CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 021995/S-014
`
`
`JANUVIA
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`
`
`Sitagliptin
`
`Merck & Co., Inc.
`
`02/26/2010
`
`JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor
`indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 021995/S-014
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`X
`X
`
`
`
`
`
`X
`
`
`X
`
`
`
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 021995/S-014
`NDA 021995/8-014
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`NDA 021995/S-010, S-011, S-012 and S-014
`
`Merck Sharp and Dohme Corp.
`Attention: Richard J. Swanson, Ph.D.
`Director, Regulatory Affairs
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
`
`Dear Dr. Swanson:
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`
`December 18, 2008 (S-010), December 19, 2008 (S-011), February 23, 2009 (S-012) and
`November 13, 2009 (S-014), submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Januvia (sitagliptin) tablets.
`
`We also acknowledge receipt of your submissions dated February 17, 2010 (S-010 and S-011),
`January 6 and 20, and February 17, 2010 (S-012) and December 21 and 31, 2009, and January 5,
`15, 20 and 21, and February 4, 8, 19 and 23, 2010 (S-014).
`
`Your submissions of February 17, 2010 (S-010 and S-011), and January 20, 2010 (S-012),
`constitute a complete response to our January 25, 2010 and December 21, 2009 action letters,
`
`respectively.
`
`The “Prior Approval” supplemental applications S-010, S-011 and S-012 provide for the use of
`Januvia (sitagliptin) in combination with metformin and a PPARγ agonist as an adjunct to diet
`and exercise in adult patients with type 2 diabetes mellitus who are inadequately controlled on
`combination therapy with metformin and a PPARγ agonist (S-010), for the use of Januvia
`(sitagliptin) as combination therapy with a PPARγ agonist (S-011), and for the use of Januvia in
`combination with insulin, alone or in combination with metformin (S-012). The “Prior
`Approval” supplement S-014 contains proposed safety related labeling changes to the Package
`Insert regarding the risk of pancreatitis as well as a newly created Medication Guide, and a
`proposed Risk Evaluation and Mitigation Strategy (REMS). The Package Insert containing the
`pancreatitis-related changes was approved under supplemental application S-013 on
`December 28, 2009.
`
`We have completed our review of these applications, as amended. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 2
`
`
`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)(1)(i)] in structured product labeling (SPL) format as
`described at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed
`labeling (text for the package insert and the Medication Guide). For administrative purposes,
`please designate this submission, “SPL for approved NDA 021995/S-010, S-011, S-012 and
`S-014”.
`
`We request that the revised 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 container labels that are identical to the enclosed representative
`carton and immediate container labels submitted on February 23, 2010, 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 (October 2005). 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 021995/S-014”. Approval of this submission by FDA is not required before
`the labeling is used.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a REMS if FDA
`becomes aware of new safety information and makes a determination that such a strategy is
`necessary to ensure that the benefits of the drug outweigh the risks (section 505-1(a)).
`
`Since Januvia (sitagliptin) was approved on October 16, 2006, we have become aware of 88
`cases of pancreatitis associated with the use of sitagliptin in FDA’s Adverse Event Reporting
`System (AERS) database. These include two cases of necrotizing pancreatitis. We consider this
`
`information to be “new safety information” as defined in section 505-1(b)(3) of the FDCA.
`
`Your proposed REMS, submitted on November 13, 2009, amended on January 5, 15 and 20, and
`February 4, 8 and 19, 2010, and appended to this letter, is approved. The REMS consists of the
`Medication Guide included with this letter and the timetable for submission of assessments of the
`
`REMS.
`
`Your assessment of the REMS should include an evaluation of patients’ understanding of the
`serious risks of Januvia (sitagliptin).
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include, in
`section 505-1(g)(3)(B) and (C), requirements for information on the status of any postapproval
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 3
`
`
`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.
`
`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 of
`the REMS with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 021995 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 021995
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`
`NEW SUPPLEMENT FOR (NEW INDICATION FOR USE)
`FOR NDA 021995
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) 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
`(section 505(o)(3)(A)).
`
`Since Januvia (sitagliptin) was approved on October 16, 2006, we have become aware of “new
`
`safety information” as described above.
`
`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 a signal of a serious risk
`of acute pancreatitis, including necrotizing forms, associated with the use of Januvia (sitagliptin).
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 4
`
`
`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 this serious
`risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1602: A 3-month pancreatic safety study in a diabetic rodent model treated with
`sitagliptin.
`
`The timetable you submitted on January 21, 2010, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`June 15, 2010
`
`March 15, 2011
`
`June 15, 2011
`
`
`
`Submit the protocol to your IND, with a cross-reference letter to this NDA. Submit all final
`reports 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
`
`
`All promotional materials for your drug product that include representations about your drug
`product must be promptly revised to make it consistent with the labeling changes approved in
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 5
`
`
`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`your promotional materials should include prominent disclosure of the important new safety
`information that appears in the revised package labeling. Within 7 days of receipt of this letter,
`submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the following address or
`by facsimile at 301-847-8444:
`
`
`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
`
`
`In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
`promotional materials, and the package insert(s), at the time of initial dissemination or
`
`publication, accompanied by a Form FDA-2253, directly to the above address. For instruction
`
`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 (DDMAC), 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:
`
`
`
`MedWatch
`
`Food and Drug Administration
`
`5600 Fishers Lane, Room 12B05
`
`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).
`
`
`
`

