study protocol, (3) study medication tracking, disposition, and accountability, and (4) informed consent.

9 subjects (14% of 65 enrolled): Subject case history files (subject diary/log book) contained the following recordkeeping deficiencies:o Correction without adequately noting why, when, and by whom (4 subjects, 6%)o Inconsistent plaster application and/or removal times (5 subjects, 8%)o Incomplete and/or inaccurate records for Visits 13, 14 and 15 (1 subject, 2%)o Adverse event (AE) and use of concomitant medication not recorded/reported until

noted by monitor (1 subject, 2%)

Subjects (10 subjects, 15%): Isolated or limited missing log book data, which consisted of: (1) plaster application and/or removal dates or times (most); and (2) subject responses to logbook questions about hematoma or other anticipated AEs (few)Comment: This deficiency observation involved recordkeeping by the subject (log book), over which the CI’s control was limited to subject training, log book review, and documentation of review findings (queries, corrections, clarifications, and audit trail). While the study was on-going, the CI apparently did not consider the outcome of log book review as recordable study data or reportable protocol deviations.

Subjects (6 subjects, 9%): After Day 3 of the 14-day treatment period, the study medication plaster was not consistently applied for at least 20 consecutive hours, yet these protocol deviations were not reported.Comment: The primary efficacy endpoint was evaluated at Day 3. This protocol deviation appeared unlikely to be significant.

2 subjects (3%): The signature dates on the informed consent document (ICD) were inconsistent, discrepant by one day (subject’s date versus CI’s date) or by nearly 3 months (subject’s date of apparent birth date versus CI’s date).

3 subjects (5%): Drug accountability records were inadequate to reconcile the disposition of 15 plasters (3 per subject), whether unreturned by the subject to the study site (as claimed by the CI) or unreturned from the study site to the sponsor.

Overall Comments for CI Site: The audited study was conducted 10 years ago. While the study was on-going, the CI apparently did not consider many of the deficiency observations as reportable protocol deviations or GCP deficiencies. At inspection, the CI acknowledged all observations as being inconsistent with GCP, and appeared confident that the cited observations are recordkeeping deficiencies without impact on the study outcome. An addendum to this CIS will be forwarded to the review division if significant findings are discovered in follow up of this inspection, currently on-going as of this CIS.


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The observed regulatory deficiencies appeared minor and unlikely to be significant to impact data reliability or the rights, safety, or welfare of subjects. All audited NDA data were adequately verifiable against source records and case report forms (CRFs). The data from this CI site appear reliable as reported in the NDA.

2. Jacek Kwarecki, M.D., Ph.D. (Elzbieta Kurmin-Gryz, M.D., current Medical Director)Study 06EU/FHp03, Site 01: 90 subjects were screened and enrolled, and 88 completed the study. Case records were reviewed in detail for all subjects. A Form FDA 483 was issued for inadequate: maintenance of subject case history files and informed consent.

4 subjects (4% of 90 enrolled): Case histories (subject log books) were incomplete or otherwise unclear about plaster application (dates and times), rescue medication use, adverse events, and/or pain assessment (potentially reportable protocol deviations).

3 subjects (3%): The following minor protocol deviations were reported to the sponsor, but apparently were not reported in the NDA (by sponsor).o Subject (active control): did not use 2 of the 8 intended plasters, achieved

adequate pain relief, and did not require rescue medication.o Subject (active control): used a second plaster on one day (first fell off), did

not achieve adequate pain relief, and required rescue medication on Days 2 and 3.o Subject (placebo): used a second plaster on one day (first fell off), achieved

adequate pain relief, and did not require rescue medication.

6 subjects (7%): The ICD did not plainly identify the study as a research study and lacked an adequate explanation of the research and its implications for the subject.

These deficiency observations appeared minor and unlikely to be significant to impact data reliability or the rights, safety, or welfare of subjects. Study conduct appeared GCP-compliant overall, including sponsor oversight of study conduct. All audited NDA data were adequately verifiable against source records and CRFs. The data from this CI site appear reliable as reported in the NDA.

