JANUVIA- sitagliptin tablet, film coated
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1. Patient Information
2. What Is Januvia?
3. Do Not Take Januvia If:
4. You Are Allergic To Any Of The Ingredients In Januvia. Before You Take Januvia, Tell Your Doctor If You:
5. Are Pregnant Or Plan To Become Pregnant. It Is Not Known If Januvia Will Harm Your Unborn Baby. If You Are Pregnant, Talk With Your Doctor About The Best Way To Control Your Blood Sugar While You Are Pregnant.pregnancy Registry:
6. How Should I Take Januvia?
7. What Are The Ingredients In Januvia?
8. What Is Type 2 Diabetes?

Patient Information ⮝

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

17.1 Instructions

Patients should be informed of the potential risks and benefits of JANUVIA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to
Serious side effects can happen in people taking JANUVIA,including:

1.

Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis.
Before you start taking JANUVIA,tell your doctor if you have ever had:

pancreatitis

high blood triglyceride levels

stones in your gallbladder (gallstones)

kidney problems

a history of alcoholism

Stop taking JANUVIA and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.

Heart failure. Heart failure means your heart does not pump blood well enough.
Before you start taking JANUVIA,tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:

increasing shortness of breath or trouble breathing, especially when you lie down

swelling or fluid retention, especially in the feet, ankles or legs

an unusually fast increase in weight

unusual tiredness

These may be symptoms of heart failure.

What Is Januvia? ⮝

1.

JANUVIA is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

2.

JANUVIA is not for people with type 1 diabetes.

3.

JANUVIA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

4.

If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take JANUVIA.

5.

It is not known if JANUVIA is safe and effective when used in children under 18 years of age.

Do Not Take Januvia If: ⮝

1.

You Are Allergic To Any Of The Ingredients In Januvia. Before You Take Januvia, Tell Your Doctor If You: ⮝

have or have had inflammation of your pancreas (pancreatitis).

have kidney problems.

have any other medical conditions.

Are Pregnant Or Plan To Become Pregnant. It Is Not Known If Januvia Will Harm Your Unborn Baby. If You Are Pregnant, Talk With Your Doctor About The Best Way To Control Your Blood Sugar While You Are Pregnant.pregnancy Registry: ⮝

If you take JANUVIA at any time during your pregnancy, talk with your doctor about how you can join the JANUVIA pregnancy registry. The purpose of this registry is to collect information about the health of you and your baby. You can enroll in this registry by calling 1-800-986-8999.

are breast-feeding or plan to breast-feed. It is not known if JANUVIA will pass into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking JANUVIA.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How Should I Take Januvia? ⮝

Take JANUVIA 1 time each day exactly as your doctor tells you.

You can take JANUVIA with or without food.

Your doctor may do blood tests from time to time to
Serious side effects have happened in people taking JANUVIA.

Store JANUVIA at 68 F to 77 F (20 C to 25 C).
Keep JANUVIA and all medicines out of the reach of children.

General information about the use of JANUVIA
Medicines are sometimes prescribed for purposes that are not listed in Medication Guides. Do not use JANUVIA for a condition for which it was not prescribed. Do not give JANUVIA to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about JANUVIA. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for additional information about JANUVIA that is written for health professionals. For more information, go to www.JANUVIA.com or call 1-800-622-4477.

What Are The Ingredients In Januvia? ⮝

Active ingredient: sitagliptin
Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The tablet film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.

What Is Type 2 Diabetes? ⮝

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.
High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC.,Whitehouse Station, NJ 08889, USA
For patent information: www.merck.com/product/patent/home.html. The trademarks depicted herein are owned by their respective companies. Copyright 2010-2017 Merck Sharp & Dohme Corp., a subsidiary ofMerck & Co., Inc.
All rights reserved. usmg-mk0431-t-1708r016

