JANUVIA

1 INDICATIONS AND USAGE JANUVIA ® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 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 ) Limitations of Use: • JANUVIA should not be used in patients with type 1 diabetes ( 1 ) • JANUVIA has not been studied in patients with a history of pancreatitis. ( 1 , 5.1 ) Limitations of Use JANUVIA should not be used in patients with type 1 diabetes. 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 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 eGFR less than 45 mL/min/1.73 m 2 . ( 2.2 ) Dosage Adjustment in Patients with Renal Impairment ( 2.2 ) eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 eGFR less than 30 mL/min/1.73 m 2 (including patients with end stage renal disease [ESRD] on dialysis) 50 mg once daily 25 mg once daily 2.1 Recommended Dosing The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of JANUVIA and periodically thereafter. For patients with an estimated glomerular filtration rate [eGFR] greater than or equal to 45 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 , no dosage adjustment for JANUVIA is required. For patients with moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 ), the dose of JANUVIA is 50 mg once daily. For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) 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.

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. Tablets: 100 mg, 50 mg, and 25 mg ( 3 )

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) .] History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema ( 5.5 , 6.2 )

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Pancreatitis [see Warnings and Precautions (5.1) ] Heart Failure [see Warnings and Precautions (5.2) ] Acute Renal Failure [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.6) ] Bullous Pemphigoid [see Warnings and Precautions (5.7) ] 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 LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Intent-to-treat population 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 Nasopharyng …

7 DRUG INTERACTIONS 7.1 Insulin Secretagogues or Insulin Coadministration of JANUVIA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. [See Warnings and Precautions (5.4) .]

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The limited available data with JANUVIA in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ]. No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC [see Data ] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a Hemoglobin A1c >7% and has been reported to be as high as 20-25% in women with a Hemoglobin A1c >10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1000 mg/kg. 8.2 Lactation Risk Summary There is no information regarding the presence of JANUVIA in human milk, the effects on the breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk [see Data ] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for JANUVIA and any potential adverse effects on the breastfed infant from JANUVIA or from the underlying maternal condition. Data Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. 8.4 Pediatric Use The safety and effectiveness of JANUVIA have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (HbA1c 6.5-10% for patients not on insulin, HbA1c 7-10% for patients on insulin). At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy. The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation. In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1c in patients treated with JANUVIA (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% …

12.1 Mechanism of Action Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, 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, sitagliptin 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.

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-[(3 R )-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 C 16 H 15 F 6 N 5 O•H 3 PO 4 •H 2 O 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, sodium stearyl fumarate, and propyl gallate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide. image of sitagliptin chemical structure

10 OVERDOSAGE In the event of an overdose with JANUVIA, contact the Poison Control Center. In the event of an overdose, it is reasonable to employ 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets are supplied as follows: Contents Description How Supplied NDC 25 mg sitagliptin pink, round, film-coated tablets with “221” on one side Unit-of-use bottles of 30 Unit-of-use bottles of 90 Unit dose blister package of 100 NDC 0006-0221-31 NDC 0006-0221-54 NDC 0006-0221-28 50 mg sitagliptin light beige, round, film-coated tablets with “112” on one side unit-of-use bottles of 30 unit-of-use bottles of 90 unit dose blister packages of 100 NDC 0006-0112-31 NDC 0006-0112-54 NDC 0006-0112-28 100 mg sitagliptin beige, round, film-coated tablets with “277” on one side unit-of-use bottles of 30 unit-of-use bottles of 90 unit-of-use blister calendar package of 30 unit-of-use blister calendar package of 30 unit dose blister packages of 100 bottles of 1000. NDC 0006-0277-31 NDC 0006-0277-54 NDC 0006-0277-02 NDC 0006-0277-33 NDC 0006-0277-28 NDC 0006-0277-82 Storage Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]