{See appended electronic signature page}John Lee, M.D.Good Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}Janice K. Pohlman, M.D., M.P.H.Team LeaderGood Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations


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{See appended electronic signature page}Kassa Ayalew, M.D., M.P.H.Branch ChiefGood Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CC:DAAAP / Division Director / Sharon HertzDAAAP / Deputy Division Director / Ellen FieldsDAAAP / Medical Officer / Christina FangDAAAP / Regulatory Project Manager / Spiros NicolsOSI / Office Director / David BurrowOSI / DCCE / Division Director / Ni KhinOSI / DCCE / GCPAB / Branch Chief / Kassa AyalewOSI / DCCE / GCPAB / Team Leader / Janice PohlmanOSI / DCCE / GCPAB / Medical Officer / John LeeOSI / DCCE / GCPAB / Program Analyst / Yolanda PatagueOSI / Database Project Manager / Dana Walters



JONG HOON LEE03/08/2017

JANICE K POHLMAN03/09/2017

KASSA AYALEW03/09/2017


DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Division of Pediatric and Maternal HealthOffice of New Drugs

Center for Drug Evaluation and Research Food and Drug Administration

Silver Spring, MD 20993Tel 301-796-2200

FAX 301-796-9744

Division of Pediatric and Maternal Health Close-out Memorandum

Date: January 30, 2017 Date consulted: July 8, 2016

From: Christos Mastroyannis, M.D., Medical Officer, Maternal Health, Division of Pediatric and Maternal Health (DPMH)

Through: Tamara Johnson, MD, MS, Team Leader, Maternal HealthDivision of Pediatric and Maternal Health

To: Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Drug: Licart (diclofenac topical system1.3%

NDA: 206976

Applicant: IBSA Institut Biochimique SA (IBSA)

Subject: Pregnancy and Lactation Labeling

ProposedIndication: Licart is indicated for the topical treatment of acute pain due to minor

strains, sprains, and contusions

Consult Question:DAAAP requests DPMH assistance with pregnancy and lactation labeling for this NDA.

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INTRODUCTIONThe Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) consulted the Division of Pediatric and Maternal Health (DPMH) on July 8, 2016, to provide input for appropriate labeling of the pregnancy and lactation subsections of Licart (diclofenac epolamine, 1.3%/ labeling with conversion to Pregnancy and Lactation Labeling Rule (PLLR) format.

Licart is under premarket NDA review and was submitted as a 505(b)(2) application. The reference listed drug (RLD) is Flector (NDA 21,234) that was approved on January 31, 2007. NDA 206976 was initially submitted on March 4, 2015, and the Agency issued a refuse–to-file letter (RTF) identifying a number of deficiencies that needed to be corrected before the application could be accepted. IBSA addressed all of the issues enumerated in the RTF letter and resubmitted the application on May 26, 2016.

The proposed indication is “for the topical treatment of acute pain due to minor strains, sprains, and contusions” in adults only, which is the same indication as for the RLD.

REGULATORY STATUSHeparin is believed to control the release of the drug; therefore it is considered a critical attribute for the product’s performance. However, upon review of the applicant’s submission by the Agency’s drug product group, the assay for the excipient Heparin is not acceptable. The Division and the Agency’s drug product group considered that an extension of the review clock for 3 months is not enough time for the applicant to rectify the issue and develop a new method; therefore, they are recommending a Complete Response (CR).

CONCLUSIONSSince a CR is being recommended, DPMH will not provide a review on labeling recommendations at this time. During the labeling meeting of January 10, 2017, DPMH provided preliminary labeling recommendations; however, DPMH will provide a full review and final labeling recommendations in the next review cycle when the Complete Response is addressed by the applicant.


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CHRISTOS MASTROYANNIS01/31/2017

TAMARA N JOHNSON01/31/2017


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LABEL AND LABELING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: January 13, 2017

Requesting Office or Division: Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Application Type and Number: NDA 206976

Product Name and Strength: diclofenac epolamine topical system 1.3%

Product Type: Single ingredient

Rx or OTC: Rx

Applicant Name: IBSA Institut Biochimique SA

Submission Date: May 26, 2016

OSE RCM #: 2016-1331

DMEPA Primary Reviewer: Millie Shah, PharmD, BCPS

DMEPA Team Leader: Vicky Borders-Hemphill, PharmD


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1 REASON FOR REVIEW

IBSA Institut Biochimique SA submitted NDA 206976 for diclofenac epolamine topical system 1.3%. Thus, the Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) requested we review the labels, labeling, and packaging from a medication error perspective.

