`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 022341
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`
`
` NDA APPROVAL
`
`
`
`
`Novo Nordisk Inc.
`Attention: Mary Ann McElligott, Ph.D.
`Associate Vice President, Regulatory Affairs
`100 College Road West
`Princeton, NJ 08540
`
`
`Dear Dr. McElligott:
`
`Please refer to your March 23, 2008, new drug application (NDA) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Victoza (liraglutide [rDNA
`origin]) injection, solution for subcutaneous use.
`
`We acknowledge receipt of your submissions dated May 23, June 18, July 8 and 11, August 14
`and 25, September 17 and 23, October 3, 7, and 14, November 6 and 14, and December 17, 19,
`23 (2), and 24, 2008, January 14, 16, and 21, February 11, 13 (2), 20, 25, and 26, March 27 and
`30, April 17 and 22, May 8, 18, 22, and 28, June 22 and 25, July 8, 17, 20, and 29, August 5, 6,
`11, 12, 25, 27, and 28, September 2, 4 (2), 11, 16, 17, 22, 23, 25, 29, and 30, October 5, 7, 8, 13,
`21, and 26, November 3, 11, 16, 23 (2), and 25, and December 1, 3, 4 (2),10, 21, 22 (2), and 28,
`2009, and January 4, 7, 11, 21, and 22, 2010.
`
`This new drug application provides for the use of Victoza (liraglutide [rDNA origin]) injection),
`solution for subcutaneous use, as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus.
`
`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.
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. The
`
`content of labeling must be identical to the submitted labeling (package insert submitted January
`22, 2010, and Medication Guide submitted January 21, 2010). The content of labeling should be
`
`
`provided by submitting a link to your SPL file submitted to the drug establishment registration
`and labeling system. The drug establishment and labeling system will transmit the labeling to
`the National Library of Medicine for public dissemination. For administrative purposes, please
`designate this submission, “SPL for approved NDA 022341.”
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`NDA 022341
`Page 2
`
`
`
`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 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 titled Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
`Product Applications and Related Submissions Using the eCTD Specifications. 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 022341.” 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 indications in pediatric patients unless this requirement is waived,
`
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for ages 0 to 9 years (inclusive) because the
`necessary studies are impossible or highly impractical. This is because there are too few children
`in this age range with type 2 diabetes mellitus to study.
`
`We are deferring submission of your pediatric studies for ages 10 to 16 years (inclusive) until
`May 17, 2013, because this product is ready for approval for use in adults and the pediatric
`studies have not been completed.
`
`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
`postmarketing studies. The status of these postmarketing studies must be reported annually
`according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are
`listed below.
`
`
`
`1583-1: A phase 1 pharmacokinetic pediatric study to determine doses for the
`subsequent phase 3b study that will be conducted under PREA to evaluate the efficacy
`and safety of liraglutide for the treatment of type 2 diabetes mellitus in pediatric patients
`
`ages 10 to 16 years 11 months.
`
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`NDA 022341
`Page 3
`
`
`
`The timetable you submitted on January 7, 2010, states that you will submit this
`study report according to the following schedule:
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`
`
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`Study Completion Date:
`Final Report Submission:
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` June 30, 2010
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`October 31, 2010
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`
`1583-2: A randomized and controlled pediatric study under PREA to evaluate the
`efficacy and safety of liraglutide for the treatment of type 2 diabetes mellitus in pediatric
`patients ages 10 to 16 years 11 months.
`
`This study must not be initiated until at least 1 month after you have submitted the
`complete study report for your postmarketing requirement 1583-5 (13-week mouse study
`to determine if liraglutide-induced focal C-cell hyperplasia depends on a thyroid GLP-1
`receptor and rearranged-during-transfection [RET] proto-oncogene activation).
`
`The timetable you submitted on January 7, 2010, states that you will submit this
`study report according to the following schedule:
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`
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`
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`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
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`July 31, 2012
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`November 30, 2015
`
`March 30, 2016
`
`
`Submit all final study reports to NDA 022341. Use the following designator to prominently
`label all submissions:
`
`
`
`
`Required Pediatric Assessment
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`
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`
`Section 505(o) of the 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 (section 505(o)(3)(A)).
`
`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 the signal of a serious
`risk of medullary thyroid carcinoma, a signal of a serious risk of cardiovascular events, and the
`signal of a serious risk of acute pancreatitis, including necrotizing pancreatitis.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`NDA 022341
`Page 4
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`
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`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
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`
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`July 31, 2010
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`January 31, 2013
`
`July 31, 2013
`
`1583-3: A 2-year study in mice to determine if 26 weeks of liraglutide treatment
`increases the lifetime risk of thyroid C-cell tumors. The study must include a 26-
`week interim sacrifice group to determine the incidence of focal C-cell hyperplasia
`and tumors at the end of the treatment period.