1. Highlights Of Prescribing Information
2. Recent Major Changes
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Use In Specific Populations
10. 1 Indications And Usage
11. 2 Dosage And Administration
12. 3 Dosage Forms And Strengths
13. 4 Contraindications
14. 5 Warnings And Precautions
15. 6 Adverse Reactions
16. 7 Drug Interactions
17. 8 Use In Specific Populations
18. 10 Overdosage
19. 11 Description
20. 12 Clinical Pharmacology
21. 13 Nonclinical Toxicology
22. 14 Clinical Studies
23. 16 How Supplied/storage And Handling
24. Package/label Display Panel
25. Sitagliptin
26. Package/label Display Panel
27. Principal Display Panel - 25 Mg Tablet Bottle Label
28. Principal Display Panel - 50 Mg Tablet Bottle Label
29. Principal Display Panel - 100 Mg Tablet Bottle Label

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 ⮝

Warnings and Precautions
Heart Failure (5.2)	08/2017
Bullous Pemphigoid (5.7)	01/2017

Indications And Usage ⮝

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. (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
Moderate CrCl 30 to <50 mL/min ~Serum Cr levels [mg/dL] Men: >1.7 3.0; Women: >1.5 2.5	Severe and ESRD CrCl <30 mL/min ~Serum Cr levels [mg/dL] Men: >3.0; Women: >2.5; or on dialysis

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 (5.5, 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)

Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of JANUVIA in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2)

There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. 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, 5.3, 6.2)

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, 5.4)

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. (5.5, 6.2)

Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.6)

There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JANUVIA. (5.7)

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. (5.8)

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 Medication Guide.

Revised: 12/2018

1 Indications And Usage ⮝

1.1 Monotherapy and Combination Therapy

JANUVIA 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).]

2 Dosage And Administration ⮝

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] greater than or equal to 50 mL/min, approximately corresponding to serum creatinine levels of less than or equal to 1.7 mg/dL in men and less than or equal to 1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than 50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

For patients with severe renal insufficiency (CrCl less than 30 mL/min, approximately corresponding to serum creatinine levels of greater than 3.0 mg/dL in men and greater than 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 dialysis.

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).] There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.

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 (5.4).]

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 (5.5); 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 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 Heart Failure

An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of JANUVIA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of JANUVIA.

5.3 Renal Impairment

Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. 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).] Caution should be used to ensure that the correct dose of JANUVIA is prescribed for patients with moderate (creatinine clearance 30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment.

There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating JANUVIA if another etiology is deemed likely to have precipitated the acute worsening of renal function.

JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.

5.4 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).]

5.5 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. 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).]

Angioedema has also been reported with other DPP-4 inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.

5.6 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.7 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.8 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

6 Adverse Reactions ⮝

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.

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 (%)
Monotherapy (18 or 24 weeks)	JANUVIA 100 mg	Placebo
	N = 443	N = 363
Nasopharyngitis	23 (5.2)	12 (3.3)
Combination with Pioglitazone (24 weeks)	JANUVIA 100 mg + Pioglitazone	Placebo + Pioglitazone
	N = 175	N = 178
Upper Respiratory Tract Infection	11 (6.3)	6 (3.4)
Headache	9 (5.1)	7 (3.9)
Combination with Metformin + Rosiglitazone (18 weeks)	JANUVIA 100 mg + Metformin + Rosiglitazone	Placebo + Metformin + Rosiglitazone
	N = 181	N = 97
Upper Respiratory Tract Infection	10 (5.5)	5 (5.2)
Nasopharyngitis	11 (6.1)	4 (4.1)
Combination with Glimepiride (+/- Metformin) (24 weeks)	JANUVIA 100 mg + Glimepiride (+/- Metformin)	Placebo + Glimepiride (+/- Metformin)
	N = 222	N = 219
Nasopharyngitis	14 (6.3)	10 (4.6)
Headache	13 (5.9)	5 (2.3)

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.

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 (%)
	Placebo	Sitagliptin (JANUVIA) 100 mg QD	Metformin 500 or 1000 mg bid	Sitagliptin 50 mg bid + Metformin 500 or 1000 mg bid
	N = 176	N = 179	N = 364	N = 372
Upper Respiratory Infection	9 (5.1)	8 (4.5)	19 (5.2)	23 (6.2)
Headache	5 (2.8)	2 (1.1)	14 (3.8)	22 (5.9)

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.