2 MATERIALS REVIEWED

We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed. Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B

Human Factors Study C-N/A

ISMP Newsletters D

FDA Adverse Event Reporting System (FAERS)* E-N/A

Information Request and Applicant’s Response F

Labels and Labeling G

N/A=not applicable for this review*We do not typically search FAERS for label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED

We performed a risk assessment of the proposed envelope labels, carton labeling, prescribing information (PI), and Instructions for Use (IFU) to identify deficiencies that may lead to medication errors and other areas for improvement.

IBSA Institut Biochimique SA submitted NDA 206976 for diclofenac epolamine topical system 1.3%. The proposed topical system is to the approved Flector (diclofenac epolamine topical patch) 1.3%, except for the presence of heparin in the proposed topical system, which is an inactive ingredient. Both products will co-exist on the market. The dosing frequency for the proposed topical system is once daily, whereas the dosing frequency for Flector is twice daily. The discard instructions for the proposed topical system are to discard unused topical systems 6 months after opening the envelope, whereas the instructions for Flector are to discard unused patches 3 months after opening the envelope.

Envelope Labels and Carton Labeling

Our review of the envelope labels and carton labeling of the proposed topical system determined that the size and organization of product information is displayed exactly the same


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as Flector; however, the colors for the labels and labeling of the proposed topical system are different, which allows differentiation between Flector and the proposed topical system.

We identified the labels and labeling present the established name as “(diclofenac epolamine 1.3% topical .”

ccording to OPQ, the approved dosage form is “topical system.” Therefore, in

concurrence with OPQ, we recommend all labels and labeling present the approved dosage form and provide this recommendation in Section 4.2 below.

. We found the proposed proprietary name

“Licart” acceptable in OSE# 2016-8610912a dated August 26, 2016.

. The

container labels and carton labeling present the proprietary name as “Licart ” The Applicant submitted the proposed proprietary name “Licart,” which we found acceptable.

a Schlick J. Proprietary Name Review for Licart (diclofenac epolamine) topical (NDA 206976). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016- AUG-26. 29p. OSE RCM No.: 2016-8610912.


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We note the Applicant submitted carton configurations for the proposed topical system, which includes 6 envelopes per carton with 5 topical systems per envelope

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thus we provide a recommendation to include this information for clarity in Section 4.2 below.

We note that the instructions to apply the proposed topical system are the same as Flector and the IFU for the proposed topical system is the same as Flector, except for the frequency of application and discard instructions, which differ between the systems. The frequency of administration and discard instructions are bolded. Thus, we do not have recommendations for the IFU.

Our review of the envelope label determined that the barcode is missing. We determined that Step 6 of the IFU states, “Discard unused 6 months after opening envelope.” However, there is not a space to write the date that the envelope was first opened. We recommend including the statement “Date of first opening ____/_____/____” the statement “Discard unused topical systemes 6 months after opening envelope” in order to alert users to write the complete date of opening on the envelope and minimize the risk for using expired topical systems. Thus, we provide these recommendations in Section 4.2 below.

Post-marketing Surveillance of Flector

Since the proposed topical system is similar to the approved Flector product, we reviewed the most recent Periodic Safety Report for Flector (reporting period 01Feb2015-31Jan2016) to inform our review. We found reports of adhesion issues, which align with findings from our weekly review of medication error cases submitted to FAERS. The Applicant proposes to change the PI to include the compulsory use of (1) a sleeve for topical systems used on articulating surfaces, and (2) non-allergenic tape for topical systems located on other parts of the body. We discussed our concerns of adhesion with OPQ. OPQ is requesting that the Applicant complete an appropriately powered and designed adhesion study. We will provide recommendations at a later date in response to the adhesion study findings and use of sleeves or non-allergenic tape from a medication error perspective.