`
`The timetable you submitted on January 7, 2010, states that you will submit this
`study report according to the following schedule:
`
`
`
`
`
`1583-4: A 3-month study of the effects of liraglutide on the exocrine pancreas in a
`rodent model of insulin-resistant type 2 diabetes mellitus. This study must include
`monitoring biomarkers for pancreatitis (amylase, lipase) and glucose-lowering
`efficacy (HbA1c) during the treatment period and a thorough assessment of
`macroscopic and microscopic pathology of the pancreas including pancreatic
`exocrine cell and ductal cell proliferation/metaplasia. Reversibility of any effects on
`the pancreas must also be determined.
`
`The timetable you submitted on January 14, 2010, states that you will conduct this
`study according to the following schedule:
`
`July 31, 2010
`
`May 30, 2011
`
`July 31, 2011
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`
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`
`
`
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`
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`
`
`1583-5: A 13-week mouse study to determine if liraglutide-induced focal C-cell
`hyperplasia depends on a thyroid glucagon-like peptide-1 (GLP-1) receptor and
`rearranged-during-transfection (RET) proto-oncogene activation. Autoradiographic
`ligand binding in thyroid tissue sections can be used to determine GLP-1 receptor
`localization in mice with and without focal C-cell hyperplasia. RET activation and
`downstream signaling must be assessed in normal C-cells and focal hyperplastic C-
`cells from mouse thyroid tissue sections.
`
`The timetable you submitted on January 14, 2010 states that you will conduct this
`study according to the following schedule:
`
`
`
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`
`
`
`
`
`
`
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`July 31, 2010
`
`May 30, 2011
`
`July 31, 2011
`
`
`1583-6: A five-year prospective epidemiological study using a large healthcare
`claims database to determine the incidence of thyroid cancer among patients with
`type 2 diabetes exposed to Victoza (liraglutide [rDNA origin]) Injection and patients
`with type 2 diabetes not exposed to Victoza (liraglutide [rDNA origin]) Injection, as
`
`
`
`
`
`
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`NDA 022341
`Page 5
`
`
`
`well as the incidence of serious hypoglycemia, pancreatitis, hypersensitivity, and
`overall malignant neoplasms.
`
`The timetable you submitted on January 7, 2010 states that you will conduct this
`study according to the following schedule:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`
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`
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`April 30, 2010
`
`July 31, 2015
`
`January 31, 2016
`
`
`
`1583-7: A medullary thyroid carcinoma case series registry of at least 15 years
`duration to systematically monitor the annual incidence of medullary thyroid
`carcinoma in the United States and to identify any increase related to the introduction
`of Victoza (liraglutide [rDNA origin]) Injection into the marketplace. This study
`will also establish a registry of incident cases of medullary thyroid carcinoma and
`characterize their medical histories related to diabetes and use of Victoza (liraglutide
`[rDNA origin]) Injection.
`
`The timetable you submitted on January 7, 2010 states that you will conduct this
`study according to the following schedule:
`
`
`
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`
`
`
`
`
`
`
`
`July 31, 2010
`September 15, 2025
`
`September 15, 2026
`
`
`1583-8: Submission of the complete final study report for Study 1797, a head-to-
`head efficacy and safety comparison of Victoza (liraglutide [rDNA origin]) Injection
`and exenatide.
`
`The timetable you submitted on January 7, 2010 states that you will submit this trial
`report according to the following schedule:
`
`
`
`Final Report Submission:
`
`
`
`
`
`February 26, 2010
`
`
`Finally, there have been signals of a serious risk of cardiovascular events with some medications
`developed for the treatment of type 2 diabetes mellitus, and available data have not definitively
`excluded the potential for this serious risk with Victoza (liraglutide [rDNA origin]) Injection.
`We have determined that only a clinical trial (rather than a nonclinical or observational study)
`will be sufficient to assess a signal of a serious risk of cardiovascular events with antidiabetic
`medications, including Victoza (liraglutide [rDNA origin]) injection. Therefore, based on
`appropriate scientific data, FDA has determined that you are required to conduct the following:
`
`1583-9: A randomized, double-blind, controlled trial evaluating the effect of Victoza
`(liraglutide [rDNA origin]) injection on the incidence of major adverse
`cardiovascular events in patients with type 2 diabetes mellitus. This trial must also
`assess adverse events of interest including the long-term effects of Victoza
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`NDA 022341
`Page 6
`
`
`
`(liraglutide [rDNA origin]) injection on potential biomarkers of medullary thyroid
`carcinoma (e.g., serum calcitonin) as well as the long-term effects of Victoza
`(liraglutide [rDNA origin]) injection on pancreatitis, renal safety, serious
`hypoglycemia, immunological reactions, and neoplasms.
`
`The timetable you submitted on January 7, 2010 states that you will conduct this
`trial according to the following timetable:
`
`
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`
`
`
`
`March 14, 2010
`
`
`September 14, 2015
`
`
`April 30, 2016
`
`
`
`
`Submit the protocols to your IND, with a cross-reference letter to NDA 022341. Submit all final
`reports to NDA 022341. 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.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the 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)).