`

`
`
`
`
`
`
` NDA 021995/S-010, S-011, S-012 and S-014
`Page 6
`
`
`If you have any questions, call Mehreen Hai, Ph.D., Regulatory Project Manager, at
`(301) 796-5073.
`
`
`Sincerely,
`
`
`
`
` {See appended electronic signature page}
`
`Mary H. Parks, M.D.
`
` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`Enclosures:
`Package Insert
`Medication Guide
`REMS
`Carton and Container Labeling
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21995
`
`Submission
`Type/Number
`--------------------
`SUPPL-12
`
`Submitter Name
`
`Product Name
`
`--------------------
`MERCK CO INC
`
`------------------------------------------
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`JANUVIA 100MG (SITAGLIPTIN
`PHOSPHATE)
`
`NDA-21995
`
`SUPPL-14
`
`MERCK CO INC
`
`NDA-21995
`
`SUPPL-11
`
`MERCK CO INC
`
`NDA-21995
`
`SUPPL-10
`
`MERCK CO INC
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`02/26/2010
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 021995/S-014
`NDA 021995/8-014
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`12/2009
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`JANUVIA safely and effectively. See full prescribing information
`for JANUVIA.
`
`JANUVIA® (sitagliptin) Tablets
`Initial U.S. Approval: 2006
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Indications and Usage
`Important Limitations of Use (1.2)
`Dosage and Administration
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or
`with Insulin (2.3)
`XX/20XX
`Warnings and Precautions
`
`Pancreatitis (5.1)
`12/2009
`Use with Medications Known to Cause Hypoglycemia (5.3) XX/20XX
`----------------------------INDICATIONS AND USAGE ----------------------------
`JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inh bitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus. (1.1)
`
`Important Limitations of Use:
`• JANUVIA should not be used in patients with type 1 diabetes or for
`the treatment of diabetic ketoacidosis. (1.2)
`• JANUVIA has not been studied in patients with a history of
`pancreatitis. (1.2, 5.1)
`----------------------- DOSAGE AND ADMINISTRATION------------------------
`The recommended dose of JANUVIA is 100 mg once daily. JANUVIA
`can be taken with or without food. (2.1)
`
`Dosage adjustment is recommended for patients with moderate or
`severe renal insufficiency or end-stage renal disease. (2.2)
`
`Dosage Adjustment in Patients With Moderate, Severe and End Stage
`Renal Disease (ESRD) (2.2)
`50 mg once daily
`25 mg once daily
`Severe and ESRD
`Moderate
`
`
`CrCl ≥30 to <50 mL/min
`CrCl <30 mL/min
`~Serum Cr levels [mg/dL]
`~Serum Cr levels [mg/dL]
`Men: >3.0;
`Men: >1.7– ≤3.0;
`Women: >2.5;
`Women: >1.5– ≤2.5
`or on dialysis
`
`
`
`XXXXXXX
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets: 100 mg, 50 mg, and 25 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`History of a serious hypersensitivity reaction to sitagliptin, such as
`anaphylaxis or angioedema (5.4, 6.2)
`------------------------WARNINGS AND PRECAUTIONS------------------------
`• There have been postmarketing reports of acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
`If pancreatitis is suspected, promptly discontinue JANUVIA. (5.1)
`• Dosage adjustment is recommended in patients with moderate or
`severe renal insufficiency and in patients with ESRD. Assessment of
`renal function is recommended prior to initiating JANUVIA and
`periodically thereafter. (2.2, 5.2)
`• There is an increased risk of hypoglycemia when JANUVIA is added
`to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy.
`Consider lowering the dose of the sulfonylurea or insulin to reduce
`the risk of hypoglycemia. (2.3, 5.3)
`• There have been postmarketing reports of serious allergic and
`hypersensitivity reactions in patients treated with JANUVIA such as
`anaphylaxis, angioedema, and exfoliative skin conditions including
`Stevens-Johnson syndrome.
`In such cases, promptly stop
`JANUVIA, assess for other potential causes, institute appropriate
`monitoring and treatment, and initiate alternative treatment for
`diabetes. (5.4, 6.2)
`• There have been no clinical studies establishing conclusive
`evidence of macrovascular risk reduction with JANUVIA or any
`other anti-diabetic drug. (5.5)
`------------------------------ ADVERSE REACTIONS-------------------------------
`Adverse reactions reported in ≥5% of patients treated with JANUVIA
`and more commonly than in patients treated with placebo are: upper
`respiratory tract infection, nasopharyngitis and headache. In the add-
`on to sulfonylurea and add-on to insulin studies, hypoglycemia was
`also more commonly reported in patients treated with JANUVIA
`compared to placebo. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`• Safety and effectiveness of JANUVIA in children under 18 years
`have not been established. (8.4)
`• There are no adequate and well-controlled studies in pregnant
`women. To report drug exposure during pregnancy call 1-800-986-
`8999. (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`
`
`Revised: XX/20XX
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Monotherapy and Combination Therapy
`1.2
`Important Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Patients with Renal Insufficiency
`2.3 Concomitant Use with an
`Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Use in Patients with Renal Insufficiency
`5.3 Use with Medications Known to Cause Hypoglycemia
`5.4 Hypersensitivity Reactions
`5.5 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Digoxin
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Monotherapy
`14.2 Combination Therapy
`
`