In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). [See Warnings and Precautions (5.1).]

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 coadministered 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

Add-On to Glimepiride (+/- Metformin) (24 weeks)	JANUVIA 100 mg + Glimepiride (+/- Metformin)	Placebo + Glimepiride (+/- Metformin)
	N = 222	N = 219
Overall (%)	27 (12.2)	4 (1.8)
Rate (episodes/patient-year)	0.59	0.24
Severe (%)	0 (0.0)	0 (0.0)
Add-On to Insulin (+/- Metformin) (24 weeks)	JANUVIA 100 mg + Insulin (+/- Metformin)	Placebo + Insulin (+/- Metformin)
	N = 322	N = 319
Overall (%)	50 (15.5)	25 (7.8)
Rate (episodes/patient-year)	1.06	0.51
Severe (%)	2 (0.6)	1 (0.3)

In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.

In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on JANUVIA and 1.0% in patients given add-on placebo.

In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin.

In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin.

Laboratory Tests

Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of JANUVIA as monotherapy and/or in combination with other antihyperglycemic agents. 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.

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.5)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.2); Warnings and Precautions (5.1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.3)]; severe and disabling arthralgia [see Warnings and Precautions (5.6)]; bullous pemphigoid [see Warnings and Precautions (5.7)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.

7 Drug Interactions ⮝

7.1 Digoxin

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category B:

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

8.3 Nursing Mothers

Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter [see Dosage and Administration (2.2); Clinical Pharmacology (12.3)].

10 Overdosage ⮝

During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg JANUVIA, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with JANUVIA with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

11 Description ⮝

JANUVIA Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.

The empirical formula is C16H15F6N5O H3PO4 H2O and the molecular weight is 523.32. The structural formula is:

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

12.2 Pharmacodynamics

General

In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.

In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100 mg, JANUVIA 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.

In patients with type 2 diabetes administered JANUVIA 100 mg (N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

12.3 Pharmacokinetics

The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 M hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

Absorption

The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.

Distribution

The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metabolism

Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Excretion

Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Special Populations

Renal Insufficiency

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of JANUVIA (50 mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses. Creatinine clearance was measured by 24 hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula:

CrCl = [140 - age (years)] x weight (kg) {x 0.85 for female patients}
[72 x serum creatinine (mg/dL)]

Compared to normal healthy control subjects, an approximate 1.1- to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring dialysis. [See Dosage and Administration (2.2).]

Hepatic Insufficiency

In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild or moderate hepatic insufficiency.

There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).

Body Mass Index (BMI)

No dosage adjustment is necessary based on BMI. Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Gender

No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Geriatric

No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

Pediatric

Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.

Race

No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.

Drug Interactions

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.

Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.

In Vivo Assessment of Drug Interactions

Effects of Sitagliptin on Other Drugs

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.

Metformin: Coadministration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.

Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.

Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.

Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA is not an inhibitor of CYP2C8-mediated metabolism.

Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Oral Contraceptives: Coadministration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

Effects of Other Drugs on Sitagliptin

Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by coadministered medications.

Metformin: Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100 mg oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

14 Clinical Studies ⮝

There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.

In patients with type 2 diabetes, treatment with JANUVIA produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.

14.1 Monotherapy

A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of JANUVIA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the 24-week study 741 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or JANUVIA.

Treatment with JANUVIA at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 4). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving JANUVIA 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with JANUVIA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given JANUVIA, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. The effect of JANUVIA on lipid endpoints was similar to placebo. Body weight did not increase from baseline with JANUVIA therapy in either study, compared to a small reduction in patients given placebo.