`
`Your proposed REMS, submitted on January 21, 2010, and appended to this letter, is approved.
`The REMS consists of a Medication Guide, a communication plan, and a timetable for
`submission of assessments of the REMS.
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`NDA 022341
`Page 7
`
`
` The REMS assessment plan should include, but is not limited to, the following:
`
`
`
`
`
`A. Evaluation of patients’ understanding of the serious risks of Victoza (liraglutide [rDNA
`
`origin])
`
`
`
`B. Evaluation of healthcare providers’ understanding of the serious risks of Victoza
`(liraglutide [rDNA origin])
`
`
`
`C. An assessment of healthcare providers’ awareness of:
`
`
`
`a. appropriate patient population characteristics, and
`
`
`b. the potential risk for medullary thyroid carcinoma
`
`c. the need for prompt evaluation of patients who develop symptoms suggestive of
`pancreatitis
`
`
`
`D. Evaluation of healthcare providers’ identification and treatment of:
`
`
`
`a. medullary thyroid carcinoma after initiation of Victoza (liraglutide [rDNA
`
`origin])
`
`b. acute pancreatitis after initiation of Victoza (liraglutide [rDNA origin])
`
`
`E. Evaluation of the extent to which the elements of the REMS are meeting the goals of the
`REMS and whether modifications to the elements or goals are needed
`
`
`
`F. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24
`
`
`
`G. A report on failures to adhere to distribution and dispensing requirements, and corrective
`actions taken to address noncompliance
`
`
`
`H. An assessment of the number of Victoza (liraglutide [rDNA origin]) prescribers
`identified to receive the Dear Health Care Provider (DHCP) Letter and the number of
`DHCP letters mailed
`
`
`
`I. An assessment of the percentage of targeted physicians who are presented with the
`Highlighted Information for Prescribers via Sales Specialists, the website, or medical
`information department
`
`
`Assessments of an approved REMS must include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. You can satisfy these requirements in your
`REMS assessments by referring to relevant information included in the most recent annual report
`required under section 506B and 21 CFR 314.81(b)(2)(vii) and including any updates to the
`status information since the annual report was prepared. Failure to comply with the REMS
`assessments provisions in 505-1(g) could result in enforcement action.
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`NDA 022341
`Page 8
`
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in Section 505-1(g)(2)(A) of FDCA.
`
`Prominently identify submissions containing REMS assessments or proposed modifications with
`the following wording in bold capital letters at the top of the first page of the submission:
`
`
`NDA 022341 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 022341
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE) FOR NDA 022341
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`
`If you do not submit electronically, please send five copies of REMS-related submissions.
`
`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
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`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. For instructions on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications, see
`
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you issue a letter communicating important safety-related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`
`the letter to both this NDA and to the following address:
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`NDA 022341
`Page 9
`
`
`
`MedWatch
`
`Food and Drug Administration
`
`Suite 12B-05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`We request that for a period of two years, you submit all cases of pancreatitis as 15-day alert
`reports and that you provide analyses of clinical trial and post-marketing reports of pancreatitis
`as adverse events of special interest in your periodic safety update reports.
`
`All 15-day alert reports, periodic (including quarterly) adverse drug experience reports, field
`alerts, annual reports, supplements, and other submissions should be addressed to NDA 022341.
`
`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-ACTION FEEDBACK MEETING
`
`New molecular entities and important new biologics qualify for a post-action feedback meeting.
`Such meetings are used to discuss the quality of the application and to evaluate the
`communication process throughout drug development and marketing application review. The
`purpose is to learn from successful aspects of the process and to identify areas that could benefit
`from improvement. If you would like to have such a meeting with us, contact the Division of
`Metabolism and Endocrinology Products.
`
`
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`NDA 022341
`Page 10
`
`
`If you have any questions, call John Bishai, Ph.D., Regulatory Project Manager, at
`(301) 796-1311.
`
`
`
`
`
`Enclosures:
` Package Insert
` Medication Guide
` Pen Carton Labels (1 variable dose pen (0.6-1.2-1.8 mcg), 2 variable dose pens (0.6-1.2-1.8
`mcg), 3 variable dose pens (0.6-1.2-1.8 mcg)), Pen Container Labels (1 variable dose pen
`(0.6-1.2-1.8 mcg), 2 variable dose pens (0.6-1.2-1.8 mcg), 3 variable dose pens (0.6-1.2-1.8
`mcg))
`Patient Instructions for Use
`
` REMS and REMS-related documents
`
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Curtis J. Rosebraugh, M.D., M.P.H.
`Director
`
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00010
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22341
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`NOVO NORDISK
`INC
`
`------------------------------------------
`VICTOZA (LIRAGLUTIDE)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CURTIS J ROSEBRAUGH
`01/25/2010
`
`Novo Nordisk Exhibit 2113
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00011
`
`