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4 CONCLUSION & RECOMMENDATIONS

We identified areas for improvement in the carton labeling, envelope label, and prescribing information to increase clarity of important information to promote safe use of this product.

4.1 RECOMMENDATIONS FOR THE DIVISION

We have revised the Dosage and Administration and How Supplied sections of the Full Prescribing Information (See Appendix G) and have provided a detailed summary below for review and consideration by DAAAP.

A. Full Prescribing Information1.

2.

3. The Applicant submitted the proposed proprietary name “Licart,” which we found acceptable in OSE#2016-8610912.d

4. In concurrence with OPQ, change the dosage form to “topical system.”

B. General1. We discussed our concerns of adhesion with OPQ. OPQ is requesting that the

Applicant complete an appropriately powered and designed adhesion study. DMEPA would like to be consulted to provide recommendations in response to the adhesion study findings and use of sleeves or non-allergenic tape from a medication error perspective.

4.2 RECOMMENDATIONS FOR IBSA INSTITUT BIOCHIMIQUE SA

We recommend the Applicant implement the following prior to approval of this NDA:

A. Carton Labeling

d Schlick J. Proprietary Name Review for Licart (diclofenac epolamine) topical (NDA 206976). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016- AUG-26. 29p. OSE RCM No.: 2016-8610912.


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1.

2.

3. In concurrence with OPQ, change the dosage form to “topical system.”

4. We previously reviewed the proposed proprietary name “Licart” and determined it was acceptable in OSE#2016-8610912f dated August 26, 2016.

5. In order to minimize the risk for product selection errors between the currently marketed product Flector and the proposed product, increase the prominence of the frequency statement on the principal display panel. We recommend

Change once daily.” In order to increase the prominence of this statement, relocate it above the Rx Only statement, increase the font size, and consider placing it in a box.

B. Envelope Label1. See A.1, A.2, and A.5.2. The drug barcode is often used as an additional verification before drug

administration in the inpatient setting; therefore it is an important safety feature that should be part of the label whenever possible. Therefore, we request you add the product barcode to each individual envelope label as required per 21CFR 201.25(c)(2).

3. We recommend including the statement “Date of first opening ____/_____/____” the statement “Discard unused topical systems 6 months after opening

envelope.” Use bold font for this statement. Adding this statement will alert users to write the complete date that the envelope was opened on the envelope label and minimize the risk for using expired topical systems.

C.

D.

f Schlick J. Proprietary Name Review for Licart (diclofenac epolamine) topical (NDA 206976). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016- AUG-26. 29p. OSE RCM No.: 2016-8610912.


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APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED

APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 2 presents relevant product information for diclofenac epolamine topical system that IBSA Institut Biochimique SA submitted on May 26, 2016.

Table 2. Relevant Product Information for diclofenac epolamine topical system

Initial Approval Date N/A

Active Ingredient Diclofenac epolamine

Indication topical treatment of acute pain due to minor strains, sprains, and contusions

Route of Administration topical

Dosage Form Topical system

Strength 1.3%

Dose and Frequency 1 topical system to the most painful area once a day

How Supplied/ Container Closure

supplied in re-sealable envelopes, each containing 5 Systems (10 cm × 14 cm), with 6 envelopes per box

Storage Store at excursions permitted to 15º-30ºC (59º-86ºF) [see USP Controlled Room Temperature]. Once the envelope has been opened, the system is stable up to 6 months, if stored at room temperature in the re-sealed envelope.

APPENDIX B. PREVIOUS DMEPA REVIEWSB.1 Methods

On October 18, 2016, we searched the L:drive and AIMS using the term, “206976” (NDA associated with this application) to identify reviews previously performed by DMEPA.

B.2 Results

Our search did not identify any reviews relevant to our current review.

APPENDIX C. N/A

APPENDIX D. ISMP NEWSLETTERSD.1 Methods

On November 4, 2016, we searched the Institute for Safe Medication Practices (ISMP) newsletters using the criteria below, and then individually reviewed each newsletter. We


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limited our analysis to newsletters that described medication errors or actions possibly associated with the label and labeling.