Table 4: Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of JANUVIA in Patients with Type 2 Diabetes

	18-Week Study		24-Week Study
	JANUVIA 100 mg	Placebo	JANUVIA 100 mg	Placebo
A1C (%)	N = 193	N = 103	N = 229	N = 244
Baseline (mean)	8.0	8.1	8.0	8.0
Change from baseline (adjusted mean)	-0.5	0.1	-0.6	0.2
Difference from placebo (adjusted mean) (95% CI)	-0.63 (-0.8, -0.4)		-0.8 (-1.0, -0.6)
Patients (%) achieving A1C <7%	69 (36%)	16 (16%)	93 (41%)	41 (17%)
FPG (mg/dL)	N = 201	N = 107	N = 234	N = 247
Baseline (mean)	180	184	170	176
Change from baseline (adjusted mean)	-13	7	-12	5
Difference from placebo (adjusted mean) (95% CI)	-20 ( 31, -9)		-17 ( 24, -10)
2-hour PPG (mg/dL)			N = 201	N = 204
Baseline (mean)			257	271
Change from baseline (adjusted mean)			-49	-2
Difference from placebo (adjusted mean) (95% CI)			-47 (-59, -34)

Additional Monotherapy Study

A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of JANUVIA in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of JANUVIA and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of JANUVIA were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with JANUVIA relative to those on placebo. In addition, the reductions in A1C and FPG with JANUVIA compared to placebo were generally similar to those observed in other monotherapy studies. [See Clinical Pharmacology (12.3).]

14.2 Combination Therapy

Add-on Combination Therapy with Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with metformin, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 5). Rescue glycemic therapy was used in 5% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 5: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Metformin

	JANUVIA 100 mg + Metformin	Placebo + Metformin
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted mean)	-0.7	-0.0
Difference from placebo + metformin (adjusted mean) (95% CI)	-0.7 (-0.8, -0.5)
Patients (%) achieving A1C <7%	213 (47%)	41 (18%)
FPG (mg/dL)	N = 454	N = 226
Baseline (mean)	170	174
Change from baseline (adjusted mean)	-17	9
Difference from placebo + metformin (adjusted mean) (95% CI)	-25 (-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted mean)	-62	-11
Difference from placebo + metformin (adjusted mean) (95% CI)	-51 (-61, -41)

Initial Combination Therapy with Metformin

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of JANUVIA once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Initial therapy with the combination of JANUVIA and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to JANUVIA alone (Table 6, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: JANUVIA 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.

Table 6: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy

	Placebo	Sitagliptin (JANUVIA) 100 mg QD	Metformin 500 mg bid	Metformin 1000 mg bid	Sitagliptin 50 mg bid + Metformin 500 mg bid	Sitagliptin 50 mg bid + Metformin 1000 mg bid
A1C (%)	N = 165	N = 175	N = 178	N = 177	N = 183	N = 178
Baseline (mean)	8.7	8.9	8.9	8.7	8.8	8.8
Change from baseline (adjusted mean)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo (adjusted mean) (95% CI)		-0.8 (-1.1, -0.6)	-1.0 (-1.2, -0.8)	-1.3 (-1.5, -1.1)	-1.6 (-1.8, -1.3)	-2.1 (-2.3, -1.8)
Patients (%) achieving A1C <7%	15 (9%)	35 (20%)	41 (23%)	68 (38%)	79 (43%)	118 (66%)
% Patients receiving rescue medication	32	21	17	12	8	2
FPG (mg/dL)	N = 169	N = 178	N = 179	N = 179	N = 183	N = 180
Baseline (mean)	196	201	205	197	204	197
Change from baseline (adjusted mean)	6	-17	-27	-29	-47	-64
Difference from placebo (adjusted mean) (95% CI)		-23 (-33, -14)	-33 (-43, -24)	-35 (-45, -26)	-53 (-62, -43)	-70 (-79, -60)
2-hour PPG (mg/dL)	N = 129	N = 136	N = 141	N = 138	N = 147	N = 152
Baseline (mean)	277	285	293	283	292	287
Change from baseline (adjusted mean)	0	-52	-53	-78	-93	-117
Difference from placebo (adjusted mean) (95% CI)		-52 (-67, -37)	-54 (-69, -39)	-78 (-93, -63)	-93 (-107, -78)	-117 (-131, -102)

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.