`

`JANUVIA®
`(sitagliptin) Tablets
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions
`17.2 Laboratory Tests
`
`FULL PRESCRIBING INFORMATION
`
`
`
`XXXXXXX
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`INDICATIONS AND USAGE
`1
`1.1 Monotherapy and Combination Therapy
`JANUVIA1 is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus. [See Clinical Studies (14).]
`1.2
`Important Limitations of Use
`JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic
`ketoacidosis, as it would not be effective in these settings.
`JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether
`patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using
`JANUVIA. [See Warnings and Precautions (5.1).]
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without
`food.
`2.2 Patients with Renal Insufficiency
`For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥50 mL/min, approximately
`corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage
`adjustment for JANUVIA is required.
`For patients with moderate renal insufficiency (CrCl ≥30 to <50 mL/min, approximately corresponding
`to serum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the dose of
`JANUVIA is 50 mg once daily.
`For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum
`creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease
`(ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA
`may be administered without regard to the timing of hemodialysis.
`Because there is a need for dosage adjustment based upon renal function, assessment of renal
`function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance
`can be estimated from serum creatinine using the Cockcroft-Gault formula. [See Clinical Pharmacology
`(12.3).]
`2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with
`insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of
`hypoglycemia. [See Warnings and Precautions (5.3).]
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`• 100 mg tablets are beige, round, film-coated tablets with “277” on one side.
`• 50 mg tablets are light beige, round, film-coated tablets with “112” on one side.
`• 25 mg tablets are pink, round, film-coated tablets with “221” on one side.
`
`4
`
`CONTRAINDICATIONS
`History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. [See
`Warnings and Precautions (5.4); Adverse Reactions (6.2).]
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal
`hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients
`2
`
`

`

`
`
`XXXXXXX
`
` JANUVIA®
` (sitagliptin) Tablets
`
`should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected,
`JANUVIA should promptly be discontinued and appropriate management should be initiated. It is
`unknown whether patients with a history of pancreatitis are at increased risk for the development of
`pancreatitis while using JANUVIA.
`5.2 Use in Patients with Renal Insufficiency
`A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in
`patients with ESRD requiring hemodialysis or peritoneal dialysis. [See Dosage and Administration (2.2);
`Clinical Pharmacology (12.3).]
`5.3 Use with Medications Known to Cause Hypoglycemia
`When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to
`cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in
`combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of
`sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and
`Administration (2.3).]
`5.4 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including
`Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of
`uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal
`relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of
`treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is
`suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative
`treatment for diabetes. [See Adverse Reactions (6.2).]
`5.5 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`with JANUVIA or any other anti-diabetic drug.
`
`ADVERSE REACTIONS
`6
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`In controlled clinical studies as both monotherapy and combination therapy with metformin,
`pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia,
`and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In
`combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions
`with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see
`Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
`Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included
`patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Five placebo-
`controlled add-on combination therapy studies were also conducted: one with metformin; one with
`pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and
`one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a
`stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily
`or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator
`assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily and more commonly than
`in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration.
`Incidences of hypoglycemia are shown in Table 3.
`
`3
`
`