Table 3. ISMP Newsletters Search Strategy

ISMP Newsletter(s) Acute Care, Community/Ambulatory Care, Nursing

Search Strategy and Terms Match Exact Word or Phrase: Flector

D.2 Results

Our search did not result in any newsletters.

APPENDIX E. N/A

APPENDIX F. DMEPA’S INFORMATION REQUEST AND APPLICANT’S RESPONSE F.1 Methods

On November 1, 2016, we sent the following information request:

The Applicant provided container labels and carton labeling for to the 6 envelopes that contain 5 per envelope carton configuration. The How

Supplied section of the proposed PI only states a carton configuration with 6 envelopes that contain 5 patches per envelope. Clarify this discrepancy.

F.2 Results

On November 1, 2016, the Applicant provided the following response:

The commercial configuration (for prescription/sale) is five patches in one envelope,


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APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,g along with postmarket medication error data, we reviewed the following diclofenac epolamine topical system labels and labeling submitted by IBSA Institut Biochimique SA submitted on October 28, 2016.

Container label Carton labeling Full Prescribing Information

G.2 Label and Labeling Images

g Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.



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MILLIE C BRAHMBHATT01/13/2017

BRENDA V BORDERS-HEMPHILL01/13/2017


NDA #: 206,976 Division of Pediatric and Maternal Health ConsultLicart (diclofenac epolamine, 1.3% Topical January 2017

BackgroundLicart (diclofenac epolamine, 1.3%/ is under premarket NDA review and was submitted as a 505(b)(2) application; the reference listed drug (RLD) is Flector (NDA 21,234); approved on January 31, 2007. The proposed indication is “for the topical treatment of acute pain due to minor strains, sprains, and contusions” in adults only, which is the same indication as for the RLD.

At the time of the pre-NDA meeting FDA concluded that pediatric studies under the Pediatric Research Equity Act (PREA) would not be required because the sponsor stated that there would be no new active ingredient, indication, dosage form, dosing regimen, or route of administration [letter to sponsor March 19, 2015, and Pediatric Review Committee (PeRC) minutes February 4, 2015]. The sponsor was informed that per the information on hand at that time, PREA would not apply; however the advice letter indicated that such determination and advice could change if new information were provided which might necessitate studies under PREA.

On receipt of the complete NDA package and proposed labeling, FDA determined that the candidate drug would be labeled for once daily dosing (QD) whereas the RLD is labeled for twice daily dosing (BID). Upon recognition of the newly proposed dosing regimen, DAAAP and DPMH agreed that studies under PREA might be required and that a pediatric plan should be submitted for review.

The sponsor submitted a pediatric plan to IND 111,538 (received, September 5, 2016) which is identical to the plan submitted to NDA 206,976.

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NDA #: 206,976 Division of Pediatric and Maternal Health ConsultLicart (diclofenac epolamine, 1.3% Topical January 2017

Timeline of the Pediatric Development Plan“Following approval of NDA 206976 IBSA will work with DAAAP to define the timeline for study-related milestones.”

DPMH recommended response: There is no need to delay discussion of proposed timelines for your pediatric study(s) until after approval of your NDA. Please propose a revised timeline for your pediatric development plan.

Conclusion and RecommendationsThe above labeling and iPSP recommendation were forwarded to DAAAP on November 10, 2016. In summary the use of the term in labeling should be replaced with ‘pediatric patients’, the sponsor should include a comprehensive description of the extrapolation plan for the iPSP, and the iPSP should include a revised timeline for pediatric studies, and the sponsor should submit pediatric protocol(s) and statistical plan(s) for the proposed study(s). DAAAP and Clinical Pharmacology should determine if PK sampling should be included in the pediatric study.

The reader is directed to final negotiated labeling (pending) and the agreed upon iPSP (pending) for additional details and the reader is reminded the DPMH and PeRC recommendations may differ.

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ETHAN D HAUSMAN01/10/2017

HARI C SACHS01/10/2017I agree with these recommendations.

JOHN J ALEXANDER01/10/2017


206976Orig1s000 - Food and Drug Administration...As part of the approval process for Licart...

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