Active-Controlled Study vs Glipizide in Combination with Metformin

The efficacy of JANUVIA was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of 1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of JANUVIA 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, JANUVIA and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 7). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of JANUVIA to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 7: Glycemic Parameters in a 52-Week Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)

	JANUVIA 100 mg	Glipizide
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted mean)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted mean)	-8	-8

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population)

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population)

The incidence of hypoglycemia in the JANUVIA group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with JANUVIA exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).

Add-on Combination Therapy with Pioglitazone

A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPAR agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.

In combination with pioglitazone, JANUVIA provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Pioglitazone

	JANUVIA 100 mg + Pioglitazone	Placebo + Pioglitazone
A1C (%)	N = 163	N = 174
Baseline (mean)	8.1	8.0
Change from baseline (adjusted mean)	-0.9	-0.2
Difference from placebo + pioglitazone (adjusted mean) (95% CI)	-0.7 (-0.9, -0.5)
Patients (%) achieving A1C <7%	74 (45%)	40 (23%)
FPG (mg/dL)	N = 163	N = 174
Baseline (mean)	168	166
Change from baseline (adjusted mean)	-17	1
Difference from placebo + pioglitazone (adjusted mean) (95% CI)	-18 (-24, -11)

Initial Combination Therapy with Pioglitazone

A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of JANUVIA as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of JANUVIA in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.

Initial therapy with the combination of JANUVIA and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 9). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with JANUVIA in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg). Lipid effects were generally neutral.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Combination with Pioglitazone as Initial Therapy

	JANUVIA 100 mg + Pioglitazone	Pioglitazone
A1C (%)	N = 251	N = 246
Baseline (mean)	9.5	9.4
Change from baseline (adjusted mean)	-2.4	-1.5
Difference from pioglitazone (adjusted mean) (95% CI)	-0.9 (-1.1, -0.7)
Patients (%) achieving A1C <7%	151 (60%)	68 (28%)
FPG (mg/dL)	N = 256	N = 253
Baseline (mean)	203	201
Change from baseline (adjusted mean)	-63	-40
Difference from pioglitazone (adjusted mean) (95% CI)	-23 (-30, -15)
2-hour PPG (mg/dL)	N = 216	N = 211
Baseline (mean)	283	284
Change from baseline (adjusted mean)	-114	-69
Difference from pioglitazone (adjusted mean) (95% CI)	-45 (-57, -32)

Add-on Combination Therapy with Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin and rosiglitazone. Patients on dual therapy with metformin 1500 mg/day and rosiglitazone 4 mg/day or with metformin 1500 mg/day and pioglitazone 30 mg/day (switched to rosiglitazone 4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin 1500 mg/day and rosiglitazone 4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 10) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with JANUVIA and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with JANUVIA 100 mg and 40% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.

Table 10: Glycemic Parameters at Week 18 for JANUVIA in Add-on Combination Therapy with Metformin and Rosiglitazone

	JANUVIA 100 mg + Metformin + Rosiglitazone	Placebo + Metformin + Rosiglitazone
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted mean)	-1.0	-0.4
Difference from placebo + rosiglitazone + metformin (adjusted mean) (95% CI)	-0.7 (-0.9, -0.4)
Patients (%) achieving A1C <7%	39 (22%)	9 (10%)
FPG (mg/dL)	N = 179	N = 94
Baseline (mean)	181	182
Change from baseline (adjusted mean)	-30	-11
Difference from placebo + rosiglitazone + metformin (adjusted mean) (95% CI)	-18 (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted mean)	-59	-21
Difference from placebo + rosiglitazone + metformin (adjusted mean) (95% CI)	-39 (-51, -26)

Add-on Combination Therapy with Glimepiride, with or without Metformin

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride ( 4 mg per day) alone or glimepiride in combination with metformin ( 1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with glimepiride, with or without metformin, JANUVIA provided significant improvements in A1C and FPG compared to placebo (Table 11). In the entire study population (patients on JANUVIA in combination with glimepiride and patients on JANUVIA in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with JANUVIA 100 mg and 27% of patients treated with placebo. In this study, patients treated with JANUVIA had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

Table 11: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-On Combination Therapy with Glimepiride, with or without Metformin