`

` JANUVIA®
` (sitagliptin) Tablets
`
`
`
`
`Monotherapy (18 or 24 weeks)
`
`
`Nasopharyngitis
`
`Combination with Pioglitazone (24
`weeks)
`
`Upper Respiratory Tract Infection
`Headache
`
`Combination with Metformin +
`Rosiglitazone (18 weeks)
`
`Upper Respiratory Tract Infection
`Nasopharyngitis
`
`
`
`XXXXXXX
`
`Placebo
`N = 363
`12 (3.3)
`Placebo +
`Pioglitazone
`N = 178
`6 (3.4)
`7 (3.9)
`Placebo
`+ Metformin
`+ Rosiglitazone
`N = 97
`5 (5.2)
`4 (4.1)
`Placebo
`+ Glimepiride
`(+/- Metformin)
`N = 219
`10 (4.6)
`5 (2.3)
`
`Table 1
`Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with
`Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding
`Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo,
`Regardless of Investigator Assessment of Causality†
`Number of Patients (%)
`JANUVIA 100 mg
`N = 443
`23 (5.2)
`JANUVIA 100 mg +
`Pioglitazone
`N = 175
`11 (6.3)
`9 (5.1)
`JANUVIA 100 mg
`+ Metformin
`+ Rosiglitazone
`N = 181
`10 (5.5)
`11 (6.1)
`JANUVIA 100 mg
`+ Glimepiride
`(+/- Metformin)
`N = 222
`14 (6.3)
`13 (5.9)
`
`Combination with Glimepiride
`(+/- Metformin) (24 weeks)
`
`Nasopharyngitis
`Headache
`† Intent to treat population
`In the 24-week study of patients receiving JANUVIA as add-on combination therapy with metformin,
`there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of
`patients and more commonly than in patients given placebo.
`In the 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without
`metformin), there were no adverse reactions reported regardless of investigator assessment of causality
`in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see
`Table 3).
`In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1),
`through Week 54 the adverse reactions reported regardless of investigator assessment of causality in
`≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were:
`upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%),
`peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
`In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on
`to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with
`JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%,
`0.6%), and diarrhea (3.0%, 2.3%).
`In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in
`combination with metformin, the adverse reactions reported (regardless of investigator assessment of
`causality) in ≥5% of patients are shown in Table 2.
`
`
`
`
`4
`
`

`

` JANUVIA®
` (sitagliptin) Tablets
`
`
`
`
`XXXXXXX
`
`Table 2
`Initial Therapy with Combination of Sitagliptin and Metformin:
`Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients
`Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin
`alone, and Placebo)†
`Number of Patients (%)
`
`Metformin
`500 or 1000 mg bid ††
`
`Sitagliptin
`(JANUVIA)
`100 mg QD
`
`
`
`
`
`Placebo
`
`Sitagliptin
`50 mg bid +
`Metformin
`500 or 1000 mg bid ††
`N = 372††
`23 (6.2)
`22 (5.9)
`
`
`
`
`
`Add-On to Glimepiride
`(+/- Metformin) (24 weeks)
`
`Overall (%)
`Rate (episodes/patient-year)‡
`Severe (%)§
`Add-On to Insulin
`(+/- Metformin) (24 weeks)
`
`
`Upper Respiratory Infection
`Headache
`† Intent-to-treat population.
`†† Data pooled for the patients given the lower and higher doses of metformin.
`In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no
`adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and
`more commonly than in patients given pioglitazone alone.
`No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in
`patients treated with JANUVIA.
`Hypoglycemia
`In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic
`hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports
`of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was
`co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse
`reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
`
`Table 3
`Incidence and Rate of Hypoglycemia† in Placebo-Controlled Clinical Studies when JANUVIA was used
`as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin),
`Regardless of Investigator Assessment of Causality
`Placebo
`JANUVIA 100 mg
`+ Glimepiride
`+ Glimepiride
`(