DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993

NDA 207981
NDA APPROVAL
Taiho Oncology, Inc.
Attention: Lisa Cooper, Ph.D., RAC
Associate Director, Regulatory Affairs
202 Carnegie Center, Suite, 100
Princeton, NJ 08540
Dear Dr. Cooper:
Please refer to your New Drug Application (NDA) dated December 19, 2014, received
December 19, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
Act (FDCA) for Lonsurf (trifluridine and tipiracil), tablets, 15 mg and 20 mg.
We acknowledge receipt of your amendments dated January 5, January 6, January 16,
January 26, February 3, February 12, February 13, February 18, February 19, February 27,
March 3, March 6 (2), March 9, March 13, March 16, March 19, April 17, May 12, May 20,
May 28 (2), June 3 (2), June 5, June 9, June 17, July 13, July 24, August 31, September 8,
September 11, and September 15, 2015.
This new drug application provides for the use of Lonsurf (trifluridine and tipiracil), tablets for
the treatment of patients with metastatic colorectal cancer who have been previously treated with
fluoropyrimidine-oxaliplatin-and irinotecan-based chemotherapy, an anti-VEGF biological
therapy, and if RAS wild-type, an anti-EGFR therapy.
APPROVAL & LABELING
We have completed our review of this application, as amended. It is approved, effective on the
date of this letter, for use as recommended in the enclosed agreed-upon labeling text.

Reference ID: 3823053

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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 (package insert and patient package insert).
Information on submitting SPL files using eLIST may be found in the guidance for industry SPL
Standard for Content of Labeling Technical Qs and As, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM072392.pdf.
The SPL will be accessible via publicly available labeling repositories.
CARTON AND IMMEDIATE CONTAINER LABELS
Submit final printed carton and immediate container labels that are identical to the 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 207981.” Approval of this
submission by FDA is not required before the labeling is used.
Marketing the product(s) with FPL that is not identical to the approved labeling text may render
the product misbranded and an unapproved new drug.
ADVISORY COMMITTEE
Your application for Lonsurf was not referred to an FDA advisory committee because the safety
profile is acceptable for the treatment of patients with unresectable advanced or recurrent
colorectal cancer. The application did not raise significant public health questions on the role of
Lonsurf for this indication and outside expertise was not necessary as there were no controversial
issues that would benefit from an advisory committee discussion.
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.

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We are waiving the pediatric studies requirement for this application because pediatric studies
are impossible or highly impractical as colorectal cancer because the number of pediatric patients
with colorectal cancer is so small.
POSTMARKETING REQUIREMENTS UNDER 505(o)
Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
require holders of approved drug and biological product applications to conduct postmarketing
studies and clinical trials for certain purposes, if FDA makes certain findings required by the
statute.
We have determined that an analysis of spontaneous postmarketing adverse events reported
under subsection 505(k)(1) of the FDCA will not be sufficient to assess signals of a serious risk
of impaired hepatic and renal function on the pharmacokinetics of Lonsurf (trifluridine and
tipiracil) resulting in excessive toxicity to include myelosuppression.
Furthermore, the new pharmacovigilance system that FDA is required to establish under section
505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
study) will be sufficient to assess signals of a serious risk of impaired hepatic and renal function
on the pharmacokinetics of Lonsurf (trifluridine and tipiracil) resulting in excessive toxicity to
include myelosuppression.
Therefore, based on appropriate scientific data, FDA has determined that you are required to
conduct the following:
2963-1 

Complete the ongoing clinical pharmacokinetic trial to determine an appropriate
dose of Lonsurf (trifluridine and tipiracil) in patients with moderate to severe
hepatic impairment in accordance with the FDA Guidance for Industry entitled
“Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design,
Data Analysis, and Impact on Dosing and Labeling.”

The timetable you submitted on August 31, 2015, states that you will conduct this study
according to the following schedule:
Trial Completion:
Final Report Submission:
2963-2 

Reference ID: 3823053

September 2017
December 2017

Complete the ongoing clinical pharmacokinetic trial to determine an appropriate
dose of Lonsurf (trifluridine and tipiracil) in patients with severe renal impairment
in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in
Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact
on Dosing and Labeling.”

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The timetable you submitted on August 31, 2015, states that you will conduct this study
according to the following schedule:
Trial Completion:
Final Report Submission:

September 2017
December 2017

Submit all final report(s) to your NDA. Prominently identify the submission with the following
wording in bold capital letters at the top of the first page of the submission, as appropriate:
“Required Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report
Under 505(o),” “Required Postmarketing Correspondence Under 505(o).”
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
study or clinical trial required under this section. This section also requires you to periodically
report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
report annually on the status of any postmarketing commitments or required studies or clinical
trials.
FDA will consider the submission of your annual report under section 506B and 21
CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
include a report on the status of any study or clinical trial otherwise undertaken to investigate a
safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
result in enforcement action.
PROMOTIONAL MATERIALS
You may request advisory comments on proposed introductory advertising and promotional
labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
proposed materials in draft or mock-up form with annotated references, and the package insert,
Medication Guide, and patient PI (as applicable) to:

OPDP Regulatory Project Manager

Food and Drug Administration 

Center for Drug Evaluation and Research

Office of Prescription Drug Promotion

5901-B Ammendale Road

Beltsville, MD 20705-1266

Alternatively, you may submit a request for advisory comments electronically in eCTD format.
For more information about submitting promotional materials in eCTD format, see the draft
Guidance for Industry (available at:

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM443702.pdf ).
As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
2253. 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.
REPORTING REQUIREMENTS
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
MEDWATCH-TO-MANUFACTURER PROGRAM
The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
event reports that are received directly by the FDA. New molecular entities and important new
biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
copies of reports for this product. To participate in the program, please see the enrollment
instructions and program description details at
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
POST APPROVAL FEEDBACK MEETING
New molecular entities and new biologics qualify for a post approval feedback meeting. Such
meetings are used to discuss the quality of the application and to evaluate the communication
process during drug development and marketing application review. The purpose is to learn
from successful aspects of the review process and to identify areas that could benefit from
improvement. If you would like to have such a meeting with us, call the Regulatory Project
Manager for this application.
PDUFA V APPLICANT INTERVIEW
FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
and final assessment of the Program for Enhanced Review Transparency and Communication for
NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
Letter states that these assessments will include interviews with applicants following FDA action
on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
complete responses, and withdrawals after filing. The purpose of the interview is to better
understand applicant experiences with the Program and its ability to improve transparency and
communication during FDA review.

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ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
the interview process. Your responses during the interview will be confidential with respect to
the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
identifying information to anyone outside their project team. They will report only anonymized
results and findings in the interim and final assessments. Members of the FDA review team will
be interviewed by ERG separately. While your participation in the interview is voluntary, your
feedback will be helpful to these assessments.
If you have any questions, call Gina Davis, Senior Regulatory Health Project Manager at (301)
796-0704.
Sincerely,
{See appended electronic signature page}
Richard Pazdur, M.D.
Director
Office of Hematology and Oncology Products
Center for Drugs Evaluation and Research

Enclosure(s):
Content of Labeling
Carton and Container Labeling

Reference ID: 3823053

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------RICHARD PAZDUR
09/22/2015

Reference ID: 3823053