	JANUVIA 100 mg + Glimepiride	Placebo + Glimepiride	JANUVIA 100 mg + Glimepiride + Metformin	Placebo + Glimepiride + Metformin
A1C (%)	N = 102	N = 103	N = 115	N = 105
Baseline (mean)	8.4	8.5	8.3	8.3
Change from baseline (adjusted mean)	-0.3	0.3	-0.6	0.3
Difference from placebo (adjusted mean) (95% CI)	-0.6 (-0.8, -0.3)		-0.9 (-1.1, -0.7)
Patients (%) achieving A1C <7%	11 (11%)	9 (9%)	26 (23%)	1 (1%)
FPG (mg/dL)	N = 104	N = 104	N = 115	N = 109
Baseline (mean)	183	185	179	179
Change from baseline (adjusted mean)	-1	18	-8	13
Difference from placebo (adjusted mean) (95% CI)	-19 (-32, -7)		-21 (-32, -10)

Add-on Combination Therapy with Insulin (with or without Metformin)

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin ( 1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

The median daily insulin dose at baseline was 42 units in the patients treated with JANUVIA and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 12). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with JANUVIA. [See Warnings and Precautions (5.4); Adverse Reactions (6.1).]

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-on Combination Therapy with Insulin

	JANUVIA 100 mg + Insulin (+/- Metformin)	Placebo + Insulin (+/- Metformin)
A1C (%)	N = 305	N = 312
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean)	-0.6	-0.1
Difference from placebo (adjusted mean,3) (95% CI)	-0.6 (-0.7, -0.4)
Patients (%) achieving A1C <7%	39 (12.8%)	16 (5.1%)
FPG (mg/dL)	N = 310	N = 313
Baseline (mean)	176	179
Change from baseline (adjusted mean)	-18	-4
Difference from placebo (adjusted mean) (95% CI)	-15 (-23, -7)
2-hour PPG (mg/dL)	N = 240	N = 257
Baseline (mean)	291	292
Change from baseline (adjusted mean)	-31	5
Difference from placebo (adjusted mean) (95% CI)	-36 (-47, -25)

16 How Supplied/storage And Handling ⮝

No. 6739 Tablets JANUVIA, 100 mg, are beige, round, film-coated tablets with "277" on one side. They are supplied as follows:

Bottles of approximately 1350 tablets, NDC 55154-5042-8

Storage

Store at 20-25 C (68-77 F), excursions permitted to 15-30 C (59-86 F). [See USP Controlled Room Temperature.]

Distributed By:

Cardinal Health

Dublin, OH 43017

L73091118

Package/label Display Panel ⮝

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:58118-0277(NDC:0006-0277) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 100 mg

Inactive Ingredients Ingredient Name Strength CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: L11K75P92J) croscarmellose sodium (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A) polyvinyl alcohol (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color BROWN (beige) Score no score Shape ROUND (round) Size 10mm Flavor Imprint Code 277 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:58118-0277-3 30 in 1 BOTTLE 2 NDC:58118-0277-6 60 in 1 BOTTLE 3 NDC:58118-0277-9 90 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

Labeler - Clinical Solutions Wholesale (078710347)

Registrant - Clinical Solutions Wholesale (078710347)

Establishment
Name	Address	ID/FEI	Business Operations
Clinical Solutions Wholesale		078710347	REPACK(58118-0277) , RELABEL(58118-0277)

Revised: 12/2013 Document Id: 963792a9-4029-4e7b-9759-9ad52e1b0962 34391-3 Set id: 963792a9-4029-4e7b-9759-9ad52e1b0962 Version: 1 Effective Time: 20131216 Clinical Solutions Wholesale

Sitagliptin ⮝

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-3527(NDC:0006-0221) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 25 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color PINK (pink) Score no score Shape ROUND (round) Size 6mm Flavor Imprint Code 221 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-3527-0 90 in 1 BOTTLE; Type 0: Not a Combination Product 08/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-3527)

Revised: 8/2018 Document Id: 099f7056-4268-454e-96bc-2efca26782c1 34391-3 Set id: 1b03c82f-b52e-4092-b9dc-f2c9b0d6ab40 Version: 1 Effective Time: 20180801 A-S Medication Solutions

Package/label Display Panel  ⮝

Januvia

(sitagliptin) tablets

100 mg

Contains Approximately 1350 Tablets

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-5042(NDC:0006-0277) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 100 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color BROWN (light beige) Score no score Shape ROUND (round) Size 10mm Flavor Imprint Code 277 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-5042-8 1350 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/16/2006

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

Labeler - Cardinal Health (603638201)

Revised: 5/2019 Document Id: 2c24184f-80d7-40df-b8f7-687ca56b4ee5 34391-3 Set id: 9d558f96-24a5-4788-8933-38256c17384b Version: 6 Effective Time: 20190515 Cardinal Health

Principal Display Panel - 25 Mg Tablet Bottle Label ⮝

NDC 0006-0221-31

Januvia
(sitagliptin) tablets

25 mg

Dispense the accompanying Medication
Guide to each patient.

Each tablet contains 32.13 mg sitagliptin
phosphate, equivalent to 25 mg sitagliptin.

Rx only

30 Tablets

Principal Display Panel - 50 Mg Tablet Bottle Label ⮝

NDC 0006-0112-31

Januvia
(sitagliptin) tablets

50 mg

Dispense the accompanying Medication
Guide to each patient.

Each tablet contains 64.25 mg sitagliptin
phosphate, equivalent to 50 mg sitagliptin.

Rx only

30 Tablets

Principal Display Panel - 100 Mg Tablet Bottle Label ⮝

NDC 0006-0277-31

Januvia
(sitagliptin) tablets

100 mg

Dispense the accompanying Medication
Guide to each patient.

Each tablet contains 128.5 mg
sitagliptin phosphate, equivalent
to 100 mg sitagliptin.

Rx only

30 Tablets

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0006-0221 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 25 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color PINK (pink) Score no score Shape ROUND (round) Size 6mm Flavor Imprint Code 221 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0006-0221-28 100 in 1 CARTON 10/16/2006 1 NDC:0006-0221-01 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:0006-0221-31 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 3 NDC:0006-0221-54 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0006-0112 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 50 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color BROWN (light beige) Score no score Shape ROUND (round) Size 8mm Flavor Imprint Code 112 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0006-0112-28 100 in 1 CARTON 10/16/2006 1 NDC:0006-0112-01 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:0006-0112-31 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 3 NDC:0006-0112-54 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

JANUVIA sitagliptin tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0006-0277 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SITAGLIPTIN PHOSPHATE (UNII: TS63EW8X6F) (SITAGLIPTIN - UNII:QFP0P1DV7Z) SITAGLIPTIN 100 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J) croscarmellose sodium (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color BROWN (beige) Score no score Shape ROUND (round) Size 10mm Flavor Imprint Code 277 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0006-0277-28 100 in 1 CARTON 10/16/2006 1 NDC:0006-0277-01 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:0006-0277-31 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 3 NDC:0006-0277-54 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 4 NDC:0006-0277-02 30 in 1 DOSE PACK; Type 0: Not a Combination Product 10/16/2006 5 NDC:0006-0277-33 30 in 1 DOSE PACK; Type 0: Not a Combination Product 10/16/2006 6 NDC:0006-0277-82 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 7 NDC:0006-0277-14 2 in 1 CARTON 10/12/2012 7 7 in 1 BLISTER PACK; Type 0: Not a Combination Product 8 NDC:0006-0277-27 4 in 1 CARTON 10/16/2006 09/30/2015 8 7 in 1 BLISTER PACK; Type 0: Not a Combination Product 9 NDC:0006-0277-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/16/2006 02/29/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021995 10/16/2006

Labeler - Merck Sharp & Dohme Corp. (001317601)

Revised: 8/2019 Document Id: 18128ec1-8748-4f68-a7e8-f004ec697b29 34391-3 Set id: f85a48d0-0407-4c50-b0fa-7673a160bf01 Version: 60 Effective Time: 20190812 Merck Sharp & Dohme